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Cannabidiol with clobazam for treating seizures associated with Dravet syndrome
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Cannabidiol with clobazam for treating seizures associated with Dravet syndrome
Evidence-based recommendations on cannabidiol (Epidyolex) with clobazam for seizures associated with Dravet syndrome in people aged 2 years and older.
# Recommendations
Cannabidiol with clobazam is recommended as an option for treating seizures associated with Dravet syndrome in people aged 2 years and older, only if:
the frequency of convulsive seizures is checked every 6 months, and cannabidiol is stopped if the frequency has not fallen by at least 30% compared with the 6 months before starting treatment
the company provides cannabidiol according to the commercial arrangement.
This recommendation is not intended to affect treatment with cannabidiol, with clobazam, that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place before this guidance was published, until they and their NHS clinicians consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person, or the child or young person's parents or carers.
Why the committee made these recommendations
Current treatment for Dravet syndrome includes antiepileptic drugs. People with Dravet syndrome would have cannabidiol with clobazam if their convulsive seizures are not controlled well enough after trying 2 or more antiepileptic drugs.
Clinical trials show that cannabidiol reduces the number of convulsive and non-convulsive seizures when compared with usual care.
The cost-effectiveness estimates are uncertain for cannabidiol because of some of the assumptions in the company's model. The cost-effectiveness estimates do not include the benefits of:
reducing the number of non-convulsive seizures
reducing the duration of convulsive seizures
improving the quality of life of the siblings of people with Dravet syndrome.
When taking both the uncertainties and the uncaptured benefits into account, cannabidiol is considered an appropriate use of NHS resources, and is recommended as an option for treating Dravet syndrome in the NHS.# Information about cannabidiol
# Marketing authorisation indication
Cannabidiol (Epidyolex, GW Pharma) is licensed as 'adjunctive therapy for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in conjunction with clobazam, for patients 2 years of age or older'.
# Dosage in the marketing authorisation
It is administered orally as 100 mg/ml cannabidiol solution. The recommended starting dosage is 2.5 mg/kg taken twice daily for 1 week. After 1 week, the dosage should be increased to a maintenance dosage of 5 mg/kg twice daily (10 mg/kg/day). Based on individual clinical response and tolerability, each dosage can be further increased in weekly increments of 2.5 mg/kg taken twice daily up to a maximum recommended dosage of 10 mg/kg twice daily (20 mg/kg/day). Any dosage increases above 10 mg/kg/day should take into account individual benefit and risk.
# Price
The list price of cannabidiol has been agreed with the Department of Health and Social Care, but is considered confidential by the company until January 2020. The company has a commercial arrangement. This makes cannabidiol available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by GW Pharma, a review of this submission by the evidence review group (ERG) and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
# Disease background
## Dravet syndrome severely affects the quality of life of patients, carers and their families
Dravet syndrome is a severe, lifelong and treatment-resistant genetic form of epilepsy that begins in early childhood, usually in babies aged between 6 months and 10 months. It is characterised by frequent seizures of different types. Convulsive seizures are characterised by stiffness and jerking, and can last for extended periods. The patient and carer expert explained that, of the different types of seizure, convulsive seizures have the biggest effect on quality of life because they may result in injuries and hospitalisation. The patient and carer expert noted that Dravet syndrome affects families and carers. People with the disease need round-the-clock care and help with almost all aspects of daily life. Families and carers may find looking after people with Dravet syndrome demanding, and that it prevents them from leading normal lives, including spending less time with their other children. Also, the anxiety that a child with Dravet syndrome may have status epilepticus or die can significantly affect the mental wellbeing of all family members. The committee concluded that Dravet syndrome severely affects the quality of life of patients, families and carers.
# Current treatments
## People with Dravet syndrome and their carers would value a treatment option that reduces seizure frequency and duration
The clinical, and patient and carer, experts agreed that current treatments often do not control seizures associated with Dravet syndrome. This is despite a broad range of available antiepileptic drugs, non-pharmacological interventions (such as vagus nerve stimulation and a ketogenic diet) and surgery. They stated that there is an unmet need in Dravet syndrome for an intervention that effectively reduces seizures without markedly increasing adverse events. The patient and carer expert reported that drugs which initially work can lose efficacy. The experts would welcome new treatment options, and noted that reducing the number of convulsive seizures is the main goal of treatment. They noted that an increase in the number of convulsive seizure-free days would also benefit people with Dravet syndrome. This is because it would mean having fewer nights with seizures, when there is a higher risk of sudden unexpected death in epilepsy. The patient and carer expert considered that reducing the duration of convulsive seizures and the frequency of other seizure types would improve the quality of life of people with Dravet syndrome. The committee concluded that there is an unmet need for treatments that reduce the number and duration of convulsive seizures, and that patients and their carers would value a new treatment option.
# Cannabidiol and its positioning in the treatment pathway
## The company's positioning of cannabidiol with clobazam in the treatment pathway is appropriate
The clinical experts explained that the Dravet syndrome treatment pathway is consistent with NICE's clinical guideline on epilepsies: diagnosis and management. The guideline recommends starting treatment with sodium valproate or topiramate and, if seizures are not adequately controlled, adding clobazam or stiripentol. The clinical experts added that stiripentol is increasingly being used because of evidence that using valproate, clobazam and stiripentol together improves efficacy. They noted that most people with Dravet syndrome will have tried several antiepileptic drugs by the time they are 2 years old and would be eligible for adjuvant treatment with cannabidiol. The committee was aware that the marketing authorisation for cannabidiol is for use as an adjuvant therapy with clobazam. The company proposed that cannabidiol should be considered after 2 other antiepileptic drugs. The clinical experts stated that clobazam is currently used when 2 antiepileptic drugs have not adequately controlled seizures, and that they would consider adding cannabidiol to clobazam. The committee concluded that the company's positioning of cannabidiol with clobazam after 2 treatments in the treatment pathway was appropriate.
# Clinical-effectiveness evidence
## The patients in the clinical trials reflect those who would have cannabidiol in the NHS and the subgroup taking clobazam is most relevant to the appraisal
Cannabidiol (plus usual care) has been compared with placebo (plus usual care) in 2 randomised controlled trials, GWPCARE1 and GWPCARE2. In GWPCARE2, 2 maintenance doses of cannabidiol (10 mg/kg/day and 20 mg/kg/day) were compared with placebo. In GWPCARE1, the higher maintenance dosage of 20 mg/kg/day was compared with placebo. Both trials had a follow up of 14 weeks. The licensed maintenance dosage of cannabidiol is 10 mg/kg/day, with dosage increases permitted up to a maximum of 20 mg/kg/day. An open-label extension study designed for safety, GWPCARE5, in which all patients are having cannabidiol, is ongoing. The company expects to follow patients in this study for up to 5 years. The committee recognised that this study will provide potentially important information on safety. The committee was aware that the trials did not include patients aged 18 years or older, who are included in the marketing authorisation and to whom clinicians would offer treatment. The clinical experts stated that, based on their experiences with other antiepileptic treatments, they would expect adults to benefit from cannabidiol. However, they explained that it was uncertain whether the clinical effect would be the same in adults as in children. About two-thirds of the patients in both trials were also taking clobazam. The committee agreed that the baseline characteristics of patients in the subgroup taking clobazam were similar to those with Dravet syndrome who would have cannabidiol in the NHS. It concluded that the subgroup of patients taking clobazam was most relevant to this appraisal, and that it would not consider the overall trial population further.
## Cannabidiol with clobazam reduces seizure frequency, but long-term efficacy is uncertain
The primary end point in both GWPCARE1 and GWPCARE2 was the percentage change in convulsive seizure frequency from baseline per 28 days between groups. The company provided results from the trials for the subgroup of patients taking clobazam (see section 3.4). The reduction in median convulsive seizure frequency per 28 days in GWPCARE2 for patients taking cannabidiol 10 mg/kg/day compared with placebo was 37%, which was statistically significant at the 95% confidence level (p=0.0042). The clinical and patient experts noted that this size of reduction was meaningful for people with the condition. The company did not provide evidence of how many patients taking cannabidiol with clobazam became free of convulsive seizures, but the committee was aware that this reflected only a few patients. There was also a reduction in the secondary end point of total seizure frequency per 28 days of 43% compared with placebo (p=0.0003). In GWPCARE1, with cannabidiol 20 mg/kg/day there was also a reduction in both convulsive and non-convulsive seizure frequency compared with placebo. The committee was aware that GWPCARE2 also included a 20 mg/kg/day arm, and that the European Medicines Agency concluded that there was no consistent difference in dose response between 10 mg/kg/day and 20 mg/kg/day. The committee was aware that the summary of product characteristics states that the recommended maintenance dosage of cannabidiol is 10 mg/kg/day (see section 2). It agreed that GWPCARE2 was most relevant to the decision problem. In response to consultation, the company provided interim analysis for seizure frequency after 3 years of follow up from the open-label extension, GWPCARE5, for the subgroup of patients taking cannabidiol and clobazam. This showed that reduction in seizure frequency with treatment was broadly maintained for up to 3 years. The committee concluded that cannabidiol with clobazam reduces seizure frequency compared with usual care, but that the long-term efficacy after 3 years is uncertain.
# Adverse events
## Cannabidiol is associated with adverse events that are manageable
The trial results showed that a large proportion of patients having cannabidiol with clobazam had adverse events. The most commonly occurring adverse events in this group were somnolence or sedation, decreased appetite, diarrhoea, fever, fatigue and vomiting. The clinical experts noted that people with Dravet syndrome often experience adverse effects from their medications. They also noted that cannabidiol's adverse effects are mostly, but not always, mild and tolerated. The patient and carer expert stated that the choice of treatment depends on the balance of its safety and tolerability, with adverse events representing an important consideration. The committee was concerned that the trial had a short follow up, which may not have captured all cannabidiol's adverse effects. It was aware that more data on safety would be available from GWPCARE5, which is ongoing (see section 3.4). The clinical and patient experts explained that patients would be closely monitored, and treatment would be stopped if adverse events were not manageable. The committee concluded that, while cannabidiol's adverse effects are mostly manageable, they are an important consideration when making decisions about whether to start or continue cannabidiol.
# Stopping treatment
## It is appropriate to assess response to treatment every 6 months and stop cannabidiol if it is not effective
The marketing authorisation for cannabidiol does not specify a stopping rule, that is, stopping treatment if or when it does not work. However, NHS England proposed during the technical engagement stage of the appraisal that cannabidiol should be stopped if the frequency of convulsive seizures has not reduced by at least 30% from baseline. The clinical experts noted that they took account of broadly similar criteria when advising patients, and their families and carers about whether to continue other antiepileptic drugs. The patient and carer expert explained that they would not want to continue a treatment unnecessarily when it does not work well because this would increase the drug burden and potential adverse effects. The committee was aware that the company implemented the stopping criteria proposed by NHS England in its model after 6 months of treatment with cannabidiol. At the first committee meeting, the committee had concluded that applying the stopping rule at 3 months, as suggested by clinicians, would be appropriate. This was because the timing aligned with clinical practice and the follow up in the clinical trials. At the second meeting, the company explained that stopping at 3 months would be inappropriate because titrating to a therapeutic dose is likely to take longer than 3 months. The committee was aware that the company had not provided evidence of how long titration takes in clinical practice, but agreed that it may be appropriate to increase the dose slowly for some patients. The company had also included stopping rules in its model at 12 months and 24 months. The committee considered that clinicians would likely evaluate patients more frequently, that is, every 6 months at a minimum. It therefore concluded that a stopping rule as proposed by NHS England is appropriate, and that response to treatment defined by a reduction in convulsive seizures compared with the 6 months before starting cannabidiol should be assessed every 6 months.
# Company's economic model
## The company's exploratory analysis with health states defined by narrower ranges of seizures is appropriate
The company presented a Markov state-transition cohort model to estimate the cost effectiveness of cannabidiol. In response to committee queries, the company explained that it had considered using other types of models, but did not consider that these would be better than a Markov model. It used efficacy inputs derived from the subgroup of patients in the trial who also took clobazam. The model had a time horizon of 90 years and a cycle length of 3 months. It had 4 health states, based on the number of convulsive seizures a patient had each month, to capture the costs and health effects. One health state corresponded to 0 convulsive seizures (freedom from seizures). The company derived the remaining health states by dividing the overall trial population evenly into 3 health states by the frequency of seizures at the beginning of the trials. The committee was concerned that the ranges of seizures were very wide for some health states (for example, from more than 8 seizures to 25 seizures or less) and were not based on a clinical rationale. In response to consultation, the company provided an exploratory analysis in which the health states were defined by narrower ranges of seizures. The company chose health states to ensure that most patients who had a 50% change in the number of seizures, which the company stated was clinically meaningful, would move to a different health state at the end of each cycle. The committee was aware that the company had defined the health states specifically for the subgroup of patients taking clobazam based on clinical rationale. The committee concluded that the health states with narrower ranges of seizures were appropriate for decision making.
## The company's approach to modelling the number of seizure-free days is acceptable
The company incorporated into the model the number of days each month that a patient did not have a convulsive seizure. It did this by dividing each of the 3 convulsive seizure health states into 3 substates based on different numbers of seizure-free days. This was based on an exploratory end point in the clinical trials. The company explained that it had chosen this structure because both seizure frequency and days without seizures benefit people with Dravet syndrome. In response to a committee concern, the company stated that it designed the substates so that each health state in the model was mutually exclusive to avoid 'double counting' the benefit. The committee recalled that patients value both fewer seizures and more seizure-free days (see section 3.2) so it was appropriate to capture both in the model. However, the committee considered that other approaches to modelling, such as discrete event simulation, may have been more appropriate to capture the benefits of different numbers of seizure-free days. It concluded that the company's approach was acceptable.
## The company's approach to capturing the benefit of reducing non-convulsive seizures may not be valid but these benefits should be considered
The committee recalled that the clinical trials showed that cannabidiol also reduced non-convulsive seizures (see section 3.5), but this benefit was not captured in the model. In response to consultation, the company included in its model a mechanism for capturing the benefits associated with reducing non-convulsive seizures. It did this by applying an additional disutility value in each health state derived from a public preference study of epilepsy health states (de Kinderen et al. 2016). The company assumed that patients who have fewer convulsive seizures would also benefit from having fewer non-convulsive seizures. Because cannabidiol (compared with not taking cannabidiol) reduces the frequency of non-convulsive seizures, people who take cannabidiol would avoid disutility from both. The ERG was concerned that the company's approach may have led to double counting the benefits of reducing convulsive seizures. It was also unable to reproduce the utility estimates derived by the company. While the clinical trial data showed that cannabidiol decreased the frequency of non-convulsive seizures, the company had not used these data directly in its model. The committee therefore concluded that the company's approach to capturing non-convulsive seizures in the model may not have been valid. However, it recognised that reducing non-convulsive seizures was important to patients and carers (see section 3.2), and concluded that it would take this into account in its decision making.
# Assumptions in the economic model
## The model generates more favourable results for patients that stop cannabidiol than would be expected
The ERG highlighted concerns that, when it tested the model for validity, the model estimated higher quality-adjusted life years (QALYs) for cannabidiol when setting all the clinical inputs in the model equal for both cannabidiol and usual care. The ERG expected that the estimated QALYs would be the same for both treatments, but could not identify problems in the model code. In response to consultation, the company stated that it had done further validity testing and confirmed that the model worked as designed. It explained that the issue highlighted by the ERG resulted from the way the company modelled patients who stop cannabidiol. Most patients who stopped cannabidiol in the model were in the health state with the highest seizure frequency, based on trial evidence. However, in each cycle, the company reassigned this group of patients to health states in the same proportions as patients having usual care in that cycle. Because only around 45% of patients having usual care were in the health state with the highest seizure frequency, some patients in each group who stopped cannabidiol may have been reassigned to a health state with a lower frequency of seizures than they were in before stopping cannabidiol. This resulted in the higher gain in QALYs for cannabidiol seen when setting clinical inputs equal. The company justified its assumption about what happens to people who stop cannabidiol, stating that, because it had no clinical data on outcomes for people who stop cannabidiol, it was reasonable to assume that outcomes would be the same as those who never had it. The committee questioned whether the company's assumptions were valid. It would have preferred that the patients who stopped cannabidiol were split into groups of equal size (quantiles), and that the company redistributed the patients in each quantile to the health states in the corresponding quantile in the usual care arm. This approach would have limited the number of patients redistributed from higher seizure frequency states to lower ones, and vice versa. The committee concluded that assuming patients who stopped cannabidiol had the same outcomes as those on usual care meant that the model generated more favourable results for people who stopped cannabidiol than would be expected, but that the size of this bias was unknown.
## The mean body weight from the clinical trials should be used to model the weight-based dose of cannabidiol
To model the weight-based dose of cannabidiol (see section 2), the company divided the population into 4 age groups and used the median body weight from the trials for each age group. In its first meeting, the committee recognised that good practice in health economic analyses recommends using mean (not median) weights. Moreover, because median weight in the trials was lower than mean weight, using a median weight would have underestimated the dose and cost of cannabidiol. In the second meeting, the company stated that it had done a scenario analysis using mean weights, but still preferred to use median weights because there were 'significant outliers' (patients who are overweight) in the trial. The committee recalled its previous conclusion that the patients in the trial reflected those seen in the NHS (see section 3.4). It also agreed that patients who are 'outliers' would be offered treatment in the NHS. The committee did not change its conclusion that the company should have used the mean weight from the clinical trials to reflect the costs of cannabidiol. It concluded that it would take into account results based on mean body weight.
## The company's assumption that patients on usual care remain in the same health state is appropriate
In its original base case, to model beyond the data from the randomised controlled trial, the company used data from the open-label extension study for cannabidiol. However, for usual care, it assumed that the patients returned to the health state they started in. The committee did not consider this an appropriate way to account for the lack of comparator data in the open-label extension. In response to consultation, the company changed its base-case analysis so that patients on usual care remained in the same health states from the end of cycle 2 (6 months) until the end of the model or death. It argued that this assumption disadvantaged cannabidiol because it overestimated the clinical effectiveness of usual care. It also stated that any contribution to efficacy from the psychological effects of being in a trial is likely to have been higher in the blinded clinical trial than in the open-label extension study. This would have underestimated the relative efficacy of cannabidiol compared with usual care. The company therefore included a scenario in which patients in the usual care arm returned to their baseline health states after cycle 9. The committee agreed that the company's new base-case assumption was in line with its preferences, and a suitable approach to account for the lack of a comparator arm in the extension study.
## The effectiveness of cannabidiol is likely to diminish over time and the model should account for this
In its model, the company assumed that patients on cannabidiol stayed in the same health state (defined by seizure frequency) beyond 9 cycles (27 months). That is, the treatment effect of cannabidiol was maintained until the patient stopped treatment or died. Because data from the open-label extension showed that the effect of cannabidiol had persisted for 36 months, the company assumed that the effect lasted as long as the patient took cannabidiol. The clinical experts stated that they would expect the effectiveness of cannabidiol to diminish over time, as with other antiepileptic drugs. The company considered that it had captured reduced effectiveness over time in a scenario analysis in which it increased the annual rate at which patients in all health states (except the seizure-free health state) stopped cannabidiol. Specifically, it increased the stopping rate from 5% to 10% of patients per year. The company argued that patients, their carers or clinicians would ensure the drug was stopped if it was ineffective (see section 3.7). It also noted that, while there was no evidence that the efficacy of cannabidiol would be maintained after 36 months, equally, there was no evidence that it would diminish. The committee agreed that the company had made a reasonable attempt to account for treatment waning. However, it would have preferred that the company's analysis had also accounted for a reduction in effect over time in patients before they stop cannabidiol. The committee concluded that the effectiveness of cannabidiol was likely to diminish over time. It also concluded that the company's scenario analysis captured some, but not all, of the effects on quality of life or efficacy diminishing over time.
## There is insufficient evidence to prove that cannabidiol prolongs life
The committee was aware that the trials did not show that treatment with cannabidiol prolonged life, but that the company had proposed that people taking cannabidiol live longer than those who do not take cannabidiol. In its model, the company assumed that people without convulsive seizures were less likely to die from epilepsy-related causes, and people taking cannabidiol were more likely to be free from convulsive seizures. The company used an observational study of people with epilepsy (Trinka et al. 2013) to model a 58% reduction in risk of death associated with being free from seizures. The clinical experts commented that the model overestimated the reduction in risk of death for people without convulsive seizures. In response, the company halved the reduction in risk of death associated with being seizure free in its model to 29%. It also provided a scenario analysis in which it removed the assumption that cannabidiol extends life. The committee was aware that the company had not observed a reduction in mortality associated with cannabidiol in its clinical trials either because no effect exists, or because the trial was not long enough. The committee agreed that it was plausible that people who are free of convulsive seizures may be at a lower risk of death. However, it appreciated that people who were free of seizures may be otherwise heathier than people with frequent seizures. This, at least in part, could have accounted for some of the size of the association between seizure frequency and death. The clinical experts agreed with this concern. In summary, the committee was concerned that the company's base-case assumption was not supported by trial evidence, and that the observational evidence was likely confounded. It concluded that there was insufficient evidence to prove that cannabidiol prolongs life. It preferred the company's scenario analysis that removed the assumption that cannabidiol extends life.
# Costs in the economic model
## The company's scenario analysis using an average dosage of 12 mg/kg/day is appropriate to capture the costs of increasing the dosage of cannabidiol
The summary of product characteristics for cannabidiol states that the dosage can be increased from a maintenance dosage of 10 mg/kg/day to 20 mg/kg/day (see section 2). Yet, the company assumed in its base case that all patients would have a maintenance dosage of 10 mg/kg/day for the entire treatment duration with cannabidiol. The company explained that it expected some people would be offered higher doses if they had seen a large drop in their frequency of seizures, to try to free them of seizures. At the committee's second meeting, the company explained that it expected the dosage was unlikely to be increased beyond 15 mg/kg/day in clinical practice. To capture the cost of dosing increases, the company did scenario analyses using an average dosage higher than 10 mg/kg/day for all patients. In 1 scenario it assumed that 20% of patients would increase their dose. This was based on opinion from clinical experts at the first committee meeting. It also assumed that these people would have the maximum recommended dosage of 20 mg/kg/day; this resulted in an average dosage of 12 mg/kg/day. The company stated that it expected that some people would not have the full recommended maintenance dosage of 10 mg/kg/day in clinical practice. So, it presented a scenario using an average dosage of 9 mg/kg/day. The committee noted that the company had not presented evidence that the doses used in clinical practice would be lower than those recommended in the summary of product characteristics. It concluded that it preferred the company's scenario analysis using an average dosage of 12 mg/kg/day.
# Utility values in the economic model
## The utility values from the company's vignette study are the most suitable for the company's model structure
The company collected data from responses to the Quality of Life in Childhood Epilepsy questionnaire in its clinical trials, but did not use the data in its model. It stated that there was a low response rate to the questionnaire, and that there is no algorithm to map the results to EQ‑5D utilities, NICE's preferred measure of health-related quality of life. The company also noted that data on quality of life in the literature are based on percentage reduction in seizures rather than the health states and substates it used in its model (that is, number of seizures and seizure-free days). So, the company instead asked people with Dravet syndrome and their carers to estimate the quality of life associated with each health state and substate in the model. Respondents were asked to consider 'vignettes', that is, descriptions of each health state and, using a visual analogue scale, give each a value between 0 (death) and 1 (perfect health). The company considered the quality-of-life values it used in its model to be confidential. The committee agreed that the vignette approach was justified given the lack of data in the literature; however, it also noted several limitations. It highlighted that the vignette study relied on patients and carers to value the health states rather than the general public, who may estimate quality of life differently. Using values from the general public is NICE's preferred method because someone living with, or caring for, someone with the disease may get used to the symptoms, and may have a lower expectation of attaining good health than the general public. The lowest value patients and carers could give each health state was 0, whereas the EQ‑5D scale allows for health states below 0 (that is, a quality of life worse than death). The committee considered that Dravet syndrome had features in common with other disease associated with quality-of-life values below 0. The clinical experts stated that the value the company used for the health state reflecting freedom from convulsive seizures lacked face validity. They expected the values to be lower because, despite being free from convulsive seizures, people may still have non-convulsive seizures, adverse effects and epilepsy-associated comorbidities such as cognitive impairment. The committee was also aware that the company had done a scenario analysis using values from a general population preference study in Lennox−Gastaut syndrome (Verdian et al. 2018). Although not directly comparable, these values appeared broadly similar to the company's utility values from the vignette study. The committee was aware that, because of the structure of the company's model, if it was to use the values from the literature, the model could not realise the benefits of having more days free of convulsive seizures. This was because it had to use the same values for each substate. The committee highlighted that the methods the company used to obtain the utility values had significant problems. However, it concluded that the utility values from the company's vignette study were appropriate for modelling the health-related quality of life of people with Dravet syndrome.
## It is appropriate to model the effect on carers' quality of life, and the values from the company's vignette study are the best available source
The committee recalled that caring for someone with Dravet syndrome affects carers' quality of life (see section 3.1), and that capturing this in the model is appropriate. The company included utility decrements in its model for carers of people in the 2 health states reflecting the highest frequency of seizures. The utility decrements were based on the company's vignette study. The committee recalled that the vignette study had limitations (see section 3.17). It was concerned that the company had captured the effect on the quality of life of carers only for the 2 health states reflecting the highest frequency of seizures. It considered that caring for people with fewer convulsive seizures, comorbidities, or other types of seizures would affect carers' quality of life. The committee would have preferred the company to have used values from a public preference study rather than a vignette study, but accepted that these were not available. In response to consultation, the company and patient groups stated that family members not directly involved in caring, particularly siblings, may also benefit from their relatives' seizures being better controlled. The committee concluded that it was appropriate to include carers' quality of life in the model and that, although limited, the company's vignette study was the best available source for utility values.
## The company's scenario analysis using 1.8 carers is preferable
The company assumed that people with Dravet syndrome have 2 carers based on clinical expert opinion. It did not present details on how it solicited clinical expert opinion. The company also provided a scenario analysis using a value of 1.8 carers based on evidence from the literature (Lagae et al. 2017). It noted that other family members of people with Dravet syndrome may have responsibilities for care, which would lower their quality of life (see section 3.1). The company included a scenario analysis increasing the number of carers in the model to 3 to account for this. For the analysis using 2 carers, the company doubled the decrements from the vignette study (see section 3.18) and subtracted this from the value reflecting the patient's utility. The committee was concerned that the company's approach implied that the caring burden increases linearly the more carers a patient has. However, for a patient with multiple carers, it expected there to be less effect on the quality of life of each carer because they would 'share' some of the burden; so, while the total burden for 2 carers may be greater than the burden for a sole carer, it would likely not be 2 times greater. The company stated that its vignette study accounted for 'sharing' care because it asked everyone taking part to rate their own quality of life, and most people in the study had a partner. The committee recalled that there were several limitations with the company's vignette study (see sections 3.17 and 3.18), so it was unclear whether the disutility values appropriately captured 'sharing' of care. The committee considered that the company's method of linearly multiplying the disutility values was inappropriate and could have led to perverse results, particularly if the company had modelled a high number of carers. However, in this case, using the value of 1.8 carers limited this effect. The committee acknowledged the substantial detrimental effect that caring can have on quality of life. It recognised that it would be difficult to estimate how much each additional carer reduced the burden of the other carers. The committee concluded that it preferred to use the value of 1.8 carers, which also helped to limit the effect of the inappropriate methodology used by the company to incorporate carer disutility into the model.
# Cost-effectiveness results
## Addressing the remaining uncertainties in the model would likely increase the incremental cost-effectiveness ratios
The company's updated cost-effectiveness analyses included most of the committee's preferred assumptions:
using narrower seizure frequency ranges for the health states (see section 3.8)
removing the effect of non-convulsive seizures as calculated (see section 3.10)
using the mean weight instead of the median (see section 3.12)
accounting for waning of cannabidiol's effects (see section 3.14)
not assuming that cannabidiol lengthens life (see section 3.15)
using an average dosage of 12 mg/kg/day (see section 3.16)
including health-related quality-of-life effects for 1.8 carers, which acknowledges shared burden (see section 3.19).This resulted in an incremental cost-effectiveness ratio (ICER) of £32,471 per QALY gained. These analyses did not take into account the committee's preference for stopping rules to be applied at 18 months rather than 24 months. However, the committee agreed this was unlikely to have had a substantial effect on the ICER (see section 3.7). It also recalled that there was additional uncertainty in the cost-effectiveness results because of:
the company's assumptions around people who stop treatment with cannabidiol (see section 3.11)
the way the company modelled a waning of treatment effect, which did not capture all the effects that diminishing efficacy over time would have on quality of life (see section 3.14).The committee concluded that the cumulative effect of addressing these uncertainties was likely to have increased the ICER.
# Other factors
## There are benefits of cannabidiol that are not captured in the company's model
The committee recalled that the company had not modelled the effect of reducing the duration of convulsive seizures, nor the effect on the quality of life of the siblings of children or young people with Dravet syndrome (see section 3.18). It also recalled that the company's approach to modelling fewer non-convulsive seizures was not appropriate (see section 3.8). The committee considered these factors important for improving quality of life (see section 3.1). It concluded that it would take these benefits into account in its decision making.
## Cannabidiol does not meet the criteria for an innovative treatment
The clinical experts stated that they would welcome an additional treatment option for Dravet syndrome. However, they considered that cannabidiol represents only a modest change when managing Dravet syndrome because few people became seizure free (see section 3.5). The committee concluded that cannabidiol did not meet the criteria for an innovative treatment.
## Cannabidiol is recommended for use with clobazam to treat people with Dravet syndrome
The committee recalled that it had concluded that it was appropriate to consider other benefits not captured in the company's model (see section 3.21). It recognised that some of the remaining uncertainties would be addressed in time with ongoing data collection. The committee concluded that, despite these uncertainties (see section 3.20), when it considered the uncaptured benefits, cannabidiol represents an effective treatment and a good use of NHS resources. It therefore recommended cannabidiol with clobazam to treat Dravet syndrome. It also concluded that seizure frequency should be checked every 6 months and that, if the frequency has not fallen by at least 30% compared with the 6 months before starting treatment, cannabidiol should be stopped (see section 3.7).
|
{'Recommendations': "Cannabidiol with clobazam is recommended as an option for treating seizures associated with Dravet syndrome in people aged 2\xa0years and older, only if:\n\nthe frequency of convulsive seizures is checked every 6\xa0months, and cannabidiol is stopped if the frequency has not fallen by at least 30% compared with the 6\xa0months before starting treatment\n\nthe company provides cannabidiol according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with cannabidiol, with clobazam, that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place before this guidance was published, until they and their NHS clinicians consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person, or the child or young person's parents or carers.\n\nWhy the committee made these recommendations\n\nCurrent treatment for Dravet syndrome includes antiepileptic drugs. People with Dravet syndrome would have cannabidiol with clobazam if their convulsive seizures are not controlled well enough after trying 2\xa0or more antiepileptic drugs.\n\nClinical trials show that cannabidiol reduces the number of convulsive and non-convulsive seizures when compared with usual care.\n\nThe cost-effectiveness estimates are uncertain for cannabidiol because of some of the assumptions in the company's model. The cost-effectiveness estimates do not include the benefits of:\n\nreducing the number of non-convulsive seizures\n\nreducing the duration of convulsive seizures\n\nimproving the quality of life of the siblings of people with Dravet syndrome.\n\nWhen taking both the uncertainties and the uncaptured benefits into account, cannabidiol is considered an appropriate use of NHS resources, and is recommended as an option for treating Dravet syndrome in the NHS.", 'Information about cannabidiol': "# Marketing authorisation indication\n\nCannabidiol (Epidyolex, GW Pharma) is licensed as 'adjunctive therapy for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in conjunction with clobazam, for patients 2\xa0years of age or older'.\n\n# Dosage in the marketing authorisation\n\nIt is administered orally as 100\xa0mg/ml cannabidiol solution. The recommended starting dosage is 2.5\xa0mg/kg taken twice daily for 1\xa0week. After 1\xa0week, the dosage should be increased to a maintenance dosage of 5\xa0mg/kg twice daily (10\xa0mg/kg/day). Based on individual clinical response and tolerability, each dosage can be further increased in weekly increments of 2.5\xa0mg/kg taken twice daily up to a maximum recommended dosage of 10\xa0mg/kg twice daily (20\xa0mg/kg/day). Any dosage increases above 10\xa0mg/kg/day should take into account individual benefit and risk.\n\n# Price\n\nThe list price of cannabidiol has been agreed with the Department of Health and Social Care, but is considered confidential by the company until January 2020. The company has a commercial arrangement. This makes cannabidiol available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by GW Pharma, a review of this submission by the evidence review group (ERG) and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\n# Disease background\n\n## Dravet syndrome severely affects the quality of life of patients, carers and their families\n\nDravet syndrome is a severe, lifelong and treatment-resistant genetic form of epilepsy that begins in early childhood, usually in babies aged between 6\xa0months and 10\xa0months. It is characterised by frequent seizures of different types. Convulsive seizures are characterised by stiffness and jerking, and can last for extended periods. The patient and carer expert explained that, of the different types of seizure, convulsive seizures have the biggest effect on quality of life because they may result in injuries and hospitalisation. The patient and carer expert noted that Dravet syndrome affects families and carers. People with the disease need round-the-clock care and help with almost all aspects of daily life. Families and carers may find looking after people with Dravet syndrome demanding, and that it prevents them from leading normal lives, including spending less time with their other children. Also, the anxiety that a child with Dravet syndrome may have status epilepticus or die can significantly affect the mental wellbeing of all family members. The committee concluded that Dravet syndrome severely affects the quality of life of patients, families and carers.\n\n# Current treatments\n\n## People with Dravet syndrome and their carers would value a treatment option that reduces seizure frequency and duration\n\nThe clinical, and patient and carer, experts agreed that current treatments often do not control seizures associated with Dravet syndrome. This is despite a broad range of available antiepileptic drugs, non-pharmacological interventions (such as vagus nerve stimulation and a ketogenic diet) and surgery. They stated that there is an unmet need in Dravet syndrome for an intervention that effectively reduces seizures without markedly increasing adverse events. The patient and carer expert reported that drugs which initially work can lose efficacy. The experts would welcome new treatment options, and noted that reducing the number of convulsive seizures is the main goal of treatment. They noted that an increase in the number of convulsive seizure-free days would also benefit people with Dravet syndrome. This is because it would mean having fewer nights with seizures, when there is a higher risk of sudden unexpected death in epilepsy. The patient and carer expert considered that reducing the duration of convulsive seizures and the frequency of other seizure types would improve the quality of life of people with Dravet syndrome. The committee concluded that there is an unmet need for treatments that reduce the number and duration of convulsive seizures, and that patients and their carers would value a new treatment option.\n\n# Cannabidiol and its positioning in the treatment pathway\n\n## The company's positioning of cannabidiol with clobazam in the treatment pathway is appropriate\n\nThe clinical experts explained that the Dravet syndrome treatment pathway is consistent with NICE's clinical guideline on epilepsies: diagnosis and management. The guideline recommends starting treatment with sodium valproate or topiramate and, if seizures are not adequately controlled, adding clobazam or stiripentol. The clinical experts added that stiripentol is increasingly being used because of evidence that using valproate, clobazam and stiripentol together improves efficacy. They noted that most people with Dravet syndrome will have tried several antiepileptic drugs by the time they are 2\xa0years old and would be eligible for adjuvant treatment with cannabidiol. The committee was aware that the marketing authorisation for cannabidiol is for use as an adjuvant therapy with clobazam. The company proposed that cannabidiol should be considered after 2\xa0other antiepileptic drugs. The clinical experts stated that clobazam is currently used when 2\xa0antiepileptic drugs have not adequately controlled seizures, and that they would consider adding cannabidiol to clobazam. The committee concluded that the company's positioning of cannabidiol with clobazam after 2\xa0treatments in the treatment pathway was appropriate.\n\n# Clinical-effectiveness evidence\n\n## The patients in the clinical trials reflect those who would have cannabidiol in the NHS and the subgroup taking clobazam is most relevant to the appraisal\n\nCannabidiol (plus usual care) has been compared with placebo (plus usual care) in 2\xa0randomised controlled trials, GWPCARE1 and GWPCARE2. In GWPCARE2, 2\xa0maintenance doses of cannabidiol (10\xa0mg/kg/day and 20\xa0mg/kg/day) were compared with placebo. In GWPCARE1, the higher maintenance dosage of 20\xa0mg/kg/day was compared with placebo. Both trials had a follow up of 14\xa0weeks. The licensed maintenance dosage of cannabidiol is 10\xa0mg/kg/day, with dosage increases permitted up to a maximum of 20\xa0mg/kg/day. An open-label extension study designed for safety, GWPCARE5, in which all patients are having cannabidiol, is ongoing. The company expects to follow patients in this study for up to 5\xa0years. The committee recognised that this study will provide potentially important information on safety. The committee was aware that the trials did not include patients aged 18\xa0years or older, who are included in the marketing authorisation and to whom clinicians would offer treatment. The clinical experts stated that, based on their experiences with other antiepileptic treatments, they would expect adults to benefit from cannabidiol. However, they explained that it was uncertain whether the clinical effect would be the same in adults as in children. About two-thirds of the patients in both trials were also taking clobazam. The committee agreed that the baseline characteristics of patients in the subgroup taking clobazam were similar to those with Dravet syndrome who would have cannabidiol in the NHS. It concluded that the subgroup of patients taking clobazam was most relevant to this appraisal, and that it would not consider the overall trial population further.\n\n## Cannabidiol with clobazam reduces seizure frequency, but long-term efficacy is uncertain\n\nThe primary end point in both GWPCARE1 and GWPCARE2 was the percentage change in convulsive seizure frequency from baseline per 28\xa0days between groups. The company provided results from the trials for the subgroup of patients taking clobazam (see section 3.4). The reduction in median convulsive seizure frequency per 28\xa0days in GWPCARE2 for patients taking cannabidiol 10\xa0mg/kg/day compared with placebo was 37%, which was statistically significant at the 95% confidence level (p=0.0042). The clinical and patient experts noted that this size of reduction was meaningful for people with the condition. The company did not provide evidence of how many patients taking cannabidiol with clobazam became free of convulsive seizures, but the committee was aware that this reflected only a few patients. There was also a reduction in the secondary end point of total seizure frequency per 28\xa0days of 43% compared with placebo (p=0.0003). In GWPCARE1, with cannabidiol 20\xa0mg/kg/day there was also a reduction in both convulsive and non-convulsive seizure frequency compared with placebo. The committee was aware that GWPCARE2 also included a 20\xa0mg/kg/day arm, and that the European Medicines Agency concluded that there was no consistent difference in dose response between 10\xa0mg/kg/day and 20\xa0mg/kg/day. The committee was aware that the summary of product characteristics states that the recommended maintenance dosage of cannabidiol is 10\xa0mg/kg/day (see section\xa02). It agreed that GWPCARE2 was most relevant to the decision problem. In response to consultation, the company provided interim analysis for seizure frequency after 3\xa0years of follow up from the open-label extension, GWPCARE5, for the subgroup of patients taking cannabidiol and clobazam. This showed that reduction in seizure frequency with treatment was broadly maintained for up to 3\xa0years. The committee concluded that cannabidiol with clobazam reduces seizure frequency compared with usual care, but that the long-term efficacy after 3\xa0years is uncertain.\n\n# Adverse events\n\n## Cannabidiol is associated with adverse events that are manageable\n\nThe trial results showed that a large proportion of patients having cannabidiol with clobazam had adverse events. The most commonly occurring adverse events in this group were somnolence or sedation, decreased appetite, diarrhoea, fever, fatigue and vomiting. The clinical experts noted that people with Dravet syndrome often experience adverse effects from their medications. They also noted that cannabidiol's adverse effects are mostly, but not always, mild and tolerated. The patient and carer expert stated that the choice of treatment depends on the balance of its safety and tolerability, with adverse events representing an important consideration. The committee was concerned that the trial had a short follow up, which may not have captured all cannabidiol's adverse effects. It was aware that more data on safety would be available from GWPCARE5, which is ongoing (see section\xa03.4). The clinical and patient experts explained that patients would be closely monitored, and treatment would be stopped if adverse events were not manageable. The committee concluded that, while cannabidiol's adverse effects are mostly manageable, they are an important consideration when making decisions about whether to start or continue cannabidiol.\n\n# Stopping treatment\n\n## It is appropriate to assess response to treatment every 6\xa0months and stop cannabidiol if it is not effective\n\nThe marketing authorisation for cannabidiol does not specify a stopping rule, that is, stopping treatment if or when it does not work. However, NHS England proposed during the technical engagement stage of the appraisal that cannabidiol should be stopped if the frequency of convulsive seizures has not reduced by at least 30% from baseline. The clinical experts noted that they took account of broadly similar criteria when advising patients, and their families and carers about whether to continue other antiepileptic drugs. The patient and carer expert explained that they would not want to continue a treatment unnecessarily when it does not work well because this would increase the drug burden and potential adverse effects. The committee was aware that the company implemented the stopping criteria proposed by NHS England in its model after 6\xa0months of treatment with cannabidiol. At the first committee meeting, the committee had concluded that applying the stopping rule at 3\xa0months, as suggested by clinicians, would be appropriate. This was because the timing aligned with clinical practice and the follow up in the clinical trials. At the second meeting, the company explained that stopping at 3\xa0months would be inappropriate because titrating to a therapeutic dose is likely to take longer than 3\xa0months. The committee was aware that the company had not provided evidence of how long titration takes in clinical practice, but agreed that it may be appropriate to increase the dose slowly for some patients. The company had also included stopping rules in its model at 12\xa0months and 24\xa0months. The committee considered that clinicians would likely evaluate patients more frequently, that is, every 6\xa0months at a minimum. It therefore concluded that a stopping rule as proposed by NHS England is appropriate, and that response to treatment defined by a reduction in convulsive seizures compared with the 6\xa0months before starting cannabidiol should be assessed every 6\xa0months.\n\n# Company's economic model\n\n## The company's exploratory analysis with health states defined by narrower ranges of seizures is appropriate\n\nThe company presented a Markov state-transition cohort model to estimate the cost effectiveness of cannabidiol. In response to committee queries, the company explained that it had considered using other types of models, but did not consider that these would be better than a Markov model. It used efficacy inputs derived from the subgroup of patients in the trial who also took clobazam. The model had a time horizon of 90\xa0years and a cycle length of 3\xa0months. It had 4\xa0health states, based on the number of convulsive seizures a patient had each month, to capture the costs and health effects. One health state corresponded to 0\xa0convulsive seizures (freedom from seizures). The company derived the remaining health states by dividing the overall trial population evenly into 3\xa0health states by the frequency of seizures at the beginning of the trials. The committee was concerned that the ranges of seizures were very wide for some health states (for example, from more than 8\xa0seizures to 25\xa0seizures or less) and were not based on a clinical rationale. In response to consultation, the company provided an exploratory analysis in which the health states were defined by narrower ranges of seizures. The company chose health states to ensure that most patients who had a 50% change in the number of seizures, which the company stated was clinically meaningful, would move to a different health state at the end of each cycle. The committee was aware that the company had defined the health states specifically for the subgroup of patients taking clobazam based on clinical rationale. The committee concluded that the health states with narrower ranges of seizures were appropriate for decision making.\n\n## The company's approach to modelling the number of seizure-free days is acceptable\n\nThe company incorporated into the model the number of days each month that a patient did not have a convulsive seizure. It did this by dividing each of the 3 convulsive seizure\xa0health states into 3\xa0substates based on different numbers of seizure-free days. This was based on an exploratory end point in the clinical trials. The company explained that it had chosen this structure because both seizure frequency and days without seizures benefit people with Dravet syndrome. In response to a committee concern, the company stated that it designed the substates so that each health state in the model was mutually exclusive to avoid 'double counting' the benefit. The committee recalled that patients value both fewer seizures and more seizure-free days (see section\xa03.2) so it was appropriate to capture both in the model. However, the committee considered that other approaches to modelling, such as discrete event simulation, may have been more appropriate to capture the benefits of different numbers of seizure-free days. It concluded that the company's approach was acceptable.\n\n## The company's approach to capturing the benefit of reducing non-convulsive seizures may not be valid but these benefits should be considered\n\nThe committee recalled that the clinical trials showed that cannabidiol also reduced non-convulsive seizures (see section\xa03.5), but this benefit was not captured in the model. In response to consultation, the company included in its model a mechanism for capturing the benefits associated with reducing non-convulsive seizures. It did this by applying an additional disutility value in each health state derived from a public preference study of epilepsy health states (de Kinderen et al. 2016). The company assumed that patients who have fewer convulsive seizures would also benefit from having fewer non-convulsive seizures. Because cannabidiol (compared with not taking cannabidiol) reduces the frequency of non-convulsive seizures, people who take cannabidiol would avoid disutility from both. The ERG was concerned that the company's approach may have led to double counting the benefits of reducing convulsive seizures. It was also unable to reproduce the utility estimates derived by the company. While the clinical trial data showed that cannabidiol decreased the frequency of non-convulsive seizures, the company had not used these data directly in its model. The committee therefore concluded that the company's approach to capturing non-convulsive seizures in the model may not have been valid. However, it recognised that reducing non-convulsive seizures was important to patients and carers (see section\xa03.2), and concluded that it would take this into account in its decision making.\n\n# Assumptions in the economic model\n\n## The model generates more favourable results for patients that stop cannabidiol than would be expected\n\nThe ERG highlighted concerns that, when it tested the model for validity, the model estimated higher quality-adjusted life years (QALYs) for cannabidiol when setting all the clinical inputs in the model equal for both cannabidiol and usual care. The ERG expected that the estimated QALYs would be the same for both treatments, but could not identify problems in the model code. In response to consultation, the company stated that it had done further validity testing and confirmed that the model worked as designed. It explained that the issue highlighted by the ERG resulted from the way the company modelled patients who stop cannabidiol. Most patients who stopped cannabidiol in the model were in the health state with the highest seizure frequency, based on trial evidence. However, in each cycle, the company reassigned this group of patients to health states in the same proportions as patients having usual care in that cycle. Because only around 45% of patients having usual care were in the health state with the highest seizure frequency, some patients in each group who stopped cannabidiol may have been reassigned to a health state with a lower frequency of seizures than they were in before stopping cannabidiol. This resulted in the higher gain in QALYs for cannabidiol seen when setting clinical inputs equal. The company justified its assumption about what happens to people who stop cannabidiol, stating that, because it had no clinical data on outcomes for people who stop cannabidiol, it was reasonable to assume that outcomes would be the same as those who never had it. The committee questioned whether the company's assumptions were valid. It would have preferred that the patients who stopped cannabidiol were split into groups of equal size (quantiles), and that the company redistributed the patients in each quantile to the health states in the corresponding quantile in the usual care arm. This approach would have limited the number of patients redistributed from higher seizure frequency states to lower ones, and vice versa. The committee concluded that assuming patients who stopped cannabidiol had the same outcomes as those on usual care meant that the model generated more favourable results for people who stopped cannabidiol than would be expected, but that the size of this bias was unknown.\n\n## The mean body weight from the clinical trials should be used to model the weight-based dose of cannabidiol\n\nTo model the weight-based dose of cannabidiol (see section\xa02), the company divided the population into 4\xa0age groups and used the median body weight from the trials for each age group. In its first meeting, the committee recognised that good practice in health economic analyses recommends using mean (not median) weights. Moreover, because median weight in the trials was lower than mean weight, using a median weight would have underestimated the dose and cost of cannabidiol. In the second meeting, the company stated that it had done a scenario analysis using mean weights, but still preferred to use median weights because there were 'significant outliers' (patients who are overweight) in the trial. The committee recalled its previous conclusion that the patients in the trial reflected those seen in the NHS (see section\xa03.4). It also agreed that patients who are 'outliers' would be offered treatment in the NHS. The committee did not change its conclusion that the company should have used the mean weight from the clinical trials to reflect the costs of cannabidiol. It concluded that it would take into account results based on mean body weight.\n\n## The company's assumption that patients on usual care remain in the same health state is appropriate\n\nIn its original base case, to model beyond the data from the randomised controlled trial, the company used data from the open-label extension study for cannabidiol. However, for usual care, it assumed that the patients returned to the health state they started in. The committee did not consider this an appropriate way to account for the lack of comparator data in the open-label extension. In response to consultation, the company changed its base-case analysis so that patients on usual care remained in the same health states from the end of cycle\xa02 (6\xa0months) until the end of the model or death. It argued that this assumption disadvantaged cannabidiol because it overestimated the clinical effectiveness of usual care. It also stated that any contribution to efficacy from the psychological effects of being in a trial is likely to have been higher in the blinded clinical trial than in the open-label extension study. This would have underestimated the relative efficacy of cannabidiol compared with usual care. The company therefore included a scenario in which patients in the usual care arm returned to their baseline health states after cycle\xa09. The committee agreed that the company's new base-case assumption was in line with its preferences, and a suitable approach to account for the lack of a comparator arm in the extension study.\n\n## The effectiveness of cannabidiol is likely to diminish over time and the model should account for this\n\nIn its model, the company assumed that patients on cannabidiol stayed in the same health state (defined by seizure frequency) beyond 9\xa0cycles (27\xa0months). That is, the treatment effect of cannabidiol was maintained until the patient stopped treatment or died. Because data from the open-label extension showed that the effect of cannabidiol had persisted for 36\xa0months, the company assumed that the effect lasted as long as the patient took cannabidiol. The clinical experts stated that they would expect the effectiveness of cannabidiol to diminish over time, as with other antiepileptic drugs. The company considered that it had captured reduced effectiveness over time in a scenario analysis in which it increased the annual rate at which patients in all health states (except the seizure-free health state) stopped cannabidiol. Specifically, it increased the stopping rate from 5% to 10% of patients per year. The company argued that patients, their carers or clinicians would ensure the drug was stopped if it was ineffective (see section\xa03.7). It also noted that, while there was no evidence that the efficacy of cannabidiol would be maintained after 36\xa0months, equally, there was no evidence that it would diminish. The committee agreed that the company had made a reasonable attempt to account for treatment waning. However, it would have preferred that the company's analysis had also accounted for a reduction in effect over time in patients before they stop cannabidiol. The committee concluded that the effectiveness of cannabidiol was likely to diminish over time. It also concluded that the company's scenario analysis captured some, but not all, of the effects on quality of life or efficacy diminishing over time.\n\n## There is insufficient evidence to prove that cannabidiol prolongs life\n\nThe committee was aware that the trials did not show that treatment with cannabidiol prolonged life, but that the company had proposed that people taking cannabidiol live longer than those who do not take cannabidiol. In its model, the company assumed that people without convulsive seizures were less likely to die from epilepsy-related causes, and people taking cannabidiol were more likely to be free from convulsive seizures. The company used an observational study of people with epilepsy (Trinka et al. 2013) to model a 58% reduction in risk of death associated with being free from seizures. The clinical experts commented that the model overestimated the reduction in risk of death for people without convulsive seizures. In response, the company halved the reduction in risk of death associated with being seizure free in its model to 29%. It also provided a scenario analysis in which it removed the assumption that cannabidiol extends life. The committee was aware that the company had not observed a reduction in mortality associated with cannabidiol in its clinical trials either because no effect exists, or because the trial was not long enough. The committee agreed that it was plausible that people who are free of convulsive seizures may be at a lower risk of death. However, it appreciated that people who were free of seizures may be otherwise heathier than people with frequent seizures. This, at least in part, could have accounted for some of the size of the association between seizure frequency and death. The clinical experts agreed with this concern. In summary, the committee was concerned that the company's base-case assumption was not supported by trial evidence, and that the observational evidence was likely confounded. It concluded that there was insufficient evidence to prove that cannabidiol prolongs life. It preferred the company's scenario analysis that removed the assumption that cannabidiol extends life.\n\n# Costs in the economic model\n\n## The company's scenario analysis using an average dosage of 12\xa0mg/kg/day is appropriate to capture the costs of increasing the dosage of cannabidiol\n\nThe summary of product characteristics for cannabidiol states that the dosage can be increased from a maintenance dosage of 10\xa0mg/kg/day to 20\xa0mg/kg/day (see section\xa02). Yet, the company assumed in its base case that all patients would have a maintenance dosage of 10\xa0mg/kg/day for the entire treatment duration with cannabidiol. The company explained that it expected some people would be offered higher doses if they had seen a large drop in their frequency of seizures, to try to free them of seizures. At the committee's second meeting, the company explained that it expected the dosage was unlikely to be increased beyond 15\xa0mg/kg/day in clinical practice. To capture the cost of dosing increases, the company did scenario analyses using an average dosage higher than 10\xa0mg/kg/day for all patients. In 1\xa0scenario it assumed that 20% of patients would increase their dose. This was based on opinion from clinical experts at the first committee meeting. It also assumed that these people would have the maximum recommended dosage of 20\xa0mg/kg/day; this resulted in an average dosage of 12\xa0mg/kg/day. The company stated that it expected that some people would not have the full recommended maintenance dosage of 10\xa0mg/kg/day in clinical practice. So, it presented a scenario using an average dosage of 9\xa0mg/kg/day. The committee noted that the company had not presented evidence that the doses used in clinical practice would be lower than those recommended in the summary of product characteristics. It concluded that it preferred the company's scenario analysis using an average dosage of 12\xa0mg/kg/day.\n\n# Utility values in the economic model\n\n## The utility values from the company's vignette study are the most suitable for the company's model structure\n\nThe company collected data from responses to the Quality of Life in Childhood Epilepsy questionnaire in its clinical trials, but did not use the data in its model. It stated that there was a low response rate to the questionnaire, and that there is no algorithm to map the results to EQ‑5D utilities, NICE's preferred measure of health-related quality of life. The company also noted that data on quality of life in the literature are based on percentage reduction in seizures rather than the health states and substates it used in its model (that is, number of seizures and seizure-free days). So, the company instead asked people with Dravet syndrome and their carers to estimate the quality of life associated with each health state and substate in the model. Respondents were asked to consider 'vignettes', that is, descriptions of each health state and, using a visual analogue scale, give each a value between\xa00 (death) and\xa01 (perfect health). The company considered the quality-of-life values it used in its model to be confidential. The committee agreed that the vignette approach was justified given the lack of data in the literature; however, it also noted several limitations. It highlighted that the vignette study relied on patients and carers to value the health states rather than the general public, who may estimate quality of life differently. Using values from the general public is NICE's preferred method because someone living with, or caring for, someone with the disease may get used to the symptoms, and may have a lower expectation of attaining good health than the general public. The lowest value patients and carers could give each health state was\xa00, whereas the EQ‑5D scale allows for health states below\xa00 (that is, a quality of life worse than death). The committee considered that Dravet syndrome had features in common with other disease associated with quality-of-life values below\xa00. The clinical experts stated that the value the company used for the health state reflecting freedom from convulsive seizures lacked face validity. They expected the values to be lower because, despite being free from convulsive seizures, people may still have non-convulsive seizures, adverse effects and epilepsy-associated comorbidities such as cognitive impairment. The committee was also aware that the company had done a scenario analysis using values from a general population preference study in Lennox−Gastaut syndrome (Verdian et al. 2018). Although not directly comparable, these values appeared broadly similar to the company's utility values from the vignette study. The committee was aware that, because of the structure of the company's model, if it was to use the values from the literature, the model could not realise the benefits of having more days free of convulsive seizures. This was because it had to use the same values for each substate. The committee highlighted that the methods the company used to obtain the utility values had significant problems. However, it concluded that the utility values from the company's vignette study were appropriate for modelling the health-related quality of life of people with Dravet syndrome.\n\n## It is appropriate to model the effect on carers' quality of life, and the values from the company's vignette study are the best available source\n\nThe committee recalled that caring for someone with Dravet syndrome affects carers' quality of life (see section\xa03.1), and that capturing this in the model is appropriate. The company included utility decrements in its model for carers of people in the 2\xa0health states reflecting the highest frequency of seizures. The utility decrements were based on the company's vignette study. The committee recalled that the vignette study had limitations (see section\xa03.17). It was concerned that the company had captured the effect on the quality of life of carers only for the 2\xa0health states reflecting the highest frequency of seizures. It considered that caring for people with fewer convulsive seizures, comorbidities, or other types of seizures would affect carers' quality of life. The committee would have preferred the company to have used values from a public preference study rather than a vignette study, but accepted that these were not available. In response to consultation, the company and patient groups stated that family members not directly involved in caring, particularly siblings, may also benefit from their relatives' seizures being better controlled. The committee concluded that it was appropriate to include carers' quality of life in the model and that, although limited, the company's vignette study was the best available source for utility values.\n\n## The company's scenario analysis using 1.8\xa0carers is preferable\n\nThe company assumed that people with Dravet syndrome have 2\xa0carers based on clinical expert opinion. It did not present details on how it solicited clinical expert opinion. The company also provided a scenario analysis using a value of 1.8\xa0carers based on evidence from the literature (Lagae et al. 2017). It noted that other family members of people with Dravet syndrome may have responsibilities for care, which would lower their quality of life (see section\xa03.1). The company included a scenario analysis increasing the number of carers in the model to\xa03 to account for this. For the analysis using 2\xa0carers, the company doubled the decrements from the vignette study (see section\xa03.18) and subtracted this from the value reflecting the patient's utility. The committee was concerned that the company's approach implied that the caring burden increases linearly the more carers a patient has. However, for a patient with multiple carers, it expected there to be less effect on the quality of life of each carer because they would 'share' some of the burden; so, while the total burden for 2\xa0carers may be greater than the burden for a sole carer, it would likely not be 2\xa0times greater. The company stated that its vignette study accounted for 'sharing' care because it asked everyone taking part to rate their own quality of life, and most people in the study had a partner. The committee recalled that there were several limitations with the company's vignette study (see sections 3.17 and 3.18), so it was unclear whether the disutility values appropriately captured 'sharing' of care. The committee considered that the company's method of linearly multiplying the disutility values was inappropriate and could have led to perverse results, particularly if the company had modelled a high number of carers. However, in this case, using the value of 1.8\xa0carers limited this effect. The committee acknowledged the substantial detrimental effect that caring can have on quality of life. It recognised that it would be difficult to estimate how much each additional carer reduced the burden of the other carers. The committee concluded that it preferred to use the value of 1.8\xa0carers, which also helped to limit the effect of the inappropriate methodology used by the company to incorporate carer disutility into the model.\n\n# Cost-effectiveness results\n\n## Addressing the remaining uncertainties in the model would likely increase the incremental cost-effectiveness ratios\n\nThe company's updated cost-effectiveness analyses included most of the committee's preferred assumptions:\n\nusing narrower seizure frequency ranges for the health states (see section\xa03.8)\n\nremoving the effect of non-convulsive seizures as calculated (see section\xa03.10)\n\nusing the mean weight instead of the median (see section\xa03.12)\n\naccounting for waning of cannabidiol's effects (see section\xa03.14)\n\nnot assuming that cannabidiol lengthens life (see section\xa03.15)\n\nusing an average dosage of 12\xa0mg/kg/day (see section\xa03.16)\n\nincluding health-related quality-of-life effects for 1.8\xa0carers, which acknowledges shared burden (see section\xa03.19).This resulted in an incremental cost-effectiveness ratio (ICER) of £32,471 per QALY gained. These analyses did not take into account the committee's preference for stopping rules to be applied at 18\xa0months rather than 24\xa0months. However, the committee agreed this was unlikely to have had a substantial effect on the ICER (see section\xa03.7). It also recalled that there was additional uncertainty in the cost-effectiveness results because of:\n\nthe company's assumptions around people who stop treatment with cannabidiol (see section\xa03.11)\n\nthe way the company modelled a waning of treatment effect, which did not capture all the effects that diminishing efficacy over time would have on quality of life (see section\xa03.14).The committee concluded that the cumulative effect of addressing these uncertainties was likely to have increased the ICER.\n\n# Other factors\n\n## There are benefits of cannabidiol that are not captured in the company's model\n\nThe committee recalled that the company had not modelled the effect of reducing the duration of convulsive seizures, nor the effect on the quality of life of the siblings of children or young people with Dravet syndrome (see section\xa03.18). It also recalled that the company's approach to modelling fewer non-convulsive seizures was not appropriate (see section\xa03.8). The committee considered these factors important for improving quality of life (see section\xa03.1). It concluded that it would take these benefits into account in its decision making.\n\n## Cannabidiol does not meet the criteria for an innovative treatment\n\nThe clinical experts stated that they would welcome an additional treatment option for Dravet syndrome. However, they considered that cannabidiol represents only a modest change when managing Dravet syndrome because few people became seizure free (see section\xa03.5). The committee concluded that cannabidiol did not meet the criteria for an innovative treatment.\n\n## Cannabidiol is recommended for use with clobazam to treat people with Dravet syndrome\n\nThe committee recalled that it had concluded that it was appropriate to consider other benefits not captured in the company's model (see section\xa03.21). It recognised that some of the remaining uncertainties would be addressed in time with ongoing data collection. The committee concluded that, despite these uncertainties (see section\xa03.20), when it considered the uncaptured benefits, cannabidiol represents an effective treatment and a good use of NHS resources. It therefore recommended cannabidiol with clobazam to treat Dravet syndrome. It also concluded that seizure frequency should be checked every 6\xa0months and that, if the frequency has not fallen by at least 30% compared with the 6\xa0months before starting treatment, cannabidiol should be stopped (see section\xa03.7)."}
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https://www.nice.org.uk/guidance/ta614
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Evidence-based recommendations on cannabidiol (Epidyolex) with clobazam for seizures associated with Dravet syndrome in people aged 2 years and older.
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Cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome
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Cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome
Evidence-based recommendations on cannabidiol (Epidyolex) with clobazam for seizures associated with Lennox–Gastaut syndrome in people aged 2 years and older.
# Recommendations
Cannabidiol with clobazam is recommended as an option for treating seizures associated with Lennox–Gastaut syndrome in people aged 2 years and older, only if:
the frequency of drop seizures is checked every 6 months, and cannabidiol is stopped if the frequency has not fallen by at least 30% compared with the 6 months before starting treatment
the company provides cannabidiol according to the commercial arrangement.
This recommendation is not intended to affect treatment with cannabidiol, with clobazam, that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place before this guidance was published, until they and their NHS clinicians consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person, or the child or young person's parents or carers.
Why the committee made these recommendations
Current treatment for Lennox–Gastaut syndrome includes antiepileptic drugs. People with Lennox–Gastaut syndrome would have cannabidiol with clobazam if their drop seizures are not controlled well enough after trying 2 or more antiepileptic drugs.
Clinical trials show that cannabidiol reduces the number of drop and non-drop seizures when compared with usual care.
The cost-effectiveness estimates are uncertain for cannabidiol because of some of the assumptions in the company's model. The cost-effectiveness estimates do not include the benefits of:
reducing the number of non-drop seizures
improving the quality of life of the siblings of people with Lennox–Gastaut syndrome.
When taking both the uncertainties and the uncaptured benefits into account, cannabidiol is considered an appropriate use of NHS resources, and is recommended as an option for treating Lennox–Gastaut syndrome in the NHS.# Information about cannabidiol
# Marketing authorisation indication
Cannabidiol (Epidyolex, GW Pharma) is licensed as 'adjunctive therapy for seizures associated with Lennox–Gastaut syndrome (LGS) or Dravet syndrome (DS) in conjunction with clobazam, for patients 2 years of age or older'.
# Dosage in the marketing authorisation
It is administered orally as 100 mg/ml cannabidiol solution. The recommended starting dosage is 2.5 mg/kg taken twice daily for 1 week. After 1 week, this should be increased to a maintenance dosage of 5 mg/kg twice daily (10 mg/kg/day). Based on individual clinical response and tolerability, each dosage can be further increased in weekly increments of 2.5 mg/kg taken twice daily up to a maximum recommended dosage of 10 mg/kg twice daily (20 mg/kg/day). Any dosage increases above 10 mg/kg/day should take into account individual benefit and risk.
# Price
The list price of cannabidiol has been agreed with the Department of Health and Social Care, but is considered confidential by the company until January 2020. The company has a commercial arrangement. This makes cannabidiol available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by GW Pharma, a review of this submission by the evidence review group (ERG) and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
# Disease background
## Lennox–Gastaut syndrome severely affects the quality of life of patients, carers and their families
Lennox–Gastaut syndrome is a severe, lifelong and treatment-resistant genetic form of epilepsy that begins in early childhood, usually between 2 years and 7 years. It is characterised by frequent seizures of different types. Drop seizures result in a loss of muscle tone or stiffening of muscles, and people can crash to the ground. The patient and carer experts explained that drop seizures affect quality of life because they may result in severe injuries and hospitalisation. The patient and carer experts noted that Lennox–Gastaut syndrome affects families and carers. People with the disease need round-the-clock care, and help with almost all aspects of daily life. Families and carers may find looking after people with Lennox–Gastaut syndrome demanding, and that it prevents them from leading normal lives, including spending less time with their other children. Also, the anxiety that a child with Lennox–Gastaut syndrome may be injured because of a drop seizure can significantly affect the mental wellbeing of all family members. The committee concluded that Lennox–Gastaut syndrome severely affects the quality of life of patients, families and carers.
# Current treatments
## People with Lennox–Gastaut syndrome and their carers would value a treatment option that reduces seizure frequency
The clinical, and patient and carer, experts agreed that current treatments often do not control seizures associated with Lennox–Gastaut syndrome. This is despite a broad range of available antiepileptic drugs, non-pharmacological interventions (such as vagus nerve stimulation and a ketogenic diet) and surgery. They stated that there is an unmet need in Lennox–Gastaut syndrome for an intervention that effectively reduces seizures without markedly increasing adverse events. The patient and carer experts reported that drugs which initially work can lose efficacy. The experts would welcome new treatment options, and noted that reducing the number of drop seizures is the main goal of treatment. They also considered that reducing the frequency of other seizure types would improve the quality of life of people with Lennox–Gastaut syndrome. The committee concluded that there is an unmet need for treatments that reduce the number of drop seizures, and that patients and their carers would value a new treatment option.
# Cannabidiol and its positioning in the treatment pathway
## The company's positioning of cannabidiol with clobazam in the treatment pathway is appropriate
The clinical experts explained that the Lennox–Gastaut syndrome treatment pathway is consistent with NICE's clinical guideline on epilepsies: diagnosis and management. The guideline recommends starting treatment with sodium valproate and, if seizures are not adequately controlled, adding lamotrigine. They added that they would consider trying other antiepileptic drugs if sodium valproate and lamotrigine together do not adequately control seizures. The committee was aware that the marketing authorisation for cannabidiol is for use as an adjuvant therapy with clobazam. The company proposed that cannabidiol should be considered after 2 other antiepileptic drugs. The clinical experts stated that clobazam is currently used when 2 antiepileptic drugs have not adequately controlled seizures, and that they would consider adding cannabidiol to clobazam. The committee concluded that the company's positioning of cannabidiol with clobazam after 2 treatments in the treatment pathway was appropriate.
# Clinical-effectiveness evidence
## The patients in the clinical trials reflect those who would have cannabidiol in the NHS and the subgroup taking clobazam is most relevant to the appraisal
Cannabidiol (plus usual care) has been compared with placebo (plus usual care) in 2 randomised controlled trials, GWPCARE3 and GWPCARE4. In GWPCARE3, 3 maintenance doses of cannabidiol (10 mg/kg/day and 20 mg/kg/day) were compared with placebo. In GWPCARE4, the higher maintenance dosage of 20 mg/kg/day was compared with placebo. Both trials had a follow up of 14 weeks. The licensed maintenance dosage of cannabidiol is 10 mg/kg/day, with dosage increases permitted up to a maximum of 20 mg/kg/day. An open-label extension study designed for safety, GWPCARE5, in which all patients are having cannabidiol, is ongoing. The company expects to follow patients in this study for up to 5 years. The committee recognised that this study will provide potentially important information on safety. All the studies included adult patients. About half of the patients in both trials were also taking clobazam. The committee agreed that the baseline characteristics of patients in the subgroup taking clobazam were similar to those with Lennox–Gastaut syndrome who would have cannabidiol in the NHS. It concluded that the subgroup of patients taking clobazam was most relevant to this appraisal, and that it would not consider the overall trial population further.
## Cannabidiol with clobazam reduces seizure frequency, but long-term efficacy is uncertain
The primary end point in both GWPCARE3 and GWPCARE4 was the percentage change in drop seizure frequency from baseline per 28 days between groups. The company provided results from the trials for the subgroup of patients taking clobazam (see section 3.4). The reduction in median drop seizure frequency per 28 days in GWPCARE3 for patients taking cannabidiol 10 mg/kg/day compared with placebo was 30%, which was statistically significant at the 95% confidence level (p=0.0355). The clinical and patient experts noted that this size of reduction was meaningful for people with the condition. The company did not provide evidence of how many patients taking cannabidiol with clobazam became free of drop seizures, but the committee was aware that this reflected only a few patients. There was also a reduction in the secondary end point of total seizure frequency per 28 days of 37% compared with placebo (p=0.0025). In GWPCARE4, with cannabidiol 20 mg/kg/day there was also a reduction in both drop and non-drop seizure frequency compared with placebo. The committee was aware that GWPCARE3 also included a 20 mg/kg/day arm, and that the European Medicines Agency concluded that there was no consistent difference in dose response between 10 mg/kg/day and 20 mg/kg/day. The committee was aware that the summary of product characteristics states that the recommended maintenance dosage of cannabidiol is 10 mg/kg/day (see section 2). It agreed that GWPCARE3 was most relevant to the decision problem. In response to consultation, the company provided interim analysis for seizure frequency after 3 years of follow up from the open-label extension, GWPCARE5, for the subgroup of patients taking cannabidiol and clobazam. This showed that reduction in seizure frequency with treatment was broadly maintained for up to 3 years. The committee concluded that cannabidiol with clobazam reduces seizure frequency compared with usual care, but that the long-term efficacy after 3 years is uncertain.
# Adverse events
## Cannabidiol is associated with adverse events that are manageable
The trial results showed that a large proportion of patients having cannabidiol with clobazam had adverse events. The most commonly occurring adverse events in this group were somnolence or sedation, and diarrhoea. The clinical experts noted that people with Lennox–Gastaut syndrome often experience adverse effects from their medications. They also noted that cannabidiol's adverse effects are mostly, but not always, mild and tolerated. The patient and carer experts stated that the choice of treatment depends on the balance of its safety and tolerability, with adverse events representing an important consideration. The committee was concerned that the trial had a short follow up, which may not have captured all cannabidiol's adverse effects. It was aware that more data on safety would be available from GWPCARE5, which is ongoing (see section 3.4). The clinical and patient experts explained that patients would be closely monitored, and treatment would be stopped if adverse events were not manageable. The committee concluded that, while cannabidiol's adverse effects are mostly manageable, they are an important consideration when making decisions about whether to start or continue cannabidiol.
# Stopping treatment
## It is appropriate to assess response to treatment every 6 months and stop cannabidiol if it is not effective
The marketing authorisation for cannabidiol does not specify a stopping rule, that is, stopping treatment if or when it does not work. However, NHS England proposed during the technical engagement stage of the appraisal that cannabidiol should be stopped if the frequency of drop seizures has not reduced by at least 30% from baseline. The clinical experts noted that they took account of broadly similar criteria when advising patients, and their families and carers about whether to continue other antiepileptic drugs. The patient and carer expert explained that they would not want to continue a treatment unnecessarily when it does not work well because this would increase the drug burden and potential adverse effects. The committee was aware that the company implemented the stopping criteria proposed by NHS England in its model after 6 months of treatment with cannabidiol. At the first committee meeting, the committee had concluded that applying the stopping rule at 3 months, as suggested by clinicians, would be appropriate. This was because the timing aligned with clinical practice and the follow up in the clinical trials. At the second meeting, the company explained that stopping at 3 months would be inappropriate because titrating to a therapeutic dose is likely to take longer than 3 months. The committee was aware that the company had not provided evidence of how long titration takes in clinical practice, but agreed that it may be appropriate to increase the dose slowly for some patients. The company had also included stopping rules in its model at 12 months and 24 months. The committee considered that clinicians would likely evaluate patients more frequently, that is, every 6 months at a minimum. It therefore concluded that a stopping rule as proposed by NHS England is appropriate and that response to treatment, defined by a reduction in drop seizures compared with the 6 months before starting cannabidiol, should be assessed every 6 months.
# Company's economic model
## The company's exploratory analysis with health states defined by narrower ranges of seizures is appropriate
The company presented a Markov state-transition cohort model to estimate the cost effectiveness of cannabidiol. In response to committee queries, the company explained that it had considered using other types of models, but did not consider that these would be better than a Markov model. It used efficacy inputs derived from the subgroup of patients in the trial who also took clobazam. The model had a time horizon of 90 years and a cycle length of 3 months. It had 4 health states, based on the number of drop seizures a patient had each month, to capture the costs and health effects. One health state corresponded to 0 drop seizures (freedom from seizures). The company derived the remaining health states by dividing the overall trial population evenly into 3 health states by the frequency of seizures at the beginning of the trials. The committee was concerned that the ranges of seizures were very wide for some health states (for example, from more than 45 seizures to 110 seizures or less) and were not based on a clinical rationale. In response to consultation, the company provided an exploratory analysis in which the health states were defined by narrower ranges of seizures. The company chose health states to ensure that most patients who had a 50% change in the number of seizures, which the company stated was clinically meaningful, would move to a different health state at the end of each cycle. The committee was aware that the company had defined the health states specifically for the subgroup of patients taking clobazam based on clinical rationale. The committee concluded that the health states with narrower ranges of seizures were appropriate for decision making.
## The company's approach to modelling the number of seizure-free days is acceptable
The company incorporated into the model the number of days each month that a patient did not have a drop seizure. It did this by dividing each of the 3 drop seizure health states into 3 substates based on different numbers of seizure-free days. This was based on an exploratory end point in the clinical trials. The company explained that it had chosen this structure because both seizure frequency and days without seizures benefit people with Lennox–Gastaut syndrome. In response to a committee concern, the company stated that it designed the substates so that each health state in the model was mutually exclusive to avoid 'double counting' the benefit. The committee recalled that patients value both fewer seizures and more seizure-free days (see section 3.2) so it was appropriate to capture both in the model. However, the committee considered that other approaches to modelling, such as discrete event simulation, may have been more appropriate to capture the benefits of different numbers of seizure-free days. It concluded that the company's approach was acceptable.
## The company's approach to capturing the benefit of reducing non-drop seizures may not be valid but these benefits should be considered
The committee recalled that the clinical trials showed that cannabidiol also reduced non-drop seizures (see section 3.5), but this benefit was not captured in the model. In response to consultation, the company included in its model a mechanism for capturing the benefits associated with reducing non-drop seizures. It did this by applying an additional disutility value in each health state derived from a public preference study of epilepsy health states (de Kinderen et al. 2016). The company assumed that patients who have fewer drop seizures would also benefit from having fewer non-drop seizures. Because cannabidiol (compared with not taking cannabidiol) reduces the frequency of non-drop seizures, people who take cannabidiol would avoid disutility from both. The ERG was concerned that the company's approach may have led to double counting the benefits of reducing drop seizures. It was also unable to reproduce the utility estimates derived by the company. While the clinical trial data showed that cannabidiol decreased the frequency of non-drop seizures, the company had not used these data directly in its model. The committee therefore concluded that the company's approach to capturing non-drop seizures in the model may not have been valid. However, it recognised that reducing non-drop seizures was important to patients and carers (see section 3.2), and concluded that it would take this into account in its decision making.
# Assumptions in the economic model
## The model generates more favourable results for patients that stop cannabidiol than would be expected
The ERG highlighted concerns that, when it tested the model for validity, the model estimated higher quality-adjusted life years (QALYs) for cannabidiol when setting all the clinical inputs in the model equal for both cannabidiol and usual care. The ERG expected that the estimated QALYs would be the same for both treatments, but could not identify problems in the model code. In response to consultation, the company stated that it had done further validity testing and confirmed that the model worked as designed. It explained that the issue highlighted by the ERG resulted from the way the company modelled patients who stop cannabidiol. Most patients who stopped cannabidiol in the model were in the health state with the highest seizure frequency, based on trial evidence. However, in each cycle, the company reassigned this group of patients to health states in the same proportions as patients having usual care in that cycle. Because only around 40% of patients having usual care were in the health state with the highest seizure frequency, some patients in each group who stopped cannabidiol may have been reassigned to a health state with a lower frequency of seizures than they were in before stopping cannabidiol. This resulted in the higher gain in QALYs for cannabidiol seen when setting clinical inputs equal. The company justified its assumption about what happens to people who stop cannabidiol, stating that, because it had no clinical data on outcomes for people who stop cannabidiol, it was reasonable to assume that outcomes would be the same as those who never had it. The committee questioned whether the company's assumptions were valid. It would have preferred that the patients who stopped cannabidiol were split into groups of equal size (quantiles), and that the company redistributed the patients in each quantile to the health states in the corresponding quantile in the usual care arm. This approach would have limited the number of patients redistributed from higher seizure frequency states to lower ones, and vice versa. The committee concluded that assuming patients who stopped cannabidiol had the same outcomes as those on usual care meant that the model generated more favourable results for people who stopped cannabidiol than would be expected, but that the size of this bias was unknown.
## The mean body weight from the clinical trials should be used to model the weight-based dose of cannabidiol
To model the weight-based dose of cannabidiol (see section 2), the company divided the population into 4 age groups and used the median body weight from the trials for each age group. In its first meeting, the committee recognised that good practice in health economic analyses recommends using mean (not median) weights. Moreover, because median weight in the trials was lower than mean weight, using a median weight would have underestimated the dose and cost of cannabidiol. In the second meeting, the company stated that it had done a scenario analysis using mean weights, but still preferred to use median weights because there were 'significant outliers' (patients who are overweight) in the trial. The committee recalled its previous conclusion that the patients in the trial reflected those seen in the NHS (see section 3.4). It also agreed that patients who are 'outliers' would be offered treatment in the NHS. The committee did not change its conclusion that the company should have used the mean weight from the clinical trials to reflect the costs of cannabidiol. It concluded that it would take into account results based on mean body weight.
## The company's assumption that patients on usual care remain in the same health state is appropriate
In its original base case, to model beyond the data from the randomised controlled trial, the company used data from the open-label extension study for cannabidiol. However, for usual care, it assumed that the patients returned to the health state they started in. The committee did not consider this an appropriate way to account for the lack of comparator data in the open-label extension. In response to consultation, the company changed its base-case analysis so that patients on usual care remained in the same health states from the end of cycle 2 (6 months) until the end of the model or death. It argued that this assumption disadvantaged cannabidiol because it overestimated the clinical effectiveness of usual care. It also stated that any contribution to efficacy from the psychological effects of being in a trial is likely to have been higher in the blinded clinical trial than in the open-label extension study. This would have underestimated the relative efficacy of cannabidiol compared with usual care. The company therefore included a scenario in which patients in the usual care arm returned to their baseline health states after cycle 9. The committee agreed that the company's new base-case assumption was in line with its preferences, and a suitable approach to account for the lack of a comparator arm in the extension study.
## The effectiveness of cannabidiol is likely to diminish over time and the model should account for this
In its model, the company assumed that patients on cannabidiol stayed in the same health state (defined by seizure frequency) beyond 9 cycles (27 months). That is, the treatment effect of cannabidiol was maintained until the patient stopped treatment or died. Because data from the open-label extension showed that the effect of cannabidiol had persisted for 36 months, the company assumed that the effect lasted as long as the patient took cannabidiol. The clinical experts stated that they would expect the effectiveness of cannabidiol to diminish over time, as with other antiepileptic drugs. The company considered that it had captured reduced effectiveness over time in a scenario analysis in which it increased the annual rate at which patients in all health states (except the seizure-free health state) stopped cannabidiol. Specifically, it increased the stopping rate from 5% to 10% of patients per year. The company argued that patients, their carers, or clinicians would ensure the drug was stopped if it was ineffective (see section 3.7). It also noted that, while there was no evidence that the efficacy of cannabidiol would be maintained after 36 months, equally, there was no evidence that it would diminish. The committee agreed that the company had made a reasonable attempt to account for treatment waning. However, it would have preferred that the company's analysis had also accounted for a reduction in effect over time in patients before they stop cannabidiol. The committee concluded that the effectiveness of cannabidiol was likely to diminish over time. It also concluded that the company's scenario analysis captured some, but not all, of the effects on quality of life or efficacy diminishing over time.
## There is insufficient evidence to prove that cannabidiol prolongs life
The committee was aware that the trials did not show that treatment with cannabidiol prolonged life, but that the company had proposed that people taking cannabidiol live longer than those who do not take cannabidiol. In its model, the company assumed that people without drop seizures were less likely to die from epilepsy-related causes, and people taking cannabidiol were more likely to be free from drop seizures. The company used an observational study of people with epilepsy (Trinka et al. 2013) to model a 58% reduction in risk of death associated with being free from seizures. The clinical experts commented that the model overestimated the reduction in risk of death for people without drop seizures. In response, the company halved the reduction in risk of death associated with being seizure free in its model to 29%. It also provided a scenario analysis in which it removed the assumption that cannabidiol extends life. The committee was aware that the company had not observed a reduction in mortality associated with cannabidiol in its clinical trials either because no effect exists, or because the trial was not long enough. The committee agreed that it was plausible that people who are free of drop seizures may be at a lower risk of death. However, it appreciated that people who were free of seizures may be otherwise heathier than people with frequent seizures. This, at least in part, could have accounted for some of the size of the association between seizure frequency and death. The clinical experts agreed with this concern. In summary, the committee was concerned that the company's base-case assumption was not supported by trial evidence, and that the observational evidence was likely confounded. It concluded that there was insufficient evidence to prove that cannabidiol prolongs life. It preferred the company's scenario analysis that removed the assumption that cannabidiol extends life.
# Costs in the economic model
## The company's scenario analysis using an average dosage of 12 mg/kg/day is appropriate to capture the costs of increasing the dosage of cannabidiol
The summary of product characteristics for cannabidiol states that the dosage can be increased from a maintenance dosage of 10 mg/kg/day to 20 mg/kg/day (see section 2). Yet, the company assumed in its base case that all patients would have a maintenance dosage of 10 mg/kg/day for the entire treatment duration with cannabidiol. The company explained that it expected some people would be offered higher doses if they had seen a large drop in their frequency of seizures, to try to free them of seizures. At the committee's second meeting, the company explained that it expected the dosage was unlikely to be increased beyond 15 mg/kg/day in clinical practice. To capture the cost of dosing increases, the company did scenario analyses using an average dosage higher than 10 mg/kg/day for all patients. In 1 scenario it assumed that 20% of patients would increase their dose. This was based on opinion from clinical experts at the first committee meeting. It also assumed that these people would have the maximum recommended dosage of 20 mg/kg/day; this resulted in an average dosage of 12 mg/kg/day. The company stated that it expected that some people would not have the full recommended maintenance dosage of 10 mg/kg/day in clinical practice. So, it presented a scenario using an average dosage of 9 mg/kg/day. The committee noted that the company had not presented evidence that the doses used in clinical practice would be lower than those recommended in the summary of product characteristics. It concluded that it preferred the company's scenario analysis using an average dosage of 12 mg/kg/day.
# Utility values in the economic model
## The utility values from the company's vignette study are the most suitable for the company's model structure
The company collected data from responses to the Quality of Life in Childhood Epilepsy questionnaire in its clinical trials, but did not use the data in its model. It stated that there was a low response rate to the questionnaire, and that there is no algorithm to map the results to EQ‑5D utilities, NICE's preferred measure of health-related quality of life. The company also noted that data on quality of life in the literature are based on percentage reduction in seizures rather than the health states and substates it used in its model (that is, number of seizures and seizure-free days). So, the company instead asked people with Lennox–Gastaut syndrome and their carers to estimate the quality of life associated with each health state and substate in the model. Respondents were asked to consider 'vignettes', that is, descriptions of each health state and, using a visual analogue scale, give each a value between 0 (death) and 1 (perfect health). The company considered the quality-of-life values it used in its model to be confidential. The committee agreed that the vignette approach was justified given the lack of data in the literature; however, it also noted several limitations. It highlighted that the vignette study relied on patients and carers to value the health states rather than the general public, who may estimate quality of life differently. Using values from the general public is NICE's preferred method because someone living with, or caring for someone with the disease may get used to the symptoms, and may have a lower expectation of attaining good health than the general public. The lowest value patients and carers could give each health state was 0, whereas the EQ‑5D scale allows for health states below 0 (that is, a quality of life worse than death). The committee considered that Lennox–Gastaut syndrome had features in common with other disease associated with quality-of-life values below 0. The clinical experts stated that the value the company used for the health state reflecting freedom from drop seizures lacked face validity. They expected the values to be lower because, despite being free from drop seizures, people may still have non-drop seizures, adverse effects and epilepsy-associated comorbidities such as cognitive impairment. The committee was also aware that the company had done a scenario analysis using values from a general population preference study in Lennox–Gastaut syndrome (Verdian et al. 2018). These values appeared broadly similar to the company's utility values from the vignette study. The committee was aware that, because of the structure of the company's model, if it was to use the values from the literature, the model could not realise the benefits of having more days free of drop seizures. This was because it had to use the same values for each substate. The committee highlighted that the methods the company used to obtain the utility values had significant problems, and that the methods used in Verdian et al. were better aligned with NICE's preferences. However, it concluded that the utility values from the company's vignette study were appropriate for modelling the health-related quality of life of people with Lennox–Gastaut syndrome.
## It is appropriate to model the effect on carers' quality of life, and the values from the company's vignette study are the best available source
The committee recalled that caring for someone with Lennox–Gastaut syndrome affects carers' quality of life (see section 3.1), and that capturing this in the model is appropriate. The company included utility decrements in its model for carers of people in the 2 health states reflecting the highest frequency of seizures. The utility decrements were based on the company's vignette study. The committee recalled that the vignette study had limitations (see section 3.17). It was concerned that the company had captured the effect on the quality of life of carers only for the 2 health states reflecting the highest frequency of seizures. It considered that caring for people with fewer drop seizures, comorbidities, or other types of seizures would affect carers' quality of life. The committee would have preferred the company to have used values from a public preference study rather than a vignette study, but accepted that these were not available. In response to consultation, the company and patient groups stated that family members not directly involved in caring, particularly siblings, may also benefit from their relatives' seizures being better controlled. The committee concluded that it was appropriate to include carers' quality of life in the model and that, although limited, the company's vignette study was the best available source for utility values.
## The company's scenario analysis using 1.8 carers is preferable
The company assumed that people with Lennox–Gastaut syndrome have 2 carers based on clinical expert opinion. It did not present details on how it solicited clinical expert opinion. The company also provided a scenario analysis using a value of 1.8 carers based on evidence from the literature (Lagae et al. 2017). It noted that other family members of people with Lennox–Gastaut syndrome may have responsibilities for care, which would lower their quality of life (see section 3.1). The company included a scenario analysis increasing the number of carers in the model to 3 to account for this. For the analysis using 2 carers, the company doubled the decrements from the vignette study (see section 3.18) and subtracted this from the value reflecting the patient's utility. The committee was concerned that the company's approach implied that the caring burden increases linearly the more carers a patient has. However, for a patient with multiple carers, it expected there to be less effect on the quality of life of each carer because they would 'share' some of the burden; so, while the total burden for 2 carers may be greater than the burden for a sole carer, it would likely not be 2 times greater. The company stated that its vignette study accounted for 'sharing' care because it asked everyone taking part to rate their own quality of life, and most people in the study had a partner. The committee recalled that there were several limitations with the company's vignette study (see sections 3.17 and 3.18), so it was unclear whether the disutility values appropriately captured 'sharing' of care. The committee considered that the company's method of linearly multiplying the disutility values was inappropriate and could have led to perverse results, particularly if the company had modelled a high number of carers. However, in this case, using the value of 1.8 carers limited this effect. The committee acknowledged the substantial detrimental effect that caring can have on quality of life. It recognised that it would be difficult to estimate how much each additional carer reduced the burden of the other carers. The committee concluded that it preferred to use the value of 1.8 carers, which also helped to limit the effect of the inappropriate methodology used by the company to incorporate carer disutility into the model.
# Cost-effectiveness results
## Addressing the remaining uncertainties in the model would likely increase the incremental cost-effectiveness ratios
The company's updated cost-effectiveness analyses included most of the committee's preferred assumptions:
using narrower seizure frequency ranges for the health states (see section 3.8)
removing the effect of non-drop seizures as calculated (see section 3.10)
using the mean weight instead of the median (see section 3.12)
accounting for waning of cannabidiol's effects (see section 3.14)
not assuming that cannabidiol lengthens life (see section 3.15)
using an average dosage of 12 mg/kg/day (see section 3.16)
including health-related quality-of-life effects for 1.8 carers, which acknowledges shared burden (see section 3.19).This resulted in an incremental cost-effectiveness ratio (ICER) of £33,721 per QALY gained. These analyses did not take into account the committee's preference for stopping rules to be applied at 18 months rather than 24 months. However, the committee agreed this was unlikely to have had a substantial effect on the ICER (see section 3.7). It also recalled that there was additional uncertainty in the cost-effectiveness results because of:
the company's assumptions around people who stop treatment with cannabidiol (see section 3.11)
the way the company modelled a waning of treatment effect, which did not capture all the effects that diminishing efficacy over time would have on quality of life (see section 3.14).The committee concluded that the cumulative effect of addressing these uncertainties was likely to have increased the ICER.
# Other factors
## There are benefits of cannabidiol that are not captured in the company's model
The committee recalled that the company had not modelled the effect on the quality of life of the siblings of children or young people with Lennox–Gastaut syndrome (see section 3.18). It also recalled that the company's approach to modelling fewer non-drop seizures was not appropriate (see section 3.8). The committee considered these factors important for improving quality of life (see section 3.1). It concluded that it would take these benefits into account in its decision making.
## Cannabidiol does not meet the criteria for an innovative treatment
The clinical experts stated that they would welcome an additional treatment option for Lennox–Gastaut syndrome. However, they considered that cannabidiol represents only a modest change when managing Lennox–Gastaut syndrome because few people became seizure free (see section 3.5). The committee concluded that cannabidiol did not meet the criteria for an innovative treatment.
## Cannabidiol is recommended for use with clobazam to treat people with Lennox–Gastaut syndrome
The committee recalled that it had concluded that it was appropriate to consider other benefits not captured in the company's model (see section 3.21). It recognised that some of the remaining uncertainties would be addressed in time with ongoing data collection. The committee concluded that, despite these uncertainties (see section 3.20), when it considered the uncaptured benefits, cannabidiol represents an effective treatment and a good use of NHS resources. It therefore recommended cannabidiol with clobazam to treat Lennox–Gastaut syndrome. It also concluded that seizure frequency should be checked every 6 months and that, if the frequency has not fallen by at least 30% compared with the 6 months before starting treatment, cannabidiol should be stopped (see section 3.7).
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{'Recommendations': "Cannabidiol with clobazam is recommended as an option for treating seizures associated with Lennox–Gastaut syndrome in people aged 2\xa0years and older, only if:\n\nthe frequency of drop seizures is checked every 6\xa0months, and cannabidiol is stopped if the frequency has not fallen by at least 30% compared with the 6\xa0months before starting treatment\n\nthe company provides cannabidiol according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with cannabidiol, with clobazam, that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place before this guidance was published, until they and their NHS clinicians consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person, or the child or young person's parents or carers.\n\nWhy the committee made these recommendations\n\nCurrent treatment for Lennox–Gastaut syndrome includes antiepileptic drugs. People with Lennox–Gastaut syndrome would have cannabidiol with clobazam if their drop seizures are not controlled well enough after trying 2\xa0or more antiepileptic drugs.\n\nClinical trials show that cannabidiol reduces the number of drop and non-drop seizures when compared with usual care.\n\nThe cost-effectiveness estimates are uncertain for cannabidiol because of some of the assumptions in the company's model. The cost-effectiveness estimates do not include the benefits of:\n\nreducing the number of non-drop seizures\n\nimproving the quality of life of the siblings of people with Lennox–Gastaut syndrome.\n\nWhen taking both the uncertainties and the uncaptured benefits into account, cannabidiol is considered an appropriate use of NHS resources, and is recommended as an option for treating Lennox–Gastaut syndrome in the NHS.", 'Information about cannabidiol': "# Marketing authorisation indication\n\nCannabidiol (Epidyolex, GW Pharma) is licensed as 'adjunctive therapy for seizures associated with Lennox–Gastaut syndrome (LGS) or Dravet syndrome (DS) in conjunction with clobazam, for patients 2\xa0years of age or older'.\n\n# Dosage in the marketing authorisation\n\nIt is administered orally as 100\xa0mg/ml cannabidiol solution. The recommended starting dosage is 2.5\xa0mg/kg taken twice daily for 1\xa0week. After 1\xa0week, this should be increased to a maintenance dosage of 5\xa0mg/kg twice daily (10\xa0mg/kg/day). Based on individual clinical response and tolerability, each dosage can be further increased in weekly increments of 2.5\xa0mg/kg taken twice daily up to a maximum recommended dosage of 10\xa0mg/kg twice daily (20\xa0mg/kg/day). Any dosage increases above 10\xa0mg/kg/day should take into account individual benefit and risk.\n\n# Price\n\nThe list price of cannabidiol has been agreed with the Department of Health and Social Care, but is considered confidential by the company until January 2020. The company has a commercial arrangement. This makes cannabidiol available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by GW Pharma, a review of this submission by the evidence review group (ERG) and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\n# Disease background\n\n## Lennox–Gastaut syndrome severely affects the quality of life of patients, carers and their families\n\nLennox–Gastaut syndrome is a severe, lifelong and treatment-resistant genetic form of epilepsy that begins in early childhood, usually between 2\xa0years and 7\xa0years. It is characterised by frequent seizures of different types. Drop seizures result in a loss of muscle tone or stiffening of muscles, and people can crash to the ground. The patient and carer experts explained that drop seizures affect quality of life because they may result in severe injuries and hospitalisation. The patient and carer experts noted that Lennox–Gastaut syndrome affects families and carers. People with the disease need round-the-clock care, and help with almost all aspects of daily life. Families and carers may find looking after people with Lennox–Gastaut syndrome demanding, and that it prevents them from leading normal lives, including spending less time with their other children. Also, the anxiety that a child with Lennox–Gastaut syndrome may be injured because of a drop seizure can significantly affect the mental wellbeing of all family members. The committee concluded that Lennox–Gastaut syndrome severely affects the quality of life of patients, families and carers.\n\n# Current treatments\n\n## People with Lennox–Gastaut syndrome and their carers would value a treatment option that reduces seizure frequency\n\nThe clinical, and patient and carer, experts agreed that current treatments often do not control seizures associated with Lennox–Gastaut syndrome. This is despite a broad range of available antiepileptic drugs, non-pharmacological interventions (such as vagus nerve stimulation and a ketogenic diet) and surgery. They stated that there is an unmet need in Lennox–Gastaut syndrome for an intervention that effectively reduces seizures without markedly increasing adverse events. The patient and carer experts reported that drugs which initially work can lose efficacy. The experts would welcome new treatment options, and noted that reducing the number of drop seizures is the main goal of treatment. They also considered that reducing the frequency of other seizure types would improve the quality of life of people with Lennox–Gastaut syndrome. The committee concluded that there is an unmet need for treatments that reduce the number of drop seizures, and that patients and their carers would value a new treatment option.\n\n# Cannabidiol and its positioning in the treatment pathway\n\n## The company's positioning of cannabidiol with clobazam in the treatment pathway is appropriate\n\nThe clinical experts explained that the Lennox–Gastaut syndrome treatment pathway is consistent with NICE's clinical guideline on epilepsies: diagnosis and management. The guideline recommends starting treatment with sodium valproate and, if seizures are not adequately controlled, adding lamotrigine. They added that they would consider trying other antiepileptic drugs if sodium valproate and lamotrigine together do not adequately control seizures. The committee was aware that the marketing authorisation for cannabidiol is for use as an adjuvant therapy with clobazam. The company proposed that cannabidiol should be considered after 2\xa0other antiepileptic drugs. The clinical experts stated that clobazam is currently used when 2\xa0antiepileptic drugs have not adequately controlled seizures, and that they would consider adding cannabidiol to clobazam. The committee concluded that the company's positioning of cannabidiol with clobazam after 2\xa0treatments in the treatment pathway was appropriate.\n\n# Clinical-effectiveness evidence\n\n## The patients in the clinical trials reflect those who would have cannabidiol in the NHS and the subgroup taking clobazam is most relevant to the appraisal\n\nCannabidiol (plus usual care) has been compared with placebo (plus usual care) in 2\xa0randomised controlled trials, GWPCARE3 and GWPCARE4. In GWPCARE3, 3\xa0maintenance doses of cannabidiol (10\xa0mg/kg/day and 20\xa0mg/kg/day) were compared with placebo. In GWPCARE4, the higher maintenance dosage of 20\xa0mg/kg/day was compared with placebo. Both trials had a follow up of 14\xa0weeks. The licensed maintenance dosage of cannabidiol is 10\xa0mg/kg/day, with dosage increases permitted up to a maximum of 20\xa0mg/kg/day. An open-label extension study designed for safety, GWPCARE5, in which all patients are having cannabidiol, is ongoing. The company expects to follow patients in this study for up to 5\xa0years. The committee recognised that this study will provide potentially important information on safety. All the studies included adult patients. About half of the patients in both trials were also taking clobazam. The committee agreed that the baseline characteristics of patients in the subgroup taking clobazam were similar to those with Lennox–Gastaut syndrome who would have cannabidiol in the NHS. It concluded that the subgroup of patients taking clobazam was most relevant to this appraisal, and that it would not consider the overall trial population further.\n\n## Cannabidiol with clobazam reduces seizure frequency, but long-term efficacy is uncertain\n\nThe primary end point in both GWPCARE3 and GWPCARE4 was the percentage change in drop seizure frequency from baseline per 28\xa0days between groups. The company provided results from the trials for the subgroup of patients taking clobazam (see section\xa03.4). The reduction in median drop seizure frequency per 28\xa0days in GWPCARE3 for patients taking cannabidiol 10\xa0mg/kg/day compared with placebo was 30%, which was statistically significant at the 95% confidence level (p=0.0355). The clinical and patient experts noted that this size of reduction was meaningful for people with the condition. The company did not provide evidence of how many patients taking cannabidiol with clobazam became free of drop seizures, but the committee was aware that this reflected only a few patients. There was also a reduction in the secondary end point of total seizure frequency per 28\xa0days of 37% compared with placebo (p=0.0025). In GWPCARE4, with cannabidiol 20\xa0mg/kg/day there was also a reduction in both drop and non-drop seizure frequency compared with placebo. The committee was aware that GWPCARE3 also included a 20\xa0mg/kg/day arm, and that the European Medicines Agency concluded that there was no consistent difference in dose response between 10\xa0mg/kg/day and 20\xa0mg/kg/day. The committee was aware that the summary of product characteristics states that the recommended maintenance dosage of cannabidiol is 10\xa0mg/kg/day (see section\xa02). It agreed that GWPCARE3 was most relevant to the decision problem. In response to consultation, the company provided interim analysis for seizure frequency after 3\xa0years of follow up from the open-label extension, GWPCARE5, for the subgroup of patients taking cannabidiol and clobazam. This showed that reduction in seizure frequency with treatment was broadly maintained for up to 3\xa0years. The committee concluded that cannabidiol with clobazam reduces seizure frequency compared with usual care, but that the long-term efficacy after 3\xa0years is uncertain.\n\n# Adverse events\n\n## Cannabidiol is associated with adverse events that are manageable\n\nThe trial results showed that a large proportion of patients having cannabidiol with clobazam had adverse events. The most commonly occurring adverse events in this group were somnolence or sedation, and diarrhoea. The clinical experts noted that people with Lennox–Gastaut syndrome often experience adverse effects from their medications. They also noted that cannabidiol's adverse effects are mostly, but not always, mild and tolerated. The patient and carer experts stated that the choice of treatment depends on the balance of its safety and tolerability, with adverse events representing an important consideration. The committee was concerned that the trial had a short follow up, which may not have captured all cannabidiol's adverse effects. It was aware that more data on safety would be available from GWPCARE5, which is ongoing (see section\xa03.4). The clinical and patient experts explained that patients would be closely monitored, and treatment would be stopped if adverse events were not manageable. The committee concluded that, while cannabidiol's adverse effects are mostly manageable, they are an important consideration when making decisions about whether to start or continue cannabidiol.\n\n# Stopping treatment\n\n## It is appropriate to assess response to treatment every 6\xa0months and stop cannabidiol if it is not effective\n\nThe marketing authorisation for cannabidiol does not specify a stopping rule, that is, stopping treatment if or when it does not work. However, NHS England proposed during the technical engagement stage of the appraisal that cannabidiol should be stopped if the frequency of drop seizures has not reduced by at least 30% from baseline. The clinical experts noted that they took account of broadly similar criteria when advising patients, and their families and carers about whether to continue other antiepileptic drugs. The patient and carer expert explained that they would not want to continue a treatment unnecessarily when it does not work well because this would increase the drug burden and potential adverse effects. The committee was aware that the company implemented the stopping criteria proposed by NHS England in its model after 6\xa0months of treatment with cannabidiol. At the first committee meeting, the committee had concluded that applying the stopping rule at 3\xa0months, as suggested by clinicians, would be appropriate. This was because the timing aligned with clinical practice and the follow up in the clinical trials. At the second meeting, the company explained that stopping at 3\xa0months would be inappropriate because titrating to a therapeutic dose is likely to take longer than 3\xa0months. The committee was aware that the company had not provided evidence of how long titration takes in clinical practice, but agreed that it may be appropriate to increase the dose slowly for some patients. The company had also included stopping rules in its model at 12 months\xa0and 24\xa0months. The committee considered that clinicians would likely evaluate patients more frequently, that is, every 6\xa0months at a minimum. It therefore concluded that a stopping rule as proposed by NHS England is appropriate and that response to treatment, defined by a reduction in drop seizures compared with the 6\xa0months before starting cannabidiol, should be assessed every 6\xa0months.\n\n# Company's economic model\n\n## The company's exploratory analysis with health states defined by narrower ranges of seizures is appropriate\n\nThe company presented a Markov state-transition cohort model to estimate the cost effectiveness of cannabidiol. In response to committee queries, the company explained that it had considered using other types of models, but did not consider that these would be better than a Markov model. It used efficacy inputs derived from the subgroup of patients in the trial who also took clobazam. The model had a time horizon of 90\xa0years and a cycle length of 3\xa0months. It had 4\xa0health states, based on the number of drop seizures a patient had each month, to capture the costs and health effects. One health state corresponded to 0\xa0drop seizures (freedom from seizures). The company derived the remaining health states by dividing the overall trial population evenly into 3\xa0health states by the frequency of seizures at the beginning of the trials. The committee was concerned that the ranges of seizures were very wide for some health states (for example, from more than 45\xa0seizures to 110\xa0seizures or less) and were not based on a clinical rationale. In response to consultation, the company provided an exploratory analysis in which the health states were defined by narrower ranges of seizures. The company chose health states to ensure that most patients who had a 50% change in the number of seizures, which the company stated was clinically meaningful, would move to a different health state at the end of each cycle. The committee was aware that the company had defined the health states specifically for the subgroup of patients taking clobazam based on clinical rationale. The committee concluded that the health states with narrower ranges of seizures were appropriate for decision making.\n\n## The company's approach to modelling the number of seizure-free days is acceptable\n\nThe company incorporated into the model the number of days each month that a patient did not have a drop seizure. It did this by dividing each of the 3 drop seizure\xa0health states into 3\xa0substates based on different numbers of seizure-free days. This was based on an exploratory end point in the clinical trials. The company explained that it had chosen this structure because both seizure frequency and days without seizures benefit people with Lennox–Gastaut syndrome. In response to a committee concern, the company stated that it designed the substates so that each health state in the model was mutually exclusive to avoid 'double counting' the benefit. The committee recalled that patients value both fewer seizures and more seizure-free days (see section\xa03.2) so it was appropriate to capture both in the model. However, the committee considered that other approaches to modelling, such as discrete event simulation, may have been more appropriate to capture the benefits of different numbers of seizure-free days. It concluded that the company's approach was acceptable.\n\n## The company's approach to capturing the benefit of reducing non-drop seizures may not be valid but these benefits should be considered\n\nThe committee recalled that the clinical trials showed that cannabidiol also reduced non-drop seizures (see section\xa03.5), but this benefit was not captured in the model. In response to consultation, the company included in its model a mechanism for capturing the benefits associated with reducing non-drop seizures. It did this by applying an additional disutility value in each health state derived from a public preference study of epilepsy health states (de Kinderen et al. 2016). The company assumed that patients who have fewer drop seizures would also benefit from having fewer non-drop seizures. Because cannabidiol (compared with not taking cannabidiol) reduces the frequency of non-drop seizures, people who take cannabidiol would avoid disutility from both. The ERG was concerned that the company's approach may have led to double counting the benefits of reducing drop seizures. It was also unable to reproduce the utility estimates derived by the company. While the clinical trial data showed that cannabidiol decreased the frequency of non-drop seizures, the company had not used these data directly in its model. The committee therefore concluded that the company's approach to capturing non-drop seizures in the model may not have been valid. However, it recognised that reducing non-drop seizures was important to patients and carers (see section\xa03.2), and concluded that it would take this into account in its decision making.\n\n# Assumptions in the economic model\n\n## The model generates more favourable results for patients that stop cannabidiol than would be expected\n\nThe ERG highlighted concerns that, when it tested the model for validity, the model estimated higher quality-adjusted life years (QALYs) for cannabidiol when setting all the clinical inputs in the model equal for both cannabidiol and usual care. The ERG expected that the estimated QALYs would be the same for both treatments, but could not identify problems in the model code. In response to consultation, the company stated that it had done further validity testing and confirmed that the model worked as designed. It explained that the issue highlighted by the ERG resulted from the way the company modelled patients who stop cannabidiol. Most patients who stopped cannabidiol in the model were in the health state with the highest seizure frequency, based on trial evidence. However, in each cycle, the company reassigned this group of patients to health states in the same proportions as patients having usual care in that cycle. Because only around 40% of patients having usual care were in the health state with the highest seizure frequency, some patients in each group who stopped cannabidiol may have been reassigned to a health state with a lower frequency of seizures than they were in before stopping cannabidiol. This resulted in the higher gain in QALYs for cannabidiol seen when setting clinical inputs equal. The company justified its assumption about what happens to people who stop cannabidiol, stating that, because it had no clinical data on outcomes for people who stop cannabidiol, it was reasonable to assume that outcomes would be the same as those who never had it. The committee questioned whether the company's assumptions were valid. It would have preferred that the patients who stopped cannabidiol were split into groups of equal size (quantiles), and that the company redistributed the patients in each quantile to the health states in the corresponding quantile in the usual care arm. This approach would have limited the number of patients redistributed from higher seizure frequency states to lower ones, and vice versa. The committee concluded that assuming patients who stopped cannabidiol had the same outcomes as those on usual care meant that the model generated more favourable results for people who stopped cannabidiol than would be expected, but that the size of this bias was unknown.\n\n## The mean body weight from the clinical trials should be used to model the weight-based dose of cannabidiol\n\nTo model the weight-based dose of cannabidiol (see section\xa02), the company divided the population into 4\xa0age groups and used the median body weight from the trials for each age group. In its first meeting, the committee recognised that good practice in health economic analyses recommends using mean (not median) weights. Moreover, because median weight in the trials was lower than mean weight, using a median weight would have underestimated the dose and cost of cannabidiol. In the second meeting, the company stated that it had done a scenario analysis using mean weights, but still preferred to use median weights because there were 'significant outliers' (patients who are overweight) in the trial. The committee recalled its previous conclusion that the patients in the trial reflected those seen in the NHS (see section\xa03.4). It also agreed that patients who are 'outliers' would be offered treatment in the NHS. The committee did not change its conclusion that the company should have used the mean weight from the clinical trials to reflect the costs of cannabidiol. It concluded that it would take into account results based on mean body weight.\n\n## The company's assumption that patients on usual care remain in the same health state is appropriate\n\nIn its original base case, to model beyond the data from the randomised controlled trial, the company used data from the open-label extension study for cannabidiol. However, for usual care, it assumed that the patients returned to the health state they started in. The committee did not consider this an appropriate way to account for the lack of comparator data in the open-label extension. In response to consultation, the company changed its base-case analysis so that patients on usual care remained in the same health states from the end of cycle\xa02 (6\xa0months) until the end of the model or death. It argued that this assumption disadvantaged cannabidiol because it overestimated the clinical effectiveness of usual care. It also stated that any contribution to efficacy from the psychological effects of being in a trial is likely to have been higher in the blinded clinical trial than in the open-label extension study. This would have underestimated the relative efficacy of cannabidiol compared with usual care. The company therefore included a scenario in which patients in the usual care arm returned to their baseline health states after cycle\xa09. The committee agreed that the company's new base-case assumption was in line with its preferences, and a suitable approach to account for the lack of a comparator arm in the extension study.\n\n## The effectiveness of cannabidiol is likely to diminish over time and the model should account for this\n\nIn its model, the company assumed that patients on cannabidiol stayed in the same health state (defined by seizure frequency) beyond 9\xa0cycles (27\xa0months). That is, the treatment effect of cannabidiol was maintained until the patient stopped treatment or died. Because data from the open-label extension showed that the effect of cannabidiol had persisted for 36\xa0months, the company assumed that the effect lasted as long as the patient took cannabidiol. The clinical experts stated that they would expect the effectiveness of cannabidiol to diminish over time, as with other antiepileptic drugs. The company considered that it had captured reduced effectiveness over time in a scenario analysis in which it increased the annual rate at which patients in all health states (except the seizure-free health state) stopped cannabidiol. Specifically, it increased the stopping rate from 5% to 10% of patients per year. The company argued that patients, their carers, or clinicians would ensure the drug was stopped if it was ineffective (see section\xa03.7). It also noted that, while there was no evidence that the efficacy of cannabidiol would be maintained after 36\xa0months, equally, there was no evidence that it would diminish. The committee agreed that the company had made a reasonable attempt to account for treatment waning. However, it would have preferred that the company's analysis had also accounted for a reduction in effect over time in patients before they stop cannabidiol. The committee concluded that the effectiveness of cannabidiol was likely to diminish over time. It also concluded that the company's scenario analysis captured some, but not all, of the effects on quality of life or efficacy diminishing over time.\n\n## There is insufficient evidence to prove that cannabidiol prolongs life\n\nThe committee was aware that the trials did not show that treatment with cannabidiol prolonged life, but that the company had proposed that people taking cannabidiol live longer than those who do not take cannabidiol. In its model, the company assumed that people without drop seizures were less likely to die from epilepsy-related causes, and people taking cannabidiol were more likely to be free from drop seizures. The company used an observational study of people with epilepsy (Trinka et al. 2013) to model a 58% reduction in risk of death associated with being free from seizures. The clinical experts commented that the model overestimated the reduction in risk of death for people without drop seizures. In response, the company halved the reduction in risk of death associated with being seizure free in its model to 29%. It also provided a scenario analysis in which it removed the assumption that cannabidiol extends life. The committee was aware that the company had not observed a reduction in mortality associated with cannabidiol in its clinical trials either because no effect exists, or because the trial was not long enough. The committee agreed that it was plausible that people who are free of drop seizures may be at a lower risk of death. However, it appreciated that people who were free of seizures may be otherwise heathier than people with frequent seizures. This, at least in part, could have accounted for some of the size of the association between seizure frequency and death. The clinical experts agreed with this concern. In summary, the committee was concerned that the company's base-case assumption was not supported by trial evidence, and that the observational evidence was likely confounded. It concluded that there was insufficient evidence to prove that cannabidiol prolongs life. It preferred the company's scenario analysis that removed the assumption that cannabidiol extends life.\n\n# Costs in the economic model\n\n## The company's scenario analysis using an average dosage of 12\xa0mg/kg/day is appropriate to capture the costs of increasing the dosage of cannabidiol\n\nThe summary of product characteristics for cannabidiol states that the dosage can be increased from a maintenance dosage of 10\xa0mg/kg/day to 20\xa0mg/kg/day (see section\xa02). Yet, the company assumed in its base case that all patients would have a maintenance dosage of 10\xa0mg/kg/day for the entire treatment duration with cannabidiol. The company explained that it expected some people would be offered higher doses if they had seen a large drop in their frequency of seizures, to try to free them of seizures. At the committee's second meeting, the company explained that it expected the dosage was unlikely to be increased beyond 15\xa0mg/kg/day in clinical practice. To capture the cost of dosing increases, the company did scenario analyses using an average dosage higher than 10\xa0mg/kg/day for all patients. In 1\xa0scenario it assumed that 20% of patients would increase their dose. This was based on opinion from clinical experts at the first committee meeting. It also assumed that these people would have the maximum recommended dosage of 20\xa0mg/kg/day; this resulted in an average dosage of 12\xa0mg/kg/day. The company stated that it expected that some people would not have the full recommended maintenance dosage of 10\xa0mg/kg/day in clinical practice. So, it presented a scenario using an average dosage of 9\xa0mg/kg/day. The committee noted that the company had not presented evidence that the doses used in clinical practice would be lower than those recommended in the summary of product characteristics. It concluded that it preferred the company's scenario analysis using an average dosage of 12\xa0mg/kg/day.\n\n# Utility values in the economic model\n\n## The utility values from the company's vignette study are the most suitable for the company's model structure\n\nThe company collected data from responses to the Quality of Life in Childhood Epilepsy questionnaire in its clinical trials, but did not use the data in its model. It stated that there was a low response rate to the questionnaire, and that there is no algorithm to map the results to EQ‑5D utilities, NICE's preferred measure of health-related quality of life. The company also noted that data on quality of life in the literature are based on percentage reduction in seizures rather than the health states and substates it used in its model (that is, number of seizures and seizure-free days). So, the company instead asked people with Lennox–Gastaut syndrome and their carers to estimate the quality of life associated with each health state and substate in the model. Respondents were asked to consider 'vignettes', that is, descriptions of each health state and, using a visual analogue scale, give each a value between\xa00 (death) and\xa01 (perfect health). The company considered the quality-of-life values it used in its model to be confidential. The committee agreed that the vignette approach was justified given the lack of data in the literature; however, it also noted several limitations. It highlighted that the vignette study relied on patients and carers to value the health states rather than the general public, who may estimate quality of life differently. Using values from the general public is NICE's preferred method because someone living with, or caring for someone with the disease may get used to the symptoms, and may have a lower expectation of attaining good health than the general public. The lowest value patients and carers could give each health state was\xa00, whereas the EQ‑5D scale allows for health states below\xa00 (that is, a quality of life worse than death). The committee considered that Lennox–Gastaut syndrome had features in common with other disease associated with quality-of-life values below\xa00. The clinical experts stated that the value the company used for the health state reflecting freedom from drop seizures lacked face validity. They expected the values to be lower because, despite being free from drop seizures, people may still have non-drop seizures, adverse effects and epilepsy-associated comorbidities such as cognitive impairment. The committee was also aware that the company had done a scenario analysis using values from a general population preference study in Lennox–Gastaut syndrome (Verdian et al. 2018). These values appeared broadly similar to the company's utility values from the vignette study. The committee was aware that, because of the structure of the company's model, if it was to use the values from the literature, the model could not realise the benefits of having more days free of drop seizures. This was because it had to use the same values for each substate. The committee highlighted that the methods the company used to obtain the utility values had significant problems, and that the methods used in Verdian et al. were better aligned with NICE's preferences. However, it concluded that the utility values from the company's vignette study were appropriate for modelling the health-related quality of life of people with Lennox–Gastaut syndrome.\n\n## It is appropriate to model the effect on carers' quality of life, and the values from the company's vignette study are the best available source\n\nThe committee recalled that caring for someone with Lennox–Gastaut syndrome affects carers' quality of life (see section\xa03.1), and that capturing this in the model is appropriate. The company included utility decrements in its model for carers of people in the 2\xa0health states reflecting the highest frequency of seizures. The utility decrements were based on the company's vignette study. The committee recalled that the vignette study had limitations (see section\xa03.17). It was concerned that the company had captured the effect on the quality of life of carers only for the 2\xa0health states reflecting the highest frequency of seizures. It considered that caring for people with fewer drop seizures, comorbidities, or other types of seizures would affect carers' quality of life. The committee would have preferred the company to have used values from a public preference study rather than a vignette study, but accepted that these were not available. In response to consultation, the company and patient groups stated that family members not directly involved in caring, particularly siblings, may also benefit from their relatives' seizures being better controlled. The committee concluded that it was appropriate to include carers' quality of life in the model and that, although limited, the company's vignette study was the best available source for utility values.\n\n## The company's scenario analysis using 1.8\xa0carers is preferable\n\nThe company assumed that people with Lennox–Gastaut syndrome have 2\xa0carers based on clinical expert opinion. It did not present details on how it solicited clinical expert opinion. The company also provided a scenario analysis using a value of 1.8\xa0carers based on evidence from the literature (Lagae et al. 2017). It noted that other family members of people with Lennox–Gastaut syndrome may have responsibilities for care, which would lower their quality of life (see section\xa03.1). The company included a scenario analysis increasing the number of carers in the model to\xa03 to account for this. For the analysis using 2\xa0carers, the company doubled the decrements from the vignette study (see section\xa03.18) and subtracted this from the value reflecting the patient's utility. The committee was concerned that the company's approach implied that the caring burden increases linearly the more carers a patient has. However, for a patient with multiple carers, it expected there to be less effect on the quality of life of each carer because they would 'share' some of the burden; so, while the total burden for 2\xa0carers may be greater than the burden for a sole carer, it would likely not be 2\xa0times greater. The company stated that its vignette study accounted for 'sharing' care because it asked everyone taking part to rate their own quality of life, and most people in the study had a partner. The committee recalled that there were several limitations with the company's vignette study (see sections\xa03.17\xa0and\xa03.18), so it was unclear whether the disutility values appropriately captured 'sharing' of care. The committee considered that the company's method of linearly multiplying the disutility values was inappropriate and could have led to perverse results, particularly if the company had modelled a high number of carers. However, in this case, using the value of 1.8\xa0carers limited this effect. The committee acknowledged the substantial detrimental effect that caring can have on quality of life. It recognised that it would be difficult to estimate how much each additional carer reduced the burden of the other carers. The committee concluded that it preferred to use the value of 1.8\xa0carers, which also helped to limit the effect of the inappropriate methodology used by the company to incorporate carer disutility into the model.\n\n# Cost-effectiveness results\n\n## Addressing the remaining uncertainties in the model would likely increase the incremental cost-effectiveness ratios\n\nThe company's updated cost-effectiveness analyses included most of the committee's preferred assumptions:\n\nusing narrower seizure frequency ranges for the health states (see section\xa03.8)\n\nremoving the effect of non-drop seizures as calculated (see section\xa03.10)\n\nusing the mean weight instead of the median (see section\xa03.12)\n\naccounting for waning of cannabidiol's effects (see section\xa03.14)\n\nnot assuming that cannabidiol lengthens life (see section\xa03.15)\n\nusing an average dosage of 12\xa0mg/kg/day (see section\xa03.16)\n\nincluding health-related quality-of-life effects for 1.8\xa0carers, which acknowledges shared burden (see section\xa03.19).This resulted in an incremental cost-effectiveness ratio (ICER) of £33,721 per QALY gained. These analyses did not take into account the committee's preference for stopping rules to be applied at 18\xa0months rather than 24\xa0months. However, the committee agreed this was unlikely to have had a substantial effect on the ICER (see section\xa03.7). It also recalled that there was additional uncertainty in the cost-effectiveness results because of:\n\nthe company's assumptions around people who stop treatment with cannabidiol (see section\xa03.11)\n\nthe way the company modelled a waning of treatment effect, which did not capture all the effects that diminishing efficacy over time would have on quality of life (see section\xa03.14).The committee concluded that the cumulative effect of addressing these uncertainties was likely to have increased the ICER.\n\n# Other factors\n\n## There are benefits of cannabidiol that are not captured in the company's model\n\nThe committee recalled that the company had not modelled the effect on the quality of life of the siblings of children or young people with Lennox–Gastaut syndrome (see section\xa03.18). It also recalled that the company's approach to modelling fewer non-drop seizures was not appropriate (see section\xa03.8). The committee considered these factors important for improving quality of life (see section\xa03.1). It concluded that it would take these benefits into account in its decision making.\n\n## Cannabidiol does not meet the criteria for an innovative treatment\n\nThe clinical experts stated that they would welcome an additional treatment option for Lennox–Gastaut syndrome. However, they considered that cannabidiol represents only a modest change when managing Lennox–Gastaut syndrome because few people became seizure free (see section\xa03.5). The committee concluded that cannabidiol did not meet the criteria for an innovative treatment.\n\n## Cannabidiol is recommended for use with clobazam to treat people with Lennox–Gastaut syndrome\n\nThe committee recalled that it had concluded that it was appropriate to consider other benefits not captured in the company's model (see section\xa03.21). It recognised that some of the remaining uncertainties would be addressed in time with ongoing data collection. The committee concluded that, despite these uncertainties (see section\xa03.20), when it considered the uncaptured benefits, cannabidiol represents an effective treatment and a good use of NHS resources. It therefore recommended cannabidiol with clobazam to treat Lennox–Gastaut syndrome. It also concluded that seizure frequency should be checked every 6\xa0months and that, if the frequency has not fallen by at least 30% compared with the 6\xa0months before starting treatment, cannabidiol should be stopped (see section\xa03.7)."}
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https://www.nice.org.uk/guidance/ta615
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Evidence-based recommendations on cannabidiol (Epidyolex) with clobazam for seizures associated with Lennox–Gastaut syndrome in people aged 2 years and older.
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f923ad81786a3bf5e0542a7ea4165e3f19028278
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nice
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Menopause: diagnosis and management
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Menopause: diagnosis and management
This guideline covers the diagnosis and management of menopause, including in women who have premature ovarian insufficiency. The guideline aims to improve the consistency of support and information provided to women in menopause.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Individualised care
Adopt an individualised approach at all stages of diagnosis, investigation and management of perimenopause and menopause. Follow recommendations in the NICE guideline on patient experience in adult NHS services.
# Diagnosis of perimenopause and menopause
Diagnose the following without laboratory tests in otherwise healthy women aged over 45 years with menopausal symptoms:
perimenopause based on vasomotor symptoms and irregular periods
menopause in women who have not had a period for at least 12 months and are not using hormonal contraception
menopause based on symptoms in women without a uterus.
Take into account that it can be difficult to diagnose menopause in women who are taking hormonal treatments, for example for the treatment of heavy periods.
Do not use the following laboratory and imaging tests to diagnose perimenopause or menopause in women aged over 45 years:
anti-Müllerian hormone
inhibin A
inhibin B
-estradiol
antral follicle count
-varian volume.
Do not use a serum follicle-stimulating hormone (FSH) test to diagnose menopause in women using combined oestrogen and progestogen contraception or high-dose progestogen.
Consider using a FSH test to diagnose menopause only:
in women aged 40 to 45 years with menopausal symptoms, including a change in their menstrual cycle
in women aged under 40 years in whom menopause is suspected (see also recommendations on diagnosing and managing premature ovarian insufficiency).
# Information and advice
Give information to menopausal women and their family members or carers (as appropriate) that includes:
an explanation of the stages of menopause
common symptoms (see recommendation 1.3.2) and diagnosis
lifestyle changes and interventions that could help general health and wellbeing
benefits and risks of treatments for menopausal symptoms
long-term health implications of menopause.
Explain to women that as well as a change in their menstrual cycle they may experience a variety of symptoms associated with menopause, including:
vasomotor symptoms (for example, hot flushes and sweats)
musculoskeletal symptoms (for example, joint and muscle pain)
effects on mood (for example, low mood)
urogenital symptoms (for example, vaginal dryness)
sexual difficulties (for example, low sexual desire).
Give information to menopausal women and their family members or carers (as appropriate) about the following types of treatment for menopausal symptoms:
hormonal, for example hormone replacement therapy (HRT)
non-hormonal, for example clonidine
non-pharmaceutical, for example cognitive behavioural therapy (CBT).
Give information on menopause in different ways to help encourage women to discuss their symptoms and needs.
Give information about contraception to women who are in the perimenopausal and postmenopausal phase. See guidance from the Faculty of Sexual & Reproductive Healthcare on contraception for women aged over 40 years.
Offer women who are likely to go through menopause as a result of medical or surgical treatment (including women with cancer, at high risk of hormone-sensitive cancer or having gynaecological surgery) support and:
information about menopause and fertility before they have their treatment
referral to a healthcare professional with expertise in menopause.
# Managing short-term menopausal symptoms
The recommendations in this section are not intended for women with premature ovarian insufficiency (see recommendations on the management of premature ovarian insufficiency).
Adapt a woman's treatment as needed, based on her changing symptoms.
## Vasomotor symptoms
Offer women HRT for vasomotor symptoms after discussing with them the short-term (up to 5 years) and longer-term benefits and risks. Offer a choice of preparations as follows:
-estrogen and progestogen to women with a uterus
-estrogen alone to women without a uterus.
Do not routinely offer selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) or clonidine as first-line treatment for vasomotor symptoms alone.
Explain to women that there is some evidence that isoflavones or black cohosh may relieve vasomotor symptoms. However, explain that:
multiple preparations are available and their safety is uncertain
different preparations may vary
interactions with other medicines have been reported.
## Psychological symptoms
Consider HRT to alleviate low mood that arises as a result of the menopause.
Consider CBT to alleviate low mood or anxiety that arise as a result of the menopause.
Ensure that menopausal women and healthcare professionals involved in their care understand that there is no clear evidence for SSRIs or SNRIs to ease low mood in menopausal women who have not been diagnosed with depression (see the NICE guideline on depression in adults).
## Altered sexual function
Consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective.In November 2015, this was an off-label use. See NICE's information on prescribing medicines
## Urogenital atrophy
Offer vaginal oestrogen to women with urogenital atrophy (including those on systemic HRT) and continue treatment for as long as needed to relieve symptoms.
Consider vaginal oestrogen for women with urogenital atrophy in whom systemic HRT is contraindicated, after seeking advice from a healthcare professional with expertise in menopause.
If vaginal oestrogen does not relieve symptoms of urogenital atrophy, consider increasing the dose after seeking advice from a healthcare professional with expertise in menopause.
Explain to women with urogenital atrophy that:
symptoms often come back when treatment is stopped
adverse effects from vaginal oestrogen are very rare
they should report unscheduled vaginal bleeding to their GP.
Advise women with vaginal dryness that moisturisers and lubricants can be used alone or in addition to vaginal oestrogen.
Do not offer routine monitoring of endometrial thickness during treatment for urogenital atrophy.
## Complementary therapies and unregulated preparations
Explain to women that the efficacy and safety of unregulated compounded bioidentical hormones are unknown.
Explain to women who wish to try complementary therapies that the quality, purity and constituents of products may be unknown.
Advise women with a history of, or at high risk of, breast cancer that, although there is some evidence that St John's wort may be of benefit in the relief of vasomotor symptoms, there is uncertainty about:
appropriate doses
persistence of effect
variation in the nature and potency of preparations
potential serious interactions with other drugs (including tamoxifen, anticoagulants and anticonvulsants).
## Review and referral
Discuss with women the importance of keeping up to date with nationally recommended health screening.
Review each treatment for short-term menopausal symptoms:
at 3 months to assess efficacy and tolerability
annually thereafter unless there are clinical indications for an earlier review (such as treatment ineffectiveness, side effects or adverse events).
Refer women to a healthcare professional with expertise in menopause if treatments do not improve their menopausal symptoms or they have ongoing troublesome side effects.
Consider referring women to a healthcare professional with expertise in menopause if:
they have menopausal symptoms and contraindications to HRT or
there is uncertainty about the most suitable treatment options for their menopausal symptoms.
## Starting and stopping HRT
Explain to women with a uterus that unscheduled vaginal bleeding is a common side effect of HRT within the first 3 months of treatment but should be reported at the 3-month review appointment, or promptly if it occurs after the first 3 months (see recommendations on endometrial cancer in the NICE guideline on suspected cancer).
Offer women who are stopping HRT a choice of gradually reducing or immediately stopping treatment.
Explain to women that:
gradually reducing HRT may limit recurrence of symptoms in the short term
gradually reducing or immediately stopping HRT makes no difference to their symptoms in the longer term.
## Women with, or at high risk of, breast cancer
For advice on the treatment of menopausal symptoms in women with breast cancer or at high risk of breast cancer, see recommendations on complications of local treatment and menopausal symptoms in the NICE guideline on early and locally advanced breast cancer and recommendations on risk reduction and treatment strategies in the NICE guideline on familial breast cancer.
Offer menopausal women with, or at high risk of, breast cancer:
information on all available treatment options
information that the SSRIs paroxetine and fluoxetine should not be offered to women with breast cancer who are taking tamoxifen
referral to a healthcare professional with expertise in menopause.
# Long-term benefits and risks of hormone replacement therapy
## Venous thromboembolism
Explain to women that:
the risk of venous thromboembolism (VTE) is increased by oral HRT compared with baseline population risk
the risk of VTE associated with HRT is greater for oral than transdermal preparations
the risk associated with transdermal HRT given at standard therapeutic doses is no greater than baseline population risk.
Consider transdermal rather than oral HRT for menopausal women who are at increased risk of VTE, including those with a BMI over 30 kg/m2.
Consider referring menopausal women at high risk of VTE (for example, those with a strong family history of VTE or a hereditary thrombophilia) to a haematologist for assessment before considering HRT.
## Cardiovascular disease
Ensure that menopausal women and healthcare professionals involved in their care understand that HRT:
does not increase cardiovascular disease risk when started in women aged under 60 years
does not affect the risk of dying from cardiovascular disease.
Be aware that the presence of cardiovascular risk factors is not a contraindication to HRT as long as they are optimally managed.
Using tables 1 and 2, explain to women that:
the baseline risk of coronary heart disease and stroke for women around menopausal age varies from one woman to another according to the presence of cardiovascular risk factors
HRT with oestrogen alone is associated with no, or reduced, risk of coronary heart disease
HRT with oestrogen and progestogen is associated with little or no increase in the risk of coronary heart disease.
Explain to women that taking oral (but not transdermal) oestrogen is associated with a small increase in the risk of stroke. Also explain that the baseline population risk of stroke in women aged under 60 years is very low (see table 2).
Type of HRT
Current HRT users
Treatment duration <5 years
Treatment duration 5–10 years
5 years since stopping treatment
Women on oestrogen alone (RCT estimate)
fewer
(−10 to 1)
No available data
No available data
fewer
(−9 to −2)
Women on oestrogen alone (observational estimate)
fewer
(−9 to −3)
No available data
No available data
No available data
Women on oestrogen plus progestogen (RCT estimate)
more
(−3 to 18)
No available data
No available data
more
(−1 to 11)
Women on oestrogen plus progestogen (observational estimate)
No available data
No available data
No available data
No available data
Notes: Thebaseline population risk in the UK over 7.5 years was 26.3 per 1,000 (results from Weiner 2008 were used for the baseline population risk estimation). For full source references, see Appendix M in the full guideline.
Randomised controlled trial (RCT)estimates based on women aged 50–59 years at entry to the RCT.
Observational estimates based on cohort studies with several thousand women.
Type of HRT
Current HRT users
Treatment duration <5 years
Treatment duration 5–10 years
5 years since stopping treatment
Women on oestrogen alone (RCT estimate)
(−5 to 10)
No available data
No available data
more
(−4 to 9)
Women on oestrogen alone (observational estimate)
more
(−1 to 8)
No available data
No available data
No available data
Women on oestrogen plus progestogen (RCT estimate)
more
(−2 to 21)
No available data
No available data
more
(−1 to 13)
Women on oestrogen plus progestogen (observational estimate)
more
(1 to 7)
No available data
No available data
No available data
Notes: The baseline population risk in the UK over 7.5 years was 11.3 per 1,000 (results from Weiner 2008 were used for the baseline population risk estimation). For full source references, see Appendix M in the full guideline.
Randomised controlled trial (RCT)estimates based on women aged 50–59 years at entry to the RCT.
Observational estimates based on cohort studies with several thousand women.
## Type 2 diabetes
Explain to women that taking HRT (either orally or transdermally) is not associated with an increased risk of developing type 2 diabetes.
Ensure that women with type 2 diabetes and all healthcare professionals involved in their care are aware that HRT is not generally associated with an adverse effect on blood glucose control.
Consider HRT for menopausal symptoms in women with type 2 diabetes after taking comorbidities into account and seeking specialist advice if needed.
## Breast cancer
Using the MHRA risk table, explain to women around the age of natural menopause that:
the baseline risk of breast cancer for women around menopausal age varies from one woman to another according to the presence of underlying risk factors
HRT with oestrogen alone is associated with little or no change in the risk of breast cancer
HRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer
any increase in the risk of breast cancer is related to treatment duration and reduces after stopping HRT.
## Osteoporosis
Give women advice on bone health and discuss these issues at review appointments (see the NICE guideline on osteoporosis: assessing the risk of fragility fracture).
Using table 3, explain to women that the baseline population risk of fragility fracture for women around menopausal age in the UK is low and varies from one woman to another.
Using table 3, explain to women that their risk of fragility fracture is decreased while taking HRT and that this benefit:
is maintained during treatment but decreases once treatment stops
may continue for longer in women who take HRT for longer.
Type of estimate
Current HRT users
Treatment duration <5 years
Treatment duration 5–10 years
5 years since stopping treatment
RCT estimate
fewer
(−10 to −33)
Baseline population risk: 69 per 1,000 women
(follow-up: 3.43 years)
fewer
(−9 to −37)
Baseline population risk: 78 per 1,000 women (follow-up: 3.71 years)
No available data
No available data
Observational estimate
fewer
(−15 to −18)
Baseline population risk: 15.4 per 1,000 women (follow-up: 2.8 years)
fewer
(−11 to −17)
Baseline population risk: 15.4 per 1,000 women (follow-up: 2.8 years)
fewer
(−15 to −20)
Baseline population risk: 15.4 per 1,000 women (follow-up: 2.8 years)
more
(−19 to 27)
Baseline population risk: 106 per 1,000 women (follow-up: 5 years).
Notes: For full source references, see Appendix M in the full guideline.
Absolute risks calculated by using the baseline population risk in the control arm for each analysis, following GRADE methodology.
Randomised controlled trial (RCT)estimates based on women aged 50–59 years at entry to the RCT.
Observational estimate based on cohort studies with several thousand women.
## Dementia
Explain to menopausal women that the likelihood of HRT affecting their risk of dementia is unknown.
## Loss of muscle mass and strength
Explain to women that:
there is limited evidence suggesting that HRT may improve muscle mass and strength
muscle mass and strength is maintained through, and is important for, activities of daily living.
# Diagnosing and managing premature ovarian insufficiency
## Diagnosing premature ovarian insufficiency
Take into account the woman's clinical history (for example, previous medical or surgical treatment) and family history when diagnosing premature ovarian insufficiency.
Diagnose premature ovarian insufficiency in women aged under 40 years based on:
menopausal symptoms, including no or infrequent periods (taking into account whether the woman has a uterus) and
elevated FSH levels on 2 blood samples taken 4–6 weeks apart.
Do not diagnose premature ovarian insufficiency on the basis of a single blood test.
Do not routinely use anti-Müllerian hormone testing to diagnose premature ovarian insufficiency.
If there is doubt about the diagnosis of premature ovarian insufficiency, refer the woman to a specialist with expertise in menopause or reproductive medicine.
## Managing premature ovarian insufficiency
Offer sex steroid replacement with a choice of HRT or a combined hormonal contraceptive to women with premature ovarian insufficiency, unless contraindicated (for example, in women with hormone-sensitive cancer).
Explain to women with premature ovarian insufficiency:
the importance of starting hormonal treatment either with HRT or a combined hormonal contraceptive and continuing treatment until at least the age of natural menopause (unless contraindicated)
that the baseline population risk of diseases such as breast cancer and cardiovascular disease increases with age and is very low in women aged under 40
that HRT may have a beneficial effect on blood pressure when compared with a combined oral contraceptive
that both HRT and combined oral contraceptives offer bone protection
that HRT is not a contraceptive.
Give women with premature ovarian insufficiency and contraindications to hormonal treatments advice, including on bone and cardiovascular health, and symptom management.
Consider referring women with premature ovarian insufficiency to healthcare professionals who have the relevant experience to help them manage all aspects of physical and psychosocial health related to their condition.
# Terms used in this guideline
Compounded bioidentical hormones Unregulated plant-derived hormonal combinations similar or identical to human hormones that are compounded by pharmacies to the specification of the prescriber.
Fragility fracture Fractures that result from mechanical forces that would not ordinarily result in fracture (such as a fall from a standing height or less). Reduced bone density is a major risk factor for fragility fractures, which occur most commonly in the spine, hip and wrist.
Low mood Mild depressive symptoms that impair quality of life but are usually intermittent and often associated with hormonal fluctuations in perimenopause.
Menopause A biological stage in a woman's life that occurs when she stops menstruating and reaches the end of her natural reproductive life. Usually it is defined as having occurred when a woman has not had a period for 12 consecutive months (for women reaching menopause naturally). The changes associated with menopause occur when the ovaries stop maturing eggs and secreting oestrogen and progesterone.
Menopausal women This includes women in perimenopause and postmenopause.
Perimenopause The time in which a woman has irregular cycles of ovulation and menstruation leading up to menopause and continuing until 12 months after her final period. The perimenopause is also known as the menopausal transition or climacteric.
Postmenopause The time after menopause has occurred, starting when a woman has not had a period for 12 consecutive months.
Premature ovarian insufficiency Menopause occurring before the age of 40 years (also known as premature ovarian failure or premature menopause). It can occur naturally or as a result of medical or surgical treatment.
Urogenital atrophy Thinning and shrinking of the tissues of the vulva, vagina, urethra and bladder caused by oestrogen deficiency. This results in multiple symptoms such as vaginal dryness, vaginal irritation, a frequent need to urinate and urinary tract infections.
Vasomotor symptoms Menopausal symptoms such as hot flushes and night sweats caused by constriction and dilatation of blood vessels in the skin that can lead to a sudden increase in blood flow to allow heat loss. These symptoms can have a major impact on activities of daily living.# Context
Menopause is when a woman stops having periods as she reaches the end of her natural reproductive life. This is not usually abrupt, but a gradual process during which women experience perimenopause before reaching postmenopause. The average age of menopause in the UK is 51. However, this varies widely and 1 in 100 women experience premature ovarian insufficiency (menopause occurring before the age of 40 years).
Oestrogen depletion associated with menopause causes irregular periods and has many other effects on the body. The most common symptoms are hot flushes and night sweats. Other symptoms include mood changes, memory and concentration loss, vaginal dryness, a lack of interest in sex, headaches, and joint and muscle stiffness. Quality of life may be severely affected.
Most women (8 out of 10) experience some symptoms, typically lasting about 4 years after the last period, but continuing for up to 12 years in about 10% of women. Prolonged lack of oestrogen affects the bones and cardiovascular system and postmenopausal women are at increased risk of a number of long-term conditions, such as osteoporosis.
Around a million women in the UK use treatment for their menopausal symptoms. The advice and support available is variable, and use of hormone replacement therapy (HRT) – a highly successful treatment for common symptoms of menopause – varies with socioeconomic and cultural factors. The number of prescriptions for HRT almost halved after the publication of 2 large studies: the Women's Health Initiative (2002) and the Million Women Study (2003). These studies focused on the use of HRT in chronic disease prevention and potential long-term risks rather than considering the benefits in terms of symptom relief. One of the aims of this NICE guideline was to clarify the balance of benefits and risks of HRT use for both women and their healthcare providers. Note that at the time of publication (November 2015), the MHRA is consulting with marketing authorisation holders on amending the existing warning about the risk of ovarian cancer in the Summary of Product Characteristics (SPC) information for HRT products. The current core SPC states that long‑term use of oestrogen‑only and combined oestrogen‑progestogen HRT has been associated with a slightly increased risk of ovarian cancer.
This guideline addresses the diagnosis and management of menopause. It covers women in perimenopause and postmenopause, and the particular needs of women with premature ovarian insufficiency and women with hormone-sensitive cancer (for example, breast cancer). The guideline concentrates on the clinical management of menopause-related symptoms, considers both pharmaceutical and non-pharmaceutical treatments, includes a health economic analysis, and reviews the benefits and adverse effects of HRT. It applies to all settings in which NHS services are provided.# Recommendations for research
The Guideline Development Group has made the following recommendations for research. The full set of research recommendations is detailed in the full guideline.
# Women with breast cancer
What is the safety and effectiveness of alternatives to systemic hormone replacement therapy (HRT) as treatments for menopausal symptoms in women who have had treatment for breast cancer?
Why this is important
Women with a history of breast cancer are rarely offered hormonal treatment for menopausal symptoms but the available alternatives are less effective. There is limited evidence from randomised controlled trials on the safety and effectiveness of options such as non-hormonal treatments, ospemifene, conjugated equine estrogen/bazedoxifene (CEE/BZA) or local vaginal oestrogen for menopausal symptoms in women who have had treatment for breast cancer. There is insufficient evidence on the efficacy and safety of non-pharmaceutical treatments in women with breast cancer and other hormone-sensitive conditions. Randomised controlled trials or large cohort studies are needed to understand the effects of these treatments in women with breast cancer, and to investigate if there is a difference in breast cancer recurrence, mortality and tumour aggression with different types of treatment.
# Effects of HRT on breast cancer risk
What is the difference in the risk of breast cancer in menopausal women on HRT with progesterone, progestogen or selective oestrogen receptor modulators?
Why this is important
Fear of breast cancer deters many women from taking HRT, even in the presence of debilitating menopausal symptoms. There is a lack of evidence from randomised controlled trials directly comparing the risk of breast cancer in menopausal women on HRT with progesterone, progestogen or selective oestrogen receptor modulators. There is a need for a national registry of women with breast cancer.
Optimising the risk–benefit profile of HRT will potentially reduce morbidity and mortality from breast cancer in women who need HRT over the long term because of continuing menopausal symptoms.
# Effects of HRT on venous thromboembolism risk
How does the preparation of HRT affect the risk of venous thromboembolism (VTE)?
Why this is important
An increase in the risk of VTE (deep vein thrombosis or pulmonary embolism ) is a significant side effect of HRT, particularly because PEs can be fatal. This risk appears to be greater with oral than transdermal HRT. DVT risk increases with age and BMI, among other risk factors.
The progestogen component of HRT may also influence the risk of a DVT, which may be greater with androgenic synthetic progestogens than natural progesterone (but findings from observational studies need confirmation). Most women in the UK take oral HRT comprising oestrogen combined with a synthetic progestogen, and the use of progesterone is less common.
Randomised controlled trials are needed to compare oral with transdermal HRT, and HRT containing different types of progestogens. These trials should measure coagulation factors and the incidence of VTE in women at increased risk of VTE for whom transdermal oestrogen is indicated.
# Effects of HRT on dementia risk
What are the effects of early HRT use on the risk of dementia?
Why this is important
Concern about the prospect of dementia in older age is increasing and any beneficial effect on the future risk of dementia will be important to women who are considering using HRT. There is a need for good-quality observational studies controlling for the effect of important confounders on how early HRT use affects dementia risk in women with early natural menopause, including women with premature ovarian insufficiency.
# Premature ovarian insufficiency
What are the main clinical manifestations of premature ovarian insufficiency and the short- and long-term impact of the most common therapeutic interventions?
Why this is important
Women with premature ovarian insufficiency can experience the effects of menopause for most of their adult life. This can lead to reduced quality of life and an increased risk of osteoporosis, cardiovascular disease and possibly dementia. There is uncertainty about the diagnosis, time course and management of premature ovarian insufficiency. For example, it is possible that different interventions produce different outcomes in terms of quality of life, and bone, cardiovascular and brain protection. Combined oral contraceptives are often prescribed when this might not be the best treatment in terms of quality of life and preservation of bone density and cardiovascular health. Short- and long-term outcomes of HRT versus combined hormonal contraceptives in women with premature ovarian insufficiency therefore need to be investigated.
Development of a collaborative premature ovarian insufficiency registry would allow the collection of high-quality demographic, biobank (genomic) and clinical data in order to clarify:
the diagnosis and presentation of premature ovarian insufficiency
the impact of therapeutic interventions such as combined hormonal contraceptives, HRT and androgens
the long-term impact of premature ovarian insufficiency on bone density and fracture, and cardiovascular and cognitive health
the long-term risk of cancer, which can be determined by linking with relevant cancer and mortality registries.# Finding more information and resources
You can see everything NICE says on menopause in the NICE Pathway on menopause.
To find out what NICE has said on topics related to this guideline, see our web page on gynaecological conditions.
For full details of the evidence and the guideline committee's discussions, see the full version. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Individualised care\n\nAdopt an individualised approach at all stages of diagnosis, investigation and management of perimenopause and menopause. Follow recommendations in the NICE guideline on patient experience in adult NHS services.\n\n# Diagnosis of perimenopause and menopause\n\nDiagnose the following without laboratory tests in otherwise healthy women aged over 45 years with menopausal symptoms:\n\nperimenopause based on vasomotor symptoms and irregular periods\n\nmenopause in women who have not had a period for at least 12\xa0months and are not using hormonal contraception\n\nmenopause based on symptoms in women without a uterus.\n\nTake into account that it can be difficult to diagnose menopause in women who are taking hormonal treatments, for example for the treatment of heavy periods.\n\nDo not use the following laboratory and imaging tests to diagnose perimenopause or menopause in women aged over 45 years:\n\nanti-Müllerian hormone\n\ninhibin A\n\ninhibin B\n\noestradiol\n\nantral follicle count\n\novarian volume.\n\nDo not use a serum follicle-stimulating hormone (FSH) test to diagnose menopause in women using combined oestrogen and progestogen contraception or high-dose progestogen.\n\nConsider using a FSH test to diagnose menopause only:\n\nin women aged 40 to 45 years with menopausal symptoms, including a change in their menstrual cycle\n\nin women aged under 40 years in whom menopause is suspected (see also recommendations on diagnosing and managing premature ovarian insufficiency).\n\n# Information and advice\n\nGive information to menopausal women and their family members or carers (as appropriate) that includes:\n\nan explanation of the stages of menopause\n\ncommon symptoms (see recommendation 1.3.2) and diagnosis\n\nlifestyle changes and interventions that could help general health and wellbeing\n\nbenefits and risks of treatments for menopausal symptoms\n\nlong-term health implications of menopause.\n\nExplain to women that as well as a change in their menstrual cycle they may experience a variety of symptoms associated with menopause, including:\n\nvasomotor symptoms (for example, hot flushes and sweats)\n\nmusculoskeletal symptoms (for example, joint and muscle pain)\n\neffects on mood (for example, low mood)\n\nurogenital symptoms (for example, vaginal dryness)\n\nsexual difficulties (for example, low sexual desire).\n\nGive information to menopausal women and their family members or carers (as appropriate) about the following types of treatment for menopausal symptoms:\n\nhormonal, for example hormone replacement therapy (HRT)\n\nnon-hormonal, for example clonidine\n\nnon-pharmaceutical, for example cognitive behavioural therapy (CBT).\n\nGive information on menopause in different ways to help encourage women to discuss their symptoms and needs.\n\nGive information about contraception to women who are in the perimenopausal and postmenopausal phase. See guidance from the Faculty of Sexual & Reproductive Healthcare on contraception for women aged over 40 years.\n\nOffer women who are likely to go through menopause as a result of medical or surgical treatment (including women with cancer, at high risk of hormone-sensitive cancer or having gynaecological surgery) support and:\n\ninformation about menopause and fertility before they have their treatment\n\nreferral to a healthcare professional with expertise in menopause.\n\n# Managing short-term menopausal symptoms\n\nThe recommendations in this section are not intended for women with premature ovarian insufficiency (see recommendations on the management of premature ovarian insufficiency).\n\nAdapt a woman's treatment as needed, based on her changing symptoms.\n\n## Vasomotor symptoms\n\nOffer women HRT for vasomotor symptoms after discussing with them the short-term (up to 5 years) and longer-term benefits and risks. Offer a choice of preparations as follows:\n\noestrogen and progestogen to women with a uterus\n\noestrogen alone to women without a uterus.\n\nDo not routinely offer selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) or clonidine as first-line treatment for vasomotor symptoms alone.\n\nExplain to women that there is some evidence that isoflavones or black cohosh may relieve vasomotor symptoms. However, explain that:\n\nmultiple preparations are available and their safety is uncertain\n\ndifferent preparations may vary\n\ninteractions with other medicines have been reported.\n\n## Psychological symptoms\n\nConsider HRT to alleviate low mood that arises as a result of the menopause.\n\nConsider CBT to alleviate low mood or anxiety that arise as a result of the menopause.\n\nEnsure that menopausal women and healthcare professionals involved in their care understand that there is no clear evidence for SSRIs or SNRIs to ease low mood in menopausal women who have not been diagnosed with depression (see the NICE guideline on depression in adults).\n\n## Altered sexual function\n\nConsider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective.In November 2015, this was an off-label use. See NICE's information on prescribing medicines\n\n## Urogenital atrophy\n\nOffer vaginal oestrogen to women with urogenital atrophy (including those on systemic HRT) and continue treatment for as long as needed to relieve symptoms.\n\nConsider vaginal oestrogen for women with urogenital atrophy in whom systemic HRT is contraindicated, after seeking advice from a healthcare professional with expertise in menopause.\n\nIf vaginal oestrogen does not relieve symptoms of urogenital atrophy, consider increasing the dose after seeking advice from a healthcare professional with expertise in menopause.\n\nExplain to women with urogenital atrophy that:\n\nsymptoms often come back when treatment is stopped\n\nadverse effects from vaginal oestrogen are very rare\n\nthey should report unscheduled vaginal bleeding to their GP.\n\nAdvise women with vaginal dryness that moisturisers and lubricants can be used alone or in addition to vaginal oestrogen.\n\nDo not offer routine monitoring of endometrial thickness during treatment for urogenital atrophy.\n\n## Complementary therapies and unregulated preparations\n\nExplain to women that the efficacy and safety of unregulated compounded bioidentical hormones are unknown.\n\nExplain to women who wish to try complementary therapies that the quality, purity and constituents of products may be unknown.\n\nAdvise women with a history of, or at high risk of, breast cancer that, although there is some evidence that St John's wort may be of benefit in the relief of vasomotor symptoms, there is uncertainty about:\n\nappropriate doses\n\npersistence of effect\n\nvariation in the nature and potency of preparations\n\npotential serious interactions with other drugs (including tamoxifen, anticoagulants and anticonvulsants).\n\n## Review and referral\n\nDiscuss with women the importance of keeping up to date with nationally recommended health screening.\n\nReview each treatment for short-term menopausal symptoms:\n\nat 3 months to assess efficacy and tolerability\n\nannually thereafter unless there are clinical indications for an earlier review (such as treatment ineffectiveness, side effects or adverse events).\n\nRefer women to a healthcare professional with expertise in menopause if treatments do not improve their menopausal symptoms or they have ongoing troublesome side effects.\n\nConsider referring women to a healthcare professional with expertise in menopause if:\n\nthey have menopausal symptoms and contraindications to HRT or\n\nthere is uncertainty about the most suitable treatment options for their menopausal symptoms.\n\n## Starting and stopping HRT\n\nExplain to women with a uterus that unscheduled vaginal bleeding is a common side effect of HRT within the first 3 months of treatment but should be reported at the 3-month review appointment, or promptly if it occurs after the first 3 months (see recommendations on endometrial cancer in the NICE guideline on suspected cancer).\n\nOffer women who are stopping HRT a choice of gradually reducing or immediately stopping treatment.\n\nExplain to women that:\n\ngradually reducing HRT may limit recurrence of symptoms in the short term\n\ngradually reducing or immediately stopping HRT makes no difference to their symptoms in the longer term.\n\n## Women with, or at high risk of, breast cancer\n\nFor advice on the treatment of menopausal symptoms in women with breast cancer or at high risk of breast cancer, see recommendations on complications of local treatment and menopausal symptoms in the NICE guideline on early and locally advanced breast cancer and recommendations on risk reduction and treatment strategies in the NICE guideline on familial breast cancer.\n\nOffer menopausal women with, or at high risk of, breast cancer:\n\ninformation on all available treatment options\n\ninformation that the SSRIs paroxetine and fluoxetine should not be offered to women with breast cancer who are taking tamoxifen\n\nreferral to a healthcare professional with expertise in menopause.\n\n# Long-term benefits and risks of hormone replacement therapy\n\n## Venous thromboembolism\n\nExplain to women that:\n\nthe risk of venous thromboembolism (VTE) is increased by oral HRT compared with baseline population risk\n\nthe risk of VTE associated with HRT is greater for oral than transdermal preparations\n\nthe risk associated with transdermal HRT given at standard therapeutic doses is no greater than baseline population risk.\n\nConsider transdermal rather than oral HRT for menopausal women who are at increased risk of VTE, including those with a BMI over 30 kg/m2.\n\nConsider referring menopausal women at high risk of VTE (for example, those with a strong family history of VTE or a hereditary thrombophilia) to a haematologist for assessment before considering HRT.\n\n## Cardiovascular disease\n\nEnsure that menopausal women and healthcare professionals involved in their care understand that HRT:\n\ndoes not increase cardiovascular disease risk when started in women aged under 60 years\n\ndoes not affect the risk of dying from cardiovascular disease.\n\nBe aware that the presence of cardiovascular risk factors is not a contraindication to HRT as long as they are optimally managed.\n\nUsing tables 1 and 2, explain to women that:\n\nthe baseline risk of coronary heart disease and stroke for women around menopausal age varies from one woman to another according to the presence of cardiovascular risk factors\n\nHRT with oestrogen alone is associated with no, or reduced, risk of coronary heart disease\n\nHRT with oestrogen and progestogen is associated with little or no increase in the risk of coronary heart disease.\n\nExplain to women that taking oral (but not transdermal) oestrogen is associated with a small increase in the risk of stroke. Also explain that the baseline population risk of stroke in women aged under 60 years is very low (see table 2).\n\nType of HRT\n\nCurrent HRT users\n\nTreatment duration <5 years\n\nTreatment duration 5–10 years\n\n>5 years since stopping treatment\n\nWomen on oestrogen alone (RCT estimate)\n\nfewer\n\n(−10 to 1)\n\nNo available data\n\nNo available data\n\nfewer\n\n(−9 to −2)\n\nWomen on oestrogen alone (observational estimate)\n\nfewer\n\n(−9 to −3)\n\nNo available data\n\nNo available data\n\nNo available data\n\nWomen on oestrogen plus progestogen (RCT estimate)\n\nmore\n\n(−3 to 18)\n\nNo available data\n\nNo available data\n\nmore\n\n(−1 to 11)\n\nWomen on oestrogen plus progestogen (observational estimate)\n\nNo available data\n\nNo available data\n\nNo available data\n\nNo available data\n\nNotes: Thebaseline population risk in the UK over 7.5 years was 26.3 per 1,000 (results from Weiner 2008 were used for the baseline population risk estimation). For full source references, see Appendix M in the full guideline.\n\nRandomised controlled trial (RCT)estimates based on women aged 50–59 years at entry to the RCT.\n\nObservational estimates based on cohort studies with several thousand women.\n\nType of HRT\n\nCurrent HRT users\n\nTreatment duration <5 years\n\nTreatment duration 5–10 years\n\n>5 years since stopping treatment\n\nWomen on oestrogen alone (RCT estimate)\n\n\n\n(−5 to 10)\n\nNo available data\n\nNo available data\n\nmore\n\n(−4 to 9)\n\nWomen on oestrogen alone (observational estimate)\n\nmore\n\n(−1 to 8)\n\nNo available data\n\nNo available data\n\nNo available data\n\nWomen on oestrogen plus progestogen (RCT estimate)\n\nmore\n\n(−2 to 21)\n\nNo available data\n\nNo available data\n\nmore\n\n(−1 to 13)\n\n\n\nWomen on oestrogen plus progestogen (observational estimate)\n\nmore\n\n(1 to 7)\n\nNo available data\n\nNo available data\n\nNo available data\n\nNotes: The baseline population risk in the UK over 7.5 years was 11.3 per 1,000 (results from Weiner 2008 were used for the baseline population risk estimation). For full source references, see Appendix M in the full guideline.\n\nRandomised controlled trial (RCT)estimates based on women aged 50–59 years at entry to the RCT.\n\nObservational estimates based on cohort studies with several thousand women.\n\n## Type 2 diabetes\n\nExplain to women that taking HRT (either orally or transdermally) is not associated with an increased risk of developing type 2 diabetes.\n\nEnsure that women with type 2 diabetes and all healthcare professionals involved in their care are aware that HRT is not generally associated with an adverse effect on blood glucose control.\n\nConsider HRT for menopausal symptoms in women with type 2 diabetes after taking comorbidities into account and seeking specialist advice if needed.\n\n## Breast cancer\n\nUsing the MHRA risk table, explain to women around the age of natural menopause that:\n\nthe baseline risk of breast cancer for women around menopausal age varies from one woman to another according to the presence of underlying risk factors\n\nHRT with oestrogen alone is associated with little or no change in the risk of breast cancer\n\nHRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer\n\nany increase in the risk of breast cancer is related to treatment duration and reduces after stopping HRT.\n\n## Osteoporosis\n\nGive women advice on bone health and discuss these issues at review appointments (see the NICE guideline on osteoporosis: assessing the risk of fragility fracture).\n\nUsing table 3, explain to women that the baseline population risk of fragility fracture for women around menopausal age in the UK is low and varies from one woman to another.\n\nUsing table 3, explain to women that their risk of fragility fracture is decreased while taking HRT and that this benefit:\n\nis maintained during treatment but decreases once treatment stops\n\nmay continue for longer in women who take HRT for longer.\n\nType of estimate\n\nCurrent HRT users\n\nTreatment duration <5 years\n\nTreatment duration 5–10 years\n\n>5 years since stopping treatment\n\nRCT estimate\n\nfewer\n\n(−10 to −33)\n\nBaseline population risk: 69 per 1,000 women\n\n(follow-up: 3.43 years)\n\nfewer\n\n(−9 to −37)\n\nBaseline population risk: 78 per 1,000 women (follow-up: 3.71 years)\n\nNo available data\n\nNo available data\n\nObservational estimate\n\nfewer\n\n(−15 to −18)\n\nBaseline population risk: 15.4 per 1,000 women (follow-up: 2.8 years)\n\nfewer\n\n(−11 to −17)\n\nBaseline population risk: 15.4 per 1,000 women (follow-up: 2.8 years)\n\nfewer\n\n(−15 to −20)\n\nBaseline population risk: 15.4 per 1,000 women (follow-up: 2.8 years)\n\nmore\n\n(−19 to 27)\n\nBaseline population risk: 106 per 1,000 women (follow-up: 5 years).\n\nNotes: For full source references, see Appendix M in the full guideline.\n\nAbsolute risks calculated by using the baseline population risk in the control arm for each analysis, following GRADE methodology.\n\nRandomised controlled trial (RCT)estimates based on women aged 50–59 years at entry to the RCT.\n\nObservational estimate based on cohort studies with several thousand women.\n\n## Dementia\n\nExplain to menopausal women that the likelihood of HRT affecting their risk of dementia is unknown.\n\n## Loss of muscle mass and strength\n\nExplain to women that:\n\nthere is limited evidence suggesting that HRT may improve muscle mass and strength\n\nmuscle mass and strength is maintained through, and is important for, activities of daily living.\n\n# Diagnosing and managing premature ovarian insufficiency\n\n## Diagnosing premature ovarian insufficiency\n\nTake into account the woman's clinical history (for example, previous medical or surgical treatment) and family history when diagnosing premature ovarian insufficiency.\n\nDiagnose premature ovarian insufficiency in women aged under 40 years based on:\n\nmenopausal symptoms, including no or infrequent periods (taking into account whether the woman has a uterus) and\n\nelevated FSH levels on 2 blood samples taken 4–6 weeks apart.\n\nDo not diagnose premature ovarian insufficiency on the basis of a single blood test.\n\nDo not routinely use anti-Müllerian hormone testing to diagnose premature ovarian insufficiency.\n\nIf there is doubt about the diagnosis of premature ovarian insufficiency, refer the woman to a specialist with expertise in menopause or reproductive medicine.\n\n## Managing premature ovarian insufficiency\n\nOffer sex steroid replacement with a choice of HRT or a combined hormonal contraceptive to women with premature ovarian insufficiency, unless contraindicated (for example, in women with hormone-sensitive cancer).\n\nExplain to women with premature ovarian insufficiency:\n\nthe importance of starting hormonal treatment either with HRT or a combined hormonal contraceptive and continuing treatment until at least the age of natural menopause (unless contraindicated)\n\nthat the baseline population risk of diseases such as breast cancer and cardiovascular disease increases with age and is very low in women aged under 40\n\nthat HRT may have a beneficial effect on blood pressure when compared with a combined oral contraceptive\n\nthat both HRT and combined oral contraceptives offer bone protection\n\nthat HRT is not a contraceptive.\n\nGive women with premature ovarian insufficiency and contraindications to hormonal treatments advice, including on bone and cardiovascular health, and symptom management.\n\nConsider referring women with premature ovarian insufficiency to healthcare professionals who have the relevant experience to help them manage all aspects of physical and psychosocial health related to their condition.\n\n# Terms used in this guideline\n\nCompounded bioidentical hormones Unregulated plant-derived hormonal combinations similar or identical to human hormones that are compounded by pharmacies to the specification of the prescriber.\n\nFragility fracture Fractures that result from mechanical forces that would not ordinarily result in fracture (such as a fall from a standing height or less). Reduced bone density is a major risk factor for fragility fractures, which occur most commonly in the spine, hip and wrist.\n\nLow mood Mild depressive symptoms that impair quality of life but are usually intermittent and often associated with hormonal fluctuations in perimenopause.\n\nMenopause A biological stage in a woman's life that occurs when she stops menstruating and reaches the end of her natural reproductive life. Usually it is defined as having occurred when a woman has not had a period for 12 consecutive months (for women reaching menopause naturally). The changes associated with menopause occur when the ovaries stop maturing eggs and secreting oestrogen and progesterone.\n\nMenopausal women This includes women in perimenopause and postmenopause.\n\nPerimenopause The time in which a woman has irregular cycles of ovulation and menstruation leading up to menopause and continuing until 12 months after her final period. The perimenopause is also known as the menopausal transition or climacteric.\n\nPostmenopause The time after menopause has occurred, starting when a woman has not had a period for 12 consecutive months.\n\nPremature ovarian insufficiency Menopause occurring before the age of 40 years (also known as premature ovarian failure or premature menopause). It can occur naturally or as a result of medical or surgical treatment.\n\nUrogenital atrophy Thinning and shrinking of the tissues of the vulva, vagina, urethra and bladder caused by oestrogen deficiency. This results in multiple symptoms such as vaginal dryness, vaginal irritation, a frequent need to urinate and urinary tract infections.\n\nVasomotor symptoms Menopausal symptoms such as hot flushes and night sweats caused by constriction and dilatation of blood vessels in the skin that can lead to a sudden increase in blood flow to allow heat loss. These symptoms can have a major impact on activities of daily living.", 'Context': "Menopause is when a woman stops having periods as she reaches the end of her natural reproductive life. This is not usually abrupt, but a gradual process during which women experience perimenopause before reaching postmenopause. The average age of menopause in the UK is 51. However, this varies widely and 1 in 100 women experience premature ovarian insufficiency (menopause occurring before the age of 40 years).\n\nOestrogen depletion associated with menopause causes irregular periods and has many other effects on the body. The most common symptoms are hot flushes and night sweats. Other symptoms include mood changes, memory and concentration loss, vaginal dryness, a lack of interest in sex, headaches, and joint and muscle stiffness. Quality of life may be severely affected.\n\nMost women (8 out of 10) experience some symptoms, typically lasting about 4 years after the last period, but continuing for up to 12 years in about 10% of women. Prolonged lack of oestrogen affects the bones and cardiovascular system and postmenopausal women are at increased risk of a number of long-term conditions, such as osteoporosis.\n\nAround a million women in the UK use treatment for their menopausal symptoms. The advice and support available is variable, and use of hormone replacement therapy (HRT) – a highly successful treatment for common symptoms of menopause – varies with socioeconomic and cultural factors. The number of prescriptions for HRT almost halved after the publication of 2 large studies: the Women's Health Initiative (2002) and the Million Women Study (2003). These studies focused on the use of HRT in chronic disease prevention and potential long-term risks rather than considering the benefits in terms of symptom relief. One of the aims of this NICE guideline was to clarify the balance of benefits and risks of HRT use for both women and their healthcare providers. Note that at the time of publication (November 2015), the MHRA is consulting with marketing authorisation holders on amending the existing warning about the risk of ovarian cancer in the Summary of Product Characteristics (SPC) information for HRT products. The current core SPC states that long‑term use of oestrogen‑only and combined oestrogen‑progestogen HRT has been associated with a slightly increased risk of ovarian cancer.\n\nThis guideline addresses the diagnosis and management of menopause. It covers women in perimenopause and postmenopause, and the particular needs of women with premature ovarian insufficiency and women with hormone-sensitive cancer (for example, breast cancer). The guideline concentrates on the clinical management of menopause-related symptoms, considers both pharmaceutical and non-pharmaceutical treatments, includes a health economic analysis, and reviews the benefits and adverse effects of HRT. It applies to all settings in which NHS services are provided.", 'Recommendations for research': 'The Guideline Development Group has made the following recommendations for research. The full set of research recommendations is detailed in the full guideline.\n\n# Women with breast cancer\n\nWhat is the safety and effectiveness of alternatives to systemic hormone replacement therapy (HRT) as treatments for menopausal symptoms in women who have had treatment for breast cancer?\n\nWhy this is important\n\nWomen with a history of breast cancer are rarely offered hormonal treatment for menopausal symptoms but the available alternatives are less effective. There is limited evidence from randomised controlled trials on the safety and effectiveness of options such as non-hormonal treatments, ospemifene, conjugated equine estrogen/bazedoxifene (CEE/BZA) or local vaginal oestrogen for menopausal symptoms in women who have had treatment for breast cancer. There is insufficient evidence on the efficacy and safety of non-pharmaceutical treatments in women with breast cancer and other hormone-sensitive conditions. Randomised controlled trials or large cohort studies are needed to understand the effects of these treatments in women with breast cancer, and to investigate if there is a difference in breast cancer recurrence, mortality and tumour aggression with different types of treatment.\n\n# Effects of HRT on breast cancer risk\n\nWhat is the difference in the risk of breast cancer in menopausal women on HRT with progesterone, progestogen or selective oestrogen receptor modulators?\n\nWhy this is important\n\nFear of breast cancer deters many women from taking HRT, even in the presence of debilitating menopausal symptoms. There is a lack of evidence from randomised controlled trials directly comparing the risk of breast cancer in menopausal women on HRT with progesterone, progestogen or selective oestrogen receptor modulators. There is a need for a national registry of women with breast cancer.\n\nOptimising the risk–benefit profile of HRT will potentially reduce morbidity and mortality from breast cancer in women who need HRT over the long term because of continuing menopausal symptoms.\n\n# Effects of HRT on venous thromboembolism risk\n\nHow does the preparation of HRT affect the risk of venous thromboembolism (VTE)?\n\nWhy this is important\n\nAn increase in the risk of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) is a significant side effect of HRT, particularly because PEs can be fatal. This risk appears to be greater with oral than transdermal HRT. DVT risk increases with age and BMI, among other risk factors.\n\nThe progestogen component of HRT may also influence the risk of a DVT, which may be greater with androgenic synthetic progestogens than natural progesterone (but findings from observational studies need confirmation). Most women in the UK take oral HRT comprising oestrogen combined with a synthetic progestogen, and the use of progesterone is less common.\n\nRandomised controlled trials are needed to compare oral with transdermal HRT, and HRT containing different types of progestogens. These trials should measure coagulation factors and the incidence of VTE in women at increased risk of VTE for whom transdermal oestrogen is indicated.\n\n# Effects of HRT on dementia risk\n\nWhat are the effects of early HRT use on the risk of dementia?\n\nWhy this is important\n\nConcern about the prospect of dementia in older age is increasing and any beneficial effect on the future risk of dementia will be important to women who are considering using HRT. There is a need for good-quality observational studies controlling for the effect of important confounders on how early HRT use affects dementia risk in women with early natural menopause, including women with premature ovarian insufficiency.\n\n# Premature ovarian insufficiency\n\nWhat are the main clinical manifestations of premature ovarian insufficiency and the short- and long-term impact of the most common therapeutic interventions?\n\nWhy this is important\n\nWomen with premature ovarian insufficiency can experience the effects of menopause for most of their adult life. This can lead to reduced quality of life and an increased risk of osteoporosis, cardiovascular disease and possibly dementia. There is uncertainty about the diagnosis, time course and management of premature ovarian insufficiency. For example, it is possible that different interventions produce different outcomes in terms of quality of life, and bone, cardiovascular and brain protection. Combined oral contraceptives are often prescribed when this might not be the best treatment in terms of quality of life and preservation of bone density and cardiovascular health. Short- and long-term outcomes of HRT versus combined hormonal contraceptives in women with premature ovarian insufficiency therefore need to be investigated.\n\nDevelopment of a collaborative premature ovarian insufficiency registry would allow the collection of high-quality demographic, biobank (genomic) and clinical data in order to clarify:\n\nthe diagnosis and presentation of premature ovarian insufficiency\n\nthe impact of therapeutic interventions such as combined hormonal contraceptives, HRT and androgens\n\nthe long-term impact of premature ovarian insufficiency on bone density and fracture, and cardiovascular and cognitive health\n\nthe long-term risk of cancer, which can be determined by linking with relevant cancer and mortality registries.', 'Finding more information and resources': "You can see everything NICE says on menopause in the NICE Pathway on menopause.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on gynaecological conditions.\n\nFor full details of the evidence and the guideline committee's discussions, see the full version. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}
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https://www.nice.org.uk/guidance/ng23
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This guideline covers the diagnosis and management of menopause, including in women who have premature ovarian insufficiency. The guideline aims to improve the consistency of support and information provided to women in menopause.
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0c3e0fc3a6fa462b34b4747f2ee2171774bf4988
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nice
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gammaCore for cluster headache
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gammaCore for cluster headache
Evidence-based recommendations on gammaCore for cluster headache.
# Recommendations
Evidence supports the case for adopting gammaCore to treat cluster headache in the NHS. gammaCore reduces the frequency and intensity of cluster headache attacks and improves quality of life.
gammaCore is not effective in everyone with cluster headache. Treatment with gammaCore should only continue for people whose symptoms reduce in the first 3 months.
Cost modelling estimates that, in the first year of treatment, adding gammaCore to standard care is cost saving compared with standard care alone by an average of £450 per person. This cost saving:
assumes that the first 3‑month period of gammaCore use is offered by the company free of charge
largely results from less use of subcutaneous sumatriptan.
Why the committee made these recommendations
gammaCore is a non-invasive vagus nerve stimulator that can be used to treat cluster headaches. Existing medications for cluster headaches are often only partially effective and may cause serious side effects.
Clinical evidence shows that, for some people, using gammaCore as well as standard care reduces the frequency and intensity of cluster headache attacks and reduces the need for medication. This is likely to lead to significant quality of life benefits for people living with this condition.
Cost analysis suggests that using gammaCore may lead to cost savings because people use medication less. But this depends on a free 3‑month period to identify people who benefit.# The technology
# Technology
gammaCore (electroCore) is a non-invasive vagus nerve stimulator used to treat and prevent cluster headaches. It is self-administered by the person or their carer. After applying conductive gel, gammaCore is held against the neck (over the cervical branch of the vagus nerve) and delivers a small electric current for about 2 minutes. This stimulation should be repeated 3 times. The device is small and portable. gammaCore requires RFID (radio frequency identification) card activation which is renewed every 3 months (93 days). The RFID card activation allows gammaCore to deliver a maximum of 30 stimulations in each 24‑hour period. Conductive gel is provided with each new RFID card. Additional gel can be provided at no extra cost.
# Innovative aspects
gammaCore is currently the only technology that uses non-invasive stimulation of the vagus nerve to treat cluster headache.
# Intended use
The instructions for using gammaCore state that it should be used regularly throughout the day to prevent cluster headache attacks and acutely to reduce pain during an attack. gammaCore is intended to be self-administered, or treatment can be administered by a carer. Using gammaCore requires brief training and some manual dexterity. Training for patients and staff is provided by the company for free. gammaCore should not be used by people with an active implantable medical device, people with heart disease, during pregnancy or in children.
# Costs
gammaCore is provided free of charge for the first 3 months (93 days). Subsequent treatment costs £625 for 93 days (excluding VAT).For more details, see the website for gammaCore.# Evidence
# Clinical evidence
## The clinical evidence comprises 8 published studies
The published studies comprise:
randomised trials: 2 sham-controlled (ACT1, Silberstein et al. 2016, and ACT2, Goadsby et al. 2018) and 1 open label (PREVA, Gaul et al. 2016)
post-hoc analysis of a randomised trial (Gaul et al. 2017)
a pooled analysis of 2 randomised trials (de Coo, 2019)
non-comparative cohort studies (Nesbitt et al. 2015, Marin et al. 2018, and Trimboli et al. 2018). The evidence includes 410 patients with cluster headache. For full details of the clinical evidence, see section 3 of the assessment report.
## The evidence includes the preventative and acute use of gammaCore and treatment refractory cluster headache
gammaCore was used in different ways in the studies. In the ACT1 and ACT2 studies, gammaCore was used as an acute treatment only. In all the other studies, gammaCore was used as a preventative and an acute treatment. Two cohort studies (Marin et al. 2018 and Trimboli et al. 2018) reported on gammaCore used for people classified as refractory to 1 or more standard treatments for cluster headache. In all other studies gammaCore was used in addition to standard of care treatments.
## The studies show that gammaCore can reduce the frequency of cluster headache attacks and the intensity of pain during an attack
The evidence for gammaCore comprises a small number of studies which include comparative, non-comparative and observational studies. The external assessment centre (EAC) noted, however, that large randomised trials are not likely to be possible given the very low prevalence of cluster headaches. All but one of the studies was sponsored by the company. The studies had short follow-up times so there is no evidence for the long-term benefits of using gammaCore. The trials showed that some but not all people benefit from using gammaCore. When gammaCore was used preventatively, it reduced the frequency of cluster headache attacks (Gaul et al. 2016). When gammaCore was used acutely it reduced the intensity of attacks (ACT1 and ACT2). Using gammaCore improved measures of quality of life (Gaul et al. 2016).
## The degree of clinical benefit is uncertain
In the 2 sham-controlled trials (ACT1 and ACT2), gammaCore worked better as an acute treatment for people with episodic cluster headache than for people with chronic cluster headache. The EAC noted, however, that these studies were not powered to allow such sub-group analysis. The EAC concluded that the published evidence suggests that people with cluster headache may benefit from using gammaCore (either preventatively or acutely) although the degree of benefit is uncertain.
## Adverse events are mild to moderate
The reported adverse events were mild to moderate in all studies. No-one stopped using gammaCore because of adverse events. The clinical experts told the EAC that gammaCore is safe and easy to use and that there was no need for safety monitoring. The EAC concluded that there is enough evidence that gammaCore does not cause any serious device-related adverse events in people with cluster headache. For full details of the adverse events, see section 4.8 about adverse effects.
# Cost evidence
## The cost evidence comprises 3 published studies
There were 3 published studies: Morris et al. 2016 used data from the PREVA trial, Mwamburi et al. 2017 used data from ACT 1 and ACT 2 and Pietzsch et al. 2015 used data from a randomised, sham-controlled study (Schoenen et al. 2013).
## The company says using gammaCore saves £450 per person in the first year
The company created a de novo cost analysis using a Markov model with a 1‑month cycle and 1‑year time horizon. The model only considered people with chronic cluster headache and did not include anyone with episodic cluster headache. The model considered gammaCore in addition to standard care acute treatments (oxygen, zolmitriptan and sumatriptan). Preventative medication (for example, verapamil) was not included in the model because it was assumed to be the same in both treatment arms. Data from the PREVA trial was used in the model to estimate the proportion of people whose cluster headaches responded to treatment with gammaCore; this study defined a treatment response as cluster headache frequency reduced by 50% or more. For full details of the cost evidence, see section 4 of the assessment report.
The company's model, which was unchanged by the EAC, reported that using gammaCore in addition to standard care would lead to cost savings of £450 per patient in the first year.
## Cost savings depend on a free 3‑month initial period and reduced sumatriptan use
In the model gammaCore is free for the first 3 months, and it assumes that only people whose condition responds to treatment with gammaCore continue to use it. This is called a trial; however, this refers to the user trialling the technology for 3 months and does not mean that people using gammaCore will be automatically enrolled in a clinical trial. The model included less acute medication use by people in the gammaCore responder arm, based on data from the PREVA trial. The EAC's sensitivity analyses showed that the cost savings associated with gammaCore depend on the initial 3‑month period being free of charge and less sumatriptan use in the gammaCore responder arm.
## The cost analysis has limitations because of lack of evidence
The model does not include costs for:
inpatient, outpatient or primary care
psychological support
invasive surgical procedures such as implanted sphenopalatine nerve stimulators
unlicensed medications used for treatment refractory cluster headaches, which might be avoided if gammaCore treatment is successful. These costs could not be included in the model for gammaCore because there is no evidence to base assumptions on. The EAC noted that gammaCore is likely to lead to a reduced need for care resources, and their associated costs, because people who it is effective for will have fewer, less severe cluster headaches. The EAC also noted that the data underpinning the economic model is part of a single small data set and post-hoc analysis that was only partially based in the UK. However it did not identify any other data that could be used to improve the analysis.# Committee discussion
# Clinical-effectiveness overview
## gammaCore is effective in some people
The evidence base for gammaCore is small. But cluster headache is a rare condition, and the quality of the studies was good. The committee concluded that gammaCore appears to be effective in some but not all people. In people whose condition responds, it can make a significant difference to their symptoms and quality of life. The clinical experts said that, in their experience, 25% to 50% of people have cluster headaches that respond to gammaCore.
## Cluster headache significantly worsens day to day life
The published evidence of efficacy was supported by evidence from people with cluster headache that was submitted to the committee. Sixty people with cluster headache were surveyed. They described the impact of the condition on their lives, and how it responded to gammaCore. Two patient organisations also submitted reports. The committee understood the devastating impact that this condition can have on the lives of sufferers and the desperation that can result from ineffective treatment. For example, the submission from OUCH (Organization for the Understanding of Cluster Headache) reported that on average 5 people a year in the UK end their lives because they are no longer able to live with the pain of cluster headaches. The committee noted the life-changing effects that gammaCore had had for many people in the survey.
## Vagus nerve stimulation with gammaCore could plausibly reduce pain in people with cluster headache
gammaCore is the only device available that treats cluster headache by non-invasive vagus nerve stimulation. The clinical experts described the results of studies that supported the mechanism of action of gammaCore. They explained that, patho-physiologically, vagus nerve stimulation could plausibly reduce pain in people with cluster headache. The clinical experts also explained that, while a placebo effect is likely in all treatments for chronic pain conditions, it is unlikely that the benefits of gammaCore can be explained by this alone. They said that gammaCore's response rate is higher and its therapeutic benefits more sustained than would be expected for a placebo treatment. The committee was also convinced by the experts' argument that people with such a debilitating condition welcome a treatment response regardless of its mode of action as long as it is safe and has no adverse effects.
## The free initial 3-month period means gammaCore is worth trying if there is a possibility it can reduce attacks and medication
Although the evidence for gammaCore is subject to some uncertainty, the committee noted that gammaCore would only be used in people who find it effective after the first 3 months of treatment. Cluster headache attacks have a profound negative impact on everyday life so any treatment that can help reduce this is worth trying. The committee also noted that gammaCore, as a non-drug treatment, is unlikely to interact with any other treatments and may help reduce the number of drugs that are prescribed to this patient group.
## A doctor should decide if treatment with gammaCore has been successful after 3 months, after consulting the patient
The clinical experts stated that the definitions of a successful response to 3 months of treatment with gammaCore vary and are subjective. This was also the case in the published evidence. However, they explained that it's usually clear within 3 months if someone's cluster headaches have reduced meaningfully in frequency and severity, leading to reduced medication use that justifies continuing treatment with gammaCore. The clinical experts said that people do not generally want to continue with treatments if they're not helping. The committee concluded that the decision about whether or not to continue with gammaCore after the first 3 months of treatment should be made by a doctor after consulting the patient.
## There is enough evidence of clinical benefit for people with chronic and episodic cluster headache to recommend gammaCore for both groups
The experts explained the different patterns of symptoms that people with cluster headaches have. There is a difference in particular between people with chronic and episodic cluster headache. They also explained that some people with episodic cluster headache later become chronic sufferers and vice versa. But the natural history of the condition is unpredictable. This means it's uncertain how the condition is likely to respond to an intervention. The sham-controlled randomised clinical trials (ACT1 and ACT2) were not powered to examine therapeutic benefits separately in episodic and chronic cluster headache, and they only considered acute use of gammaCore. But people with episodic cluster headache had particular benefit. In the open-label randomised controlled trial (PREVA), people with chronic cluster headache had clinical benefit. The patient survey included responses from 12 people with episodic cluster headaches, and 9 of them said they had received substantial clinical benefits from gammaCore. The clinical experts said they most often use gammaCore for people with chronic cluster headache. They said that treatment effects were more difficult to measure in episodic cluster headache. The committee concluded that overall there was enough evidence of clinical benefit for people with chronic and episodic cluster headache to recommend adopting gammaCore if treatment is successful in the first 3 months. It said it could not reliably make a therapeutic distinction between the 2 based on current evidence.
## People using gammaCore should have regular follow ups at specialist headache centres
The clinical experts said that clinical follow up of people is essential because response to treatment with gammaCore is unpredictable. People should be reassessed after the first 3 months of treatment to review attack frequency and intensity, and use of treatments to stop acute attacks (oxygen, sumatriptan, zolmitriptan). The experts advised that only people whose cluster headaches respond to treatment with gammaCore should carry on using it. The experts recommended follow up again at 12 months and every year afterwards to determine long-term benefits and to give an opportunity to stop gammaCore if it's no longer effective.
# Adverse events
## gammaCore is a non-pharmacological treatment that has no serious side effects
There are no published reports of serious adverse events with gammaCore. The experts and manufacturer representative said none had been reported to them. The patient survey confirmed that the device is well tolerated and easy to use. People with cluster headache risk side effects from conventional pharmacological treatment. Sometimes they need invasive treatment such as implanted stimulators. gammaCore could help some people avoid or delay the need for these treatments. The safety and efficacy of using gammaCore has not been evaluated in people with an implanted medical device, people with heart conditions, people who are pregnant, lactating or aged under 18 years.
# NHS considerations overview
## gammaCore should be offered in addition to standard care
The clinical experts described their experience of using gammaCore in their NHS practice. They reported that it was usually used as a second or third-line treatment option to prevent chronic cluster headache attacks after verapamil, and possibly lithium, had been tried. They also explained that verapamil and lithium can have adverse effects, they need careful monitoring, and they may be contraindicated in some people. The experts said that if people benefit therapeutically from gammaCore – and around 25% to 50% do – they usually carry on benefiting from it. They said that some of their patients have been using the technology for 3 years or more. It has been difficult for clinical services to get funding for gammaCore. The experts explained that they get it through individual patient funding requests to commissioners.
## Training is simple
People are trained to use gammaCore by specialist headache nurses. The manufacturer provides training resources free of charge. The clinical experts explained that training was simple, and that most people were able to learn how to use the device in one session. The manufacturer representative explained that if someone cannot use the device themselves because they have problems with manual dexterity, someone else can give treatment.
# Cost modelling overview
## There are limitations in the cost model but there are cost savings linked to clinical benefits
The company's cost model showed a potential £450 saving per patient over 1 year if gammaCore is used with standard treatment in people with chronic cluster headache. It noted that the cost savings were largely from a reduced need for sumatriptan to stop the symptoms of acute attacks. It also noted that they depended on the first 3 months of treatment being free of charge.
## gammaCore may reduce the need for medications and invasive procedures
The data used in the cost modelling was from one open-label randomised controlled trial (PREVA) that included patients from the UK. The committee discussed uncertainties in the cost modelling but acknowledged that they cannot be resolved by the available evidence. For example, the impact of gammaCore on other outpatient, community or inpatient services – such as occipital nerve blocks, intravenous dihydroergotamine or implanted nerve stimulators – is unclear. Reduced cluster headache symptoms could mean other treatments or care could be reduced or stopped. But with no evidence to support this, it could not be considered in the cost modelling.
## The study definition of a successful response to gammaCore may differ from a clinically meaningful response
The trial used to inform the cost model classified a successful response to gammaCore as cluster headache frequency reduced by 50% or more. The experts explained that, in clinical practice, several treatments may be needed to reduce cluster headache attacks to this degree. The clinical experts also advised that people classified as non-responders on this basis may still receive clinically meaningful benefits from gammaCore that would not be captured in the cost modelling.
# Main cost drivers
## The free 3-month initial period is a key driver of cost savings
gammaCore is offered for a free 3‑month initial period. The external assessment centre (EAC) identified this as a key driver of the cost savings. The company representatives assured the committee that the free period is a fixed part of its business model which would not change. They also clarified that there are no extra costs for conductive gel, training resources, or replacing the gammaCore device if it is broken, lost or stops working. The committee concluded that the technology costs used in the model are accurate.
## Cost savings also depend on reduced subcutaneous sumatriptan use
The experts explained to the committee the importance of the treatments that people use to stop the symptoms of an acute attack of cluster headache. These include inhaled oxygen, sumatriptan and zolmitriptan. The committee considered it plausible that, if gammaCore reduces the frequency and severity of attacks, then medication use is also likely to reduce. More than half the people in the patient survey had reduced their medication use since starting treatment with gammaCore. Reduced sumatriptan use was another key driver of the cost savings for gammaCore in the model. The committee concluded that the clinical evidence would support this.
# Cost savings
## Cost modelling for gammaCore has limitations but cost savings are likely if it is only used by people who it is effective for
The committee accepted the EAC's rationale for not changing the model because there was no relevant additional evidence. The model had a 1‑year time horizon because this was the duration of the relevant study. The annual cost of gammaCore treatment increases after the first year because the free period no longer applies. But the committee considered that this could continue to be offset by savings from reduced medications used to stop the pain of an attack, as well as reduced or avoided care or treatments not captured in the cost modelling. The committee noted that it was important that only people who benefited clinically from gammaCore should use it. People who do not benefit should stop treatment with it to avoid incurring additional costs. Overall, the committee concluded that the model's cost saving of £450 per patient in the first year is plausible.
# Further research
## Further research will help reduce uncertainty and should include long-term outcomes data
Further evidence to address the uncertainties in the current clinical evidence, including the impact of gammaCore on all treatments and care as well as its long-term benefits, would be welcome.
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{'Recommendations': 'Evidence supports the case for adopting gammaCore to treat cluster headache in the NHS. gammaCore reduces the frequency and intensity of cluster headache attacks and improves quality of life.\n\ngammaCore is not effective in everyone with cluster headache. Treatment with gammaCore should only continue for people whose symptoms reduce in the first 3\xa0months.\n\nCost modelling estimates that, in the first year of treatment, adding gammaCore to standard care is cost saving compared with standard care alone by an average of £450 per person. This cost saving:\n\nassumes that the first 3‑month period of gammaCore use is offered by the company free of charge\n\nlargely results from less use of subcutaneous sumatriptan.\n\nWhy the committee made these recommendations\n\ngammaCore is a non-invasive vagus nerve stimulator that can be used to treat cluster headaches. Existing medications for cluster headaches are often only partially effective and may cause serious side effects.\n\nClinical evidence shows that, for some people, using gammaCore as well as standard care reduces the frequency and intensity of cluster headache attacks and reduces the need for medication. This is likely to lead to significant quality of life benefits for people living with this condition.\n\nCost analysis suggests that using gammaCore may lead to cost savings because people use medication less. But this depends on a free 3‑month period to identify people who benefit.', 'The technology': '# Technology\n\ngammaCore (electroCore) is a non-invasive vagus nerve stimulator used to treat and prevent cluster headaches. It is self-administered by the person or their carer. After applying conductive gel, gammaCore is held against the neck (over the cervical branch of the vagus nerve) and delivers a small electric current for about 2\xa0minutes. This stimulation should be repeated 3\xa0times. The device is small and portable. gammaCore requires RFID (radio frequency identification) card activation which is renewed every 3\xa0months (93\xa0days). The RFID card activation allows gammaCore to deliver a maximum of 30\xa0stimulations in each 24‑hour period. Conductive gel is provided with each new RFID card. Additional gel can be provided at no extra cost.\n\n# Innovative aspects\n\ngammaCore is currently the only technology that uses non-invasive stimulation of the vagus nerve to treat cluster headache.\n\n# Intended use\n\nThe instructions for using gammaCore state that it should be used regularly throughout the day to prevent cluster headache attacks and acutely to reduce pain during an attack. gammaCore is intended to be self-administered, or treatment can be administered by a carer. Using gammaCore requires brief training and some manual dexterity. Training for patients and staff is provided by the company for free. gammaCore should not be used by people with an active implantable medical device, people with heart disease, during pregnancy or in children.\n\n# Costs\n\ngammaCore is provided free of charge for the first 3\xa0months (93\xa0days). Subsequent treatment costs £625 for 93\xa0days (excluding VAT).For more details, see the website for gammaCore.', 'Evidence': "# Clinical evidence\n\n## The clinical evidence comprises 8\xa0published studies\n\nThe published studies comprise:\n\nrandomised trials: 2\xa0sham-controlled (ACT1, Silberstein et al. 2016, and ACT2, Goadsby et al. 2018) and 1\xa0open label (PREVA, Gaul et al. 2016)\n\npost-hoc analysis of a randomised trial (Gaul et al. 2017)\n\na pooled analysis of 2\xa0randomised trials (de\xa0Coo, 2019)\n\nnon-comparative cohort studies (Nesbitt et al. 2015, Marin et al. 2018, and Trimboli et al. 2018). The evidence includes 410\xa0patients with cluster headache. For full details of the clinical evidence, see section\xa03 of the assessment report.\n\n## The evidence includes the preventative and acute use of gammaCore and treatment refractory cluster headache\n\ngammaCore was used in different ways in the studies. In the ACT1 and ACT2 studies, gammaCore was used as an acute treatment only. In all the other studies, gammaCore was used as a preventative and an acute treatment. Two cohort studies (Marin et al. 2018 and Trimboli et al. 2018) reported on gammaCore used for people classified as refractory to 1 or more standard treatments for cluster headache. In all other studies gammaCore was used in addition to standard of care treatments.\n\n## The studies show that gammaCore can reduce the frequency of cluster headache attacks and the intensity of pain during an attack\n\nThe evidence for gammaCore comprises a small number of studies which include comparative, non-comparative and observational studies. The external assessment centre (EAC) noted, however, that large randomised trials are not likely to be possible given the very low prevalence of cluster headaches. All but one of the studies was sponsored by the company. The studies had short follow-up times so there is no evidence for the long-term benefits of using gammaCore. The trials showed that some but not all people benefit from using gammaCore. When gammaCore was used preventatively, it reduced the frequency of cluster headache attacks (Gaul et al. 2016). When gammaCore was used acutely it reduced the intensity of attacks (ACT1 and ACT2). Using gammaCore improved measures of quality of life (Gaul et al. 2016).\n\n## The degree of clinical benefit is uncertain\n\nIn the 2\xa0sham-controlled trials (ACT1 and ACT2), gammaCore worked better as an acute treatment for people with episodic cluster headache than for people with chronic cluster headache. The EAC noted, however, that these studies were not powered to allow such sub-group analysis. The EAC concluded that the published evidence suggests that people with cluster headache may benefit from using gammaCore (either preventatively or acutely) although the degree of benefit is uncertain.\n\n## Adverse events are mild to moderate\n\nThe reported adverse events were mild to moderate in all studies. No-one stopped using gammaCore because of adverse events. The clinical experts told the EAC that gammaCore is safe and easy to use and that there was no need for safety monitoring. The EAC concluded that there is enough evidence that gammaCore does not cause any serious device-related adverse events in people with cluster headache. For full details of the adverse events, see section\xa04.8 about adverse effects.\n\n# Cost evidence\n\n## The cost evidence comprises 3 published studies\n\nThere were 3 published studies: Morris et al. 2016 used data from the PREVA trial, Mwamburi et al. 2017 used data from ACT 1 and ACT 2 and Pietzsch et al. 2015 used data from a randomised, sham-controlled study (Schoenen et al. 2013).\n\n## The company says using gammaCore saves £450 per person in the first year\n\nThe company created a de novo cost analysis using a Markov model with a 1‑month cycle and 1‑year time horizon. The model only considered people with chronic cluster headache and did not include anyone with episodic cluster headache. The model considered gammaCore in addition to standard care acute treatments (oxygen, zolmitriptan and sumatriptan). Preventative medication (for example, verapamil) was not included in the model because it was assumed to be the same in both treatment arms. Data from the PREVA trial was used in the model to estimate the proportion of people whose cluster headaches responded to treatment with gammaCore; this study defined a treatment response as cluster headache frequency reduced by 50% or more. For full details of the cost evidence, see section\xa04 of the assessment report.\n\nThe company's model, which was unchanged by the EAC, reported that using gammaCore in addition to standard care would lead to cost savings of £450 per patient in the first year.\n\n## Cost savings depend on a free 3‑month initial period and reduced sumatriptan use\n\nIn the model gammaCore is free for the first 3\xa0months, and it assumes that only people whose condition responds to treatment with gammaCore continue to use it. This is called a trial; however, this refers to the user trialling the technology for 3\xa0months and does not mean that people using gammaCore will be automatically enrolled in a clinical trial. The model included less acute medication use by people in the gammaCore responder arm, based on data from the PREVA trial. The EAC's sensitivity analyses showed that the cost savings associated with gammaCore depend on the initial 3‑month period being free of charge and less sumatriptan use in the gammaCore responder arm.\n\n## The cost analysis has limitations because of lack of evidence\n\nThe model does not include costs for:\n\ninpatient, outpatient or primary care\n\npsychological support\n\ninvasive surgical procedures such as implanted sphenopalatine nerve stimulators\n\nunlicensed medications used for treatment refractory cluster headaches, which might be avoided if gammaCore treatment is successful. These costs could not be included in the model for gammaCore because there is no evidence to base assumptions on. The EAC noted that gammaCore is likely to lead to a reduced need for care resources, and their associated costs, because people who it is effective for will have fewer, less severe cluster headaches. The EAC also noted that the data underpinning the economic model is part of a single small data set and post-hoc analysis that was only partially based in the UK. However it did not identify any other data that could be used to improve the analysis.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## gammaCore is effective in some people\n\nThe evidence base for gammaCore is small. But cluster headache is a rare condition, and the quality of the studies was good. The committee concluded that gammaCore appears to be effective in some but not all people. In people whose condition responds, it can make a significant difference to their symptoms and quality of life. The clinical experts said that, in their experience, 25% to 50% of people have cluster headaches that respond to gammaCore.\n\n## Cluster headache significantly worsens day to day life\n\nThe published evidence of efficacy was supported by evidence from people with cluster headache that was submitted to the committee. Sixty people with cluster headache were surveyed. They described the impact of the condition on their lives, and how it responded to gammaCore. Two patient organisations also submitted reports. The committee understood the devastating impact that this condition can have on the lives of sufferers and the desperation that can result from ineffective treatment. For example, the submission from OUCH (Organization for the Understanding of Cluster Headache) reported that on average 5\xa0people a year in the UK end their lives because they are no longer able to live with the pain of cluster headaches. The committee noted the life-changing effects that gammaCore had had for many people in the survey.\n\n## Vagus nerve stimulation with gammaCore could plausibly reduce pain in people with cluster headache\n\ngammaCore is the only device available that treats cluster headache by non-invasive vagus nerve stimulation. The clinical experts described the results of studies that supported the mechanism of action of gammaCore. They explained that, patho-physiologically, vagus nerve stimulation could plausibly reduce pain in people with cluster headache. The clinical experts also explained that, while a placebo effect is likely in all treatments for chronic pain conditions, it is unlikely that the benefits of gammaCore can be explained by this alone. They said that gammaCore's response rate is higher and its therapeutic benefits more sustained than would be expected for a placebo treatment. The committee was also convinced by the experts' argument that people with such a debilitating condition welcome a treatment response regardless of its mode of action as long as it is safe and has no adverse effects.\n\n## The free initial 3-month period means gammaCore is worth trying if there is a possibility it can reduce attacks and medication\n\nAlthough the evidence for gammaCore is subject to some uncertainty, the committee noted that gammaCore would only be used in people who find it effective after the first 3\xa0months of treatment. Cluster headache attacks have a profound negative impact on everyday life so any treatment that can help reduce this is worth trying. The committee also noted that gammaCore, as a non-drug treatment, is unlikely to interact with any other treatments and may help reduce the number of drugs that are prescribed to this patient group.\n\n## A doctor should decide if treatment with gammaCore has been successful after 3\xa0months, after consulting the patient\n\nThe clinical experts stated that the definitions of a successful response to 3\xa0months of treatment with gammaCore vary and are subjective. This was also the case in the published evidence. However, they explained that it's usually clear within 3\xa0months if someone's cluster headaches have reduced meaningfully in frequency and severity, leading to reduced medication use that justifies continuing treatment with gammaCore. The clinical experts said that people do not generally want to continue with treatments if they're not helping. The committee concluded that the decision about whether or not to continue with gammaCore after the first 3\xa0months of treatment should be made by a doctor after consulting the patient.\n\n## There is enough evidence of clinical benefit for people with chronic and episodic cluster headache to recommend gammaCore for both groups\n\nThe experts explained the different patterns of symptoms that people with cluster headaches have. There is a difference in particular between people with chronic and episodic cluster headache. They also explained that some people with episodic cluster headache later become chronic sufferers and vice versa. But the natural history of the condition is unpredictable. This means it's uncertain how the condition is likely to respond to an intervention. The sham-controlled randomised clinical trials (ACT1 and ACT2) were not powered to examine therapeutic benefits separately in episodic and chronic cluster headache, and they only considered acute use of gammaCore. But people with episodic cluster headache had particular benefit. In the open-label randomised controlled trial (PREVA), people with chronic cluster headache had clinical benefit. The patient survey included responses from 12\xa0people with episodic cluster headaches, and 9 of them said they had received substantial clinical benefits from gammaCore. The clinical experts said they most often use gammaCore for people with chronic cluster headache. They said that treatment effects were more difficult to measure in episodic cluster headache. The committee concluded that overall there was enough evidence of clinical benefit for people with chronic and episodic cluster headache to recommend adopting gammaCore if treatment is successful in the first 3\xa0months. It said it could not reliably make a therapeutic distinction between the 2 based on current evidence.\n\n## People using gammaCore should have regular follow ups at specialist headache centres\n\nThe clinical experts said that clinical follow up of people is essential because response to treatment with gammaCore is unpredictable. People should be reassessed after the first 3\xa0months of treatment to review attack frequency and intensity, and use of treatments to stop acute attacks (oxygen, sumatriptan, zolmitriptan). The experts advised that only people whose cluster headaches respond to treatment with gammaCore should carry on using it. The experts recommended follow up again at 12\xa0months and every year afterwards to determine long-term benefits and to give an opportunity to stop gammaCore if it's no longer effective.\n\n# Adverse events\n\n## gammaCore is a non-pharmacological treatment that has no serious side effects\n\nThere are no published reports of serious adverse events with gammaCore. The experts and manufacturer representative said none had been reported to them. The patient survey confirmed that the device is well tolerated and easy to use. People with cluster headache risk side effects from conventional pharmacological treatment. Sometimes they need invasive treatment such as implanted stimulators. gammaCore could help some people avoid or delay the need for these treatments. The safety and efficacy of using gammaCore has not been evaluated in people with an implanted medical device, people with heart conditions, people who are pregnant, lactating or aged under 18\xa0years.\n\n# NHS considerations overview\n\n## gammaCore should be offered in addition to standard care\n\nThe clinical experts described their experience of using gammaCore in their NHS practice. They reported that it was usually used as a second or third-line treatment option to prevent chronic cluster headache attacks after verapamil, and possibly lithium, had been tried. They also explained that verapamil and lithium can have adverse effects, they need careful monitoring, and they may be contraindicated in some people. The experts said that if people benefit therapeutically from gammaCore – and around 25% to 50% do – they usually carry on benefiting from it. They said that some of their patients have been using the technology for 3\xa0years or more. It has been difficult for clinical services to get funding for gammaCore. The experts explained that they get it through individual patient funding requests to commissioners.\n\n## Training is simple\n\nPeople are trained to use gammaCore by specialist headache nurses. The manufacturer provides training resources free of charge. The clinical experts explained that training was simple, and that most people were able to learn how to use the device in one session. The manufacturer representative explained that if someone cannot use the device themselves because they have problems with manual dexterity, someone else can give treatment.\n\n# Cost modelling overview\n\n## There are limitations in the cost model but there are cost savings linked to clinical benefits\n\nThe company's cost model showed a potential £450 saving per patient over 1\xa0year if gammaCore is used with standard treatment in people with chronic cluster headache. It noted that the cost savings were largely from a reduced need for sumatriptan to stop the symptoms of acute attacks. It also noted that they depended on the first 3\xa0months of treatment being free of charge.\n\n## gammaCore may reduce the need for medications and invasive procedures\n\nThe data used in the cost modelling was from one open-label randomised controlled trial (PREVA) that included patients from the UK. The committee discussed uncertainties in the cost modelling but acknowledged that they cannot be resolved by the available evidence. For example, the impact of gammaCore on other outpatient, community or inpatient services – such as occipital nerve blocks, intravenous dihydroergotamine or implanted nerve stimulators – is unclear. Reduced cluster headache symptoms could mean other treatments or care could be reduced or stopped. But with no evidence to support this, it could not be considered in the cost modelling.\n\n## The study definition of a successful response to gammaCore may differ from a clinically meaningful response\n\nThe trial used to inform the cost model classified a successful response to gammaCore as cluster headache frequency reduced by 50% or more. The experts explained that, in clinical practice, several treatments may be needed to reduce cluster headache attacks to this degree. The clinical experts also advised that people classified as non-responders on this basis may still receive clinically meaningful benefits from gammaCore that would not be captured in the cost modelling.\n\n# Main cost drivers\n\n## The free 3-month initial period is a key driver of cost savings\n\ngammaCore is offered for a free 3‑month initial period. The external assessment centre (EAC) identified this as a key driver of the cost savings. The company representatives assured the committee that the free period is a fixed part of its business model which would not change. They also clarified that there are no extra costs for conductive gel, training resources, or replacing the gammaCore device if it is broken, lost or stops working. The committee concluded that the technology costs used in the model are accurate.\n\n## Cost savings also depend on reduced subcutaneous sumatriptan use\n\nThe experts explained to the committee the importance of the treatments that people use to stop the symptoms of an acute attack of cluster headache. These include inhaled oxygen, sumatriptan and zolmitriptan. The committee considered it plausible that, if gammaCore reduces the frequency and severity of attacks, then medication use is also likely to reduce. More than half the people in the patient survey had reduced their medication use since starting treatment with gammaCore. Reduced sumatriptan use was another key driver of the cost savings for gammaCore in the model. The committee concluded that the clinical evidence would support this.\n\n# Cost savings\n\n## Cost modelling for gammaCore has limitations but cost savings are likely if it is only used by people who it is effective for\n\nThe committee accepted the EAC's rationale for not changing the model because there was no relevant additional evidence. The model had a 1‑year time horizon because this was the duration of the relevant study. The annual cost of gammaCore treatment increases after the first year because the free period no longer applies. But the committee considered that this could continue to be offset by savings from reduced medications used to stop the pain of an attack, as well as reduced or avoided care or treatments not captured in the cost modelling. The committee noted that it was important that only people who benefited clinically from gammaCore should use it. People who do not benefit should stop treatment with it to avoid incurring additional costs. Overall, the committee concluded that the model's cost saving of £450 per patient in the first year is plausible.\n\n# Further research\n\n## Further research will help reduce uncertainty and should include long-term outcomes data\n\nFurther evidence to address the uncertainties in the current clinical evidence, including the impact of gammaCore on all treatments and care as well as its long-term benefits, would be welcome."}
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https://www.nice.org.uk/guidance/mtg46
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Evidence-based recommendations on gammaCore for cluster headache.
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6b48c227cdfa5eab85510b3a8e3d819c304e862b
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nice
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Irreversible electroporation for primary liver cancer
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Irreversible electroporation for primary liver cancer
Evidence-based recommendations on irreversible electroporation for primary liver cancer in adults. This involves passing short electrical pulses of high-voltage current into the cancer cells.
# Recommendations
Evidence on the safety of irreversible electroporation for primary liver cancer shows serious but infrequent and well-recognised complications. Evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Patient selection should be done by a multidisciplinary team.
The procedure should only be done in specialist centres by clinicians with experience and specific training.
Further research could be in the form of case series or registry-based research. It should include: details of patient selection; tumour position and size; long-term outcomes including overall survival, progression-free survival and tumour regression; and patient-reported outcomes including quality of life.# The condition, current treatments and procedure
# The condition
The most common primary liver cancers are hepatocellular carcinoma and cholangiocarcinoma.
# Current treatments
Treatment for primary liver cancer depends on several factors, including the exact location and stage of the cancer, the patient's liver function and any patient-related comorbidities. For most patients, treatment with curative intent is not possible. The treatment options include surgical excision, chemotherapy (either systemic or local hepatic artery infusion), transarterial chemoembolisation, percutaneous ethanol injection, and thermal ablation techniques such as cryotherapy, radiofrequency and microwave ablation. Liver transplantation (with curative intent) may be appropriate for some patients.
# The procedure
The aim of irreversible electroporation (IRE) is to destroy cancerous cells by subjecting them to short pulses of high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell's homeostasis mechanisms and leading to cell death.
IRE for primary liver cancer is done with the patient under general anaesthesia. A neuromuscular blocking agent is used to prevent muscle spasms. Needle-like electrodes are introduced percutaneously into the tumour under imaging guidance (either CT or, less commonly, ultrasound). The distance between the electrodes is confirmed by imaging. This is to ensure that the electrodes are correctly placed parallel to each other, and that enough current flow would be generated to ensure IRE. The procedure may also be done through an open surgical or laparoscopic approach, although the percutaneous route is the most common.
Electrodes are repositioned under imaging guidance to extend the zone of electroporation until the entire tumour and an appropriate margin have been ablated. The number of ablations is determined by the volume of the target tumour. When the ablation procedure is completed, further imaging may be done to confirm the extent of the ablation.
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{'Recommendations': 'Evidence on the safety of irreversible electroporation for primary liver cancer shows serious but infrequent and well-recognised complications. Evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a multidisciplinary team.\n\nThe procedure should only be done in specialist centres by clinicians with experience and specific training.\n\nFurther research could be in the form of case series or registry-based research. It should include: details of patient selection; tumour position and size; long-term outcomes including overall survival, progression-free survival and tumour regression; and patient-reported outcomes including quality of life.', 'The condition, current treatments and procedure': "# The condition\n\nThe most common primary liver cancers are hepatocellular carcinoma and cholangiocarcinoma.\n\n# Current treatments\n\nTreatment for primary liver cancer depends on several factors, including the exact location and stage of the cancer, the patient's liver function and any patient-related comorbidities. For most patients, treatment with curative intent is not possible. The treatment options include surgical excision, chemotherapy (either systemic or local hepatic artery infusion), transarterial chemoembolisation, percutaneous ethanol injection, and thermal ablation techniques such as cryotherapy, radiofrequency and microwave ablation. Liver transplantation (with curative intent) may be appropriate for some patients.\n\n# The procedure\n\nThe aim of irreversible electroporation (IRE) is to destroy cancerous cells by subjecting them to short pulses of high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell's homeostasis mechanisms and leading to cell death.\n\nIRE for primary liver cancer is done with the patient under general anaesthesia. A neuromuscular blocking agent is used to prevent muscle spasms. Needle-like electrodes are introduced percutaneously into the tumour under imaging guidance (either CT or, less commonly, ultrasound). The distance between the electrodes is confirmed by imaging. This is to ensure that the electrodes are correctly placed parallel to each other, and that enough current flow would be generated to ensure IRE. The procedure may also be done through an open surgical or laparoscopic approach, although the percutaneous route is the most common.\n\nElectrodes are repositioned under imaging guidance to extend the zone of electroporation until the entire tumour and an appropriate margin have been ablated. The number of ablations is determined by the volume of the target tumour. When the ablation procedure is completed, further imaging may be done to confirm the extent of the ablation."}
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https://www.nice.org.uk/guidance/ipg664
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Evidence-based recommendations on irreversible electroporation for primary liver cancer in adults. This involves passing short electrical pulses of high-voltage current into the cancer cells.
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8b2dde01db5eca6f0ab43579f0b244c78ecc8a40
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nice
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Diverticular disease: diagnosis and management
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Diverticular disease: diagnosis and management
This guideline covers the diagnosis and management of diverticular disease in people aged 18 years and over. It aims to improve diagnosis and care and help people get timely information and advice, including advice about symptoms and when to seek help.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Diverticulosis
## Management and advice
Tell people with diverticulosis that the condition is asymptomatic and no specific treatments are needed.
Advise people to eat a healthy, balanced diet including whole grains, fruit and vegetables. Tell them that:
there is no need to avoid seeds, nuts, popcorn or fruit skins
if they have constipation and a low-fibre diet, increasing their fibre intake gradually may minimise flatulence and bloating.
Advise people to drink adequate fluid if they are increasing their fibre intake, especially if there is a risk of dehydration.
Consider bulk-forming laxatives for people with constipation.
Tell people about the benefits of exercise, and weight loss if they are overweight or obese, and stopping smoking, in reducing the risk of developing acute diverticulitis and symptomatic disease.
To find out why the committee made the recommendations on diverticulosis management and advice and how they might affect practice, see rationale and impact .
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# Diverticular disease
## Symptoms and signs
Suspect diverticular disease if a person presents with one or both of the following:
intermittent abdominal pain in the left lower quadrant with constipation, diarrhoea or occasional large rectal bleeds (the pain may be triggered by eating and relieved by the passage of stool or flatus)
tenderness in the left lower quadrant on abdominal examination.Be aware that:
in a minority of people and in people of Asian origin, pain and tenderness may be localised in the right lower quadrant
symptoms may overlap with conditions such as irritable bowel syndrome, colitis and malignancy.
To find out why the committee made the recommendation on symptoms and signs of diverticular disease and how it might affect practice, see rationale and impact .
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## Investigations and referral
Do not routinely refer people with suspected diverticular disease unless:
routine endoscopic and/or radiological investigations cannot be organised from primary care or
colitis is suspected or
the person meets the criteria for a suspected cancer pathway.
If the person meets the criteria for a suspected cancer pathway, refer by this route (see NICE's guideline on suspected cancer: recognition and referral).
To find out why the committee made the recommendations on investigations and referral for people with suspected diverticular disease and how they might affect practice, see rationale and impact .
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## Management and advice
Do not offer antibiotics to people with diverticular disease.
Advise people to avoid non-steroidal anti-inflammatory drugs and opioid analgesia if possible, because they may increase the risk of diverticular perforation.
For advice on diet, fluid intake, stopping smoking, weight loss and exercise, follow the recommendations in section 1.1 on diverticulosis.
Advise people that:
the benefits of increasing dietary fibre may take several weeks to achieve
if tolerated, a high-fibre diet should be maintained for life.
Consider bulk-forming laxatives if:
a high-fibre diet is unacceptable to the person or it is not tolerated or
the person has persistent constipation or diarrhoea.
Consider simple analgesia, for example paracetamol, as needed if the person has ongoing abdominal pain.
Consider an antispasmodic if the person has abdominal cramping.
If the person has persistent symptoms or symptoms that do not respond to treatment, think about alternative causes and investigate and manage appropriately.
To find out why the committee made the recommendations on management and advice for people with diverticular disease and how they might affect practice, see rationale and impact .
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## Recurrent diverticular disease
The committee were unable to make recommendations for practice in this area.
For a short explanation of why the committee were unable to make recommendations on recurrent diverticular disease see rationale .
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# Acute diverticulitis
## Symptoms and signs of acute diverticulitis
Suspect acute diverticulitis if a person presents with constant abdominal pain, usually severe and localising in the left lower quadrant, with any of the following:
fever or
sudden change in bowel habit and significant rectal bleeding or passage of mucus from the rectum or
tenderness in the left lower quadrant, a palpable abdominal mass or distention on abdominal examination, with a previous history of diverticulosis or diverticulitis. Be aware that in a minority of people and in people of Asian origin, pain and tenderness may be localised in the right lower quadrant.
To find out why the committee made the recommendation on symptoms and signs of acute diverticulitis and how it might affect practice, see rationale and impact .
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## Symptoms and signs of complicated acute diverticulitis
Suspect complicated acute diverticulitis and refer for same-day hospital assessment if the person has uncontrolled abdominal pain and any of the features in table 1.
Symptom or sign
Possible complication
Abdominal mass on examination or peri-rectal fullness on digital rectal examination
Intra-abdominal abscess
Abdominal rigidity and guarding on examination
Bowel perforation and peritonitis
Altered mental state, raised respiratory rate, low systolic blood pressure, raised heart rate, low tympanic temperature, no urine output or skin discolouration
Sepsis (see the NICE guideline on sepsis)
Faecaluria, pneumaturia, pyuria or the passage of faeces through the vagina
Fistula into the bladder or vagina
Colicky abdominal pain, absolute constipation (passage of no flatus or stool), vomiting or abdominal distention
Intestinal obstruction
To find out why the committee made the recommendation on symptoms and signs of complicated acute diverticulitis and how it might affect practice, see rationale and impact .
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## Investigation of suspected acute diverticulitis
For people with suspected uncomplicated acute diverticulitis who are not referred for same-day hospital assessment:
reassess in primary care if their symptoms persist or worsen and
consider referral to secondary care for further assessment.
For people with suspected complicated acute diverticulitis who have been referred for same-day hospital assessment, offer a full blood count, urea and electrolytes test and C‑reactive protein test.
If the person with suspected complicated acute diverticulitis has raised inflammatory markers, offer a contrast CT scan within 24 hours of hospital admission to confirm diagnosis and help plan management. If contrast CT is contraindicated, perform one of the following:
a non-contrast CT or
an MRI or
an ultrasound scan, depending on local expertise.
If inflammatory markers are not raised, think about the possibility of alternative diagnoses.
To find out why the committee made the recommendations on investigation of suspected acute diverticulitis and how they might affect practice, see rationale and impact .
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## Non-surgical management of acute diverticulitis
For people with acute diverticulitis who are systemically well:
consider a no antibiotic prescribing strategy
-ffer simple analgesia, for example paracetamol
advise the person to re‑present if symptoms persist or worsen.
Offer an antibiotic prescribing strategy if the person with acute diverticulitis is systemically unwell, is immunosuppressed or has significant comorbidity.
Offer oral antibiotics if the person with acute diverticulitis is systemically unwell but does not meet the criteria for referral for suspected complicated acute diverticulitis.
Offer intravenous antibiotics to people admitted to secondary care with suspected complicated acute diverticulitis.For guidance on the management of suspected sepsis see the NICE guideline on sepsis.
Review intravenous antibiotics within 48 hours or after scanning if sooner (see recommendation 1.3.5) and consider stepping down to oral antibiotics where possible.
If the person has CT-confirmed uncomplicated acute diverticulitis, review the need for antibiotics and discharge them depending on any co-existing medical conditions.
When prescribing an antibiotic for suspected or confirmed acute diverticulitis, follow the advice in table 2.
Antibiotic
Dosage and course length
First-choice oral antibiotic for suspected or confirmed
uncomplicated acute diverticulitis
Co‑amoxiclav
/125 mg three times a day for 5 days
Alternative first-choice oral antibiotics if penicillin allergy or co‑amoxiclav unsuitable
Cefalexin (caution in penicillin allergy) with metronidazole
Cefalexin: 500 mg twice or three times a day (up to 1 to 1.5 g three or four times a day for severe infection) for 5 days
Metronidazole: 400 mg three times a day for 5 days
Trimethoprim with metronidazole
Trimethoprim: 200 mg twice a day for 5 days
Metronidazole: 400 mg three times a day for 5 days
Ciprofloxacin (only if switching from IV ciprofloxacin with specialist advice; consider safety issues3) with metronidazole
Ciprofloxacin: 500 mg twice a day for 5 days
Metronidazole: 400 mg three times a day for 5 days
First-choice intravenous antibiotics
for suspected or confirmed
complicated acute diverticulitis
Co‑amoxiclav
g three times a day
Cefuroxime with metronidazole
Cefuroxime: 750 mg three or four times a day (increased to 1.5 g three or four times a day if severe infection)
Metronidazole: 500 mg three times a day
Amoxicillin with gentamicin and metronidazole
Amoxicillin: 500 mg three times a day (increased to 1 g four times a day if severe infection)
Gentamicin: Initially 5 to 7 mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration5
Metronidazole: 500 mg three times a day
Ciprofloxacin6 (consider safety issues3) with metronidazole
Ciprofloxacin: 400 mg twice or three times a day
Metronidazole: 500 mg three times a day
Alternative intravenous antibiotics
Consult local microbiologist
See BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.
A longer course may be needed based on clinical assessment. Continue antibiotics for up to 14 days in people with CT‑confirmed diverticular abscess.
See MHRA advice for restrictions and precautions for using fluoroquinolones due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution for people over 60 years and avoiding coadministration with a corticosteroid (March 2019).
Review intravenous antibiotics within 48 hours or after scanning if sooner and consider stepping down to oral antibiotics where possible.
Therapeutic drug monitoring and assessment of renal function is required (BNF, August 2019).
Only in people with allergy to penicillins and cephalosporins.
## Emergency management of complicated acute diverticulitis
When prescribing an antibiotic for suspected or confirmed complicated acute diverticulitis, follow the advice in table 2.
To find out why the committee made the recommendations on the non-surgical management of acute diverticulitis and how they might affect practice, see rationale and impact .
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For people presenting in secondary care with complicated acute diverticulitis and suspected diverticular abscess, assess and manage in line with the NICE guideline on sepsis.
Offer intravenous antibiotics to people with acute diverticulitis and suspected diverticular abscess.
When prescribing an antibiotic for diverticular abscess, follow the advice in table 2.
Offer a contrast CT scan to people with acute diverticulitis and suspected diverticular abscess. If contrast CT is contraindicated, perform one of the following:
a non-contrast CT or
an MRI or
an ultrasound scan, depending on local expertise.
Review intravenous antibiotics within 48 hours or after scanning if sooner and consider stepping down to oral antibiotics where possible.
Use the scan results to guide treatment based on the size and location of the abscess.
If a person does not have confirmed diverticular abscess, review their need for antibiotics.
Consider either percutaneous drainage (if anatomically feasible) or surgery (see recommendation 1.3.27) for abscesses greater than 3 cm.
Send samples of pus from the abscess (if it has been drained) to the microbiology laboratory to enable antibiotic treatment to be tailored to sensitivities.
For abscesses less than 3 cm switch to oral antibiotics where possible.
In people with a CT-confirmed diverticular abscess, if the condition does not improve clinically or there is deterioration, consider re-imaging to inform the management strategy.
To find out why the committee made the recommendations on the management of abscesses and how they might affect practice, see rationale and impact .
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Offer either laparoscopic lavage or resectional surgery (see recommendation 1.3.27) to people with diverticular perforation with generalised peritonitis after discussing the risks and benefits of the 2 options with them (see table 3). If faecal peritonitis is identified intraoperatively, proceed to resectional surgery.
Laparoscopic lavage
Resectional surgery
What the procedure involves
In diverticulitis this involves washing the abdominal cavity and colon using keyhole surgery.
The surgical removal of the diseased colon followed by either reattaching the remaining segments of the colon or forming an end stoma.
Effect on quality of life
There was no significant difference in quality of life scores reported for lavage and surgery.
Mortality
Although there was some benefit seen in mortality for lavage, this evidence was very uncertain.
Needing a stoma (where the bowel is connected surgically to an opening in the abdomen and stools are collected in a bag or pouch)
A stoma is not needed.
A stoma may be needed.
Pain
Less likely to relieve pain than resectional surgery.
More likely to relieve pain than lavage because the damaged bowel has been removed.
Recurrent diverticulitis
Fewer people had recurrent diverticulitis after surgery than after lavage because the diseased bowel is removed. However, the evidence was very uncertain.
Needing more operations
Evidence comparing unplanned surgery with lavage showed that fewer people needed reoperations after surgery than after lavage.
Evidence that included unplanned surgery and planned surgery (scheduled stoma reversal after resectional surgery) showed that fewer people needed reoperations after lavage.
However, in both cases the evidence was very uncertain.
Postoperative complications
There was no meaningful difference in the number of infections or in the need for further intervention between lavage and surgery. People who had surgery had a greater reduction in post-surgical abscesses than those who had lavage, but this evidence was of low quality.
To find out why the committee made the recommendation on the management of bowel perforations and how it might affect practice, see rationale and impact .
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## Anastomosis and bowel resection for people with complicated acute diverticulitis (elective and emergency surgery)
Offer people with complicated acute diverticulitis who are having surgery (either elective or emergency):
primary anastomosis (join in the bowel) with or without diverting stoma or
Hartmann's procedure (resection of the bowel with an end stoma). Take into account the person's age, any other conditions they have and how well they can carry out everyday activities (WHO performance status).
To find out why the committee made the recommendation on anastomosis for people with complicated acute diverticulitis and how it might affect practice, see rationale and impact .
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In people undergoing bowel resection, consider resecting back to the compliant bowel (that is, bowel that is soft, unthickened and unaffected by inflammation).
To find out why the committee made the recommendation on bowel resection for people with complicated acute diverticulitis and how it might affect practice, see rationale and impact .
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## Elective surgical management after resolution of complicated acute diverticulitis
Consider open or laparoscopic resection for elective surgery for people who have recovered from complicated acute diverticulitis but have continuing symptoms, for example in people with stricture or fistula.
To find out why the committee made the recommendation on elective surgical management after resolution of complicated acute diverticulitis and how it might affect practice, see rationale and impact .
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## Timing of surgery for complicated acute diverticulitis
The committee were unable to make recommendations for practice in this area. They made a recommendation for research.
For a short explanation of why the committee were unable to make recommendations on timing of surgery for complicated acute diverticulitis see rationale .
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## Management of recurrent acute diverticulitis
Do not offer an aminosalicylate or antibiotics to prevent recurrent acute diverticulitis.
To find out why the committee made the recommendation on the management of recurrent acute diverticulitis and how it might affect practice, see rationale and impact .
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# Information
## Diverticulosis
Give people with diverticulosis, and their families and carers where appropriate, verbal and written information on:
diet and lifestyle
the course of diverticulosis and the likelihood of progression
symptoms that indicate complications or progression to diverticular disease.
## Diverticular disease
Give people with diverticular disease, and their families and carers where appropriate, verbal and written information on:
diet and lifestyle
the course of diverticular disease and the likelihood of progression
symptoms and symptom management
when to seek medical advice.
## Acute diverticulitis
Give people with acute diverticulitis, and their families and carers where appropriate, verbal and written information on:
diet and lifestyle
the course of acute diverticulitis and likelihood of complicated disease or recurrent episodes
symptoms
when and how to seek further medical advice
possible investigations and treatments
risks of interventions and treatments, including antibiotic resistance, and how invasive these are
role of surgery and outcomes (postoperative bowel function and symptoms).
To find out why the committee made the recommendations on information for people with diverticulosis, diverticular disease and acute diverticulitis, and how they might affect practice, see rationale and impact.
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# Terms used in this guideline
## Acute diverticulitis
Sudden inflammation or infection associated with diverticula. Symptoms include constant abdominal pain, usually severe and localising in the left lower quadrant. Other features, including fever, may also be present.
## Colitis
Inflammation of the bowel related to Crohn's disease, ulcerative colitis, ischaemia or microscopic colitis. Symptoms may include abdominal pain and change in bowel habits with passage of blood.
## Complicated acute diverticulitis
The presence of complications associated with inflamed or infected diverticula. These complications may include abscess, fistula, stricture perforation and sepsis.
## Diverticular disease
The presence of diverticula with mild abdominal pain or tenderness and no systemic symptoms.
## Diverticulosis
The presence of diverticula without symptoms.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Non-surgical management of acute diverticulitis
What is the clinical and cost effectiveness of antibiotics for the management of acute diverticulitis in primary care?
To find out why the committee made the research recommendation on antibiotics for managing acute diverticulitis see rationale and impact .
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## Conservative management for preventing diverticular disease
What is the most clinically and cost-effective conservative management for preventing diverticular disease in people with diverticulosis?
To find out why the committee made the research recommendation on preventing diverticular disease in people with diverticulosis see rationale and impact .
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## Managing diverticular disease
What is the most clinically and cost-effective treatment for diverticular disease?
To find out why the committee made the research recommendation on managing diverticular disease see rationale and impact .
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## Information and support
What information and support do people with diverticulosis, diverticular disease or acute diverticulitis need?
To find out why the committee made the research recommendation on information and support see rationale and impact .
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## Timing of surgery for complicated acute diverticulitis
What are the clinically and cost-effective surgical approaches to managing complicated acute diverticulitis, including timing of surgery (elective or emergency)?
To find out why the committee made the research recommendation on timing of surgery for complicated acute diverticulitis see rationale .
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# Other recommendations for research
## Risk factors for diverticular disease for people with diverticulosis
What are the risk factors for diverticulosis progressing to diverticular disease?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Diverticulosis management and advice
Recommendations 1.1.1 to 1.1.5
## Why the committee made the recommendations
Diverticulosis is asymptomatic and there are no specific treatments for it. The committee therefore considered making a recommendation about lifestyle and dietary advice to address the common questions asked by newly diagnosed patients on preventing disease progression. However, although some evidence was found on the management of diverticulosis, it did not meet the criteria for inclusion in the review on what is the most clinically and cost-effective management strategy for preventing diverticular disease in people with diverticulosis.
The committee were aware of evidence (which did not meet the review criteria) that vigorous exercise was associated with a reduction in the risk of developing acute diverticulitis. Increased body mass index was also associated with an increased risk of symptomatic disease. In the absence of evidence that could be used to draft recommendations, formal consensus methods and the knowledge and experience of the committee were used instead. The recommendations should be straightforward to implement and may reduce the possibility of developing diverticular disease.
In light of the lack of evidence on this topic, and the need to know what factors might increase the risk of diverticulosis progressing to diverticular disease, the committee considered this an important area for research. They made research recommendations on risk factors for diverticular disease and on conservative management for preventing diverticular disease.
## How the recommendations might affect practice
The recommendations reflect current practice.
Full details of the evidence and the committee's discussion are in evidence review A: prevention of diverticular disease in patients with diverticulosis.
Return to recommendations
# Symptoms and signs of diverticular disease
Recommendation 1.2.1
## Why the committee made the recommendation
The evidence on symptoms and signs comprised a single study with no clinically important outcomes and was based on a population with diverticulitis rather than diverticular disease. Because of a lack of evidence, recommendations were made using formal consensus methods and the knowledge and expertise of the committee on the most common presentation of diverticular disease.
Most people experience pain on the left side of the abdomen where the diverticula most often occur in the sigmoid colon. For this reason people are often tender in the left lower quadrant. However, it was important to highlight that people of Asian origin may experience right-sided symptoms. Other symptoms are variable but people experience constipation, diarrhoea or both, with occasional rectal bleeds. The symptoms alone are not specific enough to indicate diverticular disease but should be considered in conjunction with intermittent abdominal pain. Symptoms may overlap with conditions such as irritable bowel syndrome, colitis and malignancy.
## How the recommendation might affect practice
The recommendation reflects current practice.
Full details of the evidence and the committee's discussion are in evidence review B: symptoms and signs of diverticular disease.
Return to recommendations
# Investigations and referral for diverticular disease
Recommendations 1.2.2 to 1.2.3
## Why the committee made the recommendations
There was no evidence on diagnosing diverticular disease so the guideline committee made recommendations based on their knowledge of current best practice. Where diverticular disease is suspected, current practice is to use imaging or endoscopy to confirm the presence of diverticula or exclude other diseases such as cancer. Patients will often have their bowel investigated by either endoscopy with a flexible sigmoidoscopy or colonoscopy or CT colonography. The committee agreed that these routine endoscopic and radiological investigations can sometimes be organised from primary care but that referral would be needed if this was not available.
## How the recommendations might affect practice
The recommendations reflect current practice.
Full details of the evidence and the committee's discussion are in evidence review C: diagnosis of diverticular disease.
Return to recommendations
# Management and advice for people with diverticular disease
Recommendations 1.2.4 to 1.2.11
## Why the committee made the recommendations
Very limited evidence was identified on a high fibre diet, antibiotics, aminosalicylates, probiotics, symbiotics and laxatives and there was no evidence on non-steroidal anti-inflammatory drugs (NSAIDs). The evidence that was available didn't help the committee to understand the impact of these interventions on the progression of disease or people's quality of life. The committee used formal consensus methods together with their expertise and knowledge to make recommendations on diet and lifestyle advice and how to manage pain and cramping.
Bulk-forming laxatives are effective as they help to soften the stool and can also help to solidify loose stools in people with constipation. Paracetamol is indicated for pain and the committee highlighted the importance of avoiding NSAIDs and opioid analgesia because of the risk of diverticular perforation. Some people experience abdominal cramping, and anti-spasmodics may help with this.
In line with best practice in antimicrobial stewardship, the committee made a recommendation not to use antibiotics in the absence of acute diverticulitis.
Having a greater understanding of how best to manage symptoms and prevent the disease developing into acute diverticular disease could have a positive impact on a person's health and wellbeing. It could also help avoid potential subsequent treatment costs. The committee therefore made a research recommendation in this area.
These recommendations are about managing the symptoms of diverticular disease rather than preventing progression to acute diverticulitis. However, the development of acute diverticulitis was included as an outcome in this review and in the research recommendation that was developed, because the committee considered it to be a critical factor for decision making. The committee noted the importance of considering alternative causes and further investigations in people with persistent symptoms or who do not respond to treatment.
## How the recommendations might affect practice
The recommendations reflect current practice.
Full details of the evidence and the committee's discussion are in evidence review D: management of diverticular disease.
Return to recommendations
# Recurrent diverticular disease
## Why the committee did not make any recommendations
There was no evidence included for this review and the committee were unable to make any recommendations based on their experience or opinion.
Full details of the evidence and the committee's discussion are in evidence review E: management of recurrent diverticular disease.
Return to recommendations
# Symptoms and signs of acute diverticulitis
Recommendation 1.3.1
## Why the committee made the recommendation
There was no relevant evidence on the symptoms and signs of acute diverticulitis, so recommendations were made using formal consensus methods. The committee thought that clearly defining the symptoms and signs of acute diverticulitis, along with its associated complications, would help clinicians and patients in clearly differentiating these distinct clinical conditions.
Committee members thought that diverticular disease, symptomatic diverticular disease and acute diverticulitis are often used interchangeably, creating confusion about which condition the patient has and therefore what management is appropriate. The recommendation is focused on symptoms and signs that are specific to acute diverticulitis. It is aimed at primary care to support the identification of the condition.
## How the recommendation might affect practice
The recommendation reflects current practice.
Full details of the evidence and the committee's discussion are in evidence review F: referral criteria for acute diverticulitis.
Return to recommendations
# Symptoms and signs of complicated acute diverticulitis
Recommendation 1.3.2
## Why the committee made the recommendation
There was no relevant evidence on the symptoms and signs of complicated acute diverticulitis, so a recommendation was made using formal consensus methods. The recommendation focuses on symptoms and signs that differentiate uncomplicated from complicated acute diverticulitis. If any of these symptoms and signs are present, same-day hospital assessment is necessary.
## How the recommendation might affect practice
The recommendation reflects current practice.
Full details of the evidence and the committee's discussion are in evidence review I: indications for surgery.
Return to recommendations
# Investigation of suspected acute diverticulitis
Recommendations 1.3.3 to 1.3.6
## Why the committee made the recommendations
There was insufficient evidence available on diagnostic tests for people who are not referred for same-day hospital assessment. The committee highlighted the importance of reassessment or referral if the person's symptoms persist or worsen, as this could indicate complicated acute diverticulitis or an alternative diagnosis.
For people with suspected complications of acute diverticulitis referred for urgent same-day hospital assessment, the committee agreed that less costly clinical tests of full blood count and C‑reactive protein (CRP) should be offered initially to identify inflammation. The urea and electrolytes test assesses kidney function, which will help to determine if a contrast CT can be performed. The CT could inform the decision making and help decide which patients should undergo further investigation for acute diverticulitis.
The committee acknowledged that contrast CT is recognised as the gold standard diagnostic test for acute diverticulitis and its complications. They agreed that having an early CT scan to assess for acute diverticulitis would mean that complications could be identified sooner. This would subsequently reduce length of hospital stay and the number of later colonoscopies. In addition, having the scan within 24 hours of admission would also help guide treatment planning. For example, it could identify people with uncomplicated diverticular disease who can be given oral antibiotics and discharged or have antibiotics stopped and be discharged.
Where contrast CT is contraindicated, the committee agreed that non-contrast CT, MRI or ultrasound are accepted alternatives to contrast CT. The choice of whether to perform ultrasound should depend on the availability of local expertise. Ultrasound may not be able to diagnose diverticulitis in isolation, but it may identify factors such as colonic wall thickening and inflammation. Ultrasound may be used as an adjunct to rule out other disease.
There was no evidence for colonoscopy and sigmoidoscopy in diagnosing acute diverticulitis. The committee were aware of the risk of perforation and agreed that these procedures should not be offered for acute diverticulitis.
## How the recommendations might affect practice
Full blood count and CRP are routinely used to assess for inflammation and indication of acute diverticulitis. This reflects current best practice but is not used across all NHS settings. Therefore implementing this recommendation will mean a change in practice for some providers.
Currently, 60% of people with acute diverticulitis undergo CT examination to confirm the diagnosis. This recommendation will increase the use of CT scanning. However, the increase in cost associated with this will be offset by a decrease in hospital stays, along with a decrease in use of intravenous antibiotics and potentially further endoscopy. Evidence shows that performing a CT can reduce the use of subsequent endoscopy.
Full details of the evidence and the committee's discussion are in evidence review G: diagnostic tests for acute diverticulitis.
Return to recommendations
# Non-surgical management of acute diverticulitis
Recommendations 1.3.7 to 1.3.14
## Why the committee made the recommendations
For people with suspected acute diverticulitis who are not referred for urgent same-day hospital assessment, the committee agreed that watchful waiting is an option if the person is systemically well and has no comorbidities that increase the risk of infection. This decision would be in the context of shared decision making. Simple analgesia and advice can be offered. Oral antibiotics are appropriate if the person is systemically unwell but does not meet the criteria for referral with suspected complicated acute diverticulitis.
The evidence supports current practice of treating an acute episode of diverticulitis with intravenous antibiotics in secondary care. If CT confirms uncomplicated acute diverticulitis, switching to oral antibiotics does not affect outcomes. The committee recommended antibiotics for this group because they were aware of evidence that watchful waiting could increase recurrence rates and the probability of further surgery. In support of antibiotic stewardship and to avoid antibiotic resistance the committee recommended that the person should be reassessed if necessary and the need for antibiotic treatment should be reviewed.
The need for intravenous antibiotics should be reviewed, including whether to stop them, within 48 hours in line with current good practice on antibiotic prescribing or after the CT scan. The CT will confirm if the person has an abscess or not. The total course of antibiotic treatment should be for a maximum of 5 days and then reviewed. The duration may need to be longer in people with diverticular abscess. The duration of antibiotics used in the studies was variable and 5 days was based on current clinical practice and the knowledge and expertise of the committee.
In light of the lack of evidence on this topic, and the need to prevent antibiotic resistance, the committee considered this an important area for research. It made a research recommendation on antibiotics for people with acute diverticulitis managed in primary care.
## How the recommendations might affect practice
The recommendation to offer an initial treatment of intravenous antibiotics before CT scanning for confirmation reflects current practice, so there should be no change in practice. Using oral antibiotics beyond this point in place of intravenous antibiotics may reduce the resource requirement in caring for people with acute diverticulitis.
Full details of the evidence and the committee's discussion are in evidence review H: non-surgical management of acute diverticulitis.
Return to recommendations
# Management of abscesses in complicated acute diverticulitis
Recommendations 1.3.15 to 1.3.25
## Why the committee made the recommendations
The quality of the evidence for this topic meant that it was not possible to demonstrate greater effectiveness of one intervention over another. The results showed harms as well as benefits of treatment. The committee therefore made recommendations based on their clinical expertise and the approaches taken in the studies. The committee highlighted the risk of sepsis and agreed that it is important to refer people with suspected diverticular abscess to secondary care for same-day assessment and treatment with intravenous antibiotics in line with the NICE guideline on sepsis. The committee considered this to be standard practice.
The need for intravenous antibiotics should be reviewed within 48 hours in line with current good practice on antibiotic prescribing or after the CT scan. The CT will confirm if the person has an abscess or not.
The committee agreed that offering a CT scan to people with suspected diverticular abscess may help to determine the most appropriate treatment for each person based on the characteristics of the abscesses, such as size and location. This was based on clinical experience and the fact that most of the included studies used CT scans to confirm and assess abscesses. Non-contrast CT, MRI or ultrasound (depending on local expertise) should be offered if contrast CT is contraindicated.
The committee also decided that only abscesses greater than 3 cm should be considered for percutaneous drainage because of technical difficulties in performing this procedure on smaller abscesses. This was based on clinical expertise and was the approach taken by most of the included studies.
The committee agreed that if percutaneous drainage is an anatomically feasible option this could be considered alongside a discussion with the patient about the risks and benefits of surgery. In people with a CT-confirmed diverticular abscess, re-imaging may be considered if the condition does not improve clinically of if there is deterioration. This will guide the management strategy – for example, if further surgery is needed or if a previous collection that was not drainable percutaneously (for example because it was too small) is now drainable.
## How the recommendations might affect practice
The recommendations reflect current practice.
Full details of the evidence and the committee's discussion are in evidence review N: percutaneous drainage versus resectional surgery for the management of abscesses.
Return to recommendations
# Management of bowel perforations in complicated acute diverticulitis
Recommendation 1.3.26
## Why the committee made the recommendation
The committee noted that, based on the evidence, there appeared to be few differences between resection of the bowel and lavage in terms of patient outcomes. The committee agreed that for people with diverticular perforations with generalised peritonitis, both options should be discussed and a decision made based on patient preferences. A patient decision table has been developed to support this discussion.
No evidence was found for the treatment of faecal peritonitis (also known as Hinchey stage IV perforation). But the committee agreed that resection of the bowel is better than lavage because it is the only way to prevent further faecal contamination of the peritoneal cavity.This is because of the more serious nature of this condition indicated by the presence of faeces in the peritoneal cavity.
## How the recommendation might affect practice
The committee considered that lavage is not commonly used in the UK for treating diverticular perforation. Implementing this recommendation may therefore require a change from current practice by the majority of providers.
Full details of the evidence and the committee's discussion are in evidence review O: laparoscopic lavage for the management of bowel perforations.
Return to recommendations
# Anastomosis for people with complicated acute diverticulitis
Recommendation 1.3.27
## Why the committee made the recommendation
The committee agreed that there was too much uncertainty surrounding most of the evidence to recommend one intervention over the other for complicated acute diverticulitis. Very few outcomes indicated a clinical benefit of either primary anastomosis or temporary stoma. For this reason, the committee concluded that both primary anastomosis (which is a join in the bowel, with or without diverting stoma) and Hartmann's procedure should be options for people admitted to surgery for this condition. Based on the expertise and knowledge of the committee, surgeon experience, the patient's age, any other conditions the patient has and how well they can carry out everyday activities and patient condition should be considered.
In the emergency setting frail patients with multiple medical problems who have sepsis at the time of surgery may benefit from a Hartmann's procedure instead of a primary anastomosis (with or without diverting stoma) as this removes the risk of a subsequent anastomotic leak. However, the committee recognised that patients having a stoma in this setting often find these are permanent and not reversed.
## How the recommendation might affect practice
The recommendation reflects current practice.
Full details of the evidence and the committee's discussion are in evidence review M: primary versus secondary anastomosis (timing of anastomosis) in complicated acute diverticulitis.
Return to recommendations
# Bowel resection for people with complicated acute diverticulitis
Recommendation 1.3.28
## Why the committee made the recommendation
No evidence was found on the extent of bowel resection for people with acute diverticulitis. A recommendation was developed based on the experience of the surgeons on the committee. Committee members discussed the difference between resecting back to normal bowel and resecting back to compliant bowel. The committee agreed that 'normal bowel' could be interpreted by some as bowel without diverticula, rather than bowel that is soft, unthickened and unaffected by inflammation. To avoid this confusion, resecting back to the compliant bowel, which refers to bowel that is functional and is not restricted in terms of movement, was included in the recommendation and reflects the current advice by national bodies.
## How the recommendation might affect practice
The recommendation reflects current practice.
Full details of the evidence and the committee's discussion are in evidence review L: management of complicated acute diverticulitis – extent of colectomy.
Return to recommendations
# Elective surgical management after resolution of complicated acute diverticulitis
Recommendation 1.3.29
## Why the committee made the recommendation
The committee concluded that there was insufficient evidence to say whether laparoscopic resection or open resection was the better management option for people who have recovered from complicated acute diverticulitis but who have continuing symptoms.
## How the recommendation might affect practice
The recommendation reflects current practice.
Full details of the evidence and the committee's discussion are in evidence review K: laparoscopic versus open sigmoid resection for acute diverticulitis.
Return to recommendations
# Timing of surgery for complicated acute diverticulitis
## Why the committee did not make any recommendations
In the studies in the evidence reviewed people were offered an intervention based on demographic and clinical characteristics. This meant it was difficult to assess the true effect of interventions on patient outcomes. Therefore the committee decided not to make any practice recommendations.
The committee thought this was an area that needed further research and therefore developed a research recommendation.
Full details of the evidence and the committee's discussion are in evidence review J: timing of surgery for complicated acute diverticulitis.
Return to recommendations
# Management of recurrent acute diverticulitis
Recommendation 1.3.30
## Why the committee made the recommendation
The committee noted that the evidence supported current practice of not using an aminosalicylate in managing recurrent diverticulitis. Aminosalicylates are not licensed to treat diverticulitis in the UK and there is little evidence to support their use in this area.
The committee agreed that there was insufficient evidence to support the use of antibiotics to prevent recurrent diverticular disease. In support of antibiotic stewardship and to avoid antibiotic resistance the committee recommended not offering antibiotic treatment.
## How the recommendation might affect practice
The recommendation to not offer an aminosalicylate or antibiotics for the prevention of recurrent diverticulitis reflects current practice. Therefore the committee agreed there should be no change in practice.
Full details of the evidence and the committee's discussion are in evidence review P: management of recurrent acute diverticulitis.
Return to recommendations
# Information
Recommendations 1.4.1 to 1.4.3
## Why the committee made the recommendations
There was limited evidence on the support and information needed for people with diverticulosis, diverticular disease and diverticulitis and their families and carers. The evidence was from a symptom-based questionnaire and reported on the timing and success of surgery and symptoms. The committee agreed that it is important for those affected to have relevant information on these topics, but also used its knowledge and experience to expand on these topics in the recommendations.
The committee decided that given the limited evidence, this is an area that needs further research to identify the type of information people want. Therefore they made a research recommendation.
## How the recommendations might affect practice
The recommendation reflects current practice.
Full details of the evidence and the committee's discussion are in evidence review Q: information and support.
Return to recommendations# Context
Diverticulosis is a digestive condition characterised by small pouches (diverticula) that protrude from the walls of the large intestine.
The true prevalence of diverticulosis is difficult to determine because most patients are asymptomatic. It is age dependent and relatively uncommon in people aged under 40, although in recent years there has been a dramatic rise in the prevalence in this age group. In people aged over 65 the prevalence is up to 65%.
About 80 to 85% of people affected by diverticulosis remain asymptomatic, and 10 to 15% develop symptomatic diverticular disease including acute diverticulitis and its complications (perforation, abscess formation, haemorrhage, fistula and obstruction).
Key aspects of this guideline include the management of diverticulosis, diagnosis and management of diverticular disease, acute diverticulitis and complicated acute diverticulitis
Areas of the guideline with the potential for the greatest impact on practice include CT scanning for acute diverticulitis and offering resection or lavage for bowel perforations.# Finding more information and resources
You can see everything NICE says on diverticular disease in our interactive flowchart on diverticular disease.
To find out what NICE has said on topics related to this guideline, see our web page on digestive tract conditions.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
ISBN: 978-1-4731-3603-8
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diverticulosis\n\n## Management and advice\n\nTell people with diverticulosis that the condition is asymptomatic and no specific treatments are needed.\n\nAdvise people to eat a healthy, balanced diet including whole grains, fruit and vegetables. Tell them that:\n\nthere is no need to avoid seeds, nuts, popcorn or fruit skins\n\nif they have constipation and a low-fibre diet, increasing their fibre intake gradually may minimise flatulence and bloating.\n\nAdvise people to drink adequate fluid if they are increasing their fibre intake, especially if there is a risk of dehydration.\n\nConsider bulk-forming laxatives for people with constipation.\n\nTell people about the benefits of exercise, and weight loss if they are overweight or obese, and stopping smoking, in reducing the risk of developing acute diverticulitis and symptomatic disease.\n\nTo find out why the committee made the recommendations on diverticulosis management and advice and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Diverticular disease\n\n## Symptoms and signs\n\nSuspect diverticular disease if a person presents with one or both of the following:\n\nintermittent abdominal pain in the left lower quadrant with constipation, diarrhoea or occasional large rectal bleeds (the pain may be triggered by eating and relieved by the passage of stool or flatus)\n\ntenderness in the left lower quadrant on abdominal examination.Be aware that:\n\nin a minority of people and in people of Asian origin, pain and tenderness may be localised in the right lower quadrant\n\nsymptoms may overlap with conditions such as irritable bowel syndrome, colitis and malignancy.\n\nTo find out why the committee made the recommendation on symptoms and signs of diverticular disease and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Investigations and referral\n\nDo not routinely refer people with suspected diverticular disease unless:\n\nroutine endoscopic and/or radiological investigations cannot be organised from primary care or\n\ncolitis is suspected or\n\nthe person meets the criteria for a suspected cancer pathway.\n\nIf the person meets the criteria for a suspected cancer pathway, refer by this route (see NICE's guideline on suspected cancer: recognition and referral).\n\nTo find out why the committee made the recommendations on investigations and referral for people with suspected diverticular disease and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Management and advice\n\nDo not offer antibiotics to people with diverticular disease.\n\nAdvise people to avoid non-steroidal anti-inflammatory drugs and opioid analgesia if possible, because they may increase the risk of diverticular perforation.\n\nFor advice on diet, fluid intake, stopping smoking, weight loss and exercise, follow the recommendations in section 1.1 on diverticulosis.\n\nAdvise people that:\n\nthe benefits of increasing dietary fibre may take several weeks to achieve\n\nif tolerated, a high-fibre diet should be maintained for life.\n\nConsider bulk-forming laxatives if:\n\na high-fibre diet is unacceptable to the person or it is not tolerated or\n\nthe person has persistent constipation or diarrhoea.\n\nConsider simple analgesia, for example paracetamol, as needed if the person has ongoing abdominal pain.\n\nConsider an antispasmodic if the person has abdominal cramping.\n\nIf the person has persistent symptoms or symptoms that do not respond to treatment, think about alternative causes and investigate and manage appropriately.\n\nTo find out why the committee made the recommendations on management and advice for people with diverticular disease and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Recurrent diverticular disease\n\nThe committee were unable to make recommendations for practice in this area.\n\nFor a short explanation of why the committee were unable to make recommendations on recurrent diverticular disease see rationale\xa0.\n\nLoading. Please wait.\n\n# Acute diverticulitis\n\n## Symptoms and signs of acute diverticulitis\n\nSuspect acute diverticulitis if a person presents with constant abdominal pain, usually severe and localising in the left lower quadrant, with any of the following:\n\nfever or\n\nsudden change in bowel habit and significant rectal bleeding or passage of mucus from the rectum or\n\ntenderness in the left lower quadrant, a palpable abdominal mass or distention on abdominal examination, with a previous history of diverticulosis or diverticulitis. Be aware that in a minority of people and in people of Asian origin, pain and tenderness may be localised in the right lower quadrant.\n\nTo find out why the committee made the recommendation on symptoms and signs of acute diverticulitis and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Symptoms and signs of complicated acute diverticulitis\n\nSuspect complicated acute diverticulitis and refer for same-day hospital assessment if the person has uncontrolled abdominal pain and any of the features in table\xa01.\n\nSymptom or sign\n\nPossible complication\n\nAbdominal mass on examination or peri-rectal fullness on digital rectal examination\n\nIntra-abdominal abscess\n\nAbdominal rigidity and guarding on examination\n\nBowel perforation and peritonitis\n\nAltered mental state, raised respiratory rate, low systolic blood pressure, raised heart rate, low tympanic temperature, no urine output or skin discolouration\n\nSepsis (see the NICE guideline on sepsis)\n\nFaecaluria, pneumaturia, pyuria or the passage of faeces through the vagina\n\nFistula into the bladder or vagina\n\nColicky abdominal pain, absolute constipation (passage of no flatus or stool), vomiting or abdominal distention\n\nIntestinal obstruction\n\n\n\nTo find out why the committee made the recommendation on symptoms and signs of complicated acute diverticulitis and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Investigation of suspected acute diverticulitis\n\nFor people with suspected uncomplicated acute diverticulitis who are not referred for same-day hospital assessment:\n\nreassess in primary care if their symptoms persist or worsen and\n\nconsider referral to secondary care for further assessment.\n\nFor people with suspected complicated acute diverticulitis who have been referred for same-day hospital assessment, offer a full blood count, urea and electrolytes test and C‑reactive protein test.\n\nIf the person with suspected complicated acute diverticulitis has raised inflammatory markers, offer a contrast CT scan within 24\xa0hours of hospital admission to confirm diagnosis and help plan management. If contrast CT is contraindicated, perform one of the following:\n\na non-contrast CT or\n\nan MRI or\n\nan ultrasound scan, depending on local expertise.\n\nIf inflammatory markers are not raised, think about the possibility of alternative diagnoses.\n\nTo find out why the committee made the recommendations on investigation of suspected acute diverticulitis and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Non-surgical management of acute diverticulitis\n\nFor people with acute diverticulitis who are systemically well:\n\nconsider a no antibiotic prescribing strategy\n\noffer simple analgesia, for example paracetamol\n\nadvise the person to re‑present if symptoms persist or worsen.\n\nOffer an antibiotic prescribing strategy if the person with acute diverticulitis is systemically unwell, is immunosuppressed or has significant comorbidity.\n\nOffer oral antibiotics if the person with acute diverticulitis is systemically unwell but does not meet the criteria for referral for suspected complicated acute diverticulitis.\n\nOffer intravenous antibiotics to people admitted to secondary care with suspected complicated acute diverticulitis.For guidance on the management of suspected sepsis see the NICE guideline on sepsis.\n\nReview intravenous antibiotics within 48\xa0hours or after scanning if sooner (see recommendation 1.3.5) and consider stepping down to oral antibiotics where possible.\n\nIf the person has CT-confirmed uncomplicated acute diverticulitis, review the need for antibiotics and discharge them depending on any co-existing medical conditions.\n\nWhen prescribing an antibiotic for suspected or confirmed acute diverticulitis, follow the advice in table\xa02.\n\nAntibiotic\n \n 1\n\nDosage and course length\n \n 2\n\nFirst-choice oral antibiotic for suspected or confirmed\n uncomplicated acute diverticulitis\n\nCo‑amoxiclav\n\n/125\xa0mg three times a day for 5\xa0days\n\nAlternative first-choice oral antibiotics if penicillin allergy or co‑amoxiclav unsuitable\n\nCefalexin (caution in penicillin allergy) with metronidazole\n\nCefalexin: 500\xa0mg twice or three times a day (up to 1 to 1.5\xa0g three or four times a day for severe infection) for 5\xa0days\n\nMetronidazole: 400\xa0mg three times a day for 5\xa0days\n\n\n\nTrimethoprim with metronidazole\n\nTrimethoprim: 200\xa0mg twice a day for 5\xa0days\n\nMetronidazole: 400\xa0mg three times a day for 5\xa0days\n\nCiprofloxacin (only if switching from IV ciprofloxacin with specialist advice; consider safety issues3) with metronidazole\n\nCiprofloxacin: 500\xa0mg twice a day for 5\xa0days\n\nMetronidazole: 400\xa0mg three times a day for 5\xa0days\n\nFirst-choice intravenous antibiotics\n \n 4\n \n for suspected or confirmed\n complicated acute diverticulitis\n\nCo‑amoxiclav\n\ng three times a day\n\nCefuroxime with metronidazole\n\nCefuroxime: 750\xa0mg three or four times a day (increased to 1.5\xa0g three or four times a day if severe infection)\n\nMetronidazole: 500\xa0mg three times a day\n\n\n\nAmoxicillin with gentamicin and metronidazole\n\nAmoxicillin: 500\xa0mg three times a day (increased to 1\xa0g\xa0four times a day if severe infection)\n\nGentamicin: Initially 5 to 7\xa0mg/kg once a day, subsequent doses adjusted according to serum gentamicin concentration5\n\nMetronidazole: 500\xa0mg three times a day\n\n\n\nCiprofloxacin6 (consider safety issues3) with metronidazole\n\nCiprofloxacin: 400\xa0mg twice or three times a day\n\nMetronidazole: 500\xa0mg three times a day\n\nAlternative intravenous antibiotics\n\nConsult local microbiologist\n\nSee BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.\n\nA longer course may be needed based on clinical assessment. Continue antibiotics for up to 14\xa0days in people with CT‑confirmed diverticular abscess.\n\nSee MHRA advice for restrictions and precautions for using fluoroquinolones due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution for people over 60\xa0years and avoiding coadministration with a corticosteroid (March 2019).\n\nReview intravenous antibiotics within 48\xa0hours or after scanning if sooner and consider stepping down to oral antibiotics where possible.\n\nTherapeutic drug monitoring and assessment of renal function is required (BNF, August 2019).\n\nOnly in people with allergy to penicillins and cephalosporins.\n\n\n\n## Emergency management of complicated acute diverticulitis\n\nWhen prescribing an antibiotic for suspected or confirmed complicated acute diverticulitis, follow the advice in table\xa02.\n\nTo find out why the committee made the recommendations on the non-surgical management of acute diverticulitis and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\nFor people presenting in secondary care with complicated acute diverticulitis and suspected diverticular abscess, assess and manage in line with the NICE guideline on sepsis.\n\nOffer intravenous antibiotics to people with acute diverticulitis and suspected diverticular abscess.\n\nWhen prescribing an antibiotic for diverticular abscess, follow the advice in table\xa02.\n\nOffer a contrast CT scan to people with acute diverticulitis and suspected diverticular abscess. If contrast CT is contraindicated, perform one of the following:\n\na non-contrast CT or\n\nan MRI or\n\nan ultrasound scan, depending on local expertise.\n\nReview intravenous antibiotics within 48\xa0hours or after scanning if sooner and consider stepping down to oral antibiotics where possible.\n\nUse the scan results to guide treatment based on the size and location of the abscess.\n\nIf a person does not have confirmed diverticular abscess, review their need for antibiotics.\n\nConsider either percutaneous drainage (if anatomically feasible) or surgery (see recommendation 1.3.27) for abscesses greater than 3\xa0cm.\n\nSend samples of pus from the abscess (if it has been drained) to the microbiology laboratory to enable antibiotic treatment to be tailored to sensitivities.\n\nFor abscesses less than 3\xa0cm switch to oral antibiotics where possible.\n\nIn people with a CT-confirmed diverticular abscess, if the condition does not improve clinically or there is deterioration, consider re-imaging to inform the management strategy.\n\nTo find out why the committee made the recommendations on the management of abscesses and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\nOffer either laparoscopic lavage or resectional surgery (see recommendation 1.3.27) to people with diverticular perforation with generalised peritonitis after discussing the risks and benefits of the 2\xa0options with them (see table\xa03). If faecal peritonitis is identified intraoperatively, proceed to resectional surgery.\n\n\n\nLaparoscopic lavage\n\nResectional surgery\n\nWhat the procedure involves\n\nIn diverticulitis this involves washing the abdominal cavity and colon using keyhole surgery.\n\nThe surgical removal of the diseased colon followed by either reattaching the remaining segments of the colon or forming an end stoma.\n\nEffect on quality of life\n\nThere was no significant difference in quality of life scores reported for lavage and surgery.\n\nMortality\n\nAlthough there was some benefit seen in mortality for lavage, this evidence was very uncertain.\n\nNeeding a stoma (where the bowel is connected surgically to an opening in the abdomen and stools are collected in a bag or pouch)\n\nA stoma is not needed.\n\nA stoma may be needed.\n\nPain\n\nLess likely to relieve pain than resectional surgery.\n\nMore likely to relieve pain than lavage because the damaged bowel has been removed.\n\nRecurrent diverticulitis\n\nFewer people had recurrent diverticulitis after surgery than after lavage because the diseased bowel is removed. However, the evidence was very uncertain.\n\nNeeding more operations\n\nEvidence comparing unplanned surgery with lavage showed that fewer people needed reoperations after surgery than after lavage.\n\nEvidence that included unplanned surgery and planned surgery (scheduled stoma reversal after resectional surgery) showed that fewer people needed reoperations after lavage.\n\nHowever, in both cases the evidence was very uncertain.\n\nPostoperative complications\n\nThere was no meaningful difference in the number of infections or in the need for further intervention between lavage and surgery. People who had surgery had a greater reduction in post-surgical abscesses than those who had lavage, but this evidence was of low quality.\n\n\n\nTo find out why the committee made the recommendation on the management of bowel perforations and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Anastomosis and bowel resection for people with complicated acute diverticulitis (elective and emergency surgery)\n\nOffer people with complicated acute diverticulitis who are having surgery (either elective or emergency):\n\nprimary anastomosis (join in the bowel) with or without diverting stoma or\n\nHartmann's procedure (resection of the bowel with an end stoma). Take into account the person's age, any other conditions they have and how well they can carry out everyday activities (WHO performance status).\n\nTo find out why the committee made the recommendation on anastomosis for people with complicated acute diverticulitis and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\nIn people undergoing bowel resection, consider resecting back to the compliant bowel (that is, bowel that is soft, unthickened and unaffected by inflammation).\n\nTo find out why the committee made the recommendation on bowel resection for people with complicated acute diverticulitis and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Elective surgical management after resolution of complicated acute diverticulitis\n\nConsider open or laparoscopic resection for elective surgery for people who have recovered from complicated acute diverticulitis but have continuing symptoms, for example in people with stricture or fistula.\n\nTo find out why the committee made the recommendation on elective surgical management after resolution of complicated acute diverticulitis and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Timing of surgery for complicated acute diverticulitis\n\nThe committee were unable to make recommendations for practice in this area. They made a recommendation for research.\n\nFor a short explanation of why the committee were unable to make recommendations on timing of surgery for complicated acute diverticulitis see rationale\xa0.\n\nLoading. Please wait.\n\n\n\n## Management of recurrent acute diverticulitis\n\nDo not offer an aminosalicylate or antibiotics to prevent recurrent acute diverticulitis.\n\nTo find out why the committee made the recommendation on the management of recurrent acute diverticulitis and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Information\n\n## Diverticulosis\n\nGive people with diverticulosis, and their families and carers where appropriate, verbal and written information on:\n\ndiet and lifestyle\n\nthe course of diverticulosis and the likelihood of progression\n\nsymptoms that indicate complications or progression to diverticular disease.\n\n## Diverticular disease\n\nGive people with diverticular disease, and their families and carers where appropriate, verbal and written information on:\n\ndiet and lifestyle\n\nthe course of diverticular disease and the likelihood of progression\n\nsymptoms and symptom management\n\nwhen to seek medical advice.\n\n## Acute diverticulitis\n\nGive people with acute diverticulitis, and their families and carers where appropriate, verbal and written information on:\n\ndiet and lifestyle\n\nthe course of acute diverticulitis and likelihood of complicated disease or recurrent episodes\n\nsymptoms\n\nwhen and how to seek further medical advice\n\npossible investigations and treatments\n\nrisks of interventions and treatments, including antibiotic resistance, and how invasive these are\n\nrole of surgery and outcomes (postoperative bowel function and symptoms).\n\nTo find out why the committee made the recommendations on information for people with diverticulosis, diverticular disease and acute diverticulitis, and how they might affect practice, see rationale and impact.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Acute diverticulitis\n\nSudden inflammation or infection associated with diverticula. Symptoms include constant abdominal pain, usually severe and localising in the left lower quadrant. Other features, including fever, may also be present.\n\n## Colitis\n\nInflammation of the bowel related to Crohn's disease, ulcerative colitis, ischaemia or microscopic colitis. Symptoms may include abdominal pain and change in bowel habits with passage of blood.\n\n## Complicated acute diverticulitis\n\nThe presence of complications associated with inflamed or infected diverticula. These complications may include abscess, fistula, stricture perforation and sepsis.\n\n## Diverticular disease\n\nThe presence of diverticula with mild abdominal pain or tenderness and no systemic symptoms.\n\n## Diverticulosis\n\nThe presence of diverticula without symptoms.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Non-surgical management of acute diverticulitis\n\nWhat is the clinical and cost effectiveness of antibiotics for the management of acute diverticulitis in primary care?\n\nTo find out why the committee made the research recommendation on antibiotics for managing acute diverticulitis see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Conservative management for preventing diverticular disease\n\nWhat is the most clinically and cost-effective conservative management for preventing diverticular disease in people with diverticulosis?\n\nTo find out why the committee made the research recommendation on preventing diverticular disease in people with diverticulosis see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Managing diverticular disease\n\nWhat is the most clinically and cost-effective treatment for diverticular disease?\n\nTo find out why the committee made the research recommendation on managing diverticular disease see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Information and support\n\nWhat information and support do people with diverticulosis, diverticular disease or acute diverticulitis need?\n\nTo find out why the committee made the research recommendation on information and support see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Timing of surgery for complicated acute diverticulitis\n\nWhat are the clinically and cost-effective surgical approaches to managing complicated acute diverticulitis, including timing of surgery (elective or emergency)?\n\nTo find out why the committee made the research recommendation on timing of surgery for complicated acute diverticulitis see rationale\xa0.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Risk factors for diverticular disease for people with diverticulosis\n\nWhat are the risk factors for diverticulosis progressing to diverticular disease?', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Diverticulosis management and advice\n\nRecommendations 1.1.1 to 1.1.5\n\n## Why the committee made the recommendations\n\nDiverticulosis is asymptomatic and there are no specific treatments for it. The committee therefore considered making a recommendation about lifestyle and dietary advice to address the common questions asked by newly diagnosed patients on preventing disease progression. However, although some evidence was found on the management of diverticulosis, it did not meet the criteria for inclusion in the review on what is the most clinically and cost-effective management strategy for preventing diverticular disease in people with diverticulosis.\n\nThe committee were aware of evidence (which did not meet the review criteria) that vigorous exercise was associated with a reduction in the risk of developing acute diverticulitis. Increased body mass index was also associated with an increased risk of symptomatic disease. In the absence of evidence that could be used to draft recommendations, formal consensus methods and the knowledge and experience of the committee were used instead. The recommendations should be straightforward to implement and may reduce the possibility of developing diverticular disease.\n\nIn light of the lack of evidence on this topic, and the need to know what factors might increase the risk of diverticulosis progressing to diverticular disease, the committee considered this an important area for research. They made research recommendations on risk factors for diverticular disease and on conservative management for preventing diverticular disease.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review A: prevention of diverticular disease in patients with diverticulosis.\n\nReturn to recommendations\n\n# Symptoms and signs of diverticular disease\n\nRecommendation 1.2.1\n\n## Why the committee made the recommendation\n\nThe evidence on symptoms and signs comprised a single study with no clinically important outcomes and was based on a population with diverticulitis rather than diverticular disease. Because of a lack of evidence, recommendations were made using formal consensus methods and the knowledge and expertise of the committee on the most common presentation of diverticular disease.\n\nMost people experience pain on the left side of the abdomen where the diverticula most often occur in the sigmoid colon. For this reason people are often tender in the left lower quadrant. However, it was important to highlight that people of Asian origin may experience right-sided symptoms. Other symptoms are variable but people experience constipation, diarrhoea or both, with occasional rectal bleeds. The symptoms alone are not specific enough to indicate diverticular disease but should be considered in conjunction with intermittent abdominal pain. Symptoms may overlap with conditions such as irritable bowel syndrome, colitis and malignancy.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review B: symptoms and signs of diverticular disease.\n\nReturn to recommendations\n\n# Investigations and referral for diverticular disease\n\nRecommendations 1.2.2 to 1.2.3\n\n## Why the committee made the recommendations\n\nThere was no evidence on diagnosing diverticular disease so the guideline committee made recommendations based on their knowledge of current best practice. Where diverticular disease is suspected, current practice is to use imaging or endoscopy to confirm the presence of diverticula or exclude other diseases such as cancer. Patients will often have their bowel investigated by either endoscopy with a flexible sigmoidoscopy or colonoscopy or CT colonography. The committee agreed that these routine endoscopic and radiological investigations can sometimes be organised from primary care but that referral would be needed if this was not available.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review C: diagnosis of diverticular disease.\n\nReturn to recommendations\n\n# Management and advice for people with diverticular disease\n\nRecommendations 1.2.4 to 1.2.11\n\n## Why the committee made the recommendations\n\nVery limited evidence was identified on a high fibre diet, antibiotics, aminosalicylates, probiotics, symbiotics and laxatives and there was no evidence on non-steroidal anti-inflammatory drugs (NSAIDs). The evidence that was available didn't help the committee to understand the impact of these interventions on the progression of disease or people's quality of life. The committee used formal consensus methods together with their expertise and knowledge to make recommendations on diet and lifestyle advice and how to manage pain and cramping.\n\nBulk-forming laxatives are effective as they help to soften the stool and can also help to solidify loose stools in people with constipation. Paracetamol is indicated for pain and the committee highlighted the importance of avoiding NSAIDs and opioid analgesia because of the risk of diverticular perforation. Some people experience abdominal cramping, and anti-spasmodics may help with this.\n\nIn line with best practice in antimicrobial stewardship, the committee made a recommendation not to use antibiotics in the absence of acute diverticulitis.\n\nHaving a greater understanding of how best to manage symptoms and prevent the disease developing into acute diverticular disease could have a positive impact on a person's health and wellbeing. It could also help avoid potential subsequent treatment costs. The committee therefore made a research recommendation in this area.\n\nThese recommendations are about managing the symptoms of diverticular disease rather than preventing progression to acute diverticulitis. However, the development of acute diverticulitis was included as an outcome in this review and in the research recommendation that was developed, because the committee considered it to be a critical factor for decision making. The committee noted the importance of considering alternative causes and further investigations in people with persistent symptoms or who do not respond to treatment.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review D: management of diverticular disease.\n\nReturn to recommendations\n\n# Recurrent diverticular disease\n\n## Why the committee did not make any recommendations\n\nThere was no evidence included for this review and the committee were unable to make any recommendations based on their experience or opinion.\n\nFull details of the evidence and the committee's discussion are in evidence review E: management of recurrent diverticular disease.\n\nReturn to recommendations\n\n# Symptoms and signs of acute diverticulitis\n\nRecommendation 1.3.1\n\n## Why the committee made the recommendation\n\nThere was no relevant evidence on the symptoms and signs of acute diverticulitis, so recommendations were made using formal consensus methods. The committee thought that clearly defining the symptoms and signs of acute diverticulitis, along with its associated complications, would help clinicians and patients in clearly differentiating these distinct clinical conditions.\n\nCommittee members thought that diverticular disease, symptomatic diverticular disease and acute diverticulitis are often used interchangeably, creating confusion about which condition the patient has and therefore what management is appropriate. The recommendation is focused on symptoms and signs that are specific to acute diverticulitis. It is aimed at primary care to support the identification of the condition.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review F: referral criteria for acute diverticulitis.\n\nReturn to recommendations\n\n# Symptoms and signs of complicated acute diverticulitis\n\nRecommendation 1.3.2\n\n## Why the committee made the recommendation\n\nThere was no relevant evidence on the symptoms and signs of complicated acute diverticulitis, so a recommendation was made using formal consensus methods. The recommendation focuses on symptoms and signs that differentiate uncomplicated from complicated acute diverticulitis. If any of these symptoms and signs are present, same-day hospital assessment is necessary.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review I: indications for surgery.\n\nReturn to recommendations\n\n# Investigation of suspected acute diverticulitis\n\nRecommendations 1.3.3 to 1.3.6\n\n## Why the committee made the recommendations\n\nThere was insufficient evidence available on diagnostic tests for people who are not referred for same-day hospital assessment. The committee highlighted the importance of reassessment or referral if the person's symptoms persist or worsen, as this could indicate complicated acute diverticulitis or an alternative diagnosis.\n\nFor people with suspected complications of acute diverticulitis referred for urgent same-day hospital assessment, the committee agreed that less costly clinical tests of full blood count and C‑reactive protein (CRP) should be offered initially to identify inflammation. The urea and electrolytes test assesses kidney function, which will help to determine if a contrast CT can be performed. The CT could inform the decision making and help decide which patients should undergo further investigation for acute diverticulitis.\n\nThe committee acknowledged that contrast CT is recognised as the gold standard diagnostic test for acute diverticulitis and its complications. They agreed that having an early CT scan to assess for acute diverticulitis would mean that complications could be identified sooner. This would subsequently reduce length of hospital stay and the number of later colonoscopies. In addition, having the scan within 24\xa0hours of admission would also help guide treatment planning. For example, it could identify people with uncomplicated diverticular disease who can be given oral antibiotics and discharged or have antibiotics stopped and be discharged.\n\nWhere contrast CT is contraindicated, the committee agreed that non-contrast CT, MRI or ultrasound are accepted alternatives to contrast CT. The choice of whether to perform ultrasound should depend on the availability of local expertise. Ultrasound may not be able to diagnose diverticulitis in isolation, but it may identify factors such as colonic wall thickening and inflammation. Ultrasound may be used as an adjunct to rule out other disease.\n\nThere was no evidence for colonoscopy and sigmoidoscopy in diagnosing acute diverticulitis. The committee were aware of the risk of perforation and agreed that these procedures should not be offered for acute diverticulitis.\n\n## How the recommendations might affect practice\n\nFull blood count and CRP are routinely used to assess for inflammation and indication of acute diverticulitis. This reflects current best practice but is not used across all NHS settings. Therefore implementing this recommendation will mean a change in practice for some providers.\n\nCurrently, 60% of people with acute diverticulitis undergo CT examination to confirm the diagnosis. This recommendation will increase the use of CT scanning. However, the increase in cost associated with this will be offset by a decrease in hospital stays, along with a decrease in use of intravenous antibiotics and potentially further endoscopy. Evidence shows that performing a CT can reduce the use of subsequent endoscopy.\n\nFull details of the evidence and the committee's discussion are in evidence review G: diagnostic tests for acute diverticulitis.\n\nReturn to recommendations\n\n# Non-surgical management of acute diverticulitis\n\nRecommendations 1.3.7 to 1.3.14\n\n## Why the committee made the recommendations\n\nFor people with suspected acute diverticulitis who are not referred for urgent same-day hospital assessment, the committee agreed that watchful waiting is an option if the person is systemically well and has no comorbidities that increase the risk of infection. This decision would be in the context of shared decision making. Simple analgesia and advice can be offered. Oral antibiotics are appropriate if the person is systemically unwell but does not meet the criteria for referral with suspected complicated acute diverticulitis.\n\nThe evidence supports current practice of treating an acute episode of diverticulitis with intravenous antibiotics in secondary care. If CT confirms uncomplicated acute diverticulitis, switching to oral antibiotics does not affect outcomes. The committee recommended antibiotics for this group because they were aware of evidence that watchful waiting could increase recurrence rates and the probability of further surgery. In support of antibiotic stewardship and to avoid antibiotic resistance the committee recommended that the person should be reassessed if necessary and the need for antibiotic treatment should be reviewed.\n\nThe need for intravenous antibiotics should be reviewed, including whether to stop them, within 48\xa0hours in line with current good practice on antibiotic prescribing or after the CT scan. The CT will confirm if the person has an abscess or not. The total course of antibiotic treatment should be for a maximum of 5\xa0days and then reviewed. The duration may need to be longer in people with diverticular abscess. The duration of antibiotics used in the studies was variable and 5\xa0days was based on current clinical practice and the knowledge and expertise of the committee.\n\nIn light of the lack of evidence on this topic, and the need to prevent antibiotic resistance, the committee considered this an important area for research. It made a research recommendation on antibiotics for people with acute diverticulitis managed in primary care.\n\n## How the recommendations might affect practice\n\nThe recommendation to offer an initial treatment of intravenous antibiotics before CT scanning for confirmation reflects current practice, so there should be no change in practice. Using oral antibiotics beyond this point in place of intravenous antibiotics may reduce the resource requirement in caring for people with acute diverticulitis.\n\nFull details of the evidence and the committee's discussion are in evidence review H: non-surgical management of acute diverticulitis.\n\nReturn to recommendations\n\n# Management of abscesses in complicated acute diverticulitis\n\nRecommendations 1.3.15 to 1.3.25\n\n## Why the committee made the recommendations\n\nThe quality of the evidence for this topic meant that it was not possible to demonstrate greater effectiveness of one intervention over another. The results showed harms as well as benefits of treatment. The committee therefore made recommendations based on their clinical expertise and the approaches taken in the studies. The committee highlighted the risk of sepsis and agreed that it is important to refer people with suspected diverticular abscess to secondary care for same-day assessment and treatment with intravenous antibiotics in line with the NICE guideline on sepsis. The committee considered this to be standard practice.\n\nThe need for intravenous antibiotics should be reviewed within 48\xa0hours in line with current good practice on antibiotic prescribing or after the CT scan. The CT will confirm if the person has an abscess or not.\n\nThe committee agreed that offering a CT scan to people with suspected diverticular abscess may help to determine the most appropriate treatment for each person based on the characteristics of the abscesses, such as size and location. This was based on clinical experience and the fact that most of the included studies used CT scans to confirm and assess abscesses. Non-contrast CT, MRI or ultrasound (depending on local expertise) should be offered if contrast CT is contraindicated.\n\nThe committee also decided that only abscesses greater than 3\xa0cm should be considered for percutaneous drainage because of technical difficulties in performing this procedure on smaller abscesses. This was based on clinical expertise and was the approach taken by most of the included studies.\n\nThe committee agreed that if percutaneous drainage is an anatomically feasible option this could be considered alongside a discussion with the patient about the risks and benefits of surgery. In people with a CT-confirmed diverticular abscess, re-imaging may be considered if the condition does not improve clinically of if there is deterioration. This will guide the management strategy – for example, if further surgery is needed or if a previous collection that was not drainable percutaneously (for example because it was too small) is now drainable.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review N: percutaneous drainage versus resectional surgery for the management of abscesses.\n\nReturn to recommendations\n\n# Management of bowel perforations in complicated acute diverticulitis\n\nRecommendation 1.3.26\n\n## Why the committee made the recommendation\n\nThe committee noted that, based on the evidence, there appeared to be few differences between resection of the bowel and lavage in terms of patient outcomes. The committee agreed that for people with diverticular perforations with generalised peritonitis, both options should be discussed and a decision made based on patient preferences. A patient decision table has been developed to support this discussion.\n\nNo evidence was found for the treatment of faecal peritonitis (also known as Hinchey stage\xa0IV perforation). But the committee agreed that resection of the bowel is better than lavage because it is the only way to prevent further faecal contamination of the peritoneal cavity.This is because of the more serious nature of this condition indicated by the presence of faeces in the peritoneal cavity.\n\n## How the recommendation might affect practice\n\nThe committee considered that lavage is not commonly used in the UK for treating diverticular perforation. Implementing this recommendation may therefore require a change from current practice by the majority of providers.\n\nFull details of the evidence and the committee's discussion are in evidence review O: laparoscopic lavage for the management of bowel perforations.\n\nReturn to recommendations\n\n# Anastomosis for people with complicated acute diverticulitis\n\nRecommendation 1.3.27\n\n## Why the committee made the recommendation\n\nThe committee agreed that there was too much uncertainty surrounding most of the evidence to recommend one intervention over the other for complicated acute diverticulitis. Very few outcomes indicated a clinical benefit of either primary anastomosis or temporary stoma. For this reason, the committee concluded that both primary anastomosis (which is a join in the bowel, with or without diverting stoma) and Hartmann's procedure should be options for people admitted to surgery for this condition. Based on the expertise and knowledge of the committee, surgeon experience, the patient's age, any other conditions the patient has and how well they can carry out everyday activities and patient condition should be considered.\n\nIn the emergency setting frail patients with multiple medical problems who have sepsis at the time of surgery may benefit from a Hartmann's procedure instead of a primary anastomosis (with or without diverting stoma) as this removes the risk of a subsequent anastomotic leak. However, the committee recognised that patients having a stoma in this setting often find these are permanent and not reversed.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review M: primary versus secondary anastomosis (timing of anastomosis) in complicated acute diverticulitis.\n\nReturn to recommendations\n\n# Bowel resection for people with complicated acute diverticulitis\n\nRecommendation 1.3.28\n\n## Why the committee made the recommendation\n\nNo evidence was found on the extent of bowel resection for people with acute diverticulitis. A recommendation was developed based on the experience of the surgeons on the committee. Committee members discussed the difference between resecting back to normal bowel and resecting back to compliant bowel. The committee agreed that 'normal bowel' could be interpreted by some as bowel without diverticula, rather than bowel that is soft, unthickened and unaffected by inflammation. To avoid this confusion, resecting back to the compliant bowel, which refers to bowel that is functional and is not restricted in terms of movement, was included in the recommendation and reflects the current advice by national bodies.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review L: management of complicated acute diverticulitis – extent of colectomy.\n\nReturn to recommendations\n\n# Elective surgical management after resolution of complicated acute diverticulitis\n\nRecommendation 1.3.29\n\n## Why the committee made the recommendation\n\nThe committee concluded that there was insufficient evidence to say whether laparoscopic resection or open resection was the better management option for people who have recovered from complicated acute diverticulitis but who have continuing symptoms.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review K: laparoscopic versus open sigmoid resection for acute diverticulitis.\n\nReturn to recommendations\n\n# Timing of surgery for complicated acute diverticulitis\n\n## Why the committee did not make any recommendations\n\nIn the studies in the evidence reviewed people were offered an intervention based on demographic and clinical characteristics. This meant it was difficult to assess the true effect of interventions on patient outcomes. Therefore the committee decided not to make any practice recommendations.\n\nThe committee thought this was an area that needed further research and therefore developed a research recommendation.\n\nFull details of the evidence and the committee's discussion are in evidence review J: timing of surgery for complicated acute diverticulitis.\n\nReturn to recommendations\n\n# Management of recurrent acute diverticulitis\n\nRecommendation 1.3.30\n\n## Why the committee made the recommendation\n\nThe committee noted that the evidence supported current practice of not using an aminosalicylate in managing recurrent diverticulitis. Aminosalicylates are not licensed to treat diverticulitis in the UK and there is little evidence to support their use in this area.\n\nThe committee agreed that there was insufficient evidence to support the use of antibiotics to prevent recurrent diverticular disease. In support of antibiotic stewardship and to avoid antibiotic resistance the committee recommended not offering antibiotic treatment.\n\n## How the recommendation might affect practice\n\nThe recommendation to not offer an aminosalicylate or antibiotics for the prevention of recurrent diverticulitis reflects current practice. Therefore the committee agreed there should be no change in practice.\n\nFull details of the evidence and the committee's discussion are in evidence review P: management of recurrent acute diverticulitis.\n\nReturn to recommendations\n\n# Information\n\nRecommendations 1.4.1 to 1.4.3\n\n## Why the committee made the recommendations\n\nThere was limited evidence on the support and information needed for people with diverticulosis, diverticular disease and diverticulitis and their families and carers. The evidence was from a symptom-based questionnaire and reported on the timing and success of surgery and symptoms. The committee agreed that it is important for those affected to have relevant information on these topics, but also used its knowledge and experience to expand on these topics in the recommendations.\n\nThe committee decided that given the limited evidence, this is an area that needs further research to identify the type of information people want. Therefore they made a research recommendation.\n\n## How the recommendations might affect practice\n\nThe recommendation reflects current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review Q: information and support.\n\nReturn to recommendations", 'Context': 'Diverticulosis is a digestive condition characterised by small pouches (diverticula) that protrude from the walls of the large intestine.\n\nThe true prevalence of diverticulosis is difficult to determine because most patients are asymptomatic. It is age dependent and relatively uncommon in people aged under 40, although in recent years there has been a dramatic rise in the prevalence in this age group. In people aged over 65 the prevalence is up to 65%.\n\nAbout 80 to 85% of people affected by diverticulosis remain asymptomatic, and 10 to 15% develop symptomatic diverticular disease including acute diverticulitis and its complications (perforation, abscess formation, haemorrhage, fistula and obstruction).\n\nKey aspects of this guideline include the management of diverticulosis, diagnosis and management of diverticular disease, acute diverticulitis and complicated acute diverticulitis\n\nAreas of the guideline with the potential for the greatest impact on practice include CT scanning for acute diverticulitis and offering resection or lavage for bowel perforations.', 'Finding more information and resources': "You can see everything NICE says on diverticular disease in our interactive flowchart on diverticular disease.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on digestive tract conditions.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.\n\nISBN: 978-1-4731-3603-8"}
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https://www.nice.org.uk/guidance/ng147
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This guideline covers the diagnosis and management of diverticular disease in people aged 18 years and over. It aims to improve diagnosis and care and help people get timely information and advice, including advice about symptoms and when to seek help.
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af9903c9ddf92618c345377b30b1a0e2e3eba9dd
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nice
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Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer
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Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer
This guideline covers care for people with a family history of breast, ovarian or another related (prostate or pancreatic) cancer. It aims to improve the long-term health of these families by describing strategies to reduce the risk of and promote early detection of breast cancer (including genetic testing and mammography). It also includes advice on treatments (tamoxifen, raloxifene) and surgery (mastectomy).
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The recommendations in this guideline apply to women and men unless otherwise specified.
# Clinical significance of a family history of breast cancer
## Accuracy of family history
When a person with no personal history of breast cancer presents with breast symptoms or has concerns about relatives with breast cancer, a first- and second-degree family history should be taken in primary care to assess risk, because this allows appropriate classification and care.
This recommendation has been deleted following a review.
In some circumstances, it may also be clinically relevant to take a family history, for example, for women older than age 35 years using an oral contraceptive pill or for women being considered for long-term HRT use.
A person should be given the opportunity to discuss concerns about their family history of breast cancer if it is raised during a consultation.
A second-degree family history (that is, including aunts, uncles and grandparents) should be taken in primary care before explaining risks and options.
A second-degree family history needs to include paternal as well as maternal relatives.
Asking people to discuss their family history with relatives is useful in gathering the most accurate information.
Tools such as family history questionnaires and computer packages exist that can aid accurate collection of family history information and they should be made available.
For referral decisions, attempts should be made to gather as accurate information as possible on:
age of diagnosis of any cancer in relatives
site of tumours
multiple cancers (including bilateral disease)
Jewish ancestry (women with Jewish ancestry are around 5 to 10 times more likely to carry BRCA1 or BRCA2 mutations than women in non-Jewish populations).
A family history should be taken when a person with no personal history of breast cancer presents with breast symptoms or has concerns about relatives with breast cancer.
A third-degree family history should be taken in secondary care where possible and appropriate.
Tools such as family history questionnaires and computer packages exist that can aid accurate collection of family history information and risk assessment and they should be made available.
A third-degree family history should be taken in a specialist genetic clinic for a person with no personal history of breast cancer, if this has not been done previously.
For accurate risk estimation, the following are required:
age of death of affected and unaffected relatives
current age of unaffected relatives.
In general, it is not necessary to validate breast cancer-only histories (via medical records/cancer registry/death certificates).
If substantial management decisions, such as risk-reducing surgery, are being considered and no mutation has been identified, clinicians should seek confirmation of breast cancer-only histories (via medical records/cancer registry/death certificates).
Where no family history verification is possible, agreement by a multidisciplinary team should be sought before proceeding with risk-reducing surgery.
Abdominal malignancies at young ages and possible sarcomas should be confirmed in specialist care.
## Family history and carrier probability
When available in secondary care, use a carrier probability calculation method with demonstrated acceptable performance (calibration and discrimination) as well as family history to determine who should be offered referral to a specialist genetic clinic. Examples of acceptable methods include BOADICEA and the Manchester scoring system.
In a specialist genetic clinic, use a carrier probability calculation method with demonstrated acceptable performance (calibration and discrimination) to assess the probability of a BRCA1 or BRCA2 mutation. Examples of acceptable methods include BOADICEA and the Manchester scoring system.
If there are problems with using or interpreting carrier probability calculation methods, use clinical judgement when deciding whether to offer genetic testing.
## Communicating cancer risk and carrier probability
People should be offered a personal risk estimate but information should also be given about the uncertainties of the estimation.
When a personal risk value is requested, it should be presented in more than one way (for example, a numerical value, if calculated, and qualitative risk).
People should be sent a written summary of their consultation in a specialist genetic clinic, which includes their personal risk information.
# Information and support
Effective care involves a balanced partnership between patients and healthcare professionals. Patients should have the opportunity to make informed choices about any treatment and care and to share in decision making.
To ensure a patient-professional partnership, patients should be offered individually tailored information, including information about sources of support (including local and national organisations).
Tailoring of information should take into account format (including whether written or taped) as well as the actual content and form that should be provided (see box 1).
Standard information should be evidence based wherever possible, and agreed at a national level if possible (NICE's information for the public provides a good starting point).
Standard information should not contradict messages from other service providers, including commonly agreed information across localities.
## Box 1 Information provision for people with concerns about familial breast cancer risk
Standard written information for all people
Risk information about population level and family history levels of risk, including a definition of family history.
The message that, if their family history alters, their risk may alter.
Breast awareness information.
Lifestyle advice regarding breast cancer risk, including information about:
HRT and oral contraceptives (women only)
lifestyle, including diet, alcohol, etc
breastfeeding, family size and timing (women only).
Contact details of those providing support and information, including local and national support groups.
People should be informed prior to appointments that they can bring a family member/friend with them to appointments.
Details of any trials or studies that may be appropriate.
For people cared for in primary care
Standard written information (as above).
Advice to return to discuss any implications if there is a change in family history or breast symptoms develop.
For people being referred to secondary care
Standard written information (as above).
Information about the risk assessment exercise that will take place and advice about how to obtain a comprehensive family history if required.
Information about potential outcomes, depending on the outcome of the risk assessment (including referral back to primary care, management within secondary care or referral to a specialist genetics service) and what may happen at each level.
For people being referred back to primary care
Standard written information (as above).
Detailed information about why secondary or a specialist genetics service are not needed.
Advice to return to primary care to discuss any implications if there is a change in family history or breast symptoms develop.
For people being cared for in secondary care
Standard written information (as above).
Details of the risk assessment outcome, including why they are not being referred to a specialist genetics service.
Details of surveillance options including risk and benefits.
For people being referred to a specialist genetic clinic
Standard written information (as above).
Details of the risk assessment outcome, including why they are being referred to a specialist genetics service.
Details of surveillance options, including risk and benefits.
Details of what should be expected in a specialist genetics service, including counselling and genetic testing.
For people being cared for in a specialist genetic clinic
Standard written information (as above).
Information about hereditary breast cancer.
Information about genetic testing, both predictive testing and mutation finding, including details of what the tests mean and how informative they are likely to be, and the likely timescale of being given the results.
Information about the risks and benefits of risk-reducing surgery when it is being considered, including both physical and psychological impact.
# Care of people in primary care
## Care and management in primary care
People without a personal history of breast cancer can be cared for in primary care if the family history shows only 1 first-degree or second-degree relative diagnosed with breast cancer at older than age 40 years (in most cases, this will equate to less than a 3% 10-year risk of breast cancer at age 40 years), provided that none of the following are present in the family history:
bilateral breast cancer
male breast cancer
-varian cancer
Jewish ancestry
sarcoma in a relative younger than age 45 years
glioma or childhood adrenal cortical carcinomas
complicated patterns of multiple cancers at a young age
paternal history of breast cancer (2 or more relatives on the father's side of the family).
People who do not meet the criteria for referral should be cared for in primary care by giving standard written information.
## Referral from primary care
People without a personal history of breast cancer who meet the following criteria should be offered referral to secondary care:
first-degree female relative diagnosed with breast cancer at younger than age 40 years or
first-degree male relative diagnosed with breast cancer at any age or
first-degree relative with bilateral breast cancer where the first primary was diagnosed at younger than age 50 years or
first-degree relatives, or 1 first-degree and 1 second-degree relative, diagnosed with breast cancer at any age or
first-degree or second-degree relative diagnosed with breast cancer at any age and 1 first-degree or second-degree relative diagnosed with ovarian cancer at any age (1 of these should be a first-degree relative) or
first-degree or second-degree relatives diagnosed with breast cancer at any age.
Advice should be sought from the designated secondary care contact if any of the following are present in the family history in addition to breast cancers in relatives not fulfilling the above criteria:
bilateral breast cancer
male breast cancer
-varian cancer
Jewish ancestry
sarcoma in a relative younger than age 45 years
glioma or childhood adrenal cortical carcinomas
complicated patterns of multiple cancers at a young age
paternal history of breast cancer (2 or more relatives on the father's side of the family).
Discussion with the designated secondary care contact should take place if the primary care health professional is uncertain about the appropriateness of referral because the family history presented is unusual or difficult to make clear decisions about, or where the person is not sufficiently reassured by the standard information provided.
Direct referral to a specialist genetics service should take place where a high-risk predisposing gene mutation has been identified (for example, BRCA1, BRCA2 or TP53).
## Patient education and information
Women who are being referred to secondary care or a specialist genetic clinic should be provided with written information about what happens at this stage.
Support mechanisms (for example, risk counselling, psychological counselling and risk management advice) need to be identified, and should be offered to women not eligible for referral and/or surveillance on the basis of age or risk level who have ongoing concerns.
## Support for primary care
Support is needed for primary care health professionals to care for women with a family history of breast cancer. Essential requirements for support for primary care are:
a single point and locally agreed mechanism of referral for women identified as being at increased risk
educational materials about familial breast cancer
decision-support systems
standardised patient information leaflets
a designated secondary care contact to discuss management of 'uncertain' cases.
# Care of people in secondary care and specialist genetic clinics
## Care and management approach in secondary care
Care of people in secondary care (such as a breast care team, family history clinic or breast clinic) should be undertaken by a multidisciplinary team. It should include the following:
written protocols for management
central, standardised resources
mammographic surveillance available to the standard of the national breast screening programmes (England – NHS Breast Screening Programme ; Wales – Breast Test Wales; Northern Ireland – NI Breast Screening Programme)
access to surveillance as described in section 1.6
access to a team offering risk-reducing surgery
standardised written information
designated/lead clinicians
a designated contact for primary care
a designated contact in a specialist genetic clinic
audit
clinical trials access
access to psychological assessment and counselling
information about support groups and voluntary organisations
administrative support.
People who meet the following criteria should be offered secondary care and do not require referral to a specialist genetic clinic:
first-degree relative diagnosed with breast cancer at younger than age 40 years or
first-degree or second-degree relatives diagnosed with breast cancer at an average age of older than 50 years or
first-degree or second-degree relatives diagnosed with breast cancer at an average age of older than 60 years or
a formal risk assessment (usually carried out in a specialist genetic clinic) or a family history pattern is likely to give risks of greater than 3 to 8% risk in the next 10 years for women aged 40 years, or a lifetime risk of 17% or greater but less than 30% (a woman's age should be assumed to be 40 for a woman in her forties; a 10-year risk should be calculated for the age range 40 to 49)provided that none of the following are present in the family history:
bilateral breast cancer
male breast cancer
-varian cancer
Jewish ancestry
sarcoma in a relative younger than 45 years of age
glioma or childhood adrenal cortical carcinomas
complicated patterns of multiple cancers at a young age
very strong paternal history (4 relatives diagnosed at younger than 60 years of age on the father's side of the family).
People whose risk does not meet the criteria for referral to secondary care (see recommendation 1.3.3) can be referred back to primary care:
with appropriate information being offered and
support mechanisms (for example, risk counselling, psychological counselling and risk management advice) need to be identified, and should be offered to people not eligible for referral and/or surveillance on the basis of age or risk level who have ongoing concerns.
## Referral to a specialist genetic clinic
People who meet the following referral criteria should be offered a referral to a specialist genetic clinic.
At least the following female breast cancers only in the family:
first-degree or second-degree relatives diagnosed with breast cancer at younger than an average age of 50 years (at least 1 must be a first-degree relative) or
first-degree or second-degree relatives diagnosed with breast cancer at younger than an average age of 60 years (at least 1 must be a first-degree relative) or
relatives diagnosed with breast cancer at any age (at least 1 must be a first-degree relative). or
Families containing 1 relative with ovarian cancer at any age and, on the same side of the family:
first-degree relative (including the relative with ovarian cancer) or second-degree relative diagnosed with breast cancer at younger than age 50 years or
first-degree or second-degree relatives diagnosed with breast cancer at younger than an average age of 60 years or
another ovarian cancer at any age. or
Families affected by bilateral cancer (each breast cancer has the same count value as 1 relative):
first-degree relative with cancer diagnosed in both breasts at younger than an average age 50 years or
first-degree or second-degree relative diagnosed with bilateral cancer and 1 first or second degree relative diagnosed with breast cancer at younger than an average age of 60 years. or
Families containing male breast cancer at any age and, on the same side of the family, at least:
first-degree or second-degree relative diagnosed with breast cancer at younger than age 50 years or
first-degree or second-degree relatives diagnosed with breast cancer at younger than an average age of 60 years. or
A formal risk assessment has given risk estimates of:
a 10% or greater chance of a gene mutation being harboured in the family (see recommendations 1.5.8 to 1.5.13) or
a greater than 8% risk of developing breast cancer in the next 10 years or
a 30% or greater lifetime risk of developing breast cancer.
Clinicians should seek further advice from a specialist genetics service for families containing any of the following, in addition to breast cancers:
triple negative breast cancer under the age of 40 years
Jewish ancestry
sarcoma in a relative younger than age 45 years
glioma or childhood adrenal cortical carcinomas
complicated patterns of multiple cancers at a young age
very strong paternal history (4 relatives diagnosed at younger than 60 years of age on the father's side of the family).
The management of high-risk people may take place in secondary care if they do not want genetic testing or risk-reducing surgery and do not wish to be referred to a specialist genetics service.
Following initial consultation in secondary care, written information should be provided to reflect the outcomes of the consultation.
## Care of people in a specialist genetic clinic
Care of people referred to a specialist genetic clinic should be undertaken by a multi-disciplinary team. In addition to having access to the components found in secondary care, it should also include the following:
clinical genetic risk assessment
verification for abdominal malignancies and possible sarcomas.
## Genetic counselling for people with no personal history of breast cancer
Women with no personal history of breast cancer meeting criteria for referral to a specialist genetic clinic should be offered a referral for genetic counselling regarding their risks and options.
Women attending genetic counselling should receive standardised information beforehand describing the process of genetic counselling, information to obtain prior to the counselling session, the range of topics to be covered and brief educational material about hereditary breast cancer and genetic testing.
Predictive genetic testing should not be offered without adequate genetic counselling.
# Genetic testing
All eligible people should have access to information on genetic tests aimed at mutation finding.
Pre-test counselling (preferably 2 sessions) should be undertaken.
Discussion of genetic testing (predictive and mutation finding) should be undertaken by a healthcare professional with appropriate training.
Eligible people and their affected relatives should be informed about the likely informativeness of the test (the meaning of a positive and a negative test) and the likely timescale of being given the results.
## Mutation tests
Tests aimed at mutation finding should first be carried out on an affected family member where possible.
If possible, the development of a genetic test for a family should usually start with the testing of an affected individual (mutation searching/screening) to try to identify a mutation in the appropriate gene (such as BRCA1, BRCA2 or TP53) (see recommendations 1.5.8 to 1.5.13).
A search/screen for a mutation in a gene (such as BRCA1, BRCA2 or TP53) should aim for as close to 100% sensitivity as possible for detecting coding alterations and the whole gene(s) should be searched.
## Carrier probability at which genetic testing should be offered
Discuss the potential risk and benefits of genetic testing. Include in the discussion the probability of finding a mutation, the implications for the individual and the family, and the implications of either a variant of uncertain significance or a null result (no mutation found).
Inform families with no clear genetic diagnosis that they can request review in the specialist genetic clinic at a future date.
Clinical genetics laboratories should record gene variants of uncertain significance and known pathogenic mutations in a searchable electronic database.
Offer genetic testing in specialist genetic clinics to a relative with a personal history of breast and/or ovarian cancer if that relative has a combined BRCA1 and BRCA2 mutation carrier probability of 10% or more.
Offer genetic testing in specialist genetic clinics to a person with no personal history of breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more and an affected relative is unavailable for testing.
Offer genetic testing in specialist genetic clinics to a person with breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more.
## Genetic testing for BRCA1, BRCA2 and TP53 mutations within 4 weeks of diagnosis of breast cancer
Offer people eligible for referral to a specialist genetic clinic a choice of accessing genetic testing during initial management or at any time thereafter.
Offer fast-track genetic testing (within 4 weeks of a diagnosis of breast cancer) only as part of a clinical trial.
Discuss the individual needs of the person with the specialist genetics team as part of the multidisciplinary approach to care.
Offer detailed consultation with a clinical geneticist or genetics counsellor to all those with breast cancer who are offered genetic testing, regardless of the timeframe for testing.
# Surveillance and strategies for early detection of breast cancer
Surveillance of women at very high risk of developing breast cancer is run by the NHS Breast Screening Programme (NHSBSP). This applies to women with a lifetime risk of 40% or greater because of a specific genetic abnormality in the woman or her family. Surveillance for women at lower levels of risk is covered by this guideline.
## Breast awareness
Women at increased risk of breast cancer should be 'breast aware' in line with Department of Health advice for all women.
## Surveillance for women with no personal history of breast cancer
Do not routinely offer ultrasound surveillance to women at moderate risk or high risk of breast cancer but consider it:
when MRI surveillance would normally be offered but is not suitable (for example, because of claustrophobia)
when results of mammography or MRI are difficult to interpret.
Offer annual mammographic surveillance to women:
aged 40 to 49 years at moderate risk of breast cancer
aged 40 to 59 years at high risk of breast cancer but with a 30% or lower probability of being a BRCA or TP53 carrier
aged 40 to 59 years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier
aged 40 to 69 years with a known BRCA1 or BRCA2 mutation.
Offer mammographic surveillance as part of the population screening programme to women:
aged 50 years and over who have not had genetic testing but have a greater than 30% probability of being a TP53 carrier
aged 60 years and over at high risk of breast cancer but with a 30% or lower probability of being a BRCA or TP53 carrier
aged 60 years and over at moderate risk of breast cancer
aged 60 years and over who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier
aged 70 years and over with a known BRCA1 or BRCA2 mutation.
Consider annual mammographic surveillance for women:
aged 30 to 39 years at high risk of breast cancer but with a 30% or lower probability of being a BRCA or TP53 carrier
aged 30 to 39 years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier
aged 30 to 39 years with a known BRCA1 or BRCA2 mutation
aged 50 to 59 years at moderate risk of breast cancer.Discuss the benefits and risks of mammographic surveillance with the person before making a shared decision, as described in recommendation 1.6.18.
Do not offer mammographic surveillance to women:
aged 29 years and under
aged 30 to 39 years at moderate risk of breast cancer
aged 30 to 49 years who have not had genetic testing but have a greater than 30% probability of being a TP53 carrier
-f any age with a known TP53 mutation.
Offer annual MRI surveillance to women:
aged 30 to 49 years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier
aged 30 to 49 years with a known BRCA1 or BRCA2 mutation
aged 20 to 49 years who have not had genetic testing but have a greater than 30% probability of being a TP53 carrier
aged 20 to 49 years with a known TP53 mutation.
Consider annual MRI surveillance for women aged 50 to 69 years with a known TP53 mutation.
Do not offer MRI to women:
-f any age at moderate risk of breast cancer
-f any age at high risk of breast cancer but with a 30% or lower probability of being a BRCA or TP53 carrier
aged 20 to 29 years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier
aged 20 to 29 years with a known BRCA1 or BRCA2 mutation
aged 50 to 69 years who have not had genetic testing but have a greater than 30% probability of being a BRCA or a TP53 carrier, unless mammography has shown a dense breast pattern
aged 50 to 69 years with a known BRCA1 or BRCA2 mutation, unless mammography has shown a dense breast pattern. Also see summary of recommendations on surveillance for women with no personal history of breast cancer.
## Surveillance for women with a personal and family history of breast cancer
Ensure that all women with breast cancer are offered annual mammography for 5 years for follow-up imaging, in line with the NICE guideline on early and locally advanced breast cancer. In conjunction with follow-up, women who remain at high risk of breast cancer and have a family history should receive surveillance as outlined in recommendations 1.6.11 to 16.15.
Offer annual mammographic surveillance to all women aged 50 to 69 years with a personal history of breast cancer who:
remain at high risk of breast cancer (including those who have a BRCA1 or BRCA2 mutation), and
do not have a TP53 mutation.
Offer mammography as part of the population screening programme for all women aged 70 years and over with a personal history of breast cancer who:
remain at high risk of breast cancer (including those who have a BRCA1 or BRCA2 mutation), and
do not have a TP53 mutation.
Offer annual MRI surveillance to all women aged 30 to 49 years with a personal history of breast cancer who remain at high risk of breast cancer, including those who have a BRCA1 or BRCA2 mutation.
Do not offer MRI surveillance to any women aged 50 years and over without a TP53 mutation unless mammography has shown a dense breast pattern.
Consider annual MRI surveillance for women aged 20 to 69 years with a known TP53 mutation or who have not had a genetic test but have a greater than 30% probability of being a TP53 carrier.
Ensure that surveillance for people with a personal history of breast cancer who remain at moderate risk of breast cancer is in line with the NICE guideline on early and locally advanced breast cancer.
## Recommendations for all women having surveillance
Offer support (for example, risk counselling, psychological counselling and risk management advice) to women who have ongoing concerns but are not eligible for surveillance additional to that offered by the national breast screening programmes (England – NHS Breast Screening Programme ; Wales – Breast Test Wales; Northern Ireland – NI Breast Screening Programme).
Before decisions on surveillance are made, discuss and give written information on the benefits and risks of surveillance, including:
the possibility that mammography might miss a cancer in women with dense breasts and the increased likelihood of further investigations
possible over diagnosis
the risk associated with exposure to radiation
the possible psychological impact of a recall visit.
Review eligibility for surveillance if family history changes (for example, if another member of the family develops breast cancer or a mutation is identified).
At the start of a surveillance programme and when there is a transition or change to the surveillance plan, give women:
information about the surveillance programme, including details of the tests, how often they will have them and the duration of the programme
information about the risks and benefits of surveillance
details of sources of support and further information.
Ensure that women know and understand the reasons for any changes to the surveillance plan.
For women under 50 years who are having mammography, use digital mammography at centres providing digital mammography to national breast screening programme standards.
Ensure that individual strategies are developed for all women having mammographic surveillance and that surveillance is:
to national breast screening programme standards
audited
-nly undertaken after written information is given about risks and benefits.
Ensure that MRI surveillance includes MRI of both breasts performed to national breast screening programme standards.
When women not known to have a genetic mutation are referred to a specialist genetic clinic, offer them assessment of their carrier probability using a carrier probability calculation method with acceptable performance (calibration and discrimination) to determine whether they meet or will meet the criteria for surveillance. (An example of an acceptable method is BOADICEA.)
Do not offer surveillance to women who have undergone a bilateral mastectomy.
# Risk reduction and treatment strategies
## Risk factors
People should be provided with standardised written information about risk, including age as a risk factor.
Modifiable risk factors should be discussed on an individual basis in the relevant care setting.
## Menstrual and reproductive factors
Healthcare professionals should be able to provide information on the effects of hormonal and reproductive factors on breast cancer risk.
## Hormonal contraceptives
Advice to women up to age 35 years with a family history of breast cancer should be in keeping with general health advice on the use of the oral contraceptive pill.
Women aged over 35 years with a family history of breast cancer should be informed of an increased risk of breast cancer associated with taking the oral contraceptive pill, given that their absolute risk increases with age.
For women with BRCA1 mutations, the conflicting effects of a potential increased risk of breast cancer under the age of 40 years and the lifetime protection against ovarian cancer risk from taking the oral contraceptive pill should be discussed.
Women should not be prescribed the oral contraceptive pill purely for prevention of cancer, although in some situations reduction in ovarian cancer risk may outweigh any increase in risk of breast cancer.
If a woman has a BRCA1 mutation and is considering a risk-reducing oophorectomy before the age of 40 years, the oral contraceptive pill should not be prescribed purely for the reduction in ovarian cancer risk.
## Breastfeeding
Women should be advised to breastfeed if possible because this is likely to reduce their risk of breast cancer, and is in accordance with general health advice.
## Hormone replacement therapy
Women with a family history of breast cancer who are considering taking, or already taking, HRT should be informed of the increase in breast cancer risk with type and duration of HRT.
Advice to individual women on the use of HRT should vary according to the individual clinical circumstances (such as asymptomatic menopausal symptoms, age, severity of menopausal symptoms, or osteoporosis).
HRT usage in a woman at familial risk should be restricted to as short a duration and as low a dose as possible. Oestrogen-only HRT should be prescribed where possible.
A woman having an early (natural or artificial) menopause should be informed of the risks and benefits of HRT, but generally HRT usage should be confined to women younger than age 50 years if at moderate or high risk (see also recommendations 1.7.53 and 1.7.54).
Alternatives to HRT should be considered for specific symptoms such as osteoporosis or menopausal symptoms (see also recommendations 1.7.53 and 1.7.54).
Consideration should be given to the type of HRT if it is being considered for use in conjunction with risk-reducing gynaecological surgery.
## Alcohol consumption
Women with a family history should be informed that alcohol may increase their risk of breast cancer slightly. However, this should be considered in conjunction with any potential benefit of moderate alcohol intake on other conditions (such as heart disease) and adverse effects associated with excessive alcohol intake.
## Smoking
Women should be advised not to smoke, in line with current health advice.
## Weight and physical activity
Women should be advised on the probable increased postmenopausal risk of breast cancer from being overweight.
Women should be advised about the potential benefits of physical exercise on breast cancer risk.
## Chemoprevention for women with no personal history of breast cancer
Healthcare professionals within secondary care or specialist genetic clinics should discuss the absolute benefits and risks of options for chemoprevention with women at high risk or moderate risk of breast cancer. Discussion, using a decision aid, should include the following to promote shared decision-making and informed preferences:
the reduced risk of invasive breast cancer
the lack of effect on mortality
the side effects of the different options
alternative approaches, such as surveillance alone and, for women at high risk, risk-reducing surgery. Women should all be given information in an accessible format.
NICE has produced patient decision aids about chemoprevention for women at moderate or high risk of breast cancer.
Offer tamoxifen for 5 years to premenopausal women at high risk of breast cancer unless they have a past history or may be at increased risk of thromboembolic disease or endometrial cancer.
Offer anastrozole for 5 years to postmenopausal women at high risk of breast cancer unless they have severe osteoporosis.In March 2017 this was an off-label use of anastrozole. See NICE's information on prescribing medicines. Women with or at risk of osteoporosis should have their bone mineral density assessed when starting treatment and then at regular intervals. Treatment or prophylaxis for osteoporosis should be started when needed and carefully monitored.
For postmenopausal women at high risk of breast cancer who have severe osteoporosis or do not wish to take anastrozole:
-ffer tamoxifen for 5 years if they have no history or increased risk of thromboembolic disease or endometrial cancer, or
consider raloxifene for 5 years for women with a uterus if they have no history or increased risk of thromboembolic disease and do not wish to take tamoxifen.In March 2017 this was an off-label use of raloxifene. See NICE's information on prescribing medicines.
Do not offer chemoprevention to women who were at high risk of breast cancer but have had bilateral risk-reducing mastectomy.
Consider tamoxifen for 5 years for premenopausal women at moderate risk of breast cancer, unless they have a past history or may be at increased risk of thromboembolic disease or endometrial cancer.
Consider anastrozole for 5 years for postmenopausal women at moderate risk of breast cancer unless they have severe osteoporosis.In March 2017 this was an off-label use of anastrozole. See NICE's information on prescribing medicines. Women with or at risk of osteoporosis should have their bone mineral density assessed when starting treatment and then at regular intervals. Treatment or prophylaxis for osteoporosis should be started when needed and carefully monitored.
For postmenopausal women at moderate risk of breast cancer who have severe osteoporosis or do not wish to take anastrozole:
consider tamoxifen for 5 years if they have no history or increased risk of thromboembolic disease or endometrial cancer, or
consider raloxifene for 5 years for women with a uterus if they have no history or increased risk of thromboembolic disease and do not wish to take tamoxifen.In March 2017 this was an off-label use of raloxifene. See NICE's information on prescribing medicines.
Do not continue chemoprevention beyond 5 years in women with no personal history of breast cancer.
Inform women that they should stop tamoxifen at least:
months before trying to conceive
weeks before elective surgery.
## Risk-reducing mastectomy for women with no personal history of breast cancer
Bilateral risk-reducing mastectomy is appropriate only for a small proportion of women who are from high-risk families and should be managed by a multidisciplinary team.
Bilateral mastectomy should be raised as a risk-reducing strategy option with all women at high risk.
Women considering bilateral risk-reducing mastectomy should have genetic counselling in a specialist cancer genetic clinic before a decision is made.
Discussion of individual breast cancer risk and its potential reduction by surgery should take place and take into account individual risk factors, including the woman's current age (especially at extremes of age ranges).
Family history should be verified where no mutation has been identified before bilateral risk-reducing mastectomy.
Where no family history verification is possible, agreement by a multidisciplinary team should be sought before proceeding with bilateral risk-reducing mastectomy.
Pre-operative counselling about psychosocial and sexual consequences of bilateral risk-reducing mastectomy should be undertaken.
The possibility of breast cancer being diagnosed histologically following a risk-reducing mastectomy should be discussed pre-operatively.
All women considering bilateral risk-reducing mastectomy should be able to discuss their breast reconstruction options (immediate and delayed) with a member of a surgical team with specialist oncoplastic or breast reconstructive skills.
A surgical team with specialist oncoplastic/breast reconstructive skills should carry out risk-reducing mastectomy and/or reconstruction.
Women considering bilateral risk-reducing mastectomy should be offered access to support groups and/or women who have undergone the procedure.
## Risk-reducing oophorectomy for women with no personal history of breast cancer
Risk-reducing bilateral oophorectomy is appropriate only for a small proportion of women who are from high-risk families and should be managed by a multidisciplinary team.
Information about bilateral oophorectomy as a potential risk-reducing strategy should be made available to women who are classified as high risk.
Family history should be verified where no mutation has been identified before bilateral risk-reducing oophorectomy.
Where no family history verification is possible, agreement by a multidisciplinary team should be sought before proceeding with bilateral risk-reducing oophorectomy.
Any discussion of bilateral oophorectomy as a risk-reducing strategy should take fully into account factors such as anxiety levels on the part of the woman concerned.
Healthcare professionals should be aware that women being offered risk-reducing bilateral oophorectomy may not have been aware of their risks of ovarian cancer as well as breast cancer and should be able to discuss this.
The effects of early menopause should be discussed with any woman considering risk-reducing bilateral oophorectomy.
Options for management of early menopause should be discussed with any woman considering risk-reducing bilateral oophorectomy, including the advantages, disadvantages and risk impact of HRT.
Women considering risk-reducing bilateral oophorectomy should have access to support groups and/or women who have undergone the procedure.
Women considering risk-reducing bilateral oophorectomy should be informed of possible psychosocial and sexual consequences of the procedure and have the opportunity to discuss these issues.
Women not at high risk who raise the possibility of risk-reducing bilateral oophorectomy should be offered appropriate information, and if seriously considering this option should be offered referral to the team that deals with women at high risk.
Women undergoing bilateral risk-reducing oophorectomy should have their fallopian tubes removed as well.
When women with no personal history of breast cancer have either a BRCA1 or BRCA2 mutation or a family history of breast cancer and they have had a bilateral salpingo-oophorectomy before their natural menopause, offer them:
combined HRT if they have a uterus
-estrogen-only HRT if they don't have a uterus up until the time they would have expected natural menopause (average age for natural menopause is 51 to 52 years).
Manage menopausal symptoms occurring when HRT is stopped in the same way as symptoms of natural menopause.
## Risk-reducing breast or ovarian surgery for people with a personal history of breast cancer
Refer women with a personal history of breast cancer who wish to consider risk-reducing surgery for appropriate genetic and psychological counselling before surgery.
Discuss the risks and benefits of risk-reducing mastectomy with women with a known or suspected BRCA1, BRCA2 or TP53 mutation.
For a woman considering risk-reducing mastectomy, include in the discussion of risks and benefits:
the likely prognosis of their breast cancer, including their risk of developing a distal recurrence of their previous breast cancer
a clear quantification of the risk of developing breast cancer in the other breast
the potential negative impact of mastectomy on body image and sexuality
the very different appearance and feel of the breasts after reconstructive surgery
the potential benefits of reducing the risk in the other breast and relieving the anxiety about developing breast cancer.
Give all women considering a risk-reducing mastectomy the opportunity to discuss their options for breast reconstruction (immediate and delayed) with a member of a surgical team with specialist skills in oncoplastic surgery or breast reconstruction.
Ensure that risk-reducing mastectomy and breast reconstruction are carried out by a surgical team with specialist skills in oncoplastic surgery and breast reconstruction.
Offer women who have BRCA1, BRCA2 or TP53 mutations but who decide against risk-reducing mastectomy, surveillance according to their level of risk.
Discuss the risks and benefits of risk-reducing bilateral salpingo-oophorectomy with women with a known or suspected BRCA1, BRCA2 or TP53 mutation. Include in the discussion the positive effects of reducing the risk of breast and ovarian cancer and the negative effects of a surgically induced menopause.
Defer risk-reducing bilateral salpingo-oophorectomy until women have completed their family.
Do not offer risk-reducing surgery to people with comorbidities that would considerably increase the risks of surgery.
Do not offer risk-reducing surgery to people who have a limited life expectancy from their cancer or other conditions.
## Treatment options for people with a personal history of breast cancer who are TP53 mutation carriers
When a person has invasive breast cancer or ductal carcinoma in situ and is known to have a TP53 mutation or a 30% probability of a TP53 mutation:
inform them of all the possible treatment options
make sure they know about the uncertainties associated with these treatment options
inform them of the risks associated with each treatment (for example, the risk of recurrence, the risk of new primary breast cancer and the risks of malignancy associated with radiotherapy and chemotherapy).
Offer people with invasive breast cancer or ductal carcinoma in situ and a 30% probability of a TP53 mutation, genetic testing to help determine their treatment options.
# Summary of recommendations on surveillance for women with no personal history of breast cancer
Age (years)
A 30% or lower probability of being a BRCA or TP53 carrier
Untested but greater than 30% BRCA carrier probability
Known BRCA1 or BRCA2 mutation
Untested but greater than 30% TP53 carrier probability
Known TP53 mutation
to 29
Do not offer mammography
Do not offer MRI
Do not offer mammography
Do not offer MRI
Do not offer mammography
Do not offer MRI
Do not offer mammography
Annual MRI
Do not offer mammography
Annual MRI
to 39
Consider annual mammography
Do not offer MRI
Annual MRI and consider annual mammography
Annual MRI and consider annual mammography
Do not offer mammography
Annual MRI
Do not offer mammography
Annual MRI
to 49
Annual mammography
Do not offer MRI
Annual mammography and annual MRI
Annual mammography and annual MRI
Do not offer mammography
Annual MRI
Do not offer mammography
Annual MRI
to 59
Annual mammography
Do not offer MRI
Annual mammography
Do not offer MRI unless dense breast pattern
Annual mammography
Do not offer MRI unless dense breast pattern
Mammography as part of the population screening programme
Do not offer MRI unless dense breast pattern
Do not offer mammography
Consider annual MRI
to 69
Mammography as part of the population screening programme
Do not offer MRI
Mammography as part of the population screening programme
Do not offer MRI unless dense breast pattern
Annual mammography
Do not offer MRI unless dense breast pattern
Mammography as part of the population screening programme
Do not offer MRI unless dense breast pattern
Do not offer mammography
Consider annual MRI
and over
Mammography as part of the population screening programme
Mammography as part of the population screening programme
Mammography as part of the population screening programme
Mammography as part of the population screening programme
Do not offer mammography
High risk of breast cancer (but with a 30% or lower probability of being a BRCA or TP53 carrier) – lifetime risk of at least 30%. High risk group includes rare conditions that carry an increased risk of breast cancer, such as Peutz-Jegher syndrome, (STK11), Cowden (PTEN), familial diffuse gastric cancer (E-Cadherin).
High risk of breast cancer (untested but greater than 30% BRCA carrier probability) – surveillance recommendations reflect the fact that women who at first assessment had a 30% or greater BRCA carrier probability and reach 60 years of age without developing breast or ovarian cancer will now have a lower than 30% carrier probability and should no longer be offered MRI surveillance.
High risk of breast cancer (untested but greater than 30% TP53 carrier probability) – surveillance recommendations reflect the fact that women who at first assessment had a 30% or greater TP53 carrier probability and reach 50 years of age without developing breast cancer or any other TP53-related malignancy will now have a lower than 30% carrier probability and should no longer be offered MRI surveillance.
Age (years)
Moderate risk of breast cancer
to 29
Do not offer mammography
Do not offer MRI
to 39
Do not offer mammography
Do not offer MRI
to 49
Annual mammography
Do not offer MRI
to 59
Consider annual mammography
Do not offer MRI
to 69
Mammography as part of the population screening programme
Do not offer MRI
and over
Mammography as part of the population screening programme
# Terms used in this guideline
Near population risk of breast cancer
Moderate risk of breast cancer
High risk of breast cancer
Lifetime risk from age 20
Less than 17%
Greater than 17% but less than 30%
% or greater
Risk between ages 40 and 50
Less than 3%
to 8%
Greater than 8%
The high-risk group includes known BRCA1, BRCA2 and TP53 mutations and rare conditions that carry an increased risk of breast cancer such as Peutz-Jegher syndrome (STK11), Cowden (PTEN) and familial diffuse gastric cancer (E-Cadherin).
## First-degree relatives
Mother, father, daughter, son, sister, brother.
## Second-degree relatives
Grandparent, grandchild, aunt, uncle, niece, nephew, half-sister, half-brother.
## Severe osteoporosis
In this guideline severe osteoporosis is defined as having a T-score of at least –2.5 SD as measured by DEXA (dual-energy X-ray absorptiometry). This definition is in line with the NICE technology appraisal guidance on the primary prevention of osteoporotic fragility fractures in postmenopausal women and the World Health Organization. The T-score is a measure of how far a person's bone mineral density is below the mean value of young adults.
## Third-degree relatives
Great grandparent, great aunt, great uncle, first cousin, great grandchild, grand nephew, grand niece.
## Triple negative breast cancer
Oestrogen receptor, progesterone receptor, HER2 negative breast cancer.# Context
Familial breast cancer typically occurs in people with an unusually high number of family members affected by breast, ovarian or a related cancer. If more cases of breast, ovarian or a related cancer are seen in a family than would be expected by chance alone, this can be a sign that genes have caused or contributed to its development. Breast cancer in people who have a family history of breast, ovarian or a related cancer may need different management from that in people without a family history of these cancers. This is because of differences in the future risk of developing contralateral breast cancer.
The risk of developing breast cancer depends on the:
nature of the family history
number of relatives who have developed breast, ovarian or a related cancer
age at which relatives developed breast cancer
age of the person.
This guideline describes the classification and care of people at risk of familial breast cancer. It also covers people with a diagnosis of breast cancer and a family history of breast, ovarian or a related cancer. It includes recommendations on genetic testing thresholds, surveillance and risk reduction and treatment strategies. These areas are not covered by the NICE guideline on early and locally advanced breast cancer.
We have updated recommendations on chemoprevention for women with no personal history of breast cancer and have added a new recommendation on genetic testing for women with triple negative breast cancer but no family history.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
As part of the 2017 update, the standing committee made an additional research recommendation on BRCA1 mutations in unselected basal phenotype and triple negative breast cancer. The committee also extended the research recommendation on chemoprevention to include the aromatase inhibitors exemestane and letrozole. Details can be found in the 2017 addendum.
# Carrier probability calculation models
Further research is recommended into developing and validating models for calculating carrier probability, which incorporate additional data, such as the molecular pathology of tumours and the prevalence of mutations in different ethnic groups.
## Why this is important
This guideline recommends offering genetic testing to people with a 10% likelihood of carrying a BRCA1/2 mutation. Models to assess the likelihood of a BRCA1/2 mutation need to be improved because their estimates still have wide confidence margins. Models are sensitive to population prevalence of mutations and need adjustment for pathological subtypes of breast and ovarian cancer, which are particularly associated with BRCA1 mutations. Improving the predictive powers of these models will provide more cost-effective testing.
# Rapid genetic testing
Research is recommended to determine the benefits and harms of creating rapid access to genetic testing for people with newly diagnosed breast cancer. This research should address the optimum model for service delivery and organisation, the clinical and cost effectiveness of such a change, uptake outcomes and patients' experience.
## Why this is important
There is no clear evidence base for rapid genetic testing at the time of diagnosis of primary breast cancer. Knowledge of genetic status may increase uptake of risk-reducing mastectomy and in future guide first-line chemotherapy. To be useful for such decision-making, results of genetic tests are needed within 4 weeks of diagnosis. This creates logistic problems in providing enough information for considered decision-making and delivering results of genetic tests in a supportive environment. Some guideline committee members were of the opinion that people had enough to cope with shortly after diagnosis without additional worries about genetic testing. However, others thought that early knowledge of genetic status would help decisions about surgery thus avoiding the need to consider this at a future date. For example, initial treatment by wide local excision often necessitates radiotherapy, which makes an acceptable cosmetic operation more challenging. Genetic counselling to facilitate such decisions soon after diagnosis would require reorganisation of current services.
# Benefits of MRI surveillance in women over 50 years
Research is recommended to establish the risk and benefits of MRI surveillance compared with mammography in women over 50 years with a personal history of breast cancer. Studies should include sub-analysis for breast density.
## Why this is important
There have been at least 6 large trials of MRI surveillance in women at high risk of breast cancer. However, none of these contained enough women to assess the potential benefit of MRI over mammography alone in women over 50 years. After 50 years of age, mammography becomes more sensitive and the trade-off between sensitivity and specificity may make MRI less cost effective. Although breast density decreases with age, and particularly after the menopause, there is no sudden change at any particular age. For this reason breast density should be included as a confounding variable.
# Chemoprevention to reduce incidence of breast cancer
What is the clinical and cost effectiveness of aromatase inhibitors (particularly exemestane and letrozole) compared with tamoxifen and raloxifene for reducing the incidence of breast cancer in women with a family history of breast or ovarian cancer?
## Why this is important
One randomised controlled trial (RCT) showed anastrozole to be effective for the primary prevention of breast cancer. However, there has been no RCT of other third-generation aromatase inhibitors, such as exemestane and letrozole. Exemestane is not strictly from the same class as anastrozole (and may therefore have different modes of action). More information on the efficacy of these other aromatase inhibitors may offer more options for chemoprevention for women at risk of breast cancer.
# Impact of risk-reducing surgery
Further research is recommended to compare psychosocial and clinical outcomes in women who choose and women who do not choose to have risk-reducing surgery.
## Why this is important
Many women are happy with their decision to undergo risk-reducing surgery. However, some women do subsequently regret this choice. A greater understanding of the factors that predict satisfaction or regret will help to guide women's choices in the future. Studies show that risk-reducing surgery significantly reduces risk of breast cancer, but there is insufficient evidence to decide between, for example, skin-sparing mastectomy and total mastectomy. The pros and cons of risk-reducing surgery in women with a diagnosis of cancer also need further study.
# Prevalence of BRCA1 mutations in unselected basal phenotype breast cancer compared with unselected triple negative breast cancer
What is the prevalence of BRCA1 mutations in unselected basal phenotype breast cancer compared with unselected triple negative breast cancer?
## Why this is important
The association of breast cancer with BRCA1 mutations was originally with the basal phenotype. Although triple negative breast cancer has been used as a proxy for the basal phenotype, they do not fully overlap. Badve et al. (2010) found that 71% of triple negative breast cancers were basal like and 77% of basal-like cancers were triple negative. Triple negative breast cancer has been adopted as a proxy for the basal phenotype because most pathology laboratories test for triple negative cancer as a standard. Rakha et al. (2009) found that the basal phenotype has a high positive predictive for the BRCA1 mutation. A study of the prevalence of BRCA1 mutations would be useful because we may be missing these in basal phenotype breast cancers that are not are not tested as standard. This information would indicate whether BRCA1 testing is helpful for basal phenotype cancers.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations in this guideline apply to women and men unless otherwise specified.\n\n# Clinical significance of a family history of breast cancer\n\n## Accuracy of family history\n\nWhen a person with no personal history of breast cancer presents with breast symptoms or has concerns about relatives with breast cancer, a first- and second-degree family history should be taken in primary care to assess risk, because this allows appropriate classification and care. \n\nThis recommendation has been deleted following a review.\n\nIn some circumstances, it may also be clinically relevant to take a family history, for example, for women older than age 35\xa0years using an oral contraceptive pill or for women being considered for long-term HRT use. \n\nA person should be given the opportunity to discuss concerns about their family history of breast cancer if it is raised during a consultation. \n\nA second-degree family history (that is, including aunts, uncles and grandparents) should be taken in primary care before explaining risks and options. \n\nA second-degree family history needs to include paternal as well as maternal relatives. \n\nAsking people to discuss their family history with relatives is useful in gathering the most accurate information. \n\nTools such as family history questionnaires and computer packages exist that can aid accurate collection of family history information and they should be made available. \n\nFor referral decisions, attempts should be made to gather as accurate information as possible on:\n\nage of diagnosis of any cancer in relatives\n\nsite of tumours\n\nmultiple cancers (including bilateral disease)\n\nJewish ancestry (women with Jewish ancestry are around 5 to 10 times more likely to carry BRCA1 or BRCA2 mutations than women in non-Jewish populations). \n\nA family history should be taken when a person with no personal history of breast cancer presents with breast symptoms or has concerns about relatives with breast cancer. \n\nA third-degree family history should be taken in secondary care where possible and appropriate. \n\nTools such as family history questionnaires and computer packages exist that can aid accurate collection of family history information and risk assessment and they should be made available. \n\nA third-degree family history should be taken in a specialist genetic clinic for a person with no personal history of breast cancer, if this has not been done previously. \n\nFor accurate risk estimation, the following are required:\n\nage of death of affected and unaffected relatives\n\ncurrent age of unaffected relatives. \n\nIn general, it is not necessary to validate breast cancer-only histories (via medical records/cancer registry/death certificates). \n\nIf substantial management decisions, such as risk-reducing surgery, are being considered and no mutation has been identified, clinicians should seek confirmation of breast cancer-only histories (via medical records/cancer registry/death certificates). \n\nWhere no family history verification is possible, agreement by a multidisciplinary team should be sought before proceeding with risk-reducing surgery. \n\nAbdominal malignancies at young ages and possible sarcomas should be confirmed in specialist care. \n\n## Family history and carrier probability\n\nWhen available in secondary care, use a carrier probability calculation method with demonstrated acceptable performance (calibration and discrimination) as well as family history to determine who should be offered referral to a specialist genetic clinic. Examples of acceptable methods include BOADICEA and the Manchester scoring system. \n\nIn a specialist genetic clinic, use a carrier probability calculation method with demonstrated acceptable performance (calibration and discrimination) to assess the probability of a BRCA1 or BRCA2 mutation. Examples of acceptable methods include BOADICEA and the Manchester scoring system. \n\nIf there are problems with using or interpreting carrier probability calculation methods, use clinical judgement when deciding whether to offer genetic testing. \n\n## Communicating cancer risk and carrier probability\n\nPeople should be offered a personal risk estimate but information should also be given about the uncertainties of the estimation. \n\nWhen a personal risk value is requested, it should be presented in more than one way (for example, a numerical value, if calculated, and qualitative risk). \n\nPeople should be sent a written summary of their consultation in a specialist genetic clinic, which includes their personal risk information. \n\n# Information and support\n\nEffective care involves a balanced partnership between patients and healthcare professionals. Patients should have the opportunity to make informed choices about any treatment and care and to share in decision making. \n\nTo ensure a patient-professional partnership, patients should be offered individually tailored information, including information about sources of support (including local and national organisations). \n\nTailoring of information should take into account format (including whether written or taped) as well as the actual content and form that should be provided (see box 1). \n\nStandard information should be evidence based wherever possible, and agreed at a national level if possible (NICE's information for the public provides a good starting point). \n\nStandard information should not contradict messages from other service providers, including commonly agreed information across localities. \n\n## Box 1 Information provision for people with concerns about familial breast cancer risk\n\nStandard written information for all people\n\nRisk information about population level and family history levels of risk, including a definition of family history.\n\nThe message that, if their family history alters, their risk may alter.\n\nBreast awareness information.\n\nLifestyle advice regarding breast cancer risk, including information about:\n\n\n\nHRT and oral contraceptives (women only)\n\nlifestyle, including diet, alcohol, etc\n\nbreastfeeding, family size and timing (women only).\n\n\n\nContact details of those providing support and information, including local and national support groups.\n\nPeople should be informed prior to appointments that they can bring a family member/friend with them to appointments.\n\nDetails of any trials or studies that may be appropriate.\n\nFor people cared for in primary care\n\nStandard written information (as above).\n\nAdvice to return to discuss any implications if there is a change in family history or breast symptoms develop.\n\nFor people being referred to secondary care\n\nStandard written information (as above).\n\nInformation about the risk assessment exercise that will take place and advice about how to obtain a comprehensive family history if required.\n\nInformation about potential outcomes, depending on the outcome of the risk assessment (including referral back to primary care, management within secondary care or referral to a specialist genetics service) and what may happen at each level.\n\nFor people being referred back to primary care\n\nStandard written information (as above).\n\nDetailed information about why secondary or a specialist genetics service are not needed.\n\nAdvice to return to primary care to discuss any implications if there is a change in family history or breast symptoms develop.\n\nFor people being cared for in secondary care\n\nStandard written information (as above).\n\nDetails of the risk assessment outcome, including why they are not being referred to a specialist genetics service.\n\nDetails of surveillance options including risk and benefits.\n\nFor people being referred to a specialist genetic clinic\n\nStandard written information (as above).\n\nDetails of the risk assessment outcome, including why they are being referred to a specialist genetics service.\n\nDetails of surveillance options, including risk and benefits.\n\nDetails of what should be expected in a specialist genetics service, including counselling and genetic testing.\n\nFor people being cared for in a specialist genetic clinic\n\nStandard written information (as above).\n\nInformation about hereditary breast cancer.\n\nInformation about genetic testing, both predictive testing and mutation finding, including details of what the tests mean and how informative they are likely to be, and the likely timescale of being given the results.\n\nInformation about the risks and benefits of risk-reducing surgery when it is being considered, including both physical and psychological impact.\n\n# Care of people in primary care\n\n## Care and management in primary care\n\nPeople without a personal history of breast cancer can be cared for in primary care if the family history shows only 1 first-degree or second-degree relative diagnosed with breast cancer at older than age 40\xa0years (in most cases, this will equate to less than a 3% 10-year risk of breast cancer at age 40\xa0years), provided that none of the following are present in the family history:\n\nbilateral breast cancer\n\nmale breast cancer\n\novarian cancer\n\nJewish ancestry\n\nsarcoma in a relative younger than age 45\xa0years\n\nglioma or childhood adrenal cortical carcinomas\n\ncomplicated patterns of multiple cancers at a young age\n\npaternal history of breast cancer (2 or more relatives on the father's side of the family). \n\nPeople who do not meet the criteria for referral should be cared for in primary care by giving standard written information. \n\n## Referral from primary care\n\nPeople without a personal history of breast cancer who meet the following criteria should be offered referral to secondary care:\n\nfirst-degree female relative diagnosed with breast cancer at younger than age 40\xa0years or\n\nfirst-degree male relative diagnosed with breast cancer at any age or\n\nfirst-degree relative with bilateral breast cancer where the first primary was diagnosed at younger than age 50\xa0years or\n\nfirst-degree relatives, or 1 first-degree and 1 second-degree relative, diagnosed with breast cancer at any age or\n\nfirst-degree or second-degree relative diagnosed with breast cancer at any age and 1 first-degree or second-degree relative diagnosed with ovarian cancer at any age (1 of these should be a first-degree relative) or\n\nfirst-degree or second-degree relatives diagnosed with breast cancer at any age. \n\nAdvice should be sought from the designated secondary care contact if any of the following are present in the family history in addition to breast cancers in relatives not fulfilling the above criteria:\n\nbilateral breast cancer\n\nmale breast cancer\n\novarian cancer\n\nJewish ancestry\n\nsarcoma in a relative younger than age 45\xa0years\n\nglioma or childhood adrenal cortical carcinomas\n\ncomplicated patterns of multiple cancers at a young age\n\npaternal history of breast cancer (2 or more relatives on the father's side of the family). \n\nDiscussion with the designated secondary care contact should take place if the primary care health professional is uncertain about the appropriateness of referral because the family history presented is unusual or difficult to make clear decisions about, or where the person is not sufficiently reassured by the standard information provided. \n\nDirect referral to a specialist genetics service should take place where a high-risk predisposing gene mutation has been identified (for example, BRCA1, BRCA2 or TP53). \n\n## Patient education and information\n\nWomen who are being referred to secondary care or a specialist genetic clinic should be provided with written information about what happens at this stage. \n\nSupport mechanisms (for example, risk counselling, psychological counselling and risk management advice) need to be identified, and should be offered to women not eligible for referral and/or surveillance on the basis of age or risk level who have ongoing concerns. \n\n## Support for primary care\n\nSupport is needed for primary care health professionals to care for women with a family history of breast cancer. Essential requirements for support for primary care are:\n\na single point and locally agreed mechanism of referral for women identified as being at increased risk\n\neducational materials about familial breast cancer\n\ndecision-support systems\n\nstandardised patient information leaflets\n\na designated secondary care contact to discuss management of 'uncertain' cases. \n\n# Care of people in secondary care and specialist genetic clinics\n\n## Care and management approach in secondary care\n\nCare of people in secondary care (such as a breast care team, family history clinic or breast clinic) should be undertaken by a multidisciplinary team. It should include the following:\n\nwritten protocols for management\n\ncentral, standardised resources\n\nmammographic surveillance available to the standard of the national breast screening programmes (England – NHS Breast Screening Programme [NHSBSP]; Wales – Breast Test Wales; Northern Ireland – NI Breast Screening Programme)\n\naccess to surveillance as described in section 1.6 \n\naccess to a team offering risk-reducing surgery\n\nstandardised written information\n\ndesignated/lead clinicians\n\na designated contact for primary care\n\na designated contact in a specialist genetic clinic\n\naudit\n\nclinical trials access\n\naccess to psychological assessment and counselling\n\ninformation about support groups and voluntary organisations\n\nadministrative support. \n\nPeople who meet the following criteria should be offered secondary care and do not require referral to a specialist genetic clinic:\n\nfirst-degree relative diagnosed with breast cancer at younger than age 40\xa0years or\n\nfirst-degree or second-degree relatives diagnosed with breast cancer at an average age of older than 50\xa0years or\n\nfirst-degree or second-degree relatives diagnosed with breast cancer at an average age of older than 60\xa0years or\n\na formal risk assessment (usually carried out in a specialist genetic clinic) or a family history pattern is likely to give risks of greater than 3 to 8% risk in the next 10\xa0years for women aged 40\xa0years, or a lifetime risk of 17% or greater but less than 30% (a woman's age should be assumed to be 40 for a woman in her forties; a 10-year risk should be calculated for the age range 40 to 49)provided that none of the following are present in the family history:\n\nbilateral breast cancer\n\nmale breast cancer\n\novarian cancer\n\nJewish ancestry\n\nsarcoma in a relative younger than 45\xa0years of age\n\nglioma or childhood adrenal cortical carcinomas\n\ncomplicated patterns of multiple cancers at a young age\n\nvery strong paternal history (4 relatives diagnosed at younger than 60\xa0years of age on the father's side of the family). \n\nPeople whose risk does not meet the criteria for referral to secondary care (see recommendation 1.3.3) can be referred back to primary care:\n\nwith appropriate information being offered and\n\nsupport mechanisms (for example, risk counselling, psychological counselling and risk management advice) need to be identified, and should be offered to people not eligible for referral and/or surveillance on the basis of age or risk level who have ongoing concerns. \n\n## Referral to a specialist genetic clinic\n\nPeople who meet the following referral criteria should be offered a referral to a specialist genetic clinic.\n\nAt least the following female breast cancers only in the family:\n\n\n\nfirst-degree or second-degree relatives diagnosed with breast cancer at younger than an average age of 50\xa0years (at least 1 must be a first-degree relative) or\n\nfirst-degree or second-degree relatives diagnosed with breast cancer at younger than an average age of 60\xa0years (at least 1 must be a first-degree relative) or\n\nrelatives diagnosed with breast cancer at any age (at least 1 must be a first-degree relative). or\n\n\n\nFamilies containing 1 relative with ovarian cancer at any age and, on the same side of the family:\n\n\n\nfirst-degree relative (including the relative with ovarian cancer) or second-degree relative diagnosed with breast cancer at younger than age 50\xa0years or\n\nfirst-degree or second-degree relatives diagnosed with breast cancer at younger than an average age of 60\xa0years or\n\nanother ovarian cancer at any age. or\n\n\n\nFamilies affected by bilateral cancer (each breast cancer has the same count value as 1 relative):\n\n\n\nfirst-degree relative with cancer diagnosed in both breasts at younger than an average age 50\xa0years or\n\nfirst-degree or second-degree relative diagnosed with bilateral cancer and 1 first or second degree relative diagnosed with breast cancer at younger than an average age of 60\xa0years. or\n\n\n\nFamilies containing male breast cancer at any age and, on the same side of the family, at least:\n\n\n\nfirst-degree or second-degree relative diagnosed with breast cancer at younger than age 50\xa0years or\n\nfirst-degree or second-degree relatives diagnosed with breast cancer at younger than an average age of 60\xa0years. or\n\n\n\nA formal risk assessment has given risk estimates of:\n\n\n\na 10% or greater chance of a gene mutation being harboured in the family (see recommendations 1.5.8 to 1.5.13) or\n\na greater than 8% risk of developing breast cancer in the next 10\xa0years or\n\na 30% or greater lifetime risk of developing breast cancer. \n\n\n\nClinicians should seek further advice from a specialist genetics service for families containing any of the following, in addition to breast cancers:\n\ntriple negative breast cancer under the age of 40\xa0years \n\nJewish ancestry \n\nsarcoma in a relative younger than age 45\xa0years \n\nglioma or childhood adrenal cortical carcinomas \n\ncomplicated patterns of multiple cancers at a young age \n\nvery strong paternal history (4 relatives diagnosed at younger than 60\xa0years of age on the father's side of the family). \n\nThe management of high-risk people may take place in secondary care if they do not want genetic testing or risk-reducing surgery and do not wish to be referred to a specialist genetics service. \n\nFollowing initial consultation in secondary care, written information should be provided to reflect the outcomes of the consultation. \n\n## Care of people in a specialist genetic clinic\n\nCare of people referred to a specialist genetic clinic should be undertaken by a multi-disciplinary team. In addition to having access to the components found in secondary care, it should also include the following:\n\nclinical genetic risk assessment\n\nverification for abdominal malignancies and possible sarcomas. \n\n## Genetic counselling for people with no personal history of breast cancer\n\nWomen with no personal history of breast cancer meeting criteria for referral to a specialist genetic clinic should be offered a referral for genetic counselling regarding their risks and options. \n\nWomen attending genetic counselling should receive standardised information beforehand describing the process of genetic counselling, information to obtain prior to the counselling session, the range of topics to be covered and brief educational material about hereditary breast cancer and genetic testing. \n\nPredictive genetic testing should not be offered without adequate genetic counselling. \n\n# Genetic testing\n\nAll eligible people should have access to information on genetic tests aimed at mutation finding. \n\nPre-test counselling (preferably 2 sessions) should be undertaken. \n\nDiscussion of genetic testing (predictive and mutation finding) should be undertaken by a healthcare professional with appropriate training. \n\nEligible people and their affected relatives should be informed about the likely informativeness of the test (the meaning of a positive and a negative test) and the likely timescale of being given the results. \n\n## Mutation tests\n\nTests aimed at mutation finding should first be carried out on an affected family member where possible. \n\nIf possible, the development of a genetic test for a family should usually start with the testing of an affected individual (mutation searching/screening) to try to identify a mutation in the appropriate gene (such as BRCA1, BRCA2 or TP53) (see recommendations 1.5.8 to 1.5.13). \n\nA search/screen for a mutation in a gene (such as BRCA1, BRCA2 or TP53) should aim for as close to 100% sensitivity as possible for detecting coding alterations and the whole gene(s) should be searched. \n\n## Carrier probability at which genetic testing should be offered\n\nDiscuss the potential risk and benefits of genetic testing. Include in the discussion the probability of finding a mutation, the implications for the individual and the family, and the implications of either a variant of uncertain significance or a null result (no mutation found). \n\nInform families with no clear genetic diagnosis that they can request review in the specialist genetic clinic at a future date. \n\nClinical genetics laboratories should record gene variants of uncertain significance and known pathogenic mutations in a searchable electronic database. \n\nOffer genetic testing in specialist genetic clinics to a relative with a personal history of breast and/or ovarian cancer if that relative has a combined BRCA1 and BRCA2 mutation carrier probability of 10% or more. \n\nOffer genetic testing in specialist genetic clinics to a person with no personal history of breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more and an affected relative is unavailable for testing. \n\nOffer genetic testing in specialist genetic clinics to a person with breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more. \n\n## Genetic testing for BRCA1, BRCA2 and TP53 mutations within 4\xa0weeks of diagnosis of breast cancer\n\nOffer people eligible for referral to a specialist genetic clinic a choice of accessing genetic testing during initial management or at any time thereafter. \n\nOffer fast-track genetic testing (within 4\xa0weeks of a diagnosis of breast cancer) only as part of a clinical trial. \n\nDiscuss the individual needs of the person with the specialist genetics team as part of the multidisciplinary approach to care. \n\nOffer detailed consultation with a clinical geneticist or genetics counsellor to all those with breast cancer who are offered genetic testing, regardless of the timeframe for testing. \n\n# Surveillance and strategies for early detection of breast cancer\n\nSurveillance of women at very high risk of developing breast cancer is run by the NHS Breast Screening Programme (NHSBSP). This applies to women with a lifetime risk of 40% or greater because of a specific genetic abnormality in the woman or her family. Surveillance for women at lower levels of risk is covered by this guideline.\n\n## Breast awareness\n\nWomen at increased risk of breast cancer should be 'breast aware' in line with Department of Health advice for all women. \n\n## Surveillance for women with no personal history of breast cancer\n\nDo not routinely offer ultrasound surveillance to women at moderate risk or high risk of breast cancer but consider it:\n\nwhen MRI surveillance would normally be offered but is not suitable (for example, because of claustrophobia)\n\nwhen results of mammography or MRI are difficult to interpret. \n\nOffer annual mammographic surveillance to women:\n\naged 40 to 49\xa0years at moderate risk of breast cancer\n\naged 40 to 59\xa0years at high risk of breast cancer but with a 30% or lower probability of being a BRCA or TP53 carrier\n\naged 40 to 59\xa0years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier\n\naged 40 to 69\xa0years with a known BRCA1 or BRCA2 mutation. \n\nOffer mammographic surveillance as part of the population screening programme to women:\n\naged 50\xa0years and over who have not had genetic testing but have a greater than 30% probability of being a TP53 carrier\n\naged 60\xa0years and over at high risk of breast cancer but with a 30% or lower probability of being a BRCA or TP53 carrier\n\naged 60\xa0years and over at moderate risk of breast cancer\n\naged 60\xa0years and over who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier\n\naged 70\xa0years and over with a known BRCA1 or BRCA2 mutation. \n\nConsider annual mammographic surveillance for women:\n\naged 30 to 39\xa0years at high risk of breast cancer but with a 30% or lower probability of being a BRCA or TP53 carrier\n\naged 30 to 39\xa0years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier\n\naged 30 to 39\xa0years with a known BRCA1 or BRCA2 mutation\n\naged 50 to 59\xa0years at moderate risk of breast cancer.Discuss the benefits and risks of mammographic surveillance with the person before making a shared decision, as described in recommendation 1.6.18. [2013, amended 2019]\n\nDo not offer mammographic surveillance to women:\n\naged 29\xa0years and under\n\naged 30 to 39\xa0years at moderate risk of breast cancer\n\naged 30 to 49\xa0years who have not had genetic testing but have a greater than 30% probability of being a TP53 carrier\n\nof any age with a known TP53 mutation. \n\nOffer annual MRI surveillance to women:\n\naged 30 to 49\xa0years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier\n\naged 30 to 49\xa0years with a known BRCA1 or BRCA2 mutation\n\naged 20 to 49\xa0years who have not had genetic testing but have a greater than 30% probability of being a TP53 carrier\n\naged 20 to 49\xa0years with a known TP53 mutation. \n\nConsider annual MRI surveillance for women aged 50 to 69\xa0years with a known TP53 mutation. \n\nDo not offer MRI to women:\n\nof any age at moderate risk of breast cancer\n\nof any age at high risk of breast cancer but with a 30% or lower probability of being a BRCA or TP53 carrier\n\naged 20 to 29\xa0years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier\n\naged 20 to 29\xa0years with a known BRCA1 or BRCA2 mutation\n\naged 50 to 69\xa0years who have not had genetic testing but have a greater than 30% probability of being a BRCA or a TP53 carrier, unless mammography has shown a dense breast pattern\n\naged 50 to 69\xa0years with a known BRCA1 or BRCA2 mutation, unless mammography has shown a dense breast pattern. Also see summary of recommendations on surveillance for women with no personal history of breast cancer.\n\n## Surveillance for women with a personal and family history of breast cancer\n\nEnsure that all women with breast cancer are offered annual mammography for 5\xa0years for follow-up imaging, in line with the NICE guideline on early and locally advanced breast cancer. In conjunction with follow-up, women who remain at high risk of breast cancer and have a family history should receive surveillance as outlined in recommendations 1.6.11 to 16.15. \n\nOffer annual mammographic surveillance to all women aged 50 to 69\xa0years with a personal history of breast cancer who:\n\nremain at high risk of breast cancer (including those who have a BRCA1 or BRCA2 mutation), and\n\ndo not have a TP53 mutation. \n\nOffer mammography as part of the population screening programme for all women aged 70\xa0years and over with a personal history of breast cancer who:\n\nremain at high risk of breast cancer (including those who have a BRCA1 or BRCA2 mutation), and\n\ndo not have a TP53 mutation. \n\nOffer annual MRI surveillance to all women aged 30 to 49\xa0years with a personal history of breast cancer who remain at high risk of breast cancer, including those who have a BRCA1 or BRCA2 mutation. \n\nDo not offer MRI surveillance to any women aged 50\xa0years and over without a TP53 mutation unless mammography has shown a dense breast pattern. \n\nConsider annual MRI surveillance for women aged 20 to 69\xa0years with a known TP53 mutation or who have not had a genetic test but have a greater than 30% probability of being a TP53 carrier. \n\nEnsure that surveillance for people with a personal history of breast cancer who remain at moderate risk of breast cancer is in line with the NICE guideline on early and locally advanced breast cancer. \n\n## Recommendations for all women having surveillance\n\nOffer support (for example, risk counselling, psychological counselling and risk management advice) to women who have ongoing concerns but are not eligible for surveillance additional to that offered by the national breast screening programmes (England – NHS Breast Screening Programme [NHSBSP]; Wales – Breast Test Wales; Northern Ireland – NI Breast Screening Programme). [2004, amended 2013]\n\nBefore decisions on surveillance are made, discuss and give written information on the benefits and risks of surveillance, including:\n\nthe possibility that mammography might miss a cancer in women with dense breasts and the increased likelihood of further investigations \n\npossible over diagnosis\n\nthe risk associated with exposure to radiation\n\nthe possible psychological impact of a recall visit. [2004, amended 2013]\n\nReview eligibility for surveillance if family history changes (for example, if another member of the family develops breast cancer or a mutation is identified). \n\nAt the start of a surveillance programme and when there is a transition or change to the surveillance plan, give women:\n\ninformation about the surveillance programme, including details of the tests, how often they will have them and the duration of the programme\n\ninformation about the risks and benefits of surveillance\n\ndetails of sources of support and further information. [2006, amended 2013]\n\nEnsure that women know and understand the reasons for any changes to the surveillance plan. [2006, amended 2013]\n\nFor women under 50\xa0years who are having mammography, use digital mammography at centres providing digital mammography to national breast screening programme standards. \n\nEnsure that individual strategies are developed for all women having mammographic surveillance and that surveillance is:\n\nto national breast screening programme standards\n\naudited\n\nonly undertaken after written information is given about risks and benefits. \n\nEnsure that MRI surveillance includes MRI of both breasts performed to national breast screening programme standards. [2006, amended 2013]\n\nWhen women not known to have a genetic mutation are referred to a specialist genetic clinic, offer them assessment of their carrier probability using a carrier probability calculation method with acceptable performance (calibration and discrimination) to determine whether they meet or will meet the criteria for surveillance. (An example of an acceptable method is BOADICEA.) \n\nDo not offer surveillance to women who have undergone a bilateral mastectomy. \n\n# Risk reduction and treatment strategies\n\n## Risk factors\n\nPeople should be provided with standardised written information about risk, including age as a risk factor. \n\nModifiable risk factors should be discussed on an individual basis in the relevant care setting. \n\n## Menstrual and reproductive factors\n\nHealthcare professionals should be able to provide information on the effects of hormonal and reproductive factors on breast cancer risk. \n\n## Hormonal contraceptives\n\nAdvice to women up to age 35\xa0years with a family history of breast cancer should be in keeping with general health advice on the use of the oral contraceptive pill. \n\nWomen aged over 35\xa0years with a family history of breast cancer should be informed of an increased risk of breast cancer associated with taking the oral contraceptive pill, given that their absolute risk increases with age. \n\nFor women with BRCA1 mutations, the conflicting effects of a potential increased risk of breast cancer under the age of 40\xa0years and the lifetime protection against ovarian cancer risk from taking the oral contraceptive pill should be discussed. \n\nWomen should not be prescribed the oral contraceptive pill purely for prevention of cancer, although in some situations reduction in ovarian cancer risk may outweigh any increase in risk of breast cancer. \n\nIf a woman has a BRCA1 mutation and is considering a risk-reducing oophorectomy before the age of 40\xa0years, the oral contraceptive pill should not be prescribed purely for the reduction in ovarian cancer risk. \n\n## Breastfeeding\n\nWomen should be advised to breastfeed if possible because this is likely to reduce their risk of breast cancer, and is in accordance with general health advice. \n\n## Hormone replacement therapy\n\nWomen with a family history of breast cancer who are considering taking, or already taking, HRT should be informed of the increase in breast cancer risk with type and duration of HRT. \n\nAdvice to individual women on the use of HRT should vary according to the individual clinical circumstances (such as asymptomatic menopausal symptoms, age, severity of menopausal symptoms, or osteoporosis). \n\nHRT usage in a woman at familial risk should be restricted to as short a duration and as low a dose as possible. Oestrogen-only HRT should be prescribed where possible. \n\nA woman having an early (natural or artificial) menopause should be informed of the risks and benefits of HRT, but generally HRT usage should be confined to women younger than age 50\xa0years if at moderate or high risk (see also recommendations 1.7.53 and 1.7.54). \n\nAlternatives to HRT should be considered for specific symptoms such as osteoporosis or menopausal symptoms (see also recommendations 1.7.53 and 1.7.54). \n\nConsideration should be given to the type of HRT if it is being considered for use in conjunction with risk-reducing gynaecological surgery. \n\n## Alcohol consumption\n\nWomen with a family history should be informed that alcohol may increase their risk of breast cancer slightly. However, this should be considered in conjunction with any potential benefit of moderate alcohol intake on other conditions (such as heart disease) and adverse effects associated with excessive alcohol intake. \n\n## Smoking\n\nWomen should be advised not to smoke, in line with current health advice. \n\n## Weight and physical activity\n\nWomen should be advised on the probable increased postmenopausal risk of breast cancer from being overweight. \n\nWomen should be advised about the potential benefits of physical exercise on breast cancer risk. \n\n## Chemoprevention for women with no personal history of breast cancer\n\nHealthcare professionals within secondary care or specialist genetic clinics should discuss the absolute benefits and risks of options for chemoprevention with women at high risk or moderate risk of breast cancer. Discussion, using a decision aid, should include the following to promote shared decision-making and informed preferences:\n\nthe reduced risk of invasive breast cancer\n\nthe lack of effect on mortality\n\nthe side effects of the different options\n\nalternative approaches, such as surveillance alone and, for women at high risk, risk-reducing surgery. Women should all be given information in an accessible format. [2013, amended 2017]\n\nNICE has produced patient decision aids about chemoprevention for women at moderate or high risk of breast cancer.\n\nOffer tamoxifen for 5\xa0years to premenopausal women at high risk of breast cancer unless they have a past history or may be at increased risk of thromboembolic disease or endometrial cancer. \n\nOffer anastrozole for 5\xa0years to postmenopausal women at high risk of breast cancer unless they have severe osteoporosis.In March 2017 this was an off-label use of anastrozole. See NICE's information on prescribing medicines. Women with or at risk of osteoporosis should have their bone mineral density assessed when starting treatment and then at regular intervals. Treatment or prophylaxis for osteoporosis should be started when needed and carefully monitored. \n\nFor postmenopausal women at high risk of breast cancer who have severe osteoporosis or do not wish to take anastrozole:\n\noffer tamoxifen for 5\xa0years if they have no history or increased risk of thromboembolic disease or endometrial cancer, or\n\nconsider raloxifene for 5\xa0years for women with a uterus if they have no history or increased risk of thromboembolic disease and do not wish to take tamoxifen.In March 2017 this was an off-label use of raloxifene. See NICE's information on prescribing medicines. \n\nDo not offer chemoprevention to women who were at high risk of breast cancer but have had bilateral risk-reducing mastectomy. [2013, amended 2017]\n\nConsider tamoxifen for 5\xa0years for premenopausal women at moderate risk of breast cancer, unless they have a past history or may be at increased risk of thromboembolic disease or endometrial cancer. \n\nConsider anastrozole for 5\xa0years for postmenopausal women at moderate risk of breast cancer unless they have severe osteoporosis.In March 2017 this was an off-label use of anastrozole. See NICE's information on prescribing medicines. Women with or at risk of osteoporosis should have their bone mineral density assessed when starting treatment and then at regular intervals. Treatment or prophylaxis for osteoporosis should be started when needed and carefully monitored. \n\nFor postmenopausal women at moderate risk of breast cancer who have severe osteoporosis or do not wish to take anastrozole:\n\nconsider tamoxifen for 5\xa0years if they have no history or increased risk of thromboembolic disease or endometrial cancer, or\n\nconsider raloxifene for 5\xa0years for women with a uterus if they have no history or increased risk of thromboembolic disease and do not wish to take tamoxifen.In March 2017 this was an off-label use of raloxifene. See NICE's information on prescribing medicines. \n\nDo not continue chemoprevention beyond 5\xa0years in women with no personal history of breast cancer. [2013, amended 2017]\n\nInform women that they should stop tamoxifen at least:\n\nmonths before trying to conceive\n\nweeks before elective surgery. \n\n## Risk-reducing mastectomy for women with no personal history of breast cancer\n\nBilateral risk-reducing mastectomy is appropriate only for a small proportion of women who are from high-risk families and should be managed by a multidisciplinary team. \n\nBilateral mastectomy should be raised as a risk-reducing strategy option with all women at high risk. \n\nWomen considering bilateral risk-reducing mastectomy should have genetic counselling in a specialist cancer genetic clinic before a decision is made. \n\nDiscussion of individual breast cancer risk and its potential reduction by surgery should take place and take into account individual risk factors, including the woman's current age (especially at extremes of age ranges). \n\nFamily history should be verified where no mutation has been identified before bilateral risk-reducing mastectomy. \n\nWhere no family history verification is possible, agreement by a multidisciplinary team should be sought before proceeding with bilateral risk-reducing mastectomy. \n\nPre-operative counselling about psychosocial and sexual consequences of bilateral risk-reducing mastectomy should be undertaken. \n\nThe possibility of breast cancer being diagnosed histologically following a risk-reducing mastectomy should be discussed pre-operatively. \n\nAll women considering bilateral risk-reducing mastectomy should be able to discuss their breast reconstruction options (immediate and delayed) with a member of a surgical team with specialist oncoplastic or breast reconstructive skills. \n\nA surgical team with specialist oncoplastic/breast reconstructive skills should carry out risk-reducing mastectomy and/or reconstruction. \n\nWomen considering bilateral risk-reducing mastectomy should be offered access to support groups and/or women who have undergone the procedure. \n\n## Risk-reducing oophorectomy for women with no personal history of breast cancer\n\nRisk-reducing bilateral oophorectomy is appropriate only for a small proportion of women who are from high-risk families and should be managed by a multidisciplinary team. \n\nInformation about bilateral oophorectomy as a potential risk-reducing strategy should be made available to women who are classified as high risk. \n\nFamily history should be verified where no mutation has been identified before bilateral risk-reducing oophorectomy. \n\nWhere no family history verification is possible, agreement by a multidisciplinary team should be sought before proceeding with bilateral risk-reducing oophorectomy. \n\nAny discussion of bilateral oophorectomy as a risk-reducing strategy should take fully into account factors such as anxiety levels on the part of the woman concerned. \n\nHealthcare professionals should be aware that women being offered risk-reducing bilateral oophorectomy may not have been aware of their risks of ovarian cancer as well as breast cancer and should be able to discuss this. \n\nThe effects of early menopause should be discussed with any woman considering risk-reducing bilateral oophorectomy. \n\nOptions for management of early menopause should be discussed with any woman considering risk-reducing bilateral oophorectomy, including the advantages, disadvantages and risk impact of HRT. \n\nWomen considering risk-reducing bilateral oophorectomy should have access to support groups and/or women who have undergone the procedure. \n\nWomen considering risk-reducing bilateral oophorectomy should be informed of possible psychosocial and sexual consequences of the procedure and have the opportunity to discuss these issues. \n\nWomen not at high risk who raise the possibility of risk-reducing bilateral oophorectomy should be offered appropriate information, and if seriously considering this option should be offered referral to the team that deals with women at high risk. \n\nWomen undergoing bilateral risk-reducing oophorectomy should have their fallopian tubes removed as well. \n\nWhen women with no personal history of breast cancer have either a BRCA1 or BRCA2 mutation or a family history of breast cancer and they have had a bilateral salpingo-oophorectomy before their natural menopause, offer them:\n\ncombined HRT if they have a uterus\n\noestrogen-only HRT if they don't have a uterus up until the time they would have expected natural menopause (average age for natural menopause is 51 to 52\xa0years). \n\nManage menopausal symptoms occurring when HRT is stopped in the same way as symptoms of natural menopause. \n\n## Risk-reducing breast or ovarian surgery for people with a personal history of breast cancer\n\nRefer women with a personal history of breast cancer who wish to consider risk-reducing surgery for appropriate genetic and psychological counselling before surgery. \n\nDiscuss the risks and benefits of risk-reducing mastectomy with women with a known or suspected BRCA1, BRCA2 or TP53 mutation. \n\nFor a woman considering risk-reducing mastectomy, include in the discussion of risks and benefits:\n\nthe likely prognosis of their breast cancer, including their risk of developing a distal recurrence of their previous breast cancer\n\na clear quantification of the risk of developing breast cancer in the other breast\n\nthe potential negative impact of mastectomy on body image and sexuality\n\nthe very different appearance and feel of the breasts after reconstructive surgery\n\nthe potential benefits of reducing the risk in the other breast and relieving the anxiety about developing breast cancer. \n\nGive all women considering a risk-reducing mastectomy the opportunity to discuss their options for breast reconstruction (immediate and delayed) with a member of a surgical team with specialist skills in oncoplastic surgery or breast reconstruction. \n\nEnsure that risk-reducing mastectomy and breast reconstruction are carried out by a surgical team with specialist skills in oncoplastic surgery and breast reconstruction. \n\nOffer women who have BRCA1, BRCA2 or TP53 mutations but who decide against risk-reducing mastectomy, surveillance according to their level of risk. \n\nDiscuss the risks and benefits of risk-reducing bilateral salpingo-oophorectomy with women with a known or suspected BRCA1, BRCA2 or TP53 mutation. Include in the discussion the positive effects of reducing the risk of breast and ovarian cancer and the negative effects of a surgically induced menopause. \n\nDefer risk-reducing bilateral salpingo-oophorectomy until women have completed their family. \n\nDo not offer risk-reducing surgery to people with comorbidities that would considerably increase the risks of surgery. \n\nDo not offer risk-reducing surgery to people who have a limited life expectancy from their cancer or other conditions. \n\n## Treatment options for people with a personal history of breast cancer who are TP53 mutation carriers\n\nWhen a person has invasive breast cancer or ductal carcinoma in situ and is known to have a TP53 mutation or a 30% probability of a TP53 mutation:\n\ninform them of all the possible treatment options\n\nmake sure they know about the uncertainties associated with these treatment options\n\ninform them of the risks associated with each treatment (for example, the risk of recurrence, the risk of new primary breast cancer and the risks of malignancy associated with radiotherapy and chemotherapy). \n\nOffer people with invasive breast cancer or ductal carcinoma in situ and a 30% probability of a TP53 mutation, genetic testing to help determine their treatment options. \n\n# Summary of recommendations on surveillance for women with no personal history of breast cancer\n\nAge (years)\n\nA 30% or lower probability of being a BRCA or TP53 carrier\n\nUntested but greater than 30% BRCA carrier probability\n\nKnown BRCA1 or BRCA2 mutation\n\nUntested but greater than 30% TP53 carrier probability\n\nKnown TP53 mutation\n\nto 29\n\nDo not offer mammography\n\nDo not offer MRI\n\nDo not offer mammography\n\nDo not offer MRI\n\nDo not offer mammography\n\nDo not offer MRI\n\nDo not offer mammography\n\nAnnual MRI\n\nDo not offer mammography\n\nAnnual MRI\n\nto 39\n\nConsider annual mammography\n\nDo not offer MRI\n\nAnnual MRI and consider annual mammography\n\nAnnual MRI and consider annual mammography\n\nDo not offer mammography\n\nAnnual MRI\n\nDo not offer mammography\n\nAnnual MRI\n\nto 49\n\nAnnual mammography\n\nDo not offer MRI\n\nAnnual mammography and annual MRI\n\nAnnual mammography and annual MRI\n\nDo not offer mammography\n\nAnnual MRI\n\nDo not offer mammography\n\nAnnual MRI\n\nto 59\n\nAnnual mammography\n\nDo not offer MRI\n\nAnnual mammography\n\nDo not offer MRI unless dense breast pattern\n\nAnnual mammography\n\nDo not offer MRI unless dense breast pattern\n\nMammography as part of the population screening programme\n\nDo not offer MRI unless dense breast pattern\n\nDo not offer mammography\n\nConsider annual MRI\n\nto 69\n\nMammography as part of the population screening programme\n\nDo not offer MRI\n\nMammography as part of the population screening programme\n\nDo not offer MRI unless dense breast pattern\n\nAnnual mammography\n\nDo not offer MRI unless dense breast pattern\n\nMammography as part of the population screening programme\n\nDo not offer MRI unless dense breast pattern\n\nDo not offer mammography\n\nConsider annual MRI\n\nand over\n\nMammography as part of the population screening programme\n\nMammography as part of the population screening programme\n\nMammography as part of the population screening programme\n\nMammography as part of the population screening programme\n\nDo not offer mammography\n\n\n\nHigh risk of breast cancer (but with a 30% or lower probability of being a BRCA or TP53 carrier) – lifetime risk of at least 30%. High risk group includes rare conditions that carry an increased risk of breast cancer, such as Peutz-Jegher syndrome, (STK11), Cowden (PTEN), familial diffuse gastric cancer (E-Cadherin).\n\nHigh risk of breast cancer (untested but greater than 30% BRCA carrier probability) – surveillance recommendations reflect the fact that women who at first assessment had a 30% or greater BRCA carrier probability and reach 60\xa0years of age without developing breast or ovarian cancer will now have a lower than 30% carrier probability and should no longer be offered MRI surveillance.\n\nHigh risk of breast cancer (untested but greater than 30% TP53 carrier probability) – surveillance recommendations reflect the fact that women who at first assessment had a 30% or greater TP53 carrier probability and reach 50\xa0years of age without developing breast cancer or any other TP53-related malignancy will now have a lower than 30% carrier probability and should no longer be offered MRI surveillance.\n\nAge (years)\n\nModerate risk of breast cancer\n\nto 29\n\nDo not offer mammography\n\nDo not offer MRI\n\nto 39\n\nDo not offer mammography\n\nDo not offer MRI\n\nto 49\n\nAnnual mammography\n\nDo not offer MRI\n\nto 59\n\nConsider annual mammography\n\nDo not offer MRI\n\nto 69\n\nMammography as part of the population screening programme\n\nDo not offer MRI\n\nand over\n\nMammography as part of the population screening programme\n\n# Terms used in this guideline\n\n\n\nNear population risk of breast cancer\n\nModerate risk of breast cancer\n\nHigh risk of breast cancer\n\nLifetime risk from age 20\n\nLess than 17%\n\nGreater than 17% but less than 30%\n\n% or greater\n\nRisk between ages 40 and 50\n\nLess than 3%\n\nto 8%\n\nGreater than 8%\n\nThe high-risk group includes known BRCA1, BRCA2 and TP53 mutations and rare conditions that carry an increased risk of breast cancer such as Peutz-Jegher syndrome (STK11), Cowden (PTEN) and familial diffuse gastric cancer (E-Cadherin).\n\n## First-degree relatives\n\nMother, father, daughter, son, sister, brother.\n\n## Second-degree relatives\n\nGrandparent, grandchild, aunt, uncle, niece, nephew, half-sister, half-brother.\n\n## Severe osteoporosis\n\nIn this guideline severe osteoporosis is defined as having a T-score of at least –2.5\xa0SD as measured by DEXA (dual-energy X-ray absorptiometry). This definition is in line with the NICE technology appraisal guidance on the primary prevention of osteoporotic fragility fractures in postmenopausal women and the World Health Organization. The T-score is a measure of how far a person's bone mineral density is below the mean value of young adults.\n\n## Third-degree relatives\n\nGreat grandparent, great aunt, great uncle, first cousin, great grandchild, grand nephew, grand niece.\n\n## Triple negative breast cancer\n\nOestrogen receptor, progesterone receptor, HER2 negative breast cancer.", 'Context': 'Familial breast cancer typically occurs in people with an unusually high number of family members affected by breast, ovarian or a related cancer. If more cases of breast, ovarian or a related cancer are seen in a family than would be expected by chance alone, this can be a sign that genes have caused or contributed to its development. Breast cancer in people who have a family history of breast, ovarian or a related cancer may need different management from that in people without a family history of these cancers. This is because of differences in the future risk of developing contralateral breast cancer.\n\nThe risk of developing breast cancer depends on the:\n\nnature of the family history\n\nnumber of relatives who have developed breast, ovarian or a related cancer\n\nage at which relatives developed breast cancer\n\nage of the person.\n\nThis guideline describes the classification and care of people at risk of familial breast cancer. It also covers people with a diagnosis of breast cancer and a family history of breast, ovarian or a related cancer. It includes recommendations on genetic testing thresholds, surveillance and risk reduction and treatment strategies. These areas are not covered by the NICE guideline on early and locally advanced breast cancer.\n\nWe have updated recommendations on chemoprevention for women with no personal history of breast cancer and have added a new recommendation on genetic testing for women with triple negative breast cancer but no family history.', 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\nAs part of the 2017 update, the standing committee made an additional research recommendation on BRCA1 mutations in unselected basal phenotype and triple negative breast cancer. The committee also extended the research recommendation on chemoprevention to include the aromatase inhibitors exemestane and letrozole. Details can be found in the 2017 addendum.\n\n# Carrier probability calculation models\n\nFurther research is recommended into developing and validating models for calculating carrier probability, which incorporate additional data, such as the molecular pathology of tumours and the prevalence of mutations in different ethnic groups. \n\n## Why this is important\n\nThis guideline recommends offering genetic testing to people with a 10% likelihood of carrying a BRCA1/2 mutation. Models to assess the likelihood of a BRCA1/2 mutation need to be improved because their estimates still have wide confidence margins. Models are sensitive to population prevalence of mutations and need adjustment for pathological subtypes of breast and ovarian cancer, which are particularly associated with BRCA1 mutations. Improving the predictive powers of these models will provide more cost-effective testing.\n\n# Rapid genetic testing\n\nResearch is recommended to determine the benefits and harms of creating rapid access to genetic testing for people with newly diagnosed breast cancer. This research should address the optimum model for service delivery and organisation, the clinical and cost effectiveness of such a change, uptake outcomes and patients' experience. \n\n## Why this is important\n\nThere is no clear evidence base for rapid genetic testing at the time of diagnosis of primary breast cancer. Knowledge of genetic status may increase uptake of risk-reducing mastectomy and in future guide first-line chemotherapy. To be useful for such decision-making, results of genetic tests are needed within 4\xa0weeks of diagnosis. This creates logistic problems in providing enough information for considered decision-making and delivering results of genetic tests in a supportive environment. Some guideline committee members were of the opinion that people had enough to cope with shortly after diagnosis without additional worries about genetic testing. However, others thought that early knowledge of genetic status would help decisions about surgery thus avoiding the need to consider this at a future date. For example, initial treatment by wide local excision often necessitates radiotherapy, which makes an acceptable cosmetic operation more challenging. Genetic counselling to facilitate such decisions soon after diagnosis would require reorganisation of current services.\n\n# Benefits of MRI surveillance in women over 50\xa0years\n\nResearch is recommended to establish the risk and benefits of MRI surveillance compared with mammography in women over 50\xa0years with a personal history of breast cancer. Studies should include sub-analysis for breast density. \n\n## Why this is important\n\nThere have been at least 6 large trials of MRI surveillance in women at high risk of breast cancer. However, none of these contained enough women to assess the potential benefit of MRI over mammography alone in women over 50\xa0years. After 50\xa0years of age, mammography becomes more sensitive and the trade-off between sensitivity and specificity may make MRI less cost effective. Although breast density decreases with age, and particularly after the menopause, there is no sudden change at any particular age. For this reason breast density should be included as a confounding variable.\n\n# Chemoprevention to reduce incidence of breast cancer\n\nWhat is the clinical and cost effectiveness of aromatase inhibitors (particularly exemestane and letrozole) compared with tamoxifen and raloxifene for reducing the incidence of breast cancer in women with a family history of breast or ovarian cancer? \n\n## Why this is important\n\nOne randomised controlled trial (RCT) showed anastrozole to be effective for the primary prevention of breast cancer. However, there has been no RCT of other third-generation aromatase inhibitors, such as exemestane and letrozole. Exemestane is not strictly from the same class as anastrozole (and may therefore have different modes of action). More information on the efficacy of these other aromatase inhibitors may offer more options for chemoprevention for women at risk of breast cancer.\n\n# Impact of risk-reducing surgery\n\nFurther research is recommended to compare psychosocial and clinical outcomes in women who choose and women who do not choose to have risk-reducing surgery. \n\n## Why this is important\n\nMany women are happy with their decision to undergo risk-reducing surgery. However, some women do subsequently regret this choice. A greater understanding of the factors that predict satisfaction or regret will help to guide women's choices in the future. Studies show that risk-reducing surgery significantly reduces risk of breast cancer, but there is insufficient evidence to decide between, for example, skin-sparing mastectomy and total mastectomy. The pros and cons of risk-reducing surgery in women with a diagnosis of cancer also need further study.\n\n# Prevalence of BRCA1 mutations in unselected basal phenotype breast cancer compared with unselected triple negative breast cancer\n\nWhat is the prevalence of BRCA1 mutations in unselected basal phenotype breast cancer compared with unselected triple negative breast cancer? \n\n## Why this is important\n\nThe association of breast cancer with BRCA1 mutations was originally with the basal phenotype. Although triple negative breast cancer has been used as a proxy for the basal phenotype, they do not fully overlap. Badve et al. (2010) found that 71% of triple negative breast cancers were basal like and 77% of basal-like cancers were triple negative. Triple negative breast cancer has been adopted as a proxy for the basal phenotype because most pathology laboratories test for triple negative cancer as a standard. Rakha et al. (2009) found that the basal phenotype has a high positive predictive for the BRCA1 mutation. A study of the prevalence of BRCA1 mutations would be useful because we may be missing these in basal phenotype breast cancers that are not are not tested as standard. This information would indicate whether BRCA1 testing is helpful for basal phenotype cancers."}
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https://www.nice.org.uk/guidance/cg164
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This guideline covers care for people with a family history of breast, ovarian or another related (prostate or pancreatic) cancer. It aims to improve the long-term health of these families by describing strategies to reduce the risk of and promote early detection of breast cancer (including genetic testing and mammography). It also includes advice on treatments (tamoxifen, raloxifene) and surgery (mastectomy).
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338223e36662c65d75406ac69d3397ba63133ccd
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nice
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Thyroid disease: assessment and management
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Thyroid disease: assessment and management
This guideline covers investigating all suspected thyroid disease and managing primary thyroid disease (related to the thyroid rather than the pituitary gland). It does not cover managing thyroid cancer or thyroid disease in pregnancy. It aims to improve quality of life by making recommendations on diagnosis, treatment, long-term care and support.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as discussed in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Information for people with thyroid disease, their families and carers
## Presenting information
Ensure that information is presented to facilitate shared decision making, as recommended in the NICE guideline on shared decision making.
## General information
Explain to people with thyroid disease who need treatment, and their family or carers if appropriate, that:
Thyroid disease usually responds well to treatment.
The goal of treatment is to alleviate symptoms and align thyroid function tests within or close to the reference range.
People may feel well even when their thyroid function tests are outside the reference range.
Even when there are no symptoms, treatment may be advised to reduce the risk of long-term complications.
Even when thyroid function tests are within the reference range, changes to treatment may improve symptoms for some people.
Symptoms may lag behind treatment changes for several weeks to months.
Day-to-day changes in unexplained symptoms are unlikely to be due to underlying thyroid disease because the body has a large reservoir of thyroxine.
Provide people with thyroid disease, and their family or carers if appropriate, with written and verbal information on:
their underlying condition, including the role and function of the thyroid gland and what the thyroid function tests mean
risks of over- and under-treatment
their medicines
need for and frequency of monitoring
when to seek advice from a healthcare professional
how thyroid disease and medicines may affect pregnancy and fertility.
See the recommendations on testing for coeliac disease in people with a diagnosis of autoimmune thyroid disease in the NICE guideline on coeliac disease.
## Hypothyroidism (underactive thyroid)
Provide people with hypothyroidism, and their family or carers if appropriate, with written and verbal information on:
possible drug interactions of thyroid hormone replacements, including interactions with over-the-counter medicines
how and when to take levothyroxine.
## Thyrotoxicosis (overactive thyroid)
Provide people with thyrotoxicosis, and their family or carers if appropriate, with written and verbal information on:
the different causes of thyrotoxicosis
the consequences of untreated thyrotoxicosis
the suitability of individual treatment options (for example, antithyroid drugs may be more suitable for mild uncomplicated Graves' disease, surgery may be best for an enlarged thyroid causing compression, radioactive iodine is not usually suitable before puberty)
the possible benefits/advantages of the treatment options (for example, antithyroid drugs and radioactive iodine are non-invasive treatments, surgery offers rapid relief of symptoms and there is no need to delay pregnancy or fathering a child)
the possible risks/disadvantages of the treatment options (for example, antithyroid drugs may have side effects, radioactive iodine means limited contact with other people for a few weeks and a need to delay pregnancy or fathering a child, surgery is an invasive treatment that leaves scarring on the neck)
the risk of and impact of different treatment options on new and existing thyroid eye disease (for example, radioactive iodine may precipitate or worsen thyroid eye disease)
the need for thyroid hormone replacement if treatment leads to life-long hypothyroidism.
## Thyroid enlargement (also known as goitre)
Provide people with thyroid enlargement, and their family or carers if appropriate, with written and verbal information on:
the causes of thyroid enlargement, including the fact that goitre and nodules are common and are usually not cancerous
red flag symptoms to look out for (for example, shortness of breath, rapid growth of nodules, hoarse voice, swallowing difficulties)
treatment options.
To find out why the committee made the recommendations on information and how they might affect practice, see the rationale and impact section on information for people with thyroid disease, their families and carers .
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# Investigating suspected thyroid dysfunction or thyroid enlargement
## Indications for tests for thyroid dysfunction
Consider tests for thyroid dysfunction for adults, children and young people if there is a clinical suspicion of thyroid disease, but bear in mind that 1 symptom alone may not be indicative of thyroid disease.
Offer tests for thyroid dysfunction to adults, children and young people with:
type 1 diabetes or other autoimmune diseases, or
new-onset atrial fibrillation.
Consider tests for thyroid dysfunction for adults, children and young people with depression or unexplained anxiety.
Consider tests for thyroid dysfunction for children and young people with abnormal growth, or unexplained change in behaviour or school performance.
Be aware that in menopausal women symptoms of thyroid dysfunction may be mistaken for menopause.
Do not test for thyroid dysfunction during an acute illness unless you suspect the acute illness is due to thyroid dysfunction, because the acute illness may affect the test results.
Do not offer testing for thyroid dysfunction solely because an adult, child or young person has type 2 diabetes.
To find out why the committee made the recommendations on indications for tests for thyroid dysfunction and how they might affect practice, see the rationale and impact section on indications for tests for thyroid dysfunction .
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## Tests when thyroid dysfunction is suspected
Consider measuring thyroid-stimulating hormone (TSH) alone for adults when secondary thyroid dysfunction (pituitary disease) is not suspected. Then:
if the TSH is above the reference range, measure free thyroxine (FT4) in the same sample
if the TSH is below the reference range, measure FT4 and free tri-iodothyronine (FT3) in the same sample.
Consider measuring both TSH and FT4 for:
adults when secondary thyroid dysfunction (pituitary disease) is suspected
children and young people. If the TSH is below the reference range, measure FT3 in the same sample.
Consider repeating the tests for thyroid dysfunction in recommendations 1.2.8 or 1.2.9 if symptoms worsen or new symptoms develop (but no sooner than 6 weeks from the most recent test).
To find out why the committee made the recommendations on tests when thyroid dysfunction is suspected and how they might affect practice, see the rationale and impact section on tests when thyroid dysfunction is suspected .
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# Managing primary hypothyroidism
## Tests for people with confirmed primary hypothyroidism
Consider measuring thyroid peroxidase antibodies (TPOAbs) for adults with TSH levels above the reference range, but do not repeat TPOAbs testing.
Measure TPOAbs for children and young people with TSH levels above the reference range, with possible repeat TPOAbs testing at the time of transition to adult services.
To find out why the committee made the recommendations on tests for people with confirmed primary hypothyroidism and how they might affect practice, see the rationale and impact section on tests for people with confirmed primary hypothyroidism .
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## Managing primary hypothyroidism
Offer levothyroxine as first-line treatment for adults, children and young people with primary hypothyroidism.
Do not routinely offer liothyronine for primary hypothyroidism, either alone or in combination with levothyroxine, because there is not enough evidence that it offers benefits over levothyroxine monotherapy, and its long-term adverse effects are uncertain.
Do not offer natural thyroid extract for primary hypothyroidism because there is not enough evidence that it offers benefits over levothyroxine, and its long-term adverse effects are uncertain.Natural thyroid extract does not have a UK marketing authorisation so its safety is uncertain.
Consider starting levothyroxine at a dosage of 1.6 micrograms per kilogram of body weight per day (rounded to the nearest 25 micrograms) for adults under 65 with primary hypothyroidism and no history of cardiovascular disease.
Consider starting levothyroxine at a dosage of 25 to 50 micrograms per day with titration for adults aged 65 and over and adults with a history of cardiovascular disease.
To find out why the committee made the recommendations on managing primary hypothyroidism and how they might affect practice, see the rationale and impact section on managing primary hypothyroidism .
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# Follow-up and monitoring of primary hypothyroidism
## Tests for follow-up and monitoring of primary hypothyroidism
Aim to maintain TSH levels within the reference range when treating primary hypothyroidism with levothyroxine. If symptoms persist, consider adjusting the dose of levothyroxine further to achieve optimal wellbeing, but avoid using doses that cause TSH suppression or thyrotoxicosis.
Be aware that the TSH level can take up to 6 months to return to the reference range for people who had a very high TSH level before starting treatment with levothyroxine or a prolonged period of untreated hypothyroidism. Take this into account when adjusting the dose of levothyroxine.
For adults who are taking levothyroxine for primary hypothyroidism, consider measuring TSH every 3 months until the level has stabilised (2 similar measurements within the reference range 3 months apart), and then once a year.
Consider measuring FT4 as well as TSH for adults who continue to have symptoms of hypothyroidism after starting levothyroxine.
For children aged 2 years and over and young people taking levothyroxine for primary hypothyroidism, consider measuring FT4 and TSH:
every 6 to 12 weeks until the TSH level has stabilised (2 similar measurements within the reference range 3 months apart), then
every 4 to 6 months until after puberty, then
-nce a year.
For children aged between 28 days and 2 years who are taking levothyroxine for primary hypothyroidism, consider measuring FT4 and TSH:
every 4 to 8 weeks until the TSH level has stabilised (2 similar measurements within the reference range 2 months apart), then
every 2 to 3 months during the first year of life, and
every 3 to 4 months during the second year of life.
To find out why the committee made the recommendations on tests for monitoring and follow-up of primary hypothyroidism and how they might affect practice, see the rationale and impact section on follow-up and monitoring of primary hypothyroidism .
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# Managing and monitoring subclinical hypothyroidism
## Tests for people with confirmed subclinical hypothyroidism
Consider measuring TPOAbs for adults with TSH levels above the reference range, but do not repeat TPOAbs testing.
## Treating subclinical hypothyroidism
When discussing whether or not to start treatment for subclinical hypothyroidism, take into account features that might suggest underlying thyroid disease, such as symptoms of hypothyroidism, previous radioactive iodine treatment or thyroid surgery, or raised levels of thyroid autoantibodies.
Consider levothyroxine for adults with subclinical hypothyroidism who have a TSH of 10 mlU/litre or higher on 2 separate occasions 3 months apart. Follow the recommendations in section 1.4 on follow-up and monitoring of hypothyroidism.
Consider a 6-month trial of levothyroxine for adults under 65 with subclinical hypothyroidism who have:
a TSH above the reference range but lower than 10 mlU/litre on 2 separate occasions 3 months apart, and
symptoms of hypothyroidism.If symptoms do not improve after starting levothyroxine, re-measure TSH and if the level remains raised, adjust the dose. If symptoms persist when serum TSH is within the reference range, consider stopping levothyroxine and follow the recommendations on monitoring untreated subclinical hypothyroidism and monitoring after stopping treatment.
Consider levothyroxine for children aged 2 years and over and young people with subclinical hypothyroidism who have:
a TSH level of 20 mlU/litre or higher, or
a TSH level between 10 and 20 mlU/litre on 2 separate occasions 3 months apart, or
a TSH level between 5 and 10 mlU/litre on 2 separate occasions 3 months apart, and
thyroid dysgenesis (an underdeveloped thyroid gland), or
signs or symptoms of thyroid dysfunction.During levothyroxine treatment, follow the recommendations in section 1.4 on follow-up and monitoring.
Consider levothyroxine for children aged between 28 days and 2 years with subclinical hypothyroidism who have a TSH level of 10 mlU/litre or higher. During levothyroxine treatment, follow the recommendations in section 1.4 on follow-up and monitoring.
## Monitoring untreated subclinical hypothyroidism and monitoring after stopping treatment
For adults with untreated subclinical hypothyroidism or adults who have stopped levothyroxine treatment for subclinical hypothyroidism, consider measuring TSH and FT4:
-nce a year if they have features suggesting underlying thyroid disease, such as previous thyroid surgery or raised levels of thyroid autoantibodies, or
-nce every 2 to 3 years if they have no features suggesting underlying thyroid disease.
Consider measuring TSH and FT4 for children aged 2 years and over and young people with untreated subclinical hypothyroidism and a TSH lower than 10 mlU/litre:
every 3 to 6 months if they have features suggesting underlying thyroid disease, such as thyroid dysgenesis (an underdeveloped thyroid gland) or raised levels of thyroid autoantibodies, or
every 6 to 12 months if they have no features suggesting underlying thyroid disease.
Consider measuring TSH and FT4 every 1 to 3 months for children aged between 28 days and 2 years with untreated subclinical hypothyroidism.
Consider stopping TSH and FT4 measurement in children and young people if the TSH level has stabilised (2 similar measurements within the reference range 3 to 6 months apart) and there are no features suggesting underlying thyroid disease.
To find out why the committee made the recommendations on managing and monitoring subclinical hypothyroidism and how they might affect practice, see the rationale and impact section on managing and monitoring subclinical hypothyroidism .
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# Managing thyrotoxicosis
## Tests for people with confirmed thyrotoxicosis
Differentiate between thyrotoxicosis with hyperthyroidism (for example, Graves' disease or toxic nodular disease) and thyrotoxicosis without hyperthyroidism (for example, transient thyroiditis) in adults by:
measuring TSH receptor antibodies (TRAbs) to confirm Graves' disease
considering technetium scanning of the thyroid gland if TRAbs are negative.
Only consider ultrasound for adults with thyrotoxicosis if they have a palpable thyroid nodule.
Differentiate between thyrotoxicosis with hyperthyroidism (Graves' disease) and thyrotoxicosis without hyperthyroidism (for example, transient thyroiditis) in children and young people by:
measuring TPOAbs and TRAbs
considering technetium scanning of the thyroid gland if TRAbs are negative.
Only offer ultrasound to children and young people with thyrotoxicosis if they have a palpable thyroid nodule or the cause of thyrotoxicosis remains unclear following thyroid autoantibody testing and technetium scanning.
To find out why the committee made the recommendations on tests for people with confirmed thyrotoxicosis and how they might affect practice, see the rationale and impact section on tests for people with confirmed thyrotoxicosis .
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## Initial treatment in primary/non-specialist care
Be aware that transient thyrotoxicosis without hyperthyroidism usually only needs supportive treatment (for example, beta-blockers).
Consider antithyroid drugs along with supportive treatment for adults with hyperthyroidism who are waiting for specialist assessment and further treatment.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019).
To find out why the committee made the recommendations on initial management in primary/non-specialist care for people with thyrotoxicosis and how they might affect practice, see the rationale and impact section on initial management in primary/non-specialist care for people with thyrotoxicosis .
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## Initial treatment in secondary/specialist care
Discuss with adults, children and young people with thyrotoxicosis with hyperthyroidism (and their families and carers as appropriate):
the possible benefits and risks of all treatment options (antithyroid drugs, radioactive iodine, surgery)
the likelihood of a good response to each option.
Ensure that people can actively participate in decisions about their treatment by following the recommendations in the NICE guidelines on patient experience in adult NHS services and shared decision making. This includes presenting information about possible outcomes in a way the person (and their families and carers as appropriate) can understand.
Offer antithyroid drugs to control hyperthyroidism in adults, children and young people who are waiting for treatment with radioactive iodine or surgery.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019). November 2019 – carbimazole use is off label for children under 2 years. See NICE's information on prescribing medicines.
Offer radioactive iodine as first-line definitive treatment for adults with Graves' disease, unless antithyroid drugs are likely to achieve remission (see recommendation 1.6.11), or it is unsuitable (for example, there are concerns about compression, malignancy is suspected, they are pregnant or trying to become pregnant or father a child within the next 4 to 6 months, or they have active thyroid eye disease).Follow the 2017 regulations on medical exposure to ionising radiation.
Offer a choice of antithyroid drugs (a 12- to 18-month course) or radioactive iodine (following the 2017 regulations on medical exposure to ionising radiation) as first-line definitive treatment for adults with Graves' disease if antithyroid drugs are likely to achieve remission (for example, mild and uncomplicated Graves' disease).Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019).
Offer antithyroid drugs (a 12- to 18-month course) as first-line definitive treatment for adults with Graves' disease if radioactive iodine and surgery are unsuitable.
Offer total thyroidectomy as first-line definitive treatment for adults with Graves' disease if:
there are concerns about compression, or
thyroid malignancy is suspected, or
radioactive iodine and antithyroid drugs are unsuitable.
Consider radioactive iodine or surgery for adults with Graves' disease who have had antithyroid drugs but have persistent or relapsed hyperthyroidism.Follow the 2017 regulations on medical exposure to ionising radiation.
To find out why the committee made the recommendations on treatment for adults with Graves' disease and how they might affect practice, see the rationale and impact section on treatment for adults with Graves' disease .
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Offer radioactive iodine as first-line definitive treatment for adults with hyperthyroidism secondary to multiple nodules unless it is unsuitable (for example, there are concerns about compression, thyroid malignancy is suspected, they are pregnant or trying to become pregnant or father a child within the next 4 to 6 months, or they have active thyroid eye disease).Follow the 2017 regulations on medical exposure to ionising radiation.
Offer total thyroidectomy or life-long antithyroid drugs as first-line definitive treatment for adults with hyperthyroidism secondary to multiple nodules if radioactive iodine is unsuitable.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019).
Offer radioactive iodine (if suitable) or surgery (hemithyroidectomy) as first-line definitive treatment for adults with hyperthyroidism secondary to a single nodule, or life-long antithyroid drugs if these options are unsuitable.
To find out why the committee made the recommendations on treatment for adults with toxic nodular goitre and how they might affect practice, see the rationale and impact section on treatment for adults with toxic nodular goitre .
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Offer antithyroid drugs for at least 2 years and possibly longer as first-line definitive treatment for children and young people with Graves' disease.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019). November 2019 – carbimazole use is off label for children under 2 years. See NICE's information on prescribing medicines.
Consider continuing or restarting antithyroid drugs or discussing radioactive iodine or surgery (total thyroidectomy) for children and young people with Graves' disease who have had a course of antithyroid drugs but have relapsed hyperthyroidism.
For children and young people with hyperthyroidism secondary to a single or multiple nodules:
-ffer antithyroid drugs using a titration regimen of carbimazole, and
discuss the role of surgery and radioactive iodine with the child, young person and family, following input from the multidisciplinary team.
To find out why the committee made the recommendations on treatment for children and young people with Graves' disease or toxic nodular goitre and how they might affect practice, see the rationale and impact section on treatment for children and young people with Graves' disease or toxic nodular goitre .
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## Antithyroid drugs for adults, children and young people with hyperthyroidism
Before starting antithyroid drugs for adults, children and young people with hyperthyroidism, check full blood count and liver function tests.
When offering antithyroid drugs as first-line definitive treatment to adults with Graves' disease, offer carbimazole for 12 to 18 months, using either a block and replace or a titration regimen, and then review the need for further treatment.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019).
When offering antithyroid drugs to children and young people with Graves' disease, offer carbimazole, using a titration regimen, and review the need for treatment every 2 years.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019). November 2019 – carbimazole use is off label for children under 2 years. See NICE's information on prescribing medicines.
When offering life-long antithyroid drugs to adults with hyperthyroidism secondary to a single or multiple toxic nodules, consider treatment with a titration regimen of carbimazole.
Consider propylthiouracil for adults:
who experience adverse reactions to carbimazole
who are pregnant or trying to become pregnant within the following 6 months
with a history of pancreatitis.
Stop and do not restart any antithyroid drugs if a person develops agranulocytosis. Consider referral to a specialist for further management options.
To find out why the committee made the recommendations on antithyroid drugs for adults, children and young people with hyperthyroidism and how they might affect practice, see the rationale and impact section on antithyroid drugs for people with hyperthyroidism .
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# Follow-up and monitoring of hyperthyroidism
## Monitoring after radioactive iodine treatment
Consider measuring TSH, FT4 and FT3 levels in adults, children and young people every 6 weeks for the first 6 months after radioactive iodine treatment until TSH is within the reference range.
For adults, children and young people who have hypothyroidism after radioactive iodine treatment and are not on antithyroid drugs, offer levothyroxine replacement therapy and follow recommendations 1.3.6 and 1.3.7 on dosage of levothyroxine for adults and 1.4.1 to 1.4.6 on monitoring of hypothyroidism.
For adults, children and young people with TSH in the reference range 6 months after radioactive iodine treatment, consider measuring TSH (with cascading) at 9 months and 12 months after treatment.
For adults, children and young people with TSH in the reference range 12 months after radioactive iodine treatment, consider measuring TSH (with cascading) every 6 months unless they develop hypothyroidism (then follow recommendation 1.7.2).
If hyperthyroidism persists after radioactive iodine treatment in adults, children and young people, consider antithyroid drugs until the 6-month appointment.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019). November 2019 – carbimazole use is off label for children under 2 years. See NICE's information on prescribing medicines.
If hyperthyroidism persists 6 months after radioactive iodine treatment in adults, children and young people, consider further treatment.
## Monitoring after surgery
Offer levothyroxine to adults, children and young people after a total thyroidectomy and follow recommendations 1.3.6 and 1.3.7 on dosage of levothyroxine for adults and 1.4.1 to 1.4.6 on monitoring of hypothyroidism.
Consider measuring TSH and FT4 at 2 and 6 months after surgery, and then TSH (with cascading) once a year for adults, children and young people who have had a hemithyroidectomy.
## Monitoring of antithyroid drugs
For adults, children and young people who are taking antithyroid drugs for hyperthyroidism, consider measuring:
TSH, FT4 and FT3 every 6 weeks until their TSH is within the reference range, then
TSH (with cascading) every 3 months until antithyroid drugs are stopped.
Do not monitor full blood count and liver function for adults, children and young people taking antithyroid drugs for hyperthyroidism unless there is a clinical suspicion of agranulocytosis or liver dysfunction.
For adults who have stopped antithyroid drugs, consider measuring:
TSH (with cascading) within 8 weeks of stopping the drug, then
TSH (with cascading) every 3 months for a year, then
TSH (with cascading) once a year.
For children and young people who have stopped antithyroid drugs, consider measuring:
TSH, FT4 and FT3 within 8 weeks of stopping the drug, then
TSH, FT4 and FT3 every 3 months for the first year, then
TSH (with cascading) every 6 months for the second year, then
TSH (with cascading) once a year.
To find out why the committee made the recommendations on follow-up and monitoring of hyperthyroidism and how they might affect practice, see the rationale and impact section on follow-up and monitoring of hyperthyroidism .
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# Managing and monitoring subclinical hyperthyroidism
## Treating subclinical hyperthyroidism
Consider seeking specialist advice on managing subclinical hyperthyroidism in adults if they have:
TSH readings lower than 0.1 Miu/litre at least 3 months apart and
evidence of thyroid disease (for example, a goitre or positive thyroid antibodies) or symptoms of thyrotoxicosis.
Consider seeking specialist advice on managing subclinical hyperthyroidism in all children and young people.
## Untreated subclinical hyperthyroidism
Consider measuring TSH every 6 months for adults with untreated subclinical hyperthyroidism. If the TSH level is outside the reference range, consider measuring FT4 and FT3 in the same sample.
Consider measuring TSH, FT4 and FT3 every 3 months for children and young people with untreated subclinical hyperthyroidism.
Consider stopping TSH measurement for adults, children and young people with untreated subclinical hyperthyroidism if the TSH level stabilises (2 similar measurements within the reference range 3 to 6 months apart).
To find out why the committee made the recommendations on managing and monitoring subclinical hyperthyroidism and how they might affect practice, see the rationale and impact section on managing and monitoring subclinical hyperthyroidism .
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# Diagnosing, managing and monitoring thyroid enlargement with normal thyroid function
## Investigating thyroid enlargement
The following recommendations apply to adults, children and young people with normal thyroid function.
Offer ultrasound to image palpable thyroid enlargement or focal nodularity in adults, children and young people with normal thyroid function if malignancy is suspected.
Consider ultrasound of incidental findings on imaging if clinical factors suggest malignancy as a possibility.
When making decisions about whether to offer fine needle aspiration cytology, use an established system for grading ultrasound appearance that takes into account:
echogenicity
microcalcifications
border
shape in transverse plane
internal vascularity
lymphadenopathy.
Reports of ultrasound findings should:
specify which grading system has been used for the assessment.
include information on the features in recommendation 1.9.3 and
provide an overall assessment of malignancy, and
confirm that both lobes have been assessed, and
document assessment of cervical lymph nodes.
Use ultrasound guidance when performing fine needle aspiration cytology.
See the NICE guideline on suspected cancer for recommendations on referral for suspected head and neck cancers (including thyroid cancer).
To find out why the committee made the recommendations on investigating thyroid enlargement and how they might affect practice, see the rationale and impact section on investigating non-malignant thyroid enlargement with normal thyroid function .
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## Managing non-malignant thyroid enlargement
Do not offer treatment to adults with non-malignant thyroid enlargement, normal thyroid function and mild or no symptoms unless:
they have breathing difficulty or
there is clinical concern, for example, because of marked airway narrowing.
Repeat thyroid ultrasound and TSH measurement for adults with non-malignant thyroid enlargement who are not receiving treatment, if:
malignancy is subsequently suspected, or
compression is suspected.
Consider repeating thyroid ultrasound and TSH measurement for adults with non-malignant thyroid enlargement who are not receiving treatment, if:
the person's symptoms worsen or
they develop symptoms, such as hoarseness, or shortness of breath.
For children and young people with non-malignant thyroid enlargement and normal thyroid function, discuss management with a specialist multidisciplinary team.
For adults with normal thyroid function and a cyst or predominantly cystic nodule with no vascular components, offer aspiration if it is causing compressive symptoms, with possible ethanol ablation if there is re-accumulation of cyst fluid later.
For adults with normal thyroid function and a non-cystic nodule or multinodular or diffuse goitre, consider the following if they have compressive symptoms relating to thyroid enlargement:
surgery, particularly if there is marked airway narrowing or
radioactive iodine ablation, if there is demonstrable radionuclide uptake, or
percutaneous thermal ablation (see the NICE interventional procedures guidance on ultrasound-guided percutaneous radiofrequency ablation for benign thyroid nodules).
To find out why the committee made the recommendations on managing thyroid enlargement and how they might affect practice, see the rationale and impact section on managing non-malignant thyroid enlargement .
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# Terms used in this guideline
## Adults
People aged 16 years and over.
## Cascading
Measuring FT4 in the same sample if TSH is above the reference range and measuring FT4 and FT3 in the same sample if TSH is below the reference range.
## Children and young people
People under 16 years.
## Hyperthyroidism
Excess production and/or secretion of thyroid hormones (overactive thyroid gland).
## Hypothyroidism
Inadequate production and secretion of thyroid hormones (underactive thyroid gland).
## Menopausal women
This includes women in perimenopause and post menopause.
## Subclinical hyperthyroidism
TSH levels below the reference range, with FT3 and FT4 within the reference range.
## Subclinical hypothyroidism
TSH levels above the reference range, with FT4 within the reference range.
## Thyrotoxicosis
Thyrotoxicosis is a disorder of excess circulating thyroid hormones caused by increased production and secretion (hyperthyroidism) or by the release of stored thyroid hormones (thyroiditis).# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Levothyroxine–liothyronine combination therapy for hypothyroidism
What is the clinical and cost effectiveness of levothyroxine (T4) and liothyronine (T3) combination therapy compared with T4 alone for people with hypothyroidism whose symptoms have not responded sufficiently to T4 alone? Does DiO2 polymorphism affect the response to combination therapy with T4 and T3?
To find out why the committee made the research recommendation on levothyroxine-liothyronine combination therapy for hypothyroidism see the rationale and impact section on managing primary hypothyroidism .
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## Long-term health outcomes for people with subclinical hyperthyroidism
What is the clinical and cost effectiveness of treatment (antithyroid drugs or radioactive iodine) for improving long-term health outcomes for people with subclinical hyperthyroidism?
To find out why the committee made the research recommendation on improving long-term health outcomes for people with subclinical hyperthyroidism see the rationale and impact section on managing and monitoring subclinical hyperthyroidism .
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## Antithyroid drugs in subgroups with Graves' disease
Are there subgroups of people with Graves' disease who have a particularly good response to antithyroid drugs?
To find out why the committee made the research recommendation on antithyroid drugs in subgroups of people with Graves' disease see the rationale and impact section on treatment for adults with Graves' disease .
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## Long-term effectiveness and safety of radioactive iodine therapy for hyperthyroidism
What is the long-term clinical and cost effectiveness, including safety, of radioactive iodine for hyperthyroidism?
To find out why the committee made the research recommendation on long-term effectiveness and safety of radioactive iodine therapy see the rationale and impact section on treatment for adults with Graves' disease .
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## Dosimetry-guided radioactive iodine therapy for hyperthyroidism
What is the clinical and cost effectiveness of dosimetry-guided radioactive iodine strategies for hyperthyroidism?
To find out why the committee made the research recommendation on the use of dosimetry-guided radioactive iodine therapy for hyperthyroidism see the rationale and impact section on treatment for adults with Graves' disease .
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# Other recommendations for research
## Antithyroid drug regimens for T3 thyrotoxicosis due to Graves' disease
What is the clinical and cost effectiveness of different durations of antithyroid drug regimens for people with T3 thyrotoxicosis due to Graves' disease?
## Levothyroxine for subclinical hypothyroidism in people under 65
What is the clinical and cost effectiveness of levothyroxine for people under 65 with symptomatic subclinical hypothyroidism?
## Antithyroid drug regimens for Graves' disease
What is the clinical and cost effectiveness of a block and replace regimen compared with a titration regimen of antithyroid drugs for Graves' disease?
## Percutaneous ablation for benign thyroid nodules
What is the clinical and cost effectiveness of percutaneous thermal ablation for benign thyroid nodules?
## Iodine for subclinical hypothyroidism
What is the clinical and cost effectiveness of iodine for people with subclinical hypothyroidism?
## Selenium for subclinical hypothyroidism
What is the clinical and cost effectiveness of selenium for people with subclinical hypothyroidism?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Information for people with thyroid disease, their families and carers
Recommendations 1.1.1 to 1.1.6
## Why the committee made the recommendations
The committee based the recommendations on the views and themes from qualitative studies combined with their own experience of treating or living with thyroid disease.
The committee agreed it was important for all people with thyroid disease to understand the disease, the goals of treatment and the complex interaction between thyroid function tests and symptoms. The specific recommendations for people with hypothyroidism centred around the use of thyroid hormone replacement. Levothyroxine is frequently taken incorrectly, which can lead to suboptimal treatment. The specific recommendations for thyrotoxicosis centred around what people should know about their treatment options and the consequences of untreated thyrotoxicosis. The specific recommendations on thyroid enlargement focused on reassuring people that enlargement is common and generally non-cancerous, while also alerting them to red flag symptoms that should prompt further action.
## How the recommendations might affect practice
The recommendations provide guidance on the type of information and support that should be provided to people with thyroid disease so that they can make informed decisions about management. The committee noted that currently there is variation in the information provided. In some areas there may be additional resource use, for example, if longer or more consultations are needed. But this may lead to later benefits and reductions in resource use, if, for example, it leads to better understanding and use of medication.
Full details of the evidence and the committee's discussion are in evidence review A: information for people with thyroid disease.
Return to recommendations
# Indications for tests for thyroid dysfunction
Recommendations 1.2.1 to 1.2.7
## Why the committee made the recommendations
The committee noted that thyroid dysfunction affects many systems in the body, and the symptoms are often non-specific. They agreed, based on evidence and their experience, that most single common symptoms alone are not predictive of thyroid dysfunction. The decision to test should be based on an overall clinical suspicion, taking into account the nature and severity of symptoms, clinical signs and coexisting conditions.
The evidence showed that type 1 diabetes, an autoimmune disease, is associated with thyroid dysfunction. In the committee's experience, this is also likely to apply to other autoimmune diseases and justifies testing for thyroid dysfunction in these conditions.
There was little evidence on thyroid disease in people with atrial fibrillation. However, the committee agreed that the potential importance of thyroid disease and its impact on the treatment of atrial fibrillation is sufficient to justify testing.
Limited evidence showed that depression can be associated with thyroid dysfunction. The committee agreed that, in their experience, this can also apply to anxiety.
The committee noted that in children and young people, thyroid dysfunction may be accompanied by abnormal growth or a change in behaviour or school performance that is unexplained by other factors. They agreed, based on their experience, that testing for thyroid dysfunction should be considered for children and young people presenting with those features. Thyroid function tests may be abnormal in people who are acutely unwell with non-thyroid disease and the committee agreed that decisions on treatment of thyroid dysfunction should not be based solely on these results. Tests for thyroid dysfunction should be performed when the acute illness has resolved, unless the acute illness may be due to thyroid dysfunction.
Evidence showed that type 2 diabetes is not associated with thyroid dysfunction, so the committee concluded that thyroid function tests should not be performed solely because a person has this condition.
## How the recommendations might affect practice.
The recommendations to test for thyroid dysfunction in people with autoimmune disease, atrial fibrillation, anxiety or depression are broadly in line with current practice. Checking thyroid function in people with type 2 diabetes and during acute illness is also current practice in some areas. The recommendations to avoid this should be cost saving for the NHS.
Full details of the evidence and the committee's discussion are in evidence review B: indications for testing.
Return to recommendations
# Tests when thyroid dysfunction is suspected
Recommendations 1.2.8 to 1.2.10
## Why the committee made the recommendations
No evidence was identified on which tests should be used when thyroid dysfunction is suspected so the committee used their experience to develop the recommendations. The committee agreed that in general TSH alone is an appropriate first test for people in whom thyroid dysfunction is suspected. Subsequent tests (cascading) are only needed if TSH is abnormal (with FT4 if the TSH suggests hypothyroidism and both FT4 and FT3 if the TSH suggests hyperthyroidism). This approach reduces unnecessary testing compared with simultaneous TSH, FT4 and FT3 testing for all people. However, tests should be done in a way to minimise potential delays and the need for additional appointments, for example, by laboratories keeping original samples and performing subsequent tests on the same samples. The committee agreed based on their experience that this approach did not apply to adults in whom secondary thyroid dysfunction is suspected or in children and young people, where both TSH and FT4 are needed by default because of the differing likely causes of dysfunction. The committee further agreed that tests may need repeating when new symptoms develop or worsen, but that this should not be within 6 weeks of the last test because this is unlikely to provide new information.
## How the recommendations might affect practice.
The recommendations broadly reflect current practice, although not all laboratories currently follow the cascading approach to testing.
Where FT4 is currently a routine test for thyroid dysfunction, cascading will reduce NHS costs by avoiding extra tests for people with a TSH within the reference range. In areas where FT3 is not currently being measured, cascading will mean a cost increase. But this will be offset by the benefits of correctly diagnosing and managing thyrotoxicosis.
Full details of the evidence and the committee's discussion are in evidence review C: thyroid function tests.
Return to recommendations
# Tests for people with confirmed primary hypothyroidism
Recommendations 1.3.1 and 1.3.2
## Why the committee made the recommendations
No evidence was identified on the use of antibodies to investigate hypothyroidism so the committee used their experience to develop the recommendations. They agreed that testing for thyroid peroxidase antibodies (TPOAbs) may be useful in the early investigation of the underlying cause of hypothyroidism. However, for adults there was no role for remeasuring TPOAbs because changes in levels are unlikely to guide treatment decisions. The committee agreed that for young people it may be useful to repeat TPOAbs at the point of transition to adult services.
## How the recommendations might affect practice
The recommendations broadly reflect current practice so the committee agreed there should be no substantial change. By avoiding re-testing in adults, there could be some cost savings.
Full details of the evidence and the committee's discussion are in evidence review D: tests for confirmed primary hypothyroidism.
Return to recommendations
# Managing primary hypothyroidism
Recommendations 1.3.3 to 1.3.7
## Why the committee made the recommendations
The committee agreed that hypothyroidism needs thyroid hormone replacement. Potential treatments are levothyroxine, usually prescribed to everyone, liothyronine, which is sometimes prescribed when levothyroxine fails, and natural thyroid extracts (which is currently unlicensed for use in the UK). Overall the evidence from 7 randomised controlled trials suggested that combination treatment with levothyroxine and liothyronine did not offer any important health benefits compared with levothyroxine monotherapy and was significantly more expensive. However, the committee noted that some of the trials did show some small benefits in specific quality of life domains and anecdotal evidence from some committee members suggested beneficial effects of combination treatment with levothyroxine and liothyronine in small subgroups of patients. The committee were aware that some people reported still feeling unwell with levothyroxine monotherapy and agreed that in this group adding liothyronine could potentially have greater benefit than in the general population with hypothyroidism, although there are no trials in this population. Some evidence suggested that combination therapy with levothyroxine and liothyronine could be harmful because it may suppress the production of TSH and its long-term adverse effects are uncertain. The committee was aware that the use of combination therapy is a critical issue in hypothyroidism. They could not recommend liothyronine either alone or in combination treatment based on the evidence available and its current list price but agreed a research recommendation to help inform future guidance in this important area. NHS England's specialist pharmacy service has produced advice on prescribing liothyronine.
The committee agreed that the evidence for natural thyroid extracts showed no benefit over levothyroxine. The committee also noted that the proportion of T3 to T4 is higher in natural thyroid extracts than produced in the human body and the adverse effects are uncertain. Natural thyroid extracts are an unlicensed medication in the UK and overall the committee agreed they should not be offered.
Some evidence showed that a high starting dose of levothyroxine produced more rapid improvements in quality of life than a lower starting dose followed by titration. The committee agreed that this was also their experience and therefore recommended a high starting dose (1.6 micrograms per kilogram body weight per day) in adults unless contraindicated (adults over 65 or with a history of cardiovascular disease). Although evidence about dosing was very limited, the committee agreed that adults over 65 years are more likely to have cardiovascular comorbidities. Most studies of hypothyroidism and subclinical hypothyroidism use 65 as a cut-off when defining older adults. The committee agreed to recommend a lower starting dose with titration for people over 65.
The committee were unable to make recommendations on iodine or selenium supplements because of a lack of evidence.
## How the recommendations might affect practice
The recommendations on thyroid hormone replacement and natural thyroid extract reinforce current practice and are not expected to have a significant cost impact. Currently everyone is offered levothyroxine as thyroid hormone replacement and small subgroups of people who do not feel well on levothyroxine are sometimes offered liothyronine.
Full details of the evidence and the committee's discussion are in evidence review E: managing hypothyroidism.
Return to recommendations
# Follow-up and monitoring of primary hypothyroidism
Recommendations 1.4.1 to 1.4.6
## Why the committee made the recommendations
Evidence showed no clinically important benefits of maintaining TSH levels in the lower rather than higher end of the TSH reference range. Given the need for additional medication to achieve a TSH level in the lower end of the reference range, with the potential for adverse effects and increased cost, the committee concluded that as a starting point TSH levels could be maintained at any point within the reference range. Nevertheless, the committee acknowledged that some people may still have troublesome symptoms even with TSH levels in the reference range. Therefore, they recommended adjusting the dose of levothyroxine if symptoms persist to achieve optimal wellbeing for individual patients. The committee also agreed that it was important not to use doses high enough to cause TSH suppression or thyrotoxicosis.
The committee agreed that TSH levels can take up to 6 months to return to the reference range if they have previously been very high or have been high for a long time. They agreed that healthcare professionals should take this into account when adjusting doses, to avoid large dose increases that could cause thyrotoxicosis.
The committee based recommendations about the timing of testing on their experience. They made separate recommendations for children under 2 years because in this age group the impact of poorly treated hypothyroidism can be most severe, and the child is developing at such a rate that frequent dose changes may be needed.
The committee used their experience to agree which thyroid function tests are needed for monitoring. They followed the general principle that once TSH has stabilised in the reference range, TSH testing alone is enough if the person has no symptoms suggesting thyroid dysfunction.
They agreed that children should have more frequent monitoring to ensure that dose adjustments are made promptly and because in the very young, under-treatment can lead to serious neurodevelopmental consequences.
## How the recommendations might affect practice
The committee agreed that generally the testing strategies are in line with current practice, although there may be some variation across the country. The recommendations should help patients (and their support groups) to advocate for their own monitoring and treatment. Doctors will have clear guidance on monitoring to assist with consultations.
Full details of the evidence and the committee's discussion are in evidence review F: monitoring thyroid disease.
Return to recommendations
# Managing and monitoring subclinical hypothyroidism
Recommendations 1.5.1 to 1.5.10
## Why the committee made the recommendations
There was little evidence on treatment for people with subclinical hypothyroidism, with most of the evidence relating to older adults. The committee agreed that as most studies used 65 years as a cut-off it was appropriate to define older adults as over 65 and make separate recommendations for this group.
The committee discussed the tendency to over-rely on TSH levels when making decisions about treatment. They agreed that factors suggesting underlying thyroid disease should also be taken into account when deciding whether or not to treat subclinical hypothyroidism.
The committee noted that a TSH level of 5 to 10 mlU/litre might return to the reference range without treatment in around half of people, whereas a TSH level above 10 mlU/litre is less likely to do so and is more often associated with symptoms. They therefore agreed that levothyroxine should be considered for all adults with a TSH level of 10 mlU/litre or more because this may improve symptoms and may have long-term benefits including on cardiovascular outcomes. For people with a TSH level lower than 10 mIU/litre, the committee agreed based on their experience that treatment was less likely to have a benefit but that the balance of risks to benefits was most favourable for adults under the age of 65. The committee noted that for people over 65 there was less likely to be an improvement in symptoms and the potential for harms from suppressing TSH (such as atrial fibrillation) is greater. The committee agreed that the trial of levothyroxine treatment should be stopped if symptoms persist with TSH levels within the reference range, as they are likely to be due to causes other than hypothyroidism.
The committee also agreed that the recommendations on testing TPOAbs in overt hypothyroidism applied to subclinical hypothyroidism because testing would help to inform the decision on whether or not to treat.
Because of the small amount of evidence available on the treatment of subclinical hypothyroidism, the committee made recommendations for research on selenium and iodine.
In children and young people there are a number of different causes of a mild increase in TSH besides autoimmune thyroid disease. These include mild congenital hypothyroidism, a low iodine intake (for example, because of a special diet), intercurrent illness, adrenal insufficiency and the paradoxical 'increase' in TSH observed in children with secondary hypothyroidism. The committee agreed that there is no urgency to treat with levothyroxine if thyroid hormone levels are appropriate for age. It is important to make a diagnosis before offering any treatment. The committee recommended caution when considering levothyroxine for children and young people whose thyroid dysfunction was unexplained. However, they also noted that in the very young it would not be appropriate to wait as long as for adults (3 months) to confirm a raised TSH with a second test.
## How the recommendations might affect practice
The committee highlighted that current practice for monitoring of subclinical hypothyroidism varies considerably, with unnecessary testing often being undertaken. They agreed that the recommendations are likely to reduce the number of tests overall.
Full details of the evidence and the committee's discussion are in evidence review G: managing subclinical hypothyroidism.
Return to recommendations
# Tests for people with confirmed thyrotoxicosis
Recommendations 1.6.1 to 1.6.4
## Why the committee made the recommendations
The committee agreed that it is crucial to determine the cause of thyrotoxicosis because this affects management decisions. Antithyroid drugs are unlikely to cure toxic nodular disease but may induce remission in Graves' disease. TRAbs testing provides confirmation of clinical features that suggest Graves' disease. Getting an accurate diagnosis sooner benefits the patient because the appropriate treatment options would be offered first. If TRAbs levels are high it is unlikely that antithyroid drugs will induce remission of Graves' disease.
Evidence suggested that in adults, the diagnostic accuracy of TRAbs testing for Graves' disease was high across different cut-off values. Evidence also showed the accuracy to be high in children. However, the evidence was limited in terms of the number of studies and the study sizes. But it was in line with the committee's experience and current practice, so they agreed to recommend TRAbs testing for Graves' disease in both adults and children and young people.
Evidence on the diagnostic accuracy of TPOAbs testing was not available in either adults or children. The committee agreed that based on their experience, TPOAbs testing alone is not likely to be as useful as TRAbs testing for the diagnosis of Graves' disease, but it could be used in children and young people where the absence of TRAbs but presence of TPOAbs indicates that thyrotoxicosis is more likely to resolve spontaneously.
Evidence for the diagnostic accuracy of ultrasound was limited in both adults and children. Based on clinical experience, the committee agreed that ultrasound was useful for the diagnosis of Graves' disease but only when there were palpable thyroid nodules.
The committee agreed that technetium scanning may be useful when TRAbs are negative and Graves' disease is suspected because generalised uptake on the scan suggests Graves' disease.
## How the recommendations might affect practice
Over recent years, TRAbs testing has become more widely available and more centres in the UK are using it to confirm the diagnosis of Graves' disease. However, some centres continue to use TPOAbs testing. If TRAbs testing allows more accurate differentiation between the different causes of thyrotoxicosis, there are likely to be reductions in unnecessary antithyroid treatment (including surgery) for people with transient thyroiditis and more timely and appropriate treatment choices for people with toxic nodular hyperthyroidism. The committee anticipates that TRAbs testing will become standard best practice for all UK centres leading to a correct diagnosis of Graves' disease for more people.
The use of technetium scanning for adults who are TRAbs negative reflects current practice in most centres.
Although thyroid ultrasound has only a limited role in the investigation of suspected Graves' disease, many healthcare professionals offer this investigation. This often results in incidental findings of doubtful clinical significance leading to further unnecessary investigations and interventions. The recommendation will discourage healthcare professionals from using thyroid ultrasound routinely in the investigation of suspected Graves' disease, which is likely to be cost saving.
Full details of the evidence and the committee's discussion are in evidence review H: tests for people with confirmed thyrotoxicosis.
Return to the recommendations
# Initial management in primary/non-specialist care for people with thyrotoxicosis
Recommendations 1.6.5 and 1.6.6.
## Why the committee made the recommendations
Based on their experience, the committee reminded healthcare professionals that transient thyrotoxicosis does not need definitive treatment. They recommended that short-term treatment with antithyroid drugs may be needed until decisions about the most appropriate treatment can be made in specialist care. The committee also agreed that treatment with antithyroid drugs before radioactive iodine would minimise the rise in circulating thyroid hormone levels following this treatment and so reduce the symptoms of thyrotoxicosis. They acknowledged that it is important to render the patient euthyroid with antithyroid drugs before surgery to ensure patient safety.
## How the recommendations might affect practice
The recommendations reflect current practice so the committee agreed there should be no change.
Full details of the evidence and the committee's discussion are in evidence reviews I, J, K, L: managing thyrotoxicosis.
Return to the recommendations
# Treatment for adults with Graves' disease
Recommendations 1.6.7 to 1.6.14
## Why the committee made the recommendations
The evidence suggested that radioactive iodine produced better long-term outcomes than antithyroid drugs in terms of thyroid status, but with a greater risk of thyroid eye disease. There was no convincing evidence of a difference between radioactive iodine and surgery. The economic evidence showed that radioactive iodine offered a better balance of benefits and costs than surgery (total thyroidectomy) and was more cost effective than antithyroid drugs. Although exposure to radiation will always lead to some small increase in relative risk of cancer, the evidence showed that this did not translate into an absolute effect that was clinically important. The committee agreed nonetheless that continued follow-up of people who have undergone radioactive iodine treatment was important and the 'as low as reasonably practicable' (ALARP) principle applied. They also agreed to make a research recommendation on the long-term effectiveness and safety of exposure to radioactive iodine.
The committee agreed, based on the clinical and economic evidence, that radioactive iodine should be offered as first-line definitive treatment for most people with hyperthyroidism secondary to Graves' disease. However they noted a number of important exceptions and specified these in the recommendations. The committee acknowledged that circulating levels of thyroid hormones are likely to rise following radioiodine administration and pre-treatment with anti-thyroid drugs would make radioactive iodine safer and lead to reduced symptoms of thyrotoxicosis. The committee also agreed that the response to antithyroid drugs is better in some people than in others. For adults who are likely to have a particularly good response to antithyroid drugs (mild uncomplicated Graves' disease), radioactive iodine and a course of antithyroid drugs could be equally appropriate options.
Some studies have suggested that some people are more likely to relapse after antithyroid drugs. These include males, younger people, people who smoke, people with a large goitre, people with high levels of thyroid hormones at the time of diagnosis and people with high levels of TRAbs. However, most of the studies were small and retrospective. The committee agreed that it would be very helpful to confirm these findings in large prospective multi-centre studies. They made a research recommendation to inform future guidance.
The evidence did not identify a clinically important difference between a calculated or fixed strategy in terms of radioactive iodine dosing. A calculated strategy has an increased cost because of the need for imaging (usually ultrasound) and uptake measurements. There are theoretical benefits from a calculated strategy to administer a more precise dose that could reduce potentially unnecessary additional radiation exposure, but the evidence did not indicate that this precision translated to clinically important benefits. The committee's experience is that, in the UK, radioactive iodine is usually given without calculating the absorbed dose. The committee agreed that there was too much uncertainty around the impact of the differing strategies to make a recommendation and chose to make a research recommendation.
The evidence suggested no clinically important difference between surgical options (total and hemithyroidectomy) for Graves' disease, but tended towards a benefit of total thyroidectomy in terms of relapse rates and harm in terms of increased risk of hypoparathyroidism. These findings were consistent with the committee's own experience. The committee agreed to recommend total thyroidectomy for adults with Graves' disease having surgery. This was based on their experience that people opting for surgery are generally seeking a definitive treatment.
## How the recommendations might affect practice
The committee was aware that the recommendations would result in radioactive iodine being offered as first-line definitive treatment to more people than currently. This is likely to be cost effective as shown by the economic evidence.
Full details of the evidence and the committee's discussion are in evidence reviews: I, J, K, L: managing thyrotoxicosis.
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# Treatment for adults with toxic nodular goitre
Recommendations 1.6.15 to 1.6.17
## Why the committee made the recommendations
The committee used their experience and an extrapolation of the evidence from Graves' disease to recommend radioactive iodine as the first-line definitive treatment for hyperthyroidism secondary to multiple nodules. Surgery or life-long antithyroid drugs could be offered in some circumstances when radioactive iodine is inappropriate (for example, young mothers, people in nursing homes or people unable to adhere to radiation protection guidance) or surgery is likely to have additional benefits (for example, if malignancy is suspected). The committee used their experience to recommend that when surgery is chosen hemithyroidectomy should be considered for people with hyperthyroidism due to a single toxic nodule, and total thyroidectomy for people with hyperthyroidism and multiple toxic nodules. A hemithyroidectomy is a shorter procedure that removes less of the thyroid gland; this requires less time in hospital and leads to a lower risk of adverse effects like hypoparathyroidism and long-term hypothyroidism but has a greater risk of relapse of hyperthyroidism. The risk of relapse is greater for multiple toxic nodules, hence the different recommendations for different populations.
## How the recommendations might affect practice
The recommendations broadly reflect current practice so the committee agreed there should be no substantial change.
Full details of the evidence and the committee's discussion are in evidence reviews I, J, K, L: managing thyrotoxicosis.
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# Treatment for children and young people with Graves' disease or toxic nodular goitre
Recommendations 1.6.18 to 1.6.20
## Why the committee made the recommendations
No evidence was identified for treatments in children and young people with hyperthyroidism. Based on their experience, the committee recommended that antithyroid drugs should be first-line definitive treatment for children and young people with Graves' disease or hyperthyroidism secondary to a single or multiple toxic nodules. The committee agreed that the risks of radioactive iodine and surgery may be greater than for adults so it is important to get input from the multidisciplinary team and discuss these options with the child and their family.
When surgery is chosen, the committee recommended that this should be total thyroidectomy for Graves' disease or bilateral thyroid nodules. They based this on their experience and evidence in adults.
## How the recommendations might affect practice
The recommendations to offer antithyroid drugs as first-line treatment are broadly in line with current practice and are unlikely to have a substantial cost impact. The potential risks and benefits (and therefore cost effectiveness) of radioactive iodine treatment in children are uncertain.
Full details of the evidence and the committee's discussion are in evidence reviews I, J, K, L: managing thyrotoxicosis.
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# Antithyroid drugs for people with hyperthyroidism
## Why the committee made the recommendations
Recommendations 1.6.21 to 1.6.26
Evidence showed a clinically important benefit in terms of normalising thyroid hormone levels and minor drug-related adverse events for methimazole or carbimazole compared with propylthiouracil. However, hypothyroidism was more frequent with methimazole or carbimazole. The committee questioned whether this was a result of over-treatment and thought hypothyroidism unlikely to be permanent. Because carbimazole, and not methimazole, is currently licensed in the UK, the committee recommended carbimazole as the drug of choice when offering an antithyroid drug for treating hyperthyroidism. The committee noted that carbimazole is not recommended in children under 2 years. In view of the potential risk of liver failure the committee agreed that propylthiouracil should not be the first choice of antithyroid drug. However, the committee noted the MHRA drug safety advice for carbimazole on contraception and the risk of acute pancreatitis and agreed that propylthiouracil is appropriate as an alternative for adults.
Evidence showed a clinically important benefit in terms of lack of relapse to hyperthyroidism and maintaining normal thyroid hormone levels with 12 to 18 months' treatment compared with 6 to 12 months' treatment. There was no clinically important difference in relapse following a longer treatment of more than 18 months.
The committee recommended that carbimazole should be offered for at least 12 to 18 months. They noted that this differed from the summary of product characteristics which advises 6 to 18 months, but agreed that the deviation was justified by the evidence. The committee agreed based on their experience and extrapolation from evidence in adults that the treatment duration for children should be reviewed every 2 years.
Evidence showed that block and replace (fixed high dose combined with levothyroxine) and titration (dose based on thyroid function tests) regimens of antithyroid drugs were similar in terms of minor drug-related adverse events (skin reactions). There were fewer relapses to hyperthyroidism with block and replace treatment compared with titration. But there was limited evidence suggesting more chance of agranulocytosis with block and replace regimens. The committee noted that block and replace treatment could theoretically provide greater stability and require fewer medical appointments than titration regimens. Therefore they recommended a choice of either regimen for adults with Graves' disease. Hyperthyroidism in children and young people should usually be managed with a dose titration regimen because of the increased risk of adverse events in this age group. The committee also made a recommendation for further research in this area.
The committee noted that people with hyperthyroidism secondary to a single or multiple toxic nodules will not go into remission and therefore discontinuing antithyroid drugs is not relevant. They agreed that titration regimens are generally more appropriate for this group.
## How the recommendations might affect current practice
Current practice in the UK, in adults and children, is a mix of block and replace (approximately 40%) and titration regimens (approximately 60%). The recommendations are broadly in line with current practice and unlikely to have significant resource impact.
Full details of the evidence and the committee's discussion are in evidence review J: management of thyrotoxicosis – antithyroid drugs.
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# Follow-up and monitoring of hyperthyroidism
Recommendations 1.7.1 to 1.7.12
## Why the committee made the recommendations
No evidence was identified on the most appropriate ways to monitor hyperthyroidism, so the committee made recommendations based on their experience. The precise timing of monitoring depends on the treatment chosen, but in general the committee aimed to minimise unnecessary testing while ensuring early treatment failures or adverse effects (for example, hypothyroidism) were identified. Regardless of treatment option chosen, the committee agreed that in the long term TSH alone is sufficient for monitoring, although TSH alongside FT4 and FT3 will be needed in the short term after treatment. Should TSH become abnormal, having been stable within the reference range for a prolonged period, further tests will be necessary. Short-term combined testing with TSH, FT4 and FT3 is needed to inform decisions about the need for additional courses of treatment or dose changes with antithyroid drugs. As no evidence was found to support a strategy of routinely monitoring full blood count and liver function tests, and these tests have a treatment burden for people with hyperthyroidism and a resource impact, the committee recommended that healthcare professionals do not test unless there is a clinical suspicion of specific adverse effects of treatment.
## How the recommendations might affect practice
More people with Graves' disease are expected to have monitoring because radioactive iodine is more likely to be offered as first-line treatment. This extra cost is likely to be justified, because radioactive iodine is more cost effective than other treatments for hyperthyroidism. In general, these recommendations reinforce best practice, with earlier detection leading to earlier treatment, reduced costs of treating complications and improved quality of life. The recommendation that there is no need to monitor full blood count and liver function after antithyroid drug treatment unless liver dysfunction or agranulocytosis are suspected is likely to be cost saving.
Full details of the evidence and the committee's discussion are in evidence review F: monitoring thyroid disease.
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# Managing and monitoring subclinical hyperthyroidism
Recommendations 1.8.1 to 1.8.5
## Why the committee made the recommendations
There was no evidence available on treating subclinical hyperthyroidism so the committee used their experience to develop the recommendations. They agreed that treatment might be suitable if subclinical hyperthyroidism is persistent and appears to be caused by intrinsic thyroid disease. However, the committee noted that there is currently no evidence that treatment offers benefits and it can have adverse effects. Overall the committee agreed that treatment decisions should be made with specialist advice. Treatment would be appropriate in those most likely to benefit, in other words those with very suppressed TSH and other features suggesting thyroid disease. The committee also agreed that they could not make specific recommendations about when to treat subclinical hyperthyroidism in children as specialist input would also be needed for this.
Several large population-based observational studies have shown that subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation, osteoporosis, dementia, and death, including death from cardiovascular disease. Although most people with subclinical hyperthyroidism have no symptoms, an important question is whether treatment could improve long-term outcomes (for example, atrial fibrillation and dementia). The committee agreed to make a research recommendation to inform future practice.
There was no evidence available on monitoring subclinical thyroid dysfunction so the committee based the recommendations on their experience.
The overall aim of these recommendations is to ensure that if the subclinical thyroid dysfunction needs treatment, this will be identified in a timely manner but without subjecting a person to a lot of unnecessary tests.
The committee agreed that for children and young people monitoring may need to be more frequent.
## How the recommendations might affect practice
Current practice in managing subclinical hyperthyroidism is variable. Some people are offered antithyroid drugs or radioactive iodine; surgery is very rare. Many people are offered no treatment. The recommendations are likely to reduce inappropriate treatment and to be cost saving.
The recommendations for monitoring subclinical thyroid dysfunction reflect good current practice.
Full details of the evidence and the committee's discussion are in evidence review M: management of subclinical thyrotoxicosis.
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# Investigating non-malignant thyroid enlargement with normal thyroid function
Recommendations 1.9.1 to 1.9.6
## Why the committee made the recommendations
Evidence showed that ultrasound using established criteria is accurate for determining whether thyroid nodules need fine needle aspiration to investigate potential malignancy. The committee noted that many referrals for thyroid ultrasound are based on incidental findings of other types of imaging (for example, CT scans performed for other indications). They agreed that thyroid ultrasound should only be performed when a full assessment indicates a likelihood of malignancy. Thyroid ultrasound of incidental findings should not be the default option because most incidental findings are not malignant and further investigation may cause harms in terms of the adverse effects of testing and patient anxiety.
The evidence showed that different ultrasound criteria generally assessed the same features and had similar accuracy for detecting malignancy. Rather than recommending a specific set of criteria, the committee chose to list the essential features of any grading system (the lesion's echogenicity, border, shape, vascularity, presence of microcalcifications and cervical lymphadenopathy). Based on their knowledge that nodule size does not determine the likelihood of malignancy, and the observation that the criterion (SRU) that includes nodule size results in significantly lower sensitivity and specificity, they agreed not to include nodule size in the list.
Because healthcare professionals need to be able to re-visit ultrasound findings, the committee agreed that the grading system used for clinical decision making, including the specific nodule features examined to assess malignancy, should be specified in ultrasound reports. For the same reason, they agreed that ultrasound reports should also confirm that both lobes have been assessed and document the assessment of cervical lymph nodes.
The committee agreed that the recommendations should apply to children and young people as well as adults.
Evidence indicated that performing fine needle aspiration under ultrasound guidance provides greater sensitivity and specificity for determining the malignancy of thyroid nodules compared with palpation guidance.
The evidence also showed that with ultrasound guidance an inadequate sample is less likely than with palpation. Inadequate sampling is likely to add to the overall cost of palpation-guided fine needle aspiration because samples may need to be repeated or require more extensive investigation. The committee also noted that there were additional benefits of ultrasound guidance because ultrasonographic characteristics identified by simultaneous imaging provide more information about the risk of malignancy before cytology results are obtained.
## How the recommendations might affect practice
Ultrasound is currently already used to assess the likelihood of thyroid malignancy, so the recommendations are not likely to make a significant impact. In the UK, the most commonly used ultrasound criteria are those of the British Thyroid Association, which are in line with the recommendations in this guideline.
The recommendation reflects current practice so the committee agreed that it should not have a significant impact.
Full details of the evidence and the committee's discussion are in evidence review N: imaging for fine needle aspiration and evidence review O: ultrasound guidance for fine needle aspiration.
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# Managing non-malignant thyroid enlargement
Recommendations 1.9.7 to 1.9.12
## Why the committee made the recommendations
The committee noted that there was little evidence on the efficacy of surgery for nodules; this was related to the challenges of comparing surgical and non-surgical interventions. In general, the committee agreed that surgery would be appropriate for nodules or enlargement causing symptoms, if there has been no response with other options or if there is true compression of nearby organs (for example, tracheal narrowing).
Aspiration is routinely done before more intensive intervention for cystic nodules because it is simple and can be done in the same appointment as preliminary investigation by a radiologist (or endocrinologist). The evidence generally showed a benefit of ethanol ablation over levothyroxine and equivalence with radiofrequency ablation.
The evidence showed no clinically important effect of levothyroxine on non-cystic nodules and a benefit of radiofrequency ablation and laser ablation. There was no evidence identified on radioactive iodine ablation although the committee noted that it is very commonly used in the UK for diffuse goitres that are causing symptoms, particularly if there is demonstrable radionuclide uptake. The committee also noted that the more recently developed techniques for percutaneous thermal ablation (for example, high-intensity focused ultrasound and microwave ablation) may be appropriate for some people but are not widely available. They made a research recommendation on percutaneous thermal ablation to inform future practice. The committee agreed not to recommend the use of levothyroxine due to the evidence suggesting no clinically important benefit for most outcomes and their awareness of adverse effects (for example, TSH suppression and increasing cardiovascular risk).
The committee noted that there was no evidence in children. They agreed that a healthcare professional should refer a child with thyroid enlargement to an appropriate multidisciplinary team, to ensure appropriate management as early as possible.
There was no evidence on monitoring thyroid enlargement but the committee agreed that, given the accuracy of ultrasound imaging, the risk of missing a malignancy or malignant transformation in an enlarged thyroid gland is low. However, they agreed that worsening symptoms or development of new symptoms may warrant repeating the ultrasound and TSH measurement. Suspicion of malignancy or compression would warrant repeating these tests.
## How the recommendations might affect practice
The recommendations on surgical referral for goitre and non-malignant thyroid nodules are broadly in line with current clinical practice and therefore not expected to have significant impact.
The recommendations on managing non-malignant thyroid enlargement are also unlikely to have substantial resource impact. Radiofrequency ablation and laser ablation are not currently widely available. However it is current practice to only provide interventions to adults with nodules causing symptoms, as outlined in the recommendations. This limits the number of adults needing these interventions. Referral of children to a multidisciplinary team is not likely to occur often because thyroid enlargement is rare in this population.
The recommendation broadly reflects current practice. The committee recognised that there may be some centres in which routine monitoring is done, and the recommendation is likely to reduce this.
Full details of the evidence and the committee's discussion are in evidence review P: management of non-malignant thyroid enlargement, and evidence review F: monitoring thyroid disease.
Return to recommendations# Context
Thyroid disease includes thyroid enlargement and thyroid hormone dysfunction. Thyroid enlargement may be benign, resulting in nodules or goitre, or malignant in people with thyroid cancer. Conditions causing thyroid dysfunction can be broadly divided into those that result in thyroid gland underactivity (hypothyroidism) or overactivity (thyrotoxicosis).
Thyroid enlargement is common. About 15% of the UK population have clinically detectable goitres or thyroid nodules, and the lifetime risk of developing a thyroid nodule is around 5 to 10%. In many cases, thyroid glands harbouring malignancy are clinically indistinguishable from those that are not. Most people with a non-malignant enlarged thyroid gland and normal thyroid function need no treatment.
Hypothyroidism is a condition of thyroid hormone deficiency and is usually caused by autoimmune Hashimoto's thyroiditis. Primary hypothyroidism refers to conditions arising from the thyroid gland rather than the pituitary gland (secondary hypothyroidism). Hypothyroidism is found in about 2% of the UK population and in more than 5% of those over 60. Women are 5 to 10 times more likely to be affected than men. Long-term consequences of hypothyroidism include cardiovascular disease and an increase in cardiovascular risk factors, including hypercholesterolaemia.
Thyrotoxicosis is a disorder of excess circulating thyroid hormones caused by increased production and secretion (hyperthyroidism) or the release of (thyroiditis) stored thyroid hormones. In the UK, autoimmune hyperthyroidism (Graves' disease) is the most common form, accounting for 60 to 80% of cases. Thyrotoxicosis is a common endocrine disorder with a prevalence of around 2% in UK women and 0.2% in men. Graves' disease is caused by a genetic predisposition to developing stimulating thyroid autoantibodies and occurs mostly in women aged 30 to 60 years. Thyrotoxicosis affects 1 to 2 children per 10,000. Children may be severely affected, with poor educational performance often being an early feature. Long-term consequences of hyperthyroidism include increased cardiovascular morbidity and mortality and bone-related complications, including osteoporosis.
Subclinical thyroid dysfunction is a biochemical diagnosis where serum thyroid-stimulating hormone (TSH) levels are outside the reference range, and circulating thyroid hormone levels (thyroxine and tri-iodothyronine ) are within the reference range. It is often detected incidentally, although some people may have symptoms of hypothyroidism or hyperthyroidism. The prevalence of subclinical thyrotoxicosis is 0.5 to 10% and that of subclinical hypothyroidism is 4 to 20%; these wide ranges reflect differences in the studied populations. Data on the long-term consequences of subclinical thyroid dysfunction largely come from people over 65. They indicate increased cardiovascular morbidity and mortality, an increased risk of osteoporosis and potential links to dementia.
This guideline covers investigating all suspected thyroid dysfunction and managing primary thyroid disease (related to the thyroid rather than the pituitary gland). There is variation in how thyroid disease is investigated and managed in primary and secondary care. There are currently no standardised diagnostic or referral criteria in the UK to guide decision making in primary care for people with structural thyroid abnormalities or enlargement. In secondary care, there is significant variation in the types of diagnostic tests and imaging used, as well as in surgical and non-surgical management and follow-up protocols. Standardisation in thyroid hormone replacement strategies for people with hypothyroidism is currently lacking. In addition, guidance on optimal treatment and follow-up strategies is needed for managing thyrotoxicosis, which is usually done by shared care between primary and secondary care. Opinions regarding the need to treat subclinical thyroid dysfunction, especially in older people, vary widely.
This guideline also aims to improve the diagnosis, management and follow-up of non-malignant thyroid enlargement associated with normal thyroid function.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as discussed in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information for people with thyroid disease, their families and carers\n\n## Presenting information\n\nEnsure that information is presented to facilitate shared decision making, as recommended in the NICE guideline on shared decision making.\n\n## General information\n\nExplain to people with thyroid disease who need treatment, and their family or carers if appropriate, that:\n\nThyroid disease usually responds well to treatment.\n\nThe goal of treatment is to alleviate symptoms and align thyroid function tests within or close to the reference range.\n\nPeople may feel well even when their thyroid function tests are outside the reference range.\n\nEven when there are no symptoms, treatment may be advised to reduce the risk of long-term complications.\n\nEven when thyroid function tests are within the reference range, changes to treatment may improve symptoms for some people.\n\nSymptoms may lag behind treatment changes for several weeks to months.\n\nDay-to-day changes in unexplained symptoms are unlikely to be due to underlying thyroid disease because the body has a large reservoir of thyroxine.\n\nProvide people with thyroid disease, and their family or carers if appropriate, with written and verbal information on:\n\ntheir underlying condition, including the role and function of the thyroid gland and what the thyroid function tests mean\n\nrisks of over- and under-treatment\n\ntheir medicines\n\nneed for and frequency of monitoring\n\nwhen to seek advice from a healthcare professional\n\nhow thyroid disease and medicines may affect pregnancy and fertility.\n\nSee the recommendations on testing for coeliac disease in people with a diagnosis of autoimmune thyroid disease in the NICE guideline on coeliac disease.\n\n## Hypothyroidism (underactive thyroid)\n\nProvide people with hypothyroidism, and their family or carers if appropriate, with written and verbal information on:\n\npossible drug interactions of thyroid hormone replacements, including interactions with over-the-counter medicines\n\nhow and when to take levothyroxine.\n\n## Thyrotoxicosis (overactive thyroid)\n\nProvide people with thyrotoxicosis, and their family or carers if appropriate, with written and verbal information on:\n\nthe different causes of thyrotoxicosis\n\nthe consequences of untreated thyrotoxicosis\n\nthe suitability of individual treatment options (for example, antithyroid drugs may be more suitable for mild uncomplicated Graves' disease, surgery may be best for an enlarged thyroid causing compression, radioactive iodine is not usually suitable before puberty)\n\nthe possible benefits/advantages of the treatment options (for example, antithyroid drugs and radioactive iodine are non-invasive treatments, surgery offers rapid relief of symptoms and there is no need to delay pregnancy or fathering a child)\n\nthe possible risks/disadvantages of the treatment options (for example, antithyroid drugs may have side effects, radioactive iodine means limited contact with other people for a few weeks and a need to delay pregnancy or fathering a child, surgery is an invasive treatment that leaves scarring on the neck)\n\nthe risk of and impact of different treatment options on new and existing thyroid eye disease (for example, radioactive iodine may precipitate or worsen thyroid eye disease)\n\nthe need for thyroid hormone replacement if treatment leads to life-long hypothyroidism.\n\n## Thyroid enlargement (also known as goitre)\n\nProvide people with thyroid enlargement, and their family or carers if appropriate, with written and verbal information on:\n\nthe causes of thyroid enlargement, including the fact that goitre and nodules are common and are usually not cancerous\n\nred flag symptoms to look out for (for example, shortness of breath, rapid growth of nodules, hoarse voice, swallowing difficulties)\n\ntreatment options.\n\nTo find out why the committee made the recommendations on information and how they might affect practice, see the rationale and impact section on information for people with thyroid disease, their families and carers\xa0.\n\nLoading. Please wait.\n\n# Investigating suspected thyroid dysfunction or thyroid enlargement\n\n## Indications for tests for thyroid dysfunction\n\nConsider tests for thyroid dysfunction for adults, children and young people if there is a clinical suspicion of thyroid disease, but bear in mind that 1 symptom alone may not be indicative of thyroid disease.\n\nOffer tests for thyroid dysfunction to adults, children and young people with:\n\ntype\xa01 diabetes or other autoimmune diseases, or\n\nnew-onset atrial fibrillation.\n\nConsider tests for thyroid dysfunction for adults, children and young people with depression or unexplained anxiety.\n\nConsider tests for thyroid dysfunction for children and young people with abnormal growth, or unexplained change in behaviour or school performance.\n\nBe aware that in menopausal women symptoms of thyroid dysfunction may be mistaken for menopause.\n\nDo not test for thyroid dysfunction during an acute illness unless you suspect the acute illness is due to thyroid dysfunction, because the acute illness may affect the test results.\n\nDo not offer testing for thyroid dysfunction solely because an adult, child or young person has type\xa02 diabetes.\n\nTo find out why the committee made the recommendations on indications for tests for thyroid dysfunction and how they might affect practice, see the rationale and impact section on indications for tests for thyroid dysfunction\xa0.\n\nLoading. Please wait.\n\n## Tests when thyroid dysfunction is suspected\n\nConsider measuring thyroid-stimulating hormone (TSH) alone for adults when secondary thyroid dysfunction (pituitary disease) is not suspected. Then:\n\nif the TSH is above the reference range, measure free thyroxine (FT4) in the same sample\n\nif the TSH is below the reference range, measure FT4 and free tri-iodothyronine (FT3) in the same sample.\n\nConsider measuring both TSH and FT4 for:\n\nadults when secondary thyroid dysfunction (pituitary disease) is suspected\n\nchildren and young people. If the TSH is below the reference range, measure FT3 in the same sample.\n\nConsider repeating the tests for thyroid dysfunction in recommendations 1.2.8 or 1.2.9 if symptoms worsen or new symptoms develop (but no sooner than 6\xa0weeks from the most recent test).\n\nTo find out why the committee made the recommendations on tests when thyroid dysfunction is suspected and how they might affect practice, see the rationale and impact section on tests when thyroid dysfunction is suspected\xa0.\n\nLoading. Please wait.\n\n# Managing primary hypothyroidism\n\n## Tests for people with confirmed primary hypothyroidism\n\nConsider measuring thyroid peroxidase antibodies (TPOAbs) for adults with TSH levels above the reference range, but do not repeat TPOAbs testing.\n\nMeasure TPOAbs for children and young people with TSH levels above the reference range, with possible repeat TPOAbs testing at the time of transition to adult services.\n\nTo find out why the committee made the recommendations on tests for people with confirmed primary hypothyroidism and how they might affect practice, see the rationale and impact section on tests for people with confirmed primary hypothyroidism\xa0.\n\nLoading. Please wait.\n\n## Managing primary hypothyroidism\n\nOffer levothyroxine as first-line treatment for adults, children and young people with primary hypothyroidism.\n\nDo not routinely offer liothyronine for primary hypothyroidism, either alone or in combination with levothyroxine, because there is not enough evidence that it offers benefits over levothyroxine monotherapy, and its long-term adverse effects are uncertain.\n\nDo not offer natural thyroid extract for primary hypothyroidism because there is not enough evidence that it offers benefits over levothyroxine, and its long-term adverse effects are uncertain.Natural thyroid extract does not have a UK marketing authorisation so its safety is uncertain.\n\nConsider starting levothyroxine at a dosage of 1.6\xa0micrograms per kilogram of body weight per day (rounded to the nearest 25\xa0micrograms) for adults under 65 with primary hypothyroidism and no history of cardiovascular disease.\n\nConsider starting levothyroxine at a dosage of 25 to 50\xa0micrograms per day with titration for adults aged 65 and over and adults with a history of cardiovascular disease.\n\nTo find out why the committee made the recommendations on managing primary hypothyroidism and how they might affect practice, see the rationale and impact section on managing primary hypothyroidism\xa0.\n\nLoading. Please wait.\n\n# Follow-up and monitoring of primary hypothyroidism\n\n## Tests for follow-up and monitoring of primary hypothyroidism\n\nAim to maintain TSH levels within the reference range when treating primary hypothyroidism with levothyroxine. If symptoms persist, consider adjusting the dose of levothyroxine further to achieve optimal wellbeing, but avoid using doses that cause TSH suppression or thyrotoxicosis.\n\nBe aware that the TSH level can take up to 6\xa0months to return to the reference range for people who had a very high TSH level before starting treatment with levothyroxine or a prolonged period of untreated hypothyroidism. Take this into account when adjusting the dose of levothyroxine.\n\nFor adults who are taking levothyroxine for primary hypothyroidism, consider measuring TSH every 3\xa0months until the level has stabilised (2 similar measurements within the reference range 3\xa0months apart), and then once a year.\n\nConsider measuring FT4 as well as TSH for adults who continue to have symptoms of hypothyroidism after starting levothyroxine.\n\nFor children aged 2\xa0years and over and young people taking levothyroxine for primary hypothyroidism, consider measuring FT4 and TSH:\n\nevery 6 to 12\xa0weeks until the TSH level has stabilised (2 similar measurements within the reference range 3\xa0months apart), then\n\nevery 4 to 6\xa0months until after puberty, then\n\nonce a year.\n\nFor children aged between 28\xa0days and 2\xa0years who are taking levothyroxine for primary hypothyroidism, consider measuring FT4 and TSH:\n\nevery 4 to 8\xa0weeks until the TSH level has stabilised (2 similar measurements within the reference range 2\xa0months apart), then\n\nevery 2 to 3\xa0months during the first year of life, and\n\nevery 3 to 4\xa0months during the second year of life.\n\nTo find out why the committee made the recommendations on tests for monitoring and follow-up of primary hypothyroidism and how they might affect practice, see the rationale and impact section on follow-up and monitoring of primary hypothyroidism\xa0.\n\nLoading. Please wait.\n\n# Managing and monitoring subclinical hypothyroidism\n\n## Tests for people with confirmed subclinical hypothyroidism\n\nConsider measuring TPOAbs for adults with TSH levels above the reference range, but do not repeat TPOAbs testing.\n\n## Treating subclinical hypothyroidism\n\nWhen discussing whether or not to start treatment for subclinical hypothyroidism, take into account features that might suggest underlying thyroid disease, such as symptoms of hypothyroidism, previous radioactive iodine treatment or thyroid surgery, or raised levels of thyroid autoantibodies.\n\nConsider levothyroxine for adults with subclinical hypothyroidism who have a TSH of 10\xa0mlU/litre or higher on 2 separate occasions 3\xa0months apart. Follow the recommendations in section 1.4 on follow-up and monitoring of hypothyroidism.\n\nConsider a 6-month trial of levothyroxine for adults under 65 with subclinical hypothyroidism who have:\n\na TSH above the reference range but lower than 10\xa0mlU/litre on 2 separate occasions 3\xa0months apart, and\n\nsymptoms of hypothyroidism.If symptoms do not improve after starting levothyroxine, re-measure TSH and if the level remains raised, adjust the dose. If symptoms persist when serum TSH is within the reference range, consider stopping levothyroxine and follow the recommendations on monitoring untreated subclinical hypothyroidism and monitoring after stopping treatment.\n\nConsider levothyroxine for children aged 2\xa0years and over and young people with subclinical hypothyroidism who have:\n\na TSH level of 20\xa0mlU/litre or higher, or\n\na TSH level between 10 and 20\xa0mlU/litre on 2 separate occasions 3\xa0months apart, or\n\na TSH level between 5 and 10\xa0mlU/litre on 2 separate occasions 3\xa0months apart, and\n\n\n\nthyroid dysgenesis (an underdeveloped thyroid gland), or\n\nsigns or symptoms of thyroid dysfunction.During levothyroxine treatment, follow the recommendations in section 1.4 on follow-up and monitoring.\n\n\n\nConsider levothyroxine for children aged between 28\xa0days and 2\xa0years with subclinical hypothyroidism who have a TSH level of 10\xa0mlU/litre or higher. During levothyroxine treatment, follow the recommendations in section 1.4 on follow-up and monitoring.\n\n## Monitoring untreated subclinical hypothyroidism and monitoring after stopping treatment\n\nFor adults with untreated subclinical hypothyroidism or adults who have stopped levothyroxine treatment for subclinical hypothyroidism, consider measuring TSH and FT4:\n\nonce a year if they have features suggesting underlying thyroid disease, such as previous thyroid surgery or raised levels of thyroid autoantibodies, or\n\nonce every 2 to 3\xa0years if they have no features suggesting underlying thyroid disease.\n\nConsider measuring TSH and FT4 for children aged 2\xa0years and over and young people with untreated subclinical hypothyroidism and a TSH lower than 10\xa0mlU/litre:\n\nevery 3 to 6\xa0months if they have features suggesting underlying thyroid disease, such as thyroid dysgenesis (an underdeveloped thyroid gland) or raised levels of thyroid autoantibodies, or\n\nevery 6 to 12\xa0months if they have no features suggesting underlying thyroid disease.\n\nConsider measuring TSH and FT4 every 1 to 3\xa0months for children aged between 28\xa0days and 2\xa0years with untreated subclinical hypothyroidism.\n\nConsider stopping TSH and FT4 measurement in children and young people if the TSH level has stabilised (2 similar measurements within the reference range 3 to 6\xa0months apart) and there are no features suggesting underlying thyroid disease.\n\nTo find out why the committee made the recommendations on managing and monitoring subclinical hypothyroidism and how they might affect practice, see the rationale and impact section on managing and monitoring subclinical hypothyroidism\xa0.\n\nLoading. Please wait.\n\n# Managing thyrotoxicosis\n\n## Tests for people with confirmed thyrotoxicosis\n\nDifferentiate between thyrotoxicosis with hyperthyroidism (for example, Graves' disease or toxic nodular disease) and thyrotoxicosis without hyperthyroidism (for example, transient thyroiditis) in adults by:\n\nmeasuring TSH receptor antibodies (TRAbs) to confirm Graves' disease\n\nconsidering technetium scanning of the thyroid gland if TRAbs are negative.\n\nOnly consider ultrasound for adults with thyrotoxicosis if they have a palpable thyroid nodule.\n\nDifferentiate between thyrotoxicosis with hyperthyroidism (Graves' disease) and thyrotoxicosis without hyperthyroidism (for example, transient thyroiditis) in children and young people by:\n\nmeasuring TPOAbs and TRAbs\n\nconsidering technetium scanning of the thyroid gland if TRAbs are negative.\n\nOnly offer ultrasound to children and young people with thyrotoxicosis if they have a palpable thyroid nodule or the cause of thyrotoxicosis remains unclear following thyroid autoantibody testing and technetium scanning.\n\nTo find out why the committee made the recommendations on tests for people with confirmed thyrotoxicosis and how they might affect practice, see the rationale and impact section on tests for people with confirmed thyrotoxicosis\xa0.\n\nLoading. Please wait.\n\n## Initial treatment in primary/non-specialist care\n\nBe aware that transient thyrotoxicosis without hyperthyroidism usually only needs supportive treatment (for example, beta-blockers).\n\nConsider antithyroid drugs along with supportive treatment for adults with hyperthyroidism who are waiting for specialist assessment and further treatment.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019).\n\nTo find out why the committee made the recommendations on initial management in primary/non-specialist care for people with thyrotoxicosis and how they might affect practice, see the rationale and impact section on initial management in primary/non-specialist care for people with thyrotoxicosis\xa0.\n\nLoading. Please wait.\n\n## Initial treatment in secondary/specialist care\n\nDiscuss with adults, children and young people with thyrotoxicosis with hyperthyroidism (and their families and carers as appropriate):\n\nthe possible benefits and risks of all treatment options (antithyroid drugs, radioactive iodine, surgery)\n\nthe likelihood of a good response to each option.\n\nEnsure that people can actively participate in decisions about their treatment by following the recommendations in the NICE guidelines on patient experience in adult NHS services and shared decision making. This includes presenting information about possible outcomes in a way the person (and their families and carers as appropriate) can understand.\n\nOffer antithyroid drugs to control hyperthyroidism in adults, children and young people who are waiting for treatment with radioactive iodine or surgery.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019). November 2019 – carbimazole use is off label for children under 2\xa0years. See NICE's information on prescribing medicines.\n\nOffer radioactive iodine as first-line definitive treatment for adults with Graves' disease, unless antithyroid drugs are likely to achieve remission (see recommendation 1.6.11), or it is unsuitable (for example, there are concerns about compression, malignancy is suspected, they are pregnant or trying to become pregnant or father a child within the next 4 to 6\xa0months, or they have active thyroid eye disease).Follow the 2017 regulations on medical exposure to ionising radiation.\n\nOffer a choice of antithyroid drugs (a 12- to 18-month course) or radioactive iodine (following the 2017 regulations on medical exposure to ionising radiation) as first-line definitive treatment for adults with Graves' disease if antithyroid drugs are likely to achieve remission (for example, mild and uncomplicated Graves' disease).Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019).\n\nOffer antithyroid drugs (a 12- to 18-month course) as first-line definitive treatment for adults with Graves' disease if radioactive iodine and surgery are unsuitable.\n\nOffer total thyroidectomy as first-line definitive treatment for adults with Graves' disease if:\n\nthere are concerns about compression, or\n\nthyroid malignancy is suspected, or\n\nradioactive iodine and antithyroid drugs are unsuitable.\n\nConsider radioactive iodine or surgery for adults with Graves' disease who have had antithyroid drugs but have persistent or relapsed hyperthyroidism.Follow the 2017 regulations on medical exposure to ionising radiation.\n\nTo find out why the committee made the recommendations on treatment for adults with Graves' disease and how they might affect practice, see the rationale and impact section on treatment for adults with Graves' disease\xa0.\n\nLoading. Please wait.\n\nOffer radioactive iodine as first-line definitive treatment for adults with hyperthyroidism secondary to multiple nodules unless it is unsuitable (for example, there are concerns about compression, thyroid malignancy is suspected, they are pregnant or trying to become pregnant or father a child within the next 4 to 6 months, or they have active thyroid eye disease).Follow the 2017 regulations on medical exposure to ionising radiation.\n\nOffer total thyroidectomy or life-long antithyroid drugs as first-line definitive treatment for adults with hyperthyroidism secondary to multiple nodules if radioactive iodine is unsuitable.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019).\n\nOffer radioactive iodine (if suitable) or surgery (hemithyroidectomy) as first-line definitive treatment for adults with hyperthyroidism secondary to a single nodule, or life-long antithyroid drugs if these options are unsuitable.\n\nTo find out why the committee made the recommendations on treatment for adults with toxic nodular goitre and how they might affect practice, see the rationale and impact section on treatment for adults with toxic nodular goitre\xa0.\n\nLoading. Please wait.\n\nOffer antithyroid drugs for at least 2\xa0years and possibly longer as first-line definitive treatment for children and young people with Graves' disease.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019). November 2019 – carbimazole use is off label for children under 2\xa0years. See NICE's information on prescribing medicines.\n\nConsider continuing or restarting antithyroid drugs or discussing radioactive iodine or surgery (total thyroidectomy) for children and young people with Graves' disease who have had a course of antithyroid drugs but have relapsed hyperthyroidism.\n\nFor children and young people with hyperthyroidism secondary to a single or multiple nodules:\n\noffer antithyroid drugs using a titration regimen of carbimazole, and\n\ndiscuss the role of surgery and radioactive iodine with the child, young person and family, following input from the multidisciplinary team.\n\nTo find out why the committee made the recommendations on treatment for children and young people with Graves' disease or toxic nodular goitre and how they might affect practice, see the rationale and impact section on treatment for children and young people with Graves' disease or toxic nodular goitre\xa0.\n\nLoading. Please wait.\n\n## Antithyroid drugs for adults, children and young people with hyperthyroidism\n\nBefore starting antithyroid drugs for adults, children and young people with hyperthyroidism, check full blood count and liver function tests.\n\nWhen offering antithyroid drugs as first-line definitive treatment to adults with Graves' disease, offer carbimazole for 12 to 18\xa0months, using either a block and replace or a titration regimen, and then review the need for further treatment.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019).\n\nWhen offering antithyroid drugs to children and young people with Graves' disease, offer carbimazole, using a titration regimen, and review the need for treatment every 2\xa0years.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019). November 2019 – carbimazole use is off label for children under 2\xa0years. See NICE's information on prescribing medicines.\n\nWhen offering life-long antithyroid drugs to adults with hyperthyroidism secondary to a single or multiple toxic nodules, consider treatment with a titration regimen of carbimazole.\n\nConsider propylthiouracil for adults:\n\nwho experience adverse reactions to carbimazole\n\nwho are pregnant or trying to become pregnant within the following 6\xa0months\n\nwith a history of pancreatitis.\n\nStop and do not restart any antithyroid drugs if a person develops agranulocytosis. Consider referral to a specialist for further management options.\n\nTo find out why the committee made the recommendations on antithyroid drugs for adults, children and young people with hyperthyroidism and how they might affect practice, see the rationale and impact section on antithyroid drugs for people with hyperthyroidism\xa0.\n\nLoading. Please wait.\n\n# Follow-up and monitoring of hyperthyroidism\n\n## Monitoring after radioactive iodine treatment\n\nConsider measuring TSH, FT4 and FT3 levels in adults, children and young people every 6\xa0weeks for the first 6\xa0months after radioactive iodine treatment until TSH is within the reference range.\n\nFor adults, children and young people who have hypothyroidism after radioactive iodine treatment and are not on antithyroid drugs, offer levothyroxine replacement therapy and follow recommendations 1.3.6 and 1.3.7 on dosage of levothyroxine for adults and 1.4.1 to 1.4.6 on monitoring of hypothyroidism.\n\nFor adults, children and young people with TSH in the reference range 6\xa0months after radioactive iodine treatment, consider measuring TSH (with cascading) at 9\xa0months and 12\xa0months after treatment.\n\nFor adults, children and young people with TSH in the reference range 12 months after radioactive iodine treatment, consider measuring TSH (with cascading) every 6 months unless they develop hypothyroidism (then follow recommendation 1.7.2).\n\nIf hyperthyroidism persists after radioactive iodine treatment in adults, children and young people, consider antithyroid drugs until the 6-month appointment.Use of carbimazole is subject to MHRA advice on contraception (Drug Safety Update, February 2019) and risk of acute pancreatitis (Drug Safety Update, February 2019). November 2019 – carbimazole use is off label for children under 2\xa0years. See NICE's information on prescribing medicines.\n\nIf hyperthyroidism persists 6\xa0months after radioactive iodine treatment in adults, children and young people, consider further treatment.\n\n## Monitoring after surgery\n\nOffer levothyroxine to adults, children and young people after a total thyroidectomy and follow recommendations 1.3.6 and 1.3.7 on dosage of levothyroxine for adults and 1.4.1 to 1.4.6 on monitoring of hypothyroidism.\n\nConsider measuring TSH and FT4 at 2 and 6\xa0months after surgery, and then TSH (with cascading) once a year for adults, children and young people who have had a hemithyroidectomy.\n\n## Monitoring of antithyroid drugs\n\nFor adults, children and young people who are taking antithyroid drugs for hyperthyroidism, consider measuring:\n\nTSH, FT4 and FT3 every 6\xa0weeks until their TSH is within the reference range, then\n\nTSH (with cascading) every 3\xa0months until antithyroid drugs are stopped.\n\nDo not monitor full blood count and liver function for adults, children and young people taking antithyroid drugs for hyperthyroidism unless there is a clinical suspicion of agranulocytosis or liver dysfunction.\n\nFor adults who have stopped antithyroid drugs, consider measuring:\n\nTSH (with cascading) within 8\xa0weeks of stopping the drug, then\n\nTSH (with cascading) every 3\xa0months for a year, then\n\nTSH (with cascading) once a year.\n\nFor children and young people who have stopped antithyroid drugs, consider measuring:\n\nTSH, FT4 and FT3 within 8\xa0weeks of stopping the drug, then\n\nTSH, FT4 and FT3 every 3\xa0months for the first year, then\n\nTSH (with cascading) every 6\xa0months for the second year, then\n\nTSH (with cascading) once a year.\n\nTo find out why the committee made the recommendations on follow-up and monitoring of hyperthyroidism and how they might affect practice, see the rationale and impact section on follow-up and monitoring of hyperthyroidism\xa0.\n\nLoading. Please wait.\n\n# Managing and monitoring subclinical hyperthyroidism\n\n## Treating subclinical hyperthyroidism\n\nConsider seeking specialist advice on managing subclinical hyperthyroidism in adults if they have:\n\nTSH readings lower than 0.1\xa0Miu/litre at least 3\xa0months apart and\n\nevidence of thyroid disease (for example, a goitre or positive thyroid antibodies) or symptoms of thyrotoxicosis.\n\nConsider seeking specialist advice on managing subclinical hyperthyroidism in all children and young people.\n\n## Untreated subclinical hyperthyroidism\n\nConsider measuring TSH every 6\xa0months for adults with untreated subclinical hyperthyroidism. If the TSH level is outside the reference range, consider measuring FT4 and FT3 in the same sample.\n\nConsider measuring TSH, FT4 and FT3 every 3\xa0months for children and young people with untreated subclinical hyperthyroidism.\n\nConsider stopping TSH measurement for adults, children and young people with untreated subclinical hyperthyroidism if the TSH level stabilises (2 similar measurements within the reference range 3\xa0to 6\xa0months apart).\n\nTo find out why the committee made the recommendations on managing and monitoring subclinical hyperthyroidism and how they might affect practice, see the rationale and impact section on managing and monitoring subclinical hyperthyroidism\xa0.\n\nLoading. Please wait.\n\n# Diagnosing, managing and monitoring thyroid enlargement with normal thyroid function\n\n## Investigating thyroid enlargement\n\nThe following recommendations apply to adults, children and young people with normal thyroid function.\n\nOffer ultrasound to image palpable thyroid enlargement or focal nodularity in adults, children and young people with normal thyroid function if malignancy is suspected.\n\nConsider ultrasound of incidental findings on imaging if clinical factors suggest malignancy as a possibility.\n\nWhen making decisions about whether to offer fine needle aspiration cytology, use an established system for grading ultrasound appearance that takes into account:\n\nechogenicity\n\nmicrocalcifications\n\nborder\n\nshape in transverse plane\n\ninternal vascularity\n\nlymphadenopathy.\n\nReports of ultrasound findings should:\n\nspecify which grading system has been used for the assessment.\n\ninclude information on the features in recommendation 1.9.3 and\n\nprovide an overall assessment of malignancy, and\n\nconfirm that both lobes have been assessed, and\n\ndocument assessment of cervical lymph nodes.\n\nUse ultrasound guidance when performing fine needle aspiration cytology.\n\nSee the NICE guideline on suspected cancer for recommendations on referral for suspected head and neck cancers (including thyroid cancer).\n\nTo find out why the committee made the recommendations on investigating thyroid enlargement and how they might affect practice, see the rationale and impact section on investigating non-malignant thyroid enlargement with normal thyroid function\xa0.\n\nLoading. Please wait.\n\n## Managing non-malignant thyroid enlargement\n\nDo not offer treatment to adults with non-malignant thyroid enlargement, normal thyroid function and mild or no symptoms unless:\n\nthey have breathing difficulty or\n\nthere is clinical concern, for example, because of marked airway narrowing.\n\nRepeat thyroid ultrasound and TSH measurement for adults with non-malignant thyroid enlargement who are not receiving treatment, if:\n\nmalignancy is subsequently suspected, or\n\ncompression is suspected.\n\nConsider repeating thyroid ultrasound and TSH measurement for adults with non-malignant thyroid enlargement who are not receiving treatment, if:\n\nthe person's symptoms worsen or\n\nthey develop symptoms, such as hoarseness, or shortness of breath.\n\nFor children and young people with non-malignant thyroid enlargement and normal thyroid function, discuss management with a specialist multidisciplinary team.\n\nFor adults with normal thyroid function and a cyst or predominantly cystic nodule with no vascular components, offer aspiration if it is causing compressive symptoms, with possible ethanol ablation if there is re-accumulation of cyst fluid later.\n\nFor adults with normal thyroid function and a non-cystic nodule or multinodular or diffuse goitre, consider the following if they have compressive symptoms relating to thyroid enlargement:\n\nsurgery, particularly if there is marked airway narrowing or\n\nradioactive iodine ablation, if there is demonstrable radionuclide uptake, or\n\npercutaneous thermal ablation (see the NICE interventional procedures guidance on ultrasound-guided percutaneous radiofrequency ablation for benign thyroid nodules).\n\nTo find out why the committee made the recommendations on managing thyroid enlargement and how they might affect practice, see the rationale and impact section on managing non-malignant thyroid enlargement\xa0.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Adults\n\nPeople aged 16\xa0years and over.\n\n## Cascading\n\nMeasuring FT4 in the same sample if TSH is above the reference range and measuring FT4 and FT3 in the same sample if TSH is below the reference range.\n\n## Children and young people\n\nPeople under 16\xa0years.\n\n## Hyperthyroidism\n\nExcess production and/or secretion of thyroid hormones (overactive thyroid gland).\n\n## Hypothyroidism\n\nInadequate production and secretion of thyroid hormones (underactive thyroid gland).\n\n## Menopausal women\n\nThis includes women in perimenopause and post menopause.\n\n## Subclinical hyperthyroidism\n\nTSH levels below the reference range, with FT3 and FT4 within the reference range.\n\n## Subclinical hypothyroidism\n\nTSH levels above the reference range, with FT4 within the reference range.\n\n## Thyrotoxicosis\n\nThyrotoxicosis is a disorder of excess circulating thyroid hormones caused by increased production and secretion (hyperthyroidism) or by the release of stored thyroid hormones (thyroiditis).", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Levothyroxine–liothyronine combination therapy for hypothyroidism\n\nWhat is the clinical and cost effectiveness of levothyroxine (T4) and liothyronine (T3) combination therapy compared with T4 alone for people with hypothyroidism whose symptoms have not responded sufficiently to T4 alone? Does DiO2 polymorphism affect the response to combination therapy with T4 and T3?\n\nTo find out why the committee made the research recommendation on levothyroxine-liothyronine combination therapy for hypothyroidism see the rationale and impact section on managing primary hypothyroidism\xa0.\n\nLoading. Please wait.\n\n## Long-term health outcomes for people with subclinical hyperthyroidism\n\nWhat is the clinical and cost effectiveness of treatment (antithyroid drugs or radioactive iodine) for improving long-term health outcomes for people with subclinical hyperthyroidism?\n\nTo find out why the committee made the research recommendation on improving long-term health outcomes for people with subclinical hyperthyroidism see the rationale and impact section on managing and monitoring subclinical hyperthyroidism\xa0.\n\nLoading. Please wait.\n\n## Antithyroid drugs in subgroups with Graves' disease\n\nAre there subgroups of people with Graves' disease who have a particularly good response to antithyroid drugs?\n\nTo find out why the committee made the research recommendation on antithyroid drugs in subgroups of people with Graves' disease see the rationale and impact section on treatment for adults with Graves' disease\xa0.\n\nLoading. Please wait.\n\n## Long-term effectiveness and safety of radioactive iodine therapy for hyperthyroidism\n\nWhat is the long-term clinical and cost effectiveness, including safety, of radioactive iodine for hyperthyroidism?\n\nTo find out why the committee made the research recommendation on long-term effectiveness and safety of radioactive iodine therapy see the rationale and impact section on treatment for adults with Graves' disease\xa0.\n\nLoading. Please wait.\n\n## Dosimetry-guided radioactive iodine therapy for hyperthyroidism\n\nWhat is the clinical and cost effectiveness of dosimetry-guided radioactive iodine strategies for hyperthyroidism?\n\nTo find out why the committee made the research recommendation on the use of dosimetry-guided radioactive iodine therapy for hyperthyroidism see the rationale and impact section on treatment for adults with Graves' disease\xa0.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Antithyroid drug regimens for T3 thyrotoxicosis due to Graves' disease\n\nWhat is the clinical and cost effectiveness of different durations of antithyroid drug regimens for people with T3 thyrotoxicosis due to Graves' disease?\n\n## Levothyroxine for subclinical hypothyroidism in people under 65\n\nWhat is the clinical and cost effectiveness of levothyroxine for people under 65 with symptomatic subclinical hypothyroidism?\n\n## Antithyroid drug regimens for Graves' disease\n\nWhat is the clinical and cost effectiveness of a block and replace regimen compared with a titration regimen of antithyroid drugs for Graves' disease?\n\n## Percutaneous ablation for benign thyroid nodules\n\nWhat is the clinical and cost effectiveness of percutaneous thermal ablation for benign thyroid nodules?\n\n## Iodine for subclinical hypothyroidism\n\nWhat is the clinical and cost effectiveness of iodine for people with subclinical hypothyroidism?\n\n## Selenium for subclinical hypothyroidism\n\nWhat is the clinical and cost effectiveness of selenium for people with subclinical hypothyroidism?", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Information for people with thyroid disease, their families and carers\n\nRecommendations 1.1.1 to 1.1.6\n\n## Why the committee made the recommendations\n\nThe committee based the recommendations on the views and themes from qualitative studies combined with their own experience of treating or living with thyroid disease.\n\nThe committee agreed it was important for all people with thyroid disease to understand the disease, the goals of treatment and the complex interaction between thyroid function tests and symptoms. The specific recommendations for people with hypothyroidism centred around the use of thyroid hormone replacement. Levothyroxine is frequently taken incorrectly, which can lead to suboptimal treatment. The specific recommendations for thyrotoxicosis centred around what people should know about their treatment options and the consequences of untreated thyrotoxicosis. The specific recommendations on thyroid enlargement focused on reassuring people that enlargement is common and generally non-cancerous, while also alerting them to red flag symptoms that should prompt further action.\n\n## How the recommendations might affect practice\n\nThe recommendations provide guidance on the type of information and support that should be provided to people with thyroid disease so that they can make informed decisions about management. The committee noted that currently there is variation in the information provided. In some areas there may be additional resource use, for example, if longer or more consultations are needed. But this may lead to later benefits and reductions in resource use, if, for example, it leads to better understanding and use of medication.\n\nFull details of the evidence and the committee's discussion are in evidence review A: information for people with thyroid disease.\n\nReturn to recommendations\n\n# Indications for tests for thyroid dysfunction\n\nRecommendations 1.2.1 to 1.2.7\n\n## Why the committee made the recommendations\n\nThe committee noted that thyroid dysfunction affects many systems in the body, and the symptoms are often non-specific. They agreed, based on evidence and their experience, that most single common symptoms alone are not predictive of thyroid dysfunction. The decision to test should be based on an overall clinical suspicion, taking into account the nature and severity of symptoms, clinical signs and coexisting conditions.\n\nThe evidence showed that type\xa01 diabetes, an autoimmune disease, is associated with thyroid dysfunction. In the committee's experience, this is also likely to apply to other autoimmune diseases and justifies testing for thyroid dysfunction in these conditions.\n\nThere was little evidence on thyroid disease in people with atrial fibrillation. However, the committee agreed that the potential importance of thyroid disease and its impact on the treatment of atrial fibrillation is sufficient to justify testing.\n\nLimited evidence showed that depression can be associated with thyroid dysfunction. The committee agreed that, in their experience, this can also apply to anxiety.\n\nThe committee noted that in children and young people, thyroid dysfunction may be accompanied by abnormal growth or a change in behaviour or school performance that is unexplained by other factors. They agreed, based on their experience, that testing for thyroid dysfunction should be considered for children and young people presenting with those features. Thyroid function tests may be abnormal in people who are acutely unwell with non-thyroid disease and the committee agreed that decisions on treatment of thyroid dysfunction should not be based solely on these results. Tests for thyroid dysfunction should be performed when the acute illness has resolved, unless the acute illness may be due to thyroid dysfunction.\n\nEvidence showed that type\xa02 diabetes is not associated with thyroid dysfunction, so the committee concluded that thyroid function tests should not be performed solely because a person has this condition.\n\n## How the recommendations might affect practice.\n\nThe recommendations to test for thyroid dysfunction in people with autoimmune disease, atrial fibrillation, anxiety or depression are broadly in line with current practice. Checking thyroid function in people with type\xa02 diabetes and during acute illness is also current practice in some areas. The recommendations to avoid this should be cost saving for the NHS.\n\nFull details of the evidence and the committee's discussion are in evidence review B: indications for testing.\n\nReturn to recommendations\n\n# Tests when thyroid dysfunction is suspected\n\nRecommendations 1.2.8 to 1.2.10\n\n## Why the committee made the recommendations\n\nNo evidence was identified on which tests should be used when thyroid dysfunction is suspected so the committee used their experience to develop the recommendations. The committee agreed that in general TSH alone is an appropriate first test for people in whom thyroid dysfunction is suspected. Subsequent tests (cascading) are only needed if TSH is abnormal (with FT4 if the TSH suggests hypothyroidism and both FT4 and FT3 if the TSH suggests hyperthyroidism). This approach reduces unnecessary testing compared with simultaneous TSH, FT4 and FT3 testing for all people. However, tests should be done in a way to minimise potential delays and the need for additional appointments, for example, by laboratories keeping original samples and performing subsequent tests on the same samples. The committee agreed based on their experience that this approach did not apply to adults in whom secondary thyroid dysfunction is suspected or in children and young people, where both TSH and FT4 are needed by default because of the differing likely causes of dysfunction. The committee further agreed that tests may need repeating when new symptoms develop or worsen, but that this should not be within 6\xa0weeks of the last test because this is unlikely to provide new information.\n\n## How the recommendations might affect practice.\n\nThe recommendations broadly reflect current practice, although not all laboratories currently follow the cascading approach to testing.\n\nWhere FT4 is currently a routine test for thyroid dysfunction, cascading will reduce NHS costs by avoiding extra tests for people with a TSH within the reference range. In areas where FT3 is not currently being measured, cascading will mean a cost increase. But this will be offset by the benefits of correctly diagnosing and managing thyrotoxicosis.\n\nFull details of the evidence and the committee's discussion are in evidence review C: thyroid function tests.\n\nReturn to recommendations\n\n# Tests for people with confirmed primary hypothyroidism\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nNo evidence was identified on the use of antibodies to investigate hypothyroidism so the committee used their experience to develop the recommendations. They agreed that testing for thyroid peroxidase antibodies (TPOAbs) may be useful in the early investigation of the underlying cause of hypothyroidism. However, for adults there was no role for remeasuring TPOAbs because changes in levels are unlikely to guide treatment decisions. The committee agreed that for young people it may be useful to repeat TPOAbs at the point of transition to adult services.\n\n## How the recommendations might affect practice\n\nThe recommendations broadly reflect current practice so the committee agreed there should be no substantial change. By avoiding re-testing in adults, there could be some cost savings.\n\nFull details of the evidence and the committee's discussion are in evidence review D: tests for confirmed primary hypothyroidism.\n\nReturn to recommendations\n\n# Managing primary hypothyroidism\n\nRecommendations 1.3.3 to 1.3.7\n\n## Why the committee made the recommendations\n\nThe committee agreed that hypothyroidism needs thyroid hormone replacement. Potential treatments are levothyroxine, usually prescribed to everyone, liothyronine, which is sometimes prescribed when levothyroxine fails, and natural thyroid extracts (which is currently unlicensed for use in the UK). Overall the evidence from 7 randomised controlled trials suggested that combination treatment with levothyroxine and liothyronine did not offer any important health benefits compared with levothyroxine monotherapy and was significantly more expensive. However, the committee noted that some of the trials did show some small benefits in specific quality of life domains and anecdotal evidence from some committee members suggested beneficial effects of combination treatment with levothyroxine and liothyronine in small subgroups of patients. The committee were aware that some people reported still feeling unwell with levothyroxine monotherapy and agreed that in this group adding liothyronine could potentially have greater benefit than in the general population with hypothyroidism, although there are no trials in this population. Some evidence suggested that combination therapy with levothyroxine and liothyronine could be harmful because it may suppress the production of TSH and its long-term adverse effects are uncertain. The committee was aware that the use of combination therapy is a critical issue in hypothyroidism. They could not recommend liothyronine either alone or in combination treatment based on the evidence available and its current list price but agreed a research recommendation to help inform future guidance in this important area. NHS England's specialist pharmacy service has produced advice on prescribing liothyronine.\n\nThe committee agreed that the evidence for natural thyroid extracts showed no benefit over levothyroxine. The committee also noted that the proportion of T3 to T4 is higher in natural thyroid extracts than produced in the human body and the adverse effects are uncertain. Natural thyroid extracts are an unlicensed medication in the UK and overall the committee agreed they should not be offered.\n\nSome evidence showed that a high starting dose of levothyroxine produced more rapid improvements in quality of life than a lower starting dose followed by titration. The committee agreed that this was also their experience and therefore recommended a high starting dose (1.6\xa0micrograms per kilogram body weight per day) in adults unless contraindicated (adults over 65 or with a history of cardiovascular disease). Although evidence about dosing was very limited, the committee agreed that adults over 65\xa0years are more likely to have cardiovascular comorbidities. Most studies of hypothyroidism and subclinical hypothyroidism use 65 as a cut-off when defining older adults. The committee agreed to recommend a lower starting dose with titration for people over 65.\n\nThe committee were unable to make recommendations on iodine or selenium supplements because of a lack of evidence.\n\n## How the recommendations might affect practice\n\nThe recommendations on thyroid hormone replacement and natural thyroid extract reinforce current practice and are not expected to have a significant cost impact. Currently everyone is offered levothyroxine as thyroid hormone replacement and small subgroups of people who do not feel well on levothyroxine are sometimes offered liothyronine.\n\nFull details of the evidence and the committee's discussion are in evidence review E: managing hypothyroidism.\n\nReturn to recommendations\n\n# Follow-up and monitoring of primary hypothyroidism\n\nRecommendations 1.4.1 to 1.4.6\n\n## Why the committee made the recommendations\n\nEvidence showed no clinically important benefits of maintaining TSH levels in the lower rather than higher end of the TSH reference range. Given the need for additional medication to achieve a TSH level in the lower end of the reference range, with the potential for adverse effects and increased cost, the committee concluded that as a starting point TSH levels could be maintained at any point within the reference range. Nevertheless, the committee acknowledged that some people may still have troublesome symptoms even with TSH levels in the reference range. Therefore, they recommended adjusting the dose of levothyroxine if symptoms persist to achieve optimal wellbeing for individual patients. The committee also agreed that it was important not to use doses high enough to cause TSH suppression or thyrotoxicosis.\n\nThe committee agreed that TSH levels can take up to 6\xa0months to return to the reference range if they have previously been very high or have been high for a long time. They agreed that healthcare professionals should take this into account when adjusting doses, to avoid large dose increases that could cause thyrotoxicosis.\n\nThe committee based recommendations about the timing of testing on their experience. They made separate recommendations for children under 2\xa0years because in this age group the impact of poorly treated hypothyroidism can be most severe, and the child is developing at such a rate that frequent dose changes may be needed.\n\nThe committee used their experience to agree which thyroid function tests are needed for monitoring. They followed the general principle that once TSH has stabilised in the reference range, TSH testing alone is enough if the person has no symptoms suggesting thyroid dysfunction.\n\nThey agreed that children should have more frequent monitoring to ensure that dose adjustments are made promptly and because in the very young, under-treatment can lead to serious neurodevelopmental consequences.\n\n## How the recommendations might affect practice\n\nThe committee agreed that generally the testing strategies are in line with current practice, although there may be some variation across the country. The recommendations should help patients (and their support groups) to advocate for their own monitoring and treatment. Doctors will have clear guidance on monitoring to assist with consultations.\n\nFull details of the evidence and the committee's discussion are in evidence review F: monitoring thyroid disease.\n\nReturn to recommendations\n\n# Managing and monitoring subclinical hypothyroidism\n\nRecommendations 1.5.1 to 1.5.10\n\n## Why the committee made the recommendations\n\nThere was little evidence on treatment for people with subclinical hypothyroidism, with most of the evidence relating to older adults. The committee agreed that as most studies used 65\xa0years as a cut-off it was appropriate to define older adults as over 65 and make separate recommendations for this group.\n\nThe committee discussed the tendency to over-rely on TSH levels when making decisions about treatment. They agreed that factors suggesting underlying thyroid disease should also be taken into account when deciding whether or not to treat subclinical hypothyroidism.\n\nThe committee noted that a TSH level of 5 to 10\xa0mlU/litre might return to the reference range without treatment in around half of people, whereas a TSH level above 10\xa0mlU/litre is less likely to do so and is more often associated with symptoms. They therefore agreed that levothyroxine should be considered for all adults with a TSH level of 10\xa0mlU/litre or more because this may improve symptoms and may have long-term benefits including on cardiovascular outcomes. For people with a TSH level lower than 10\xa0mIU/litre, the committee agreed based on their experience that treatment was less likely to have a benefit but that the balance of risks to benefits was most favourable for adults under the age of 65. The committee noted that for people over 65 there was less likely to be an improvement in symptoms and the potential for harms from suppressing TSH (such as atrial fibrillation) is greater. The committee agreed that the trial of levothyroxine treatment should be stopped if symptoms persist with TSH levels within the reference range, as they are likely to be due to causes other than hypothyroidism.\n\nThe committee also agreed that the recommendations on testing TPOAbs in overt hypothyroidism applied to subclinical hypothyroidism because testing would help to inform the decision on whether or not to treat.\n\nBecause of the small amount of evidence available on the treatment of subclinical hypothyroidism, the committee made recommendations for research on selenium and iodine.\n\nIn children and young people there are a number of different causes of a mild increase in TSH besides autoimmune thyroid disease. These include mild congenital hypothyroidism, a low iodine intake (for example, because of a special diet), intercurrent illness, adrenal insufficiency and the paradoxical 'increase' in TSH observed in children with secondary hypothyroidism. The committee agreed that there is no urgency to treat with levothyroxine if thyroid hormone levels are appropriate for age. It is important to make a diagnosis before offering any treatment. The committee recommended caution when considering levothyroxine for children and young people whose thyroid dysfunction was unexplained. However, they also noted that in the very young it would not be appropriate to wait as long as for adults (3\xa0months) to confirm a raised TSH with a second test.\n\n## How the recommendations might affect practice\n\nThe committee highlighted that current practice for monitoring of subclinical hypothyroidism varies considerably, with unnecessary testing often being undertaken. They agreed that the recommendations are likely to reduce the number of tests overall.\n\nFull details of the evidence and the committee's discussion are in evidence review G: managing subclinical hypothyroidism.\n\nReturn to recommendations\n\n# Tests for people with confirmed thyrotoxicosis\n\nRecommendations 1.6.1 to 1.6.4\n\n## Why the committee made the recommendations\n\nThe committee agreed that it is crucial to determine the cause of thyrotoxicosis because this affects management decisions. Antithyroid drugs are unlikely to cure toxic nodular disease but may induce remission in Graves' disease. TRAbs testing provides confirmation of clinical features that suggest Graves' disease. Getting an accurate diagnosis sooner benefits the patient because the appropriate treatment options would be offered first. If TRAbs levels are high it is unlikely that antithyroid drugs will induce remission of Graves' disease.\n\nEvidence suggested that in adults, the diagnostic accuracy of TRAbs testing for Graves' disease was high across different cut-off values. Evidence also showed the accuracy to be high in children. However, the evidence was limited in terms of the number of studies and the study sizes. But it was in line with the committee's experience and current practice, so they agreed to recommend TRAbs testing for Graves' disease in both adults and children and young people.\n\nEvidence on the diagnostic accuracy of TPOAbs testing was not available in either adults or children. The committee agreed that based on their experience, TPOAbs testing alone is not likely to be as useful as TRAbs testing for the diagnosis of Graves' disease, but it could be used in children and young people where the absence of TRAbs but presence of TPOAbs indicates that thyrotoxicosis is more likely to resolve spontaneously.\n\nEvidence for the diagnostic accuracy of ultrasound was limited in both adults and children. Based on clinical experience, the committee agreed that ultrasound was useful for the diagnosis of Graves' disease but only when there were palpable thyroid nodules.\n\nThe committee agreed that technetium scanning may be useful when TRAbs are negative and Graves' disease is suspected because generalised uptake on the scan suggests Graves' disease.\n\n## How the recommendations might affect practice\n\nOver recent years, TRAbs testing has become more widely available and more centres in the UK are using it to confirm the diagnosis of Graves' disease. However, some centres continue to use TPOAbs testing. If TRAbs testing allows more accurate differentiation between the different causes of thyrotoxicosis, there are likely to be reductions in unnecessary antithyroid treatment (including surgery) for people with transient thyroiditis and more timely and appropriate treatment choices for people with toxic nodular hyperthyroidism. The committee anticipates that TRAbs testing will become standard best practice for all UK centres leading to a correct diagnosis of Graves' disease for more people.\n\nThe use of technetium scanning for adults who are TRAbs negative reflects current practice in most centres.\n\nAlthough thyroid ultrasound has only a limited role in the investigation of suspected Graves' disease, many healthcare professionals offer this investigation. This often results in incidental findings of doubtful clinical significance leading to further unnecessary investigations and interventions. The recommendation will discourage healthcare professionals from using thyroid ultrasound routinely in the investigation of suspected Graves' disease, which is likely to be cost saving.\n\nFull details of the evidence and the committee's discussion are in evidence review H: tests for people with confirmed thyrotoxicosis.\n\nReturn to the recommendations\n\n# Initial management in primary/non-specialist care for people with thyrotoxicosis\n\nRecommendations 1.6.5 and 1.6.6.\n\n## Why the committee made the recommendations\n\nBased on their experience, the committee reminded healthcare professionals that transient thyrotoxicosis does not need definitive treatment. They recommended that short-term treatment with antithyroid drugs may be needed until decisions about the most appropriate treatment can be made in specialist care. The committee also agreed that treatment with antithyroid drugs before radioactive iodine would minimise the rise in circulating thyroid hormone levels following this treatment and so reduce the symptoms of thyrotoxicosis. They acknowledged that it is important to render the patient euthyroid with antithyroid drugs before surgery to ensure patient safety.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice so the committee agreed there should be no change.\n\nFull details of the evidence and the committee's discussion are in evidence reviews I, J, K, L: managing thyrotoxicosis.\n\nReturn to the recommendations\n\n# Treatment for adults with Graves' disease\n\nRecommendations 1.6.7 to 1.6.14\n\n## Why the committee made the recommendations\n\nThe evidence suggested that radioactive iodine produced better long-term outcomes than antithyroid drugs in terms of thyroid status, but with a greater risk of thyroid eye disease. There was no convincing evidence of a difference between radioactive iodine and surgery. The economic evidence showed that radioactive iodine offered a better balance of benefits and costs than surgery (total thyroidectomy) and was more cost effective than antithyroid drugs. Although exposure to radiation will always lead to some small increase in relative risk of cancer, the evidence showed that this did not translate into an absolute effect that was clinically important. The committee agreed nonetheless that continued follow-up of people who have undergone radioactive iodine treatment was important and the 'as low as reasonably practicable' (ALARP) principle applied. They also agreed to make a research recommendation on the long-term effectiveness and safety of exposure to radioactive iodine.\n\nThe committee agreed, based on the clinical and economic evidence, that radioactive iodine should be offered as first-line definitive treatment for most people with hyperthyroidism secondary to Graves' disease. However they noted a number of important exceptions and specified these in the recommendations. The committee acknowledged that circulating levels of thyroid hormones are likely to rise following radioiodine administration and pre-treatment with anti-thyroid drugs would make radioactive iodine safer and lead to reduced symptoms of thyrotoxicosis. The committee also agreed that the response to antithyroid drugs is better in some people than in others. For adults who are likely to have a particularly good response to antithyroid drugs (mild uncomplicated Graves' disease), radioactive iodine and a course of antithyroid drugs could be equally appropriate options.\n\nSome studies have suggested that some people are more likely to relapse after antithyroid drugs. These include males, younger people, people who smoke, people with a large goitre, people with high levels of thyroid hormones at the time of diagnosis and people with high levels of TRAbs. However, most of the studies were small and retrospective. The committee agreed that it would be very helpful to confirm these findings in large prospective multi-centre studies. They made a research recommendation to inform future guidance.\n\nThe evidence did not identify a clinically important difference between a calculated or fixed strategy in terms of radioactive iodine dosing. A calculated strategy has an increased cost because of the need for imaging (usually ultrasound) and uptake measurements. There are theoretical benefits from a calculated strategy to administer a more precise dose that could reduce potentially unnecessary additional radiation exposure, but the evidence did not indicate that this precision translated to clinically important benefits. The committee's experience is that, in the UK, radioactive iodine is usually given without calculating the absorbed dose. The committee agreed that there was too much uncertainty around the impact of the differing strategies to make a recommendation and chose to make a research recommendation.\n\nThe evidence suggested no clinically important difference between surgical options (total and hemithyroidectomy) for Graves' disease, but tended towards a benefit of total thyroidectomy in terms of relapse rates and harm in terms of increased risk of hypoparathyroidism. These findings were consistent with the committee's own experience. The committee agreed to recommend total thyroidectomy for adults with Graves' disease having surgery. This was based on their experience that people opting for surgery are generally seeking a definitive treatment.\n\n## How the recommendations might affect practice\n\nThe committee was aware that the recommendations would result in radioactive iodine being offered as first-line definitive treatment to more people than currently. This is likely to be cost effective as shown by the economic evidence.\n\nFull details of the evidence and the committee's discussion are in evidence reviews: I, J, K, L: managing thyrotoxicosis.\n\nReturn to the recommendations\n\n# Treatment for adults with toxic nodular goitre\n\nRecommendations 1.6.15 to 1.6.17\n\n## Why the committee made the recommendations\n\nThe committee used their experience and an extrapolation of the evidence from Graves' disease to recommend radioactive iodine as the first-line definitive treatment for hyperthyroidism secondary to multiple nodules. Surgery or life-long antithyroid drugs could be offered in some circumstances when radioactive iodine is inappropriate (for example, young mothers, people in nursing homes or people unable to adhere to radiation protection guidance) or surgery is likely to have additional benefits (for example, if malignancy is suspected). The committee used their experience to recommend that when surgery is chosen hemithyroidectomy should be considered for people with hyperthyroidism due to a single toxic nodule, and total thyroidectomy for people with hyperthyroidism and multiple toxic nodules. A hemithyroidectomy is a shorter procedure that removes less of the thyroid gland; this requires less time in hospital and leads to a lower risk of adverse effects like hypoparathyroidism and long-term hypothyroidism but has a greater risk of relapse of hyperthyroidism. The risk of relapse is greater for multiple toxic nodules, hence the different recommendations for different populations.\n\n## How the recommendations might affect practice\n\nThe recommendations broadly reflect current practice so the committee agreed there should be no substantial change.\n\nFull details of the evidence and the committee's discussion are in evidence reviews I, J, K, L: managing thyrotoxicosis.\n\nReturn to the recommendations\n\n# Treatment for children and young people with Graves' disease or toxic nodular goitre\n\nRecommendations 1.6.18 to 1.6.20\n\n## Why the committee made the recommendations\n\nNo evidence was identified for treatments in children and young people with hyperthyroidism. Based on their experience, the committee recommended that antithyroid drugs should be first-line definitive treatment for children and young people with Graves' disease or hyperthyroidism secondary to a single or multiple toxic nodules. The committee agreed that the risks of radioactive iodine and surgery may be greater than for adults so it is important to get input from the multidisciplinary team and discuss these options with the child and their family.\n\nWhen surgery is chosen, the committee recommended that this should be total thyroidectomy for Graves' disease or bilateral thyroid nodules. They based this on their experience and evidence in adults.\n\n## How the recommendations might affect practice\n\nThe recommendations to offer antithyroid drugs as first-line treatment are broadly in line with current practice and are unlikely to have a substantial cost impact. The potential risks and benefits (and therefore cost effectiveness) of radioactive iodine treatment in children are uncertain.\n\nFull details of the evidence and the committee's discussion are in evidence reviews I, J, K, L: managing thyrotoxicosis.\n\nReturn to the recommendations\n\n# Antithyroid drugs for people with hyperthyroidism\n\n## Why the committee made the recommendations\n\nRecommendations 1.6.21 to 1.6.26\n\nEvidence showed a clinically important benefit in terms of normalising thyroid hormone levels and minor drug-related adverse events for methimazole or carbimazole compared with propylthiouracil. However, hypothyroidism was more frequent with methimazole or carbimazole. The committee questioned whether this was a result of over-treatment and thought hypothyroidism unlikely to be permanent. Because carbimazole, and not methimazole, is currently licensed in the UK, the committee recommended carbimazole as the drug of choice when offering an antithyroid drug for treating hyperthyroidism. The committee noted that carbimazole is not recommended in children under 2\xa0years. In view of the potential risk of liver failure the committee agreed that propylthiouracil should not be the first choice of antithyroid drug. However, the committee noted the MHRA drug safety advice for carbimazole on contraception and the risk of acute pancreatitis and agreed that propylthiouracil is appropriate as an alternative for adults.\n\nEvidence showed a clinically important benefit in terms of lack of relapse to hyperthyroidism and maintaining normal thyroid hormone levels with 12 to 18\xa0months' treatment compared with 6 to 12\xa0months' treatment. There was no clinically important difference in relapse following a longer treatment of more than 18\xa0months.\n\nThe committee recommended that carbimazole should be offered for at least 12 to 18\xa0months. They noted that this differed from the summary of product characteristics which advises 6 to 18\xa0months, but agreed that the deviation was justified by the evidence. The committee agreed based on their experience and extrapolation from evidence in adults that the treatment duration for children should be reviewed every 2\xa0years.\n\nEvidence showed that block and replace (fixed high dose combined with levothyroxine) and titration (dose based on thyroid function tests) regimens of antithyroid drugs were similar in terms of minor drug-related adverse events (skin reactions). There were fewer relapses to hyperthyroidism with block and replace treatment compared with titration. But there was limited evidence suggesting more chance of agranulocytosis with block and replace regimens. The committee noted that block and replace treatment could theoretically provide greater stability and require fewer medical appointments than titration regimens. Therefore they recommended a choice of either regimen for adults with Graves' disease. Hyperthyroidism in children and young people should usually be managed with a dose titration regimen because of the increased risk of adverse events in this age group. The committee also made a recommendation for further research in this area.\n\nThe committee noted that people with hyperthyroidism secondary to a single or multiple toxic nodules will not go into remission and therefore discontinuing antithyroid drugs is not relevant. They agreed that titration regimens are generally more appropriate for this group.\n\n## How the recommendations might affect current practice\n\nCurrent practice in the UK, in adults and children, is a mix of block and replace (approximately 40%) and titration regimens (approximately 60%). The recommendations are broadly in line with current practice and unlikely to have significant resource impact.\n\nFull details of the evidence and the committee's discussion are in evidence review J: management of thyrotoxicosis – antithyroid drugs.\n\nReturn to recommendations\n\n# Follow-up and monitoring of hyperthyroidism\n\nRecommendations 1.7.1 to 1.7.12\n\n## Why the committee made the recommendations\n\nNo evidence was identified on the most appropriate ways to monitor hyperthyroidism, so the committee made recommendations based on their experience. The precise timing of monitoring depends on the treatment chosen, but in general the committee aimed to minimise unnecessary testing while ensuring early treatment failures or adverse effects (for example, hypothyroidism) were identified. Regardless of treatment option chosen, the committee agreed that in the long term TSH alone is sufficient for monitoring, although TSH alongside FT4 and FT3 will be needed in the short term after treatment. Should TSH become abnormal, having been stable within the reference range for a prolonged period, further tests will be necessary. Short-term combined testing with TSH, FT4 and FT3 is needed to inform decisions about the need for additional courses of treatment or dose changes with antithyroid drugs. As no evidence was found to support a strategy of routinely monitoring full blood count and liver function tests, and these tests have a treatment burden for people with hyperthyroidism and a resource impact, the committee recommended that healthcare professionals do not test unless there is a clinical suspicion of specific adverse effects of treatment.\n\n## How the recommendations might affect practice\n\nMore people with Graves' disease are expected to have monitoring because radioactive iodine is more likely to be offered as first-line treatment. This extra cost is likely to be justified, because radioactive iodine is more cost effective than other treatments for hyperthyroidism. In general, these recommendations reinforce best practice, with earlier detection leading to earlier treatment, reduced costs of treating complications and improved quality of life. The recommendation that there is no need to monitor full blood count and liver function after antithyroid drug treatment unless liver dysfunction or agranulocytosis are suspected is likely to be cost saving.\n\nFull details of the evidence and the committee's discussion are in evidence review F: monitoring thyroid disease.\n\nReturn to recommendations\n\n# Managing and monitoring subclinical hyperthyroidism\n\nRecommendations 1.8.1 to 1.8.5\n\n## Why the committee made the recommendations\n\nThere was no evidence available on treating subclinical hyperthyroidism so the committee used their experience to develop the recommendations. They agreed that treatment might be suitable if subclinical hyperthyroidism is persistent and appears to be caused by intrinsic thyroid disease. However, the committee noted that there is currently no evidence that treatment offers benefits and it can have adverse effects. Overall the committee agreed that treatment decisions should be made with specialist advice. Treatment would be appropriate in those most likely to benefit, in other words those with very suppressed TSH and other features suggesting thyroid disease. The committee also agreed that they could not make specific recommendations about when to treat subclinical hyperthyroidism in children as specialist input would also be needed for this.\n\nSeveral large population-based observational studies have shown that subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation, osteoporosis, dementia, and death, including death from cardiovascular disease. Although most people with subclinical hyperthyroidism have no symptoms, an important question is whether treatment could improve long-term outcomes (for example, atrial fibrillation and dementia). The committee agreed to make a research recommendation to inform future practice.\n\nThere was no evidence available on monitoring subclinical thyroid dysfunction so the committee based the recommendations on their experience.\n\nThe overall aim of these recommendations is to ensure that if the subclinical thyroid dysfunction needs treatment, this will be identified in a timely manner but without subjecting a person to a lot of unnecessary tests.\n\nThe committee agreed that for children and young people monitoring may need to be more frequent.\n\n## How the recommendations might affect practice\n\nCurrent practice in managing subclinical hyperthyroidism is variable. Some people are offered antithyroid drugs or radioactive iodine; surgery is very rare. Many people are offered no treatment. The recommendations are likely to reduce inappropriate treatment and to be cost saving.\n\nThe recommendations for monitoring subclinical thyroid dysfunction reflect good current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review M: management of subclinical thyrotoxicosis.\n\nReturn to recommendations\n\n# Investigating non-malignant thyroid enlargement with normal thyroid function\n\nRecommendations 1.9.1 to 1.9.6\n\n## Why the committee made the recommendations\n\nEvidence showed that ultrasound using established criteria is accurate for determining whether thyroid nodules need fine needle aspiration to investigate potential malignancy. The committee noted that many referrals for thyroid ultrasound are based on incidental findings of other types of imaging (for example, CT scans performed for other indications). They agreed that thyroid ultrasound should only be performed when a full assessment indicates a likelihood of malignancy. Thyroid ultrasound of incidental findings should not be the default option because most incidental findings are not malignant and further investigation may cause harms in terms of the adverse effects of testing and patient anxiety.\n\nThe evidence showed that different ultrasound criteria generally assessed the same features and had similar accuracy for detecting malignancy. Rather than recommending a specific set of criteria, the committee chose to list the essential features of any grading system (the lesion's echogenicity, border, shape, vascularity, presence of microcalcifications and cervical lymphadenopathy). Based on their knowledge that nodule size does not determine the likelihood of malignancy, and the observation that the criterion (SRU) that includes nodule size results in significantly lower sensitivity and specificity, they agreed not to include nodule size in the list.\n\nBecause healthcare professionals need to be able to re-visit ultrasound findings, the committee agreed that the grading system used for clinical decision making, including the specific nodule features examined to assess malignancy, should be specified in ultrasound reports. For the same reason, they agreed that ultrasound reports should also confirm that both lobes have been assessed and document the assessment of cervical lymph nodes.\n\nThe committee agreed that the recommendations should apply to children and young people as well as adults.\n\nEvidence indicated that performing fine needle aspiration under ultrasound guidance provides greater sensitivity and specificity for determining the malignancy of thyroid nodules compared with palpation guidance.\n\nThe evidence also showed that with ultrasound guidance an inadequate sample is less likely than with palpation. Inadequate sampling is likely to add to the overall cost of palpation-guided fine needle aspiration because samples may need to be repeated or require more extensive investigation. The committee also noted that there were additional benefits of ultrasound guidance because ultrasonographic characteristics identified by simultaneous imaging provide more information about the risk of malignancy before cytology results are obtained.\n\n## How the recommendations might affect practice\n\nUltrasound is currently already used to assess the likelihood of thyroid malignancy, so the recommendations are not likely to make a significant impact. In the UK, the most commonly used ultrasound criteria are those of the British Thyroid Association, which are in line with the recommendations in this guideline.\n\nThe recommendation reflects current practice so the committee agreed that it should not have a significant impact.\n\nFull details of the evidence and the committee's discussion are in evidence review N: imaging for fine needle aspiration and evidence review O: ultrasound guidance for fine needle aspiration.\n\nReturn to the recommendations\n\n# Managing non-malignant thyroid enlargement\n\nRecommendations 1.9.7 to 1.9.12\n\n## Why the committee made the recommendations\n\nThe committee noted that there was little evidence on the efficacy of surgery for nodules; this was related to the challenges of comparing surgical and non-surgical interventions. In general, the committee agreed that surgery would be appropriate for nodules or enlargement causing symptoms, if there has been no response with other options or if there is true compression of nearby organs (for example, tracheal narrowing).\n\nAspiration is routinely done before more intensive intervention for cystic nodules because it is simple and can be done in the same appointment as preliminary investigation by a radiologist (or endocrinologist). The evidence generally showed a benefit of ethanol ablation over levothyroxine and equivalence with radiofrequency ablation.\n\nThe evidence showed no clinically important effect of levothyroxine on non-cystic nodules and a benefit of radiofrequency ablation and laser ablation. There was no evidence identified on radioactive iodine ablation although the committee noted that it is very commonly used in the UK for diffuse goitres that are causing symptoms, particularly if there is demonstrable radionuclide uptake. The committee also noted that the more recently developed techniques for percutaneous thermal ablation (for example, high-intensity focused ultrasound and microwave ablation) may be appropriate for some people but are not widely available. They made a research recommendation on percutaneous thermal ablation to inform future practice. The committee agreed not to recommend the use of levothyroxine due to the evidence suggesting no clinically important benefit for most outcomes and their awareness of adverse effects (for example, TSH suppression and increasing cardiovascular risk).\n\nThe committee noted that there was no evidence in children. They agreed that a healthcare professional should refer a child with thyroid enlargement to an appropriate multidisciplinary team, to ensure appropriate management as early as possible.\n\nThere was no evidence on monitoring thyroid enlargement but the committee agreed that, given the accuracy of ultrasound imaging, the risk of missing a malignancy or malignant transformation in an enlarged thyroid gland is low. However, they agreed that worsening symptoms or development of new symptoms may warrant repeating the ultrasound and TSH measurement. Suspicion of malignancy or compression would warrant repeating these tests.\n\n## How the recommendations might affect practice\n\nThe recommendations on surgical referral for goitre and non-malignant thyroid nodules are broadly in line with current clinical practice and therefore not expected to have significant impact.\n\nThe recommendations on managing non-malignant thyroid enlargement are also unlikely to have substantial resource impact. Radiofrequency ablation and laser ablation are not currently widely available. However it is current practice to only provide interventions to adults with nodules causing symptoms, as outlined in the recommendations. This limits the number of adults needing these interventions. Referral of children to a multidisciplinary team is not likely to occur often because thyroid enlargement is rare in this population.\n\nThe recommendation broadly reflects current practice. The committee recognised that there may be some centres in which routine monitoring is done, and the recommendation is likely to reduce this.\n\nFull details of the evidence and the committee's discussion are in evidence review P: management of non-malignant thyroid enlargement, and evidence review F: monitoring thyroid disease.\n\nReturn to recommendations", 'Context': "Thyroid disease includes thyroid enlargement and thyroid hormone dysfunction. Thyroid enlargement may be benign, resulting in nodules or goitre, or malignant in people with thyroid cancer. Conditions causing thyroid dysfunction can be broadly divided into those that result in thyroid gland underactivity (hypothyroidism) or overactivity (thyrotoxicosis).\n\nThyroid enlargement is common. About 15% of the UK population have clinically detectable goitres or thyroid nodules, and the lifetime risk of developing a thyroid nodule is around 5 to 10%. In many cases, thyroid glands harbouring malignancy are clinically indistinguishable from those that are not. Most people with a non-malignant enlarged thyroid gland and normal thyroid function need no treatment.\n\nHypothyroidism is a condition of thyroid hormone deficiency and is usually caused by autoimmune Hashimoto's thyroiditis. Primary hypothyroidism refers to conditions arising from the thyroid gland rather than the pituitary gland (secondary hypothyroidism). Hypothyroidism is found in about 2% of the UK population and in more than 5% of those over 60. Women are 5 to 10 times more likely to be affected than men. Long-term consequences of hypothyroidism include cardiovascular disease and an increase in cardiovascular risk factors, including hypercholesterolaemia.\n\nThyrotoxicosis is a disorder of excess circulating thyroid hormones caused by increased production and secretion (hyperthyroidism) or the release of (thyroiditis) stored thyroid hormones. In the UK, autoimmune hyperthyroidism (Graves' disease) is the most common form, accounting for 60 to 80% of cases. Thyrotoxicosis is a common endocrine disorder with a prevalence of around 2% in UK women and 0.2% in men. Graves' disease is caused by a genetic predisposition to developing stimulating thyroid autoantibodies and occurs mostly in women aged 30 to 60 years. Thyrotoxicosis affects 1 to 2 children per 10,000. Children may be severely affected, with poor educational performance often being an early feature. Long-term consequences of hyperthyroidism include increased cardiovascular morbidity and mortality and bone-related complications, including osteoporosis.\n\nSubclinical thyroid dysfunction is a biochemical diagnosis where serum thyroid-stimulating hormone (TSH) levels are outside the reference range, and circulating thyroid hormone levels (thyroxine [T4] and tri-iodothyronine [T3]) are within the reference range. It is often detected incidentally, although some people may have symptoms of hypothyroidism or hyperthyroidism. The prevalence of subclinical thyrotoxicosis is 0.5 to 10% and that of subclinical hypothyroidism is 4 to 20%; these wide ranges reflect differences in the studied populations. Data on the long-term consequences of subclinical thyroid dysfunction largely come from people over 65. They indicate increased cardiovascular morbidity and mortality, an increased risk of osteoporosis and potential links to dementia.\n\nThis guideline covers investigating all suspected thyroid dysfunction and managing primary thyroid disease (related to the thyroid rather than the pituitary gland). There is variation in how thyroid disease is investigated and managed in primary and secondary care. There are currently no standardised diagnostic or referral criteria in the UK to guide decision making in primary care for people with structural thyroid abnormalities or enlargement. In secondary care, there is significant variation in the types of diagnostic tests and imaging used, as well as in surgical and non-surgical management and follow-up protocols. Standardisation in thyroid hormone replacement strategies for people with hypothyroidism is currently lacking. In addition, guidance on optimal treatment and follow-up strategies is needed for managing thyrotoxicosis, which is usually done by shared care between primary and secondary care. Opinions regarding the need to treat subclinical thyroid dysfunction, especially in older people, vary widely.\n\nThis guideline also aims to improve the diagnosis, management and follow-up of non-malignant thyroid enlargement associated with normal thyroid function."}
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https://www.nice.org.uk/guidance/ng145
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This guideline covers investigating all suspected thyroid disease and managing primary thyroid disease (related to the thyroid rather than the pituitary gland). It does not cover managing thyroid cancer or thyroid disease in pregnancy. It aims to improve quality of life by making recommendations on diagnosis, treatment, long-term care and support.
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ae5a3f920e1ae44fbae37e187062607196c327ae
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nice
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Workplace health: long-term sickness absence and capability to work
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Workplace health: long-term sickness absence and capability to work
This guideline covers how to help people return to work after long-term sickness absence, reduce recurring sickness absence, and help prevent people moving from short-term to long-term sickness absence.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
This guideline should be read in conjunction with NICE's guidelines on workplace health: management practices, low back pain and sciatica in over 16s and mental wellbeing at work.
This guideline focuses on managing sickness absence among all employees, regardless of whether they have a disability or long-term condition covered by the Equality Act 2010. It should be considered alongside the legal requirements for employers in relation to health and disability, and it is not a substitute for the law or relevant codes of practice.
The recommendations in sections 1.1 and 1.3 to 1.7 are for employers, senior leadership, managers and human resources personnel.
The recommendations in section 1.2 are for those assessing and certifying fitness for work.
The recommendation in section 1.8 is for those responsible for commissioning and delivering advice and support services for people not in work and who are receiving benefits relating to a health condition or disability.
# Workplace culture and policies
Make health and wellbeing a core priority for the top level of management of the organisation. See the section on organisational commitment in NICE's guideline on workplace health: management practices (this section includes making health and wellbeing a core priority, ensuring the commitment of managers, and the importance of policies and of clear communication).
Foster a caring and supportive culture that encourages a consistent, proactive approach to all employees' health and wellbeing.
Organisations (for example those with a small number of employees) that do not have formal policies should ensure that clear and accessible procedures for reporting and managing sickness are in place and are explained to all new and existing employees.
Ensure that all employees know the workplace policies or procedures for notifying and managing sickness absence, and for return to work. Make this part of the induction process for new employees and ensure that they know the sickness absence reporting system is confidential.
When developing workplace policies for managing sickness absence and return to work, ensure that these are part of a broader, strategically led approach to promoting employees' health and wellbeing (see recommendation 1.1.1).
Consider using a confidential and accessible employee assistance programme and occupational health provider if the organisation does not already do this.
Monitor and regularly review the impact of sickness absence policies and procedures to ensure that they are being implemented fairly and consistently across the organisation and that they are fit for purpose.
Consider collecting non-identifiable data that can enable the sickness absence profile and changing trends to be monitored across the organisation. The data should include information on:
the duration and frequency of absence
the cause of absence (and whether work related)
factors that may be associated with sickness absence such as job role, salary band, department and location of workplace.
Regularly review the data on trends in sickness absence to identify:
areas in which intervention may be needed to support employees' health and wellbeing and
policies or procedures that may need to be reviewed or amended.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on workplace culture and policies .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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# Assessing and certifying fitness for work
The statement of fitness for work ('fit note') should be completed by the practitioner with the most relevant recent knowledge of the person's health, reason for absence and prognosis for return to work. This can be a doctor, registered nurse, occupational therapist, pharmacist or physiotherapist.
Encourage people who are assessed as not fit for work to maintain regular contact with their workplace.
If the person is likely to be absent from work for more than 4 weeks, consider:
referral to health rehabilitation and support services, such as physiotherapy, counselling or occupational therapy
signposting them to other possible expert sources of vocational advice and support relevant to their condition.
Take account of the fact that reasons for sickness absence can be complex. Encourage the person to:
reflect on any factors in their work or personal life that may be contributing to their current absence or causing concern about returning to work and
identify any additional support they might need.
Be aware that employers need information on how the employee's health condition or treatment could affect them on their return to work. Use the statement of fitness for work to provide sufficient information in clear, non‑technical language.
For a short explanation of why the committee made these recommendations and how they might affect practice,see the rationale and impact section on assessing and certifying fitness for work .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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# Statement of fitness for work
When a statement of fitness for work ('fit note') is received indicating that someone is not fit for work, start and maintain a confidential record. This record should include:
the reason for absence, the anticipated length of absence and any recurrence of absence for the same reason and
any comments from the practitioner about how the person's condition or treatment affects their capacity for work.(Also see the section on keeping in touch with people on sickness absence).
To support the person who is currently not fit for work and plan for their return to the workplace, consider:
taking into account any additional information provided (for example from an allied health professional's health and work report) about how their condition may affect their ability to do their role
seeking information and advice on what support they might need, such as from an occupational health service or from other possible expert sources of vocational advice and support relevant to their condition (this may include online resources, or telephone advice from external bodies)
discussing with them what adjustments or other support might be needed if any ongoing health needs are anticipated for when they return to work; if adjustments need approval, discuss these with decision makers to gain sign-off.
When a statement of fitness for work indicates that a person may be fit for work, contact them as soon as possible:
Discuss what adjustments (such as flexible working, phased return, reduced hours, changes to workstations or duties) might help them return to work. Use any recommendations in the statement of fitness for work as a starting point.
Involve the employee and line managers in these discussions initially, and occupational health services if needed.
Human resources, trade unions or occupational health services (if not already participating) may also be involved, especially if the circumstances or adjustments are more complex.
If adjustments in the statement of fitness for work or requested by the employee cannot be made, explain the reasons clearly in writing to the employee. With their informed consent, send a copy to the certifying practitioner.
If a person may be fit to return to work with adjustments but those adjustments cannot be made, the person should continue to be treated as 'not fit for work', in line with the Department for Work and Pensions' guidance for employers. In such cases:
Advise the person that they should return to work only when they have sufficiently recovered and are able to perform their regular duties.
Discuss and jointly agree a plan for keeping in touch during their extended absence. Discuss any actions that may support them in making a full recovery and returning to their regular duties, and agree to regularly review these (see the section on early intervention).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on statement of fitness for work .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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# Making workplace adjustments
When any work adjustments have been agreed with a person returning from sickness absence:
Arrange additional risk assessments if needed. Guidance on these is available on the Health and Safety Executive's website.
Discuss with the returning person whether colleagues could be informed about the adjustments to help them understand the need for them. Seek the person's informed consent and, if it is given, explain the reasons why the adjustments are being made. Discuss with colleagues any concerns that they may have about the impact of adjustments.
Record any workplace adjustments agreed with the employee, including a timeframe for their implementation and how long they are expected to last, in a written return-to-work plan for the employee and their line manager.
Monitor any workplace adjustments that have been put in place to see if they are meeting the needs of both the employee and employer. Review this regularly, within a timeframe agreed by the employee and line manager in the written return-to-work plan.
Encourage the employee to raise any issues related to the workplace adjustments and discuss who to raise them with. This may be an independent, impartial person. If necessary, think about making changes to the return-to-work plan.
Ensure that the employee is aware of other interventions that may be available to support them in their workplace (see the section on early intervention).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on making workplace adjustments .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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# Keeping in touch with people on sickness absence
Ensure that the organisation regularly keeps in touch with people who are 'not fit for work' during periods of sickness absence, including people with a chronic health condition or a progressive illness or disability covered by the Equality Act 2010.
Make contact as early as possible, and within 4 weeks of them starting sickness absence, depending on the circumstances.
When contacting the employee:
Be sensitive to their individual needs and circumstances.
Be aware that communication style and content could affect their wellbeing and decision to return to work.
Ensure that they are aware that the purpose of keeping in touch is to provide support and help them return to the workplace when they feel ready.
If an early referral to support services (for example physiotherapy, counselling or occupational therapy) is available through the organisation's occupational health provider, discuss if this may be helpful.
Discuss how they would like to be contacted in future, how frequently and by whom. If the line manager is not the most appropriate person to keep in touch, offer alternatives.
Provide reassurance that anything they share about their health will be kept confidential, unless there are serious concerns for their or others' wellbeing.
Ensure that members of staff responsible for keeping in touch with people on sickness absence:
are aware of the need for sensitivity and discretion at all times
understand the organisation's policies or procedures on managing sickness absence and returning to work
are competent in relevant communication skills and are signposted to and encouraged to use online or other resources and advice to improve these skills.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on keeping in touch with people on sickness absence .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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# Early intervention
In organisations that offer access to early interventions (such as rehabilitation, counselling or an employee assistance programme) ensure that all employees are aware of their availability, remit and confidentiality.
Assure employees that all contact with the employee assistance programme is confidential.
For employees whose sickness absence is expected to continue beyond 4 weeks, in organisations with access to an occupational health provider:
discuss the possibility of a referral to occupational health for an assessment of fitness for work or
discuss the suitability for early referral to support services; if referral is appropriate, ensure that this takes place as early as possible.
If occupational health services or an employee assistance programme are not available, encourage employees whose sickness absence is expected to continue beyond 4 weeks to discuss with their GP or secondary care specialist any options for referral to support services such as physiotherapy, counselling or occupational therapy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on early intervention .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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# Sustainable return to work and reducing recurrence of absence
## Sustainable return to work for people with a musculoskeletal condition
For people who have been absent for 4 or more weeks because of a musculoskeletal condition, consider interventions to help them return to work. For example:
A programme of graded activity delivered by someone with appropriate training (for example, a physical or occupational therapist).
Problem-solving therapy.
A worksite assessment by a suitably qualified professional to review and discuss with the employee, together with a representative of the employer, the suitability of work tasks or any adjustments that could be made.
A meeting between the employee and their line manager, facilitated by an impartial person, to agree the key barriers to returning to work and what modifications could be made to the work environment to overcome these.
## Reducing recurrence of absence for people with a common mental health condition
For people who resume work after an absence of 4 or more weeks for a common mental health condition, consider a 3‑month structured support intervention to reduce the likelihood of a recurrence of absence. Involve the line manager in this process, which could be led by an impartial person. The intervention may include:
Meeting the person to identify any issues encountered since their return to work, and exploring possible solutions and support needs.
Developing an action plan to implement, which is agreed with the person's line manager.
Regular follow-up meetings with the person and their line manager to evaluate progress.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on sustainable return to work and reducing recurrence of absence .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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# People with a health condition or disability who are not currently employed
Commission an integrated programme to help people receiving benefits who have a health condition or disability to enter or return to work (paid or unpaid). The programme should include a combination of interventions such as:
an interview with a trained adviser to discuss the help they need to return to work
vocational training (for example help producing a CV, interview training and help to find a job or a work placement)
a condition management component run by local health providers to help people manage their health condition
support before and after returning to work that may include 1 or more of the following: mentoring, a job coach, occupational health support or financial advice.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary or, for public health and social care terms, the Think Local, Act Personal Care and Support Jargon Buster.
## Common mental health condition
Common mental health conditions include conditions such as depression, generalised anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder and social anxiety disorder.
## Condition management
Programmes delivered by healthcare professionals that do not treat the underlying condition, but that focus on improving the likelihood of people being able to return to, or stay in, work. These programmes may aim to improve a person's understanding of their condition, increase their confidence and improve their ability to function in the workplace, through for example, pain or stress management and building self‑esteem and confidence.
## Employee assistance programme
An employer-funded programme offering confidential services such as counselling and advice on a range of work and personal issues. Although the employer may receive an indication of numbers of employees taking up the service, no personal information is shared with the employer that would enable them to identify which employees access the service or their reason for doing so.
## Employment and support allowance
Employment and support allowance (ESA) is a 2‑tier system of benefits that will be replaced by the introduction of Universal Credit. All claimants who are out of work because of ill health or a disability are entitled to claim ESA (paid at the same rates as job seeker's allowance). Those deemed capable of work at some time in the future (by a medically administered 'work capability' test) are placed in a work‑related activity group. Those deemed not capable of work because of the severity of their physical or mental condition are placed in a support group with no conditions (and until April 2017 received a higher support allowance).
## Graded activity
Graded activity aims to increase a person's activity levels gradually using a behavioural approach. Typically, people with musculoskeletal conditions attend individually focused training sessions with a gradually increasing exercise programme.
## Long-term sickness absence
Long-term sickness absence is sometimes defined as an absence lasting more than 2 weeks, but for this guideline it is defined as 4 or more weeks (as per the scope of this guideline and previous NICE guidance). Recurring long-term sickness absence has been defined as more than 1 episode of long-term sickness absence, with each episode lasting more than 4 weeks.
## Micro-, small- and medium-sized organisations
Organisations employing fewer than 250 people. Micro-sized organisations employ between 0 and 9 people, small organisations employ between 0 and 49 people and medium-sized organisations employ between 50 and 249 people.
## Presenteeism
Inappropriately continuing to go to work despite health problems. It also describes someone's attendance at work without performing all of their usual tasks (regardless of the reason). When employees feel the need to attend work although they are not functioning fully, it can result in losses in productivity. Presenteeism can also make health problems worse.
## Problem-solving therapy
Therapy that involves learning or reactivating problem-solving skills.
## Short-term sickness absence
For this guideline it is defined as an absence lasting up to (but less than) 4 weeks. Recurring short-term sickness absence is defined as more than 1 episode of short-term sickness absence, each lasting less than 4 weeks.
## Wellbeing
Wellbeing is the subjective state of being healthy, happy, contented, comfortable and satisfied with one's quality of life.
## Vocational rehabilitation
Helps those who are ill, injured or who have a disability to access, maintain or return to employment or another useful occupation. It may involve liaison between healthcare and rehabilitation practitioners; management, human resources and other in‑house or external facilitators. It may result in transitional working arrangements, training, social support and modifications to tasks.# Recommendations for research
The guideline committee has made the following recommendations for research.
As part of the 2019 update, the guideline committee made 5 additional research recommendations.
Four of these relate to a UK focus on effective and cost-effective interventions to:
support return to work after long-term sickness absence
support return to work after recurrent short-term sickness absence
reduce long-term sickness absence and support return to work in people with common mental health conditions
and reduce recurrent short-term sickness absence and support return to work in people with common mental health conditions.
The other is on the challenges and potential solutions for UK employers and employees in managing sickness absence and return to work in micro-, small- and medium-sized organisations.
The committee removed 4 research recommendations from the original guideline on:
preventing sickness absence
evaluating interventions
return to work interventions and programmes
cost effectiveness.
The committee considered that the new research recommendations capture any research questions that still need to be addressed.
# Key recommendations for research
## Interventions after long-term sickness absence
What interventions are effective and cost effective in supporting return to work, in all workplaces including micro-, small- and medium-sized organisations, after long-term sickness absence in the UK?
For a short explanation of why the committee made the recommendation for research, see the rationale sections on workplace culture and policies and early intervention .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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## Interventions after recurrent short-term sickness absence
What interventions are effective and cost effective in supporting return to work after recurrent short-term sickness absence in the UK?
For a short explanation of why the committee made the recommendation for research, see the rationale section on workplace culture and policies .x
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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## Interventions after long-term sickness absence for mental health conditions
For people with common mental health conditions, what interventions are effective and cost effective in reducing long-term sickness absence and supporting return to work in the UK?
For a short explanation of why the committee made the recommendation for research, see the rationale section on sustainable return to work and reducing recurrence of absence .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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## Interventions after recurrent short-term sickness absence for mental health conditions
For people with common mental health conditions, what interventions are effective and cost effective in reducing recurrent short-term sickness absence and supporting return to work in the UK?
For a short explanation of why the committee made the recommendation for research, see the rationale section on sustainable return to work and reducing recurrence of absence .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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## Challenges and potential solutions for smaller employers
What are the challenges and potential solutions for UK employers and employees in micro-, small- and medium-sized organisations (which may not have easy access to additional services such as employee assistance programmes or occupational health services) in ensuring sickness policy is managed effectively and facilitating return to work?
For a short explanation of why the committee made the recommendation for research, see the rationale section on early intervention .
Full details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.
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# Other recommendations for research
## Interventions to reduce sickness absence where employees are not centrally located
Which interventions are effective and cost effective in supporting people working in organisations where employees are not centrally located to return to work after long-term sickness absence in the UK?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Workplace culture and policies
Recommendations 1.1.1 to 1.1.9
## Why the committee made the recommendations
Evidence from the UK showed that workplace policies on sickness absence and return to work may help to reduce uncertainty around the process of enabling return to work for employees and employers, but only if they are properly implemented. The committee agreed that it is important for all sizes of organisation to clearly communicate policies and procedures to staff.
However, smaller organisations may not have formal policies in place. The committee agreed that in these situations it is important that all employees are aware of the procedures for reporting and managing sickness. Regularly reviewing these policies and procedures would be good practice to ensure that they are appropriately applied and fit for purpose.
The committee discussed testimony from experts in occupational health and in employment research. The expert in occupational health was asked how the occupational health service in their NHS trust had contributed to achieving and maintaining a relatively low sickness absence rate and the barriers and facilitators to doing so. The expert in employment research was asked about common and more innovative measures used by organisations to reduce sickness absence rates.
The testimony provided by the experts identified that a commitment to employee health and wellbeing, proactively and strategically led from the top levels of management, should underpin sickness absence and return-to-work policies. The committee discussed the importance of these policies being part of a wider culture that values and promotes employee health and wellbeing.
The committee discussed that inappropriately applied return-to-work policies can result in presenteeism or longer absences from work. They highlighted the importance of ensuring that everyone is treated fairly. For this reason, they thought it important to regularly review how policies are implemented across the organisation, to ensure that those who are off work or planning a return to work are treated consistently.
The focus of this guideline is on managing sickness absence among all employees, regardless of whether they have a disability or long-term condition covered by the Equality Act 2010. Although the committee were aware that organisations should also have policies and procedures in place for managing disability leave, this area is not included within the scope of this guideline. The committee noted that there are legislative requirements about health and disability for employers and that the recommendations in this guideline should be considered alongside those requirements.
There is a small amount of low-quality evidence that employers providing early access to interventions, for example through an occupational health provider or employee assistance programme, can benefit both employees and employers. There is also some similarly limited evidence that accessing interventions early may help to reduce sickness absence rates and promote a more sustainable return to work.
Testimony from an expert in occupational health supported the evidence that was found on providing early access to interventions, when appropriate. Furthermore, the committee noted that guidance for employers on commissioning an occupational health service is available from the Society of Occupational Medicine. The committee discussed the limitations in the evidence and, in particular they noted that micro-, small- and medium-sized organisations are not represented in the evidence and may not have access to such services.
The committee also heard from experts, particularly the expert in occupational health, that organisations that are considered to be examples of good practice collect detailed data on trends in sickness absence according to factors such as job type and location. This detailed non-identifiable data can help the organisation target specific interventions and resources where they are most needed. It may also help to highlight any inequalities and identify policies or procedures that may need to be reviewed or amended.
The evidence seen by the committee focused almost entirely on supporting people to return to work after a period of long-term sickness absence (4 or more weeks). No evidence was found on preventing recurrent short-term sickness absence (of less than 4 weeks per episode) or on preventing people moving from short-term to long-term sickness absence.
Despite the lack of direct evidence the committee agreed that, in practice, interventions that were effective in supporting people to return to work after long-term sickness absence may also help to prevent recurrent short-term absences and to prevent people moving from short to long-term sickness absence. This is because they may have to overcome similar barriers and need similar support when returning to work. The recommendations therefore do not distinguish between supporting people returning from long-term or recurrent short-term sickness absences.
Because no evidence was found on preventing recurrent short-term sickness absence, the committee recommended research in this area (see research recommendation 2). They also agreed that research is needed on supporting people to return to work after long-term sickness absence in a UK context (see research recommendation 1). Most of the evidence they considered was not from the UK, but from countries with different systems for managing sickness absence. The committee therefore agreed there was a need for more evidence that was directly applicable to the UK population. The committee considered that alongside data on supporting return to work it would be helpful if studies collected data on the impact of absenteeism and presenteeism.
Although there was no evidence on preventing the move from short-term to long-term sickness absence, the committee did not make a research recommendation in this area. This is because of the potential difficulties of identifying people with short-term sickness absence that may become long-term sickness and the feasibility of recruiting them to take part in research trials before they cross the 4‑week threshold into long-term sickness absence.
## How the recommendations might affect practice
The recommendations reflect good practice. Larger organisations are more likely to already have formal policies and procedures, but they may need to develop procedures for regularly reviewing them and how they have been implemented.
The resource implications are likely to be greater for micro-, small- and medium-sized organisations that don't have formal policies or provide access to occupational health or employee assistance programme services. Larger organisations are more likely to have these in place, but the committee heard from an expert in employment research that this may not always be the case.
The committee noted from their experience that it would be good practice for smaller organisations that do not currently have access to such services to explore where additional services (such as occupational health) may be available to provide support. This would be part of a proactive approach to promoting employee health and wellbeing. If recommendations are widely implemented, it may result in a larger number of employers having appropriate policies and procedures in place and may help to encourage the spread of good practice. Implementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity.
Return to recommendations
# Assessing and certifying fitness for work
Recommendations 1.2.1 to 1.2.5
## Why the committee made the recommendations
There was evidence from a small number of UK studies that showed there can be challenges for GPs in completing fit notes. GPs may feel that they do not have the occupational health experience or the knowledge of the workplace needed to make suggestions about workplace adjustments.
The committee discussed that other medical practitioners were also likely to experience the same challenges and agreed that the best person to complete the fit note is the medical practitioner with the most relevant recent knowledge of the person's situation. In many cases this will be a GP, but it could also be a person's specialist in secondary care. The specialist may be able to provide more information than the GP on the anticipated effects of treatment, timeframes for rehabilitation and adjustments for when the person returns to work. September 2022: we changed the recommendation on who can complete a fit note in line with new legislation, to include registered nurses, occupational therapists, pharmacists and physiotherapists.
There was evidence from a small number of UK studies that showed it is important to avoid people becoming disconnected from work during their absence. Keeping in touch regularly with the workplace is important for building the person's confidence to return, monitoring their recovery and maintaining a focus on the goal of returning to work.
This evidence suggested and the committee agreed that the GP may be particularly well placed to refer people on long-term sickness absence to rehabilitation and support services, especially if these are not offered by the employer as part of occupational health provision. They noted that specialists may also refer people under their care to some rehabilitation services. They also noted that it may be helpful to signpost people to other possible expert sources of vocational advice and support relevant to their condition. This may include advice and support from the voluntary sector.
The committee did not specifically recommend keeping in touch regularly with the GP because this may have a resource impact that had not been assessed.
The committee noted that reasons for sickness absence can be complex and agreed that GPs primarily view their role as a patient advocate. GPs are therefore well placed to explore whether sickness absence is exacerbated by aspects of the person's job, home life (such as caring responsibilities) or workplace relationships that the person feels unable to discuss with their employer (such as poor relationships with line managers).
If the practitioner anticipates that the absence is likely to be long term (4 or more weeks), they could consider referral to rehabilitation and support services.
There is evidence from a small number of UK studies suggesting that patients believe the advice on fit notes can empower them in negotiating changes at work. But there is also evidence that employers can find fit notes unsatisfactory. In particular, employers have reported that fit notes may not give enough useful information on how the person's health condition may affect their ability to do their job. This can make employers wary of any risks associated with someone returning to work if they are not fully recovered.
The committee therefore agreed that it is important to encourage practitioners to state clearly how the person's health condition or treatment might affect them in their workplace, so that appropriate support and adjustments can be considered. However, this type of detail on the fit note needed to be added only with the person's agreement. The committee also discussed that unless the practitioner has specific knowledge about a person's workplace or role, it may be difficult for them to understand the implications of someone's condition on their ability to do their job.
## How the recommendations might affect practice
If specialists certify sickness absence to employers, rather than referring them to their GP, this would free up GP appointment time and may provide more useful information for employers. However, there may then be an impact on specialists' time.
The committee agreed that it is part of the GP's role to refer people on sickness absence to rehabilitation and support services and so this should not incur an additional cost. However, there may be an additional impact on support services, such as physiotherapy and counselling.
Return to recommendations
# Statement of fitness for work
Recommendations 1.3.1 to 1.3.5
## Why the committee made the recommendations
Some UK studies showed that employers think fit notes can provide useful information to support managers in communicating with people who are absent. They can help managers understand the employee's health condition and what support they might need when they return to work. This can enable them to plan for suitable adjustments to ensure a safe and sustainable return to work.
The committee agreed that it would be good practice to start a confidential record for every absence for which a fit note is received, not just when it is anticipated that the person will be taking a long-term sickness absence. This is because it may not be immediately clear when an absence may become long term, because there may be subsequent fit notes received for the same episode of absence. In addition, keeping such records may also help to identify recurrent sickness absence.
The committee agreed it is good practice to be proactive and plan ahead how to support someone once they are ready to return to the workplace. Although there was no evidence identified on planning ahead, the committee made a recommendation encouraging employers to do so, based on good practice.
The committee were aware that there are various potential sources of expert advice available to help managers understand the effects of health conditions or treatments. These can be particularly useful if the employing organisation does not have its own occupational health adviser. This may include online information and resources that give vocational advice and specific advice relevant to the employee's particular condition.
Although the committee had not reviewed these resources and they were conscious they may change over time, they noted that information from organisations, such as Public Health England, and some voluntary sector organisations may be helpful.
The committee noted that it is important to discuss adjustments that may be helpful with the returning employee. In many cases this discussion may involve only the employee and their line manager, and if necessary, occupational health. The evidence suggests that being able to have such a conversation may depend on a good relationship between line manager and employee.
The committee heard evidence from experts in occupational health and from a mental health support service, which showed that if relationships are difficult, or adjustments are more complex, it can be helpful to involve an impartial party to help reach an agreement.
The committee noted that recommendations for adjustments that a practitioner makes on a 'may be fit for work' note are advisory. Evidence shows that employers may have concerns about employee expectations and the possibility of conflict, if adjustments can't be accommodated. Also, the evidence suggested and the committee discussed that some GPs and patients have reported feeling undermined when their suggestions to employers are not acted on.
The committee agreed that guidance on what employers should do, if adjustments cannot be agreed, would minimise conflict. They recommended that the person should be treated as 'not fit for work' and noted the importance of maintaining contact with them. They also noted that when suggested adjustments can't be made it would be helpful to provide GPs, with the employee's informed consent, with feedback, so that they are aware of the person's continuing absence and are better informed about their particular workplace context.
The committee's recommendations on making adjustments to support people to return to work focus on all employees. But they noted that if someone has a chronic or progressive illness or disability covered by the Equality Act 2010, the employer has a legal obligation to make reasonable adjustments in the workplace.
This legal obligation applies to all employees with an illness or disability covered by the Act, not just those returning from sickness absence. But the committee noted that particular consideration may need to be given to adjustments when an employee with a disability or condition covered by the Act is returning from sickness leave, to provide them with the best possible support.
## How the recommendations might affect practice
Larger organisations are more likely to already have formal policies and procedures in place for making return-to-work plans.
Resource implications are likely to be greater for micro-, small- and medium-sized organisations, which may not have capacity to plan ahead for someone returning to work, or the capacity or resources to make adjustments to the workplace or duties. The committee noted that if an employee has a disability or a long-term condition that makes it difficult for them to do their job, organisations may find it helpful to explore whether they are eligible for funding to support making adaptations to the workplace.
Providing feedback to practitioners when adjustments they have recommended cannot be accommodated would be good practice. However, the committee were aware that a mechanism for providing this feedback would need to be developed and maintained and that for some organisations, particularly micro-, small- and medium- sized organisations, this may not be sustainable.
Implementing the recommendations may need resource input initially, but over time it may result in a reduction in the costs of sickness absence and improved productivity. If the resource input makes returning to work part of a proactive approach to supporting employee health and wellbeing, this investment may help to reduce the costs of sickness absences in the longer term.
Return to recommendations
# Making workplace adjustments
Recommendations 1.4.1 to 1.4.3
## Why the committee made the recommendations
The committee were aware that it is a legal requirement for employers to carry out risk assessments to ensure a healthy and safe environment in the workplace and that guidance on these is available from the Health and Safety Executive (see Regulation 3 of the Health and Safety Executive's Management of Health and Safety at Work Regulations 1999). They discussed and agreed from their experience and expertise that it is good management practice to undertake an additional risk assessment for a person returning from sick leave and before making workplace adjustments.
There is a small amount of low-quality UK evidence to suggest that some colleagues may resent adjustments being made to the returning person's role or workload. However, other similarly limited evidence noted that other staff members can be understanding about workplace and role adjustments and help with supporting their colleagues' return to work.
The committee noted that to maintain relationships and productivity in the wider team it may be helpful to explain the reasons for the adjustments and give colleagues the opportunity to raise any concerns. It is important that this is only done after discussion with the returning person and with their informed consent.
The committee agreed that it is important to keep a written record of the adjustments that have been agreed in a written return-to-work plan. This should be based on the individual employee's needs and their role in the organisation and as such there will need to be some flexibility in terms of what the plan covers. The committee agreed it is important to regularly review the return-to-work plans to ensure that they continue to meet the person's needs as their recovery progresses and to amend them if necessary. It can also be helpful, when reviewing how the adjustments are working, to remind the person of any other interventions the employer may provide, if these are available.
## How the recommendations might affect practice
Larger organisations are more likely to already have formal policies and procedures in place for making return-to-work adjustments. They may need to develop additional procedures and provide resources or training for risk assessment of return-to-work plans, developing written return-to-work plans and monitoring how well workplace adjustments are working.
Resource implications are likely to be greater for micro-, small- and medium-sized organisations, which may not have capacity to make adjustments.
The committee noted that the capacity of organisations to provide risk assessment training may need to be considered.
Implementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity.
Return to recommendations
# Keeping in touch with people on sickness absence
Recommendations 1.5.1 to 1.5.4
## Why the committee made the recommendations
Evidence from UK studies shows that keeping in touch with people who are on extended periods of sick leave can help them feel supported, valued and more confident about returning to work. The committee agreed that a positive commitment to keeping in touch should form part of the organisation's sickness absence and return-to-work policies.
The committee discussed that managers may have concerns about contacting and keeping in touch with those who are off work, and that employees may feel that this is putting additional pressure on them to return to work. Evidence from UK studies supported this discussion.
The committee also noted that if people are absent for reasons that relate to an illness or disability that is covered by the Equality Act 2010, managers may feel additional concern about the appropriateness of contacting them. These concerns may lead to those who have an illness or disability covered by the Act being disadvantaged compared with others if their employers do not contact them for fear it may be inappropriate to do so. The committee agreed that policies on keeping in touch should be followed with everyone who takes sickness absence.
The timing of initial contact should take into account the personal circumstances of the employee and their reason for, and anticipated length of, absence. In addition to making the employee feel supported, the aim is to help prevent a short-term absence becoming a long-term absence.
For this reason, the committee recommended getting in touch with the employee as soon as possible and within 4 weeks. However, they were mindful of the need to keep this flexible, particularly when sickness absences may be planned or when recovery will clearly take longer than 4 weeks. For example, for recovery from surgery or cancer treatments.
The committee discussed the limitations in the evidence, but noted that it has shown that relationships with managers are an important factor in people's decisions about returning to work. The committee noted that this may be particularly pertinent when there is a mental health component to the absence. It is therefore important to establish from the employee's perspective whether the line manager is the best person to keep in touch with them.
The committee noted that it is important to reassure people that anything they share about their health will remain confidential. However, they acknowledged that in circumstances when there are serious concerns for the wellbeing of the employee or others, information may have to be disclosed in order to meet an employers' duty of care, or to meet professional or legal obligations.
The evidence suggested, and the committee agreed, that the communication style of the person with responsibility for keeping in touch with the employee and the content of the communication can affect the employee's wellbeing and decisions about returning to work.
For this reason, the committee recommended that organisations should provide those with keeping in touch responsibilities access to communication skills training and encourage them to access online resources and advice to ensure that they are competent and confident in this area. Resources to help employers with this include the NHS Employers website, and Public Health England's website.
## How the recommendations might affect practice
Micro-, small- and medium-sized organisations may find it more difficult to offer alternatives to the line manager as a contact person for people on sickness absence. They may be less likely to have formal procedures or policies on keeping in touch with people on sickness absence.
Resource implications are likely to be minimal and focus mainly on communication skills training. Formal training may be more likely to be offered by larger organisations, but there are useful online resources and advice that can be used by and adapted for smaller organisations.
Implementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity.
Return to recommendations
# Early intervention
Recommendations 1.6.1 to 1.6.4
## Why the committee made the recommendations
There was a small amount of low-quality evidence from UK studies that providing free-to-access employee assistance programmes and occupational health services is regarded as good employer practice. It is valued by employees as an indication that the organisation cares about the health and wellbeing of the workforce.
However, the evidence suggested that employees are not always aware that these services are available or what their remit is. This possible lack of awareness was discussed by the committee and also identified by the expert testimony from the occupational health expert. Particular reference was made to employee assistance programmes, for which there may be a misperception that programmes focus only on mental health and there can be stigma associated with this. In reality, they can also offer practical advice on other issues such as debt counselling.
The committee further discussed that employees may have concerns about the confidentiality of employee assistance programmes. Within this discussion the committee noted that the services provided by these programmes are confidential. They also recognised the importance of employees having information on how to access the programmes independently and without needing to ask their employer.
The committee discussed evidence and expert testimony from the occupational health expert that early access to interventions offered by occupational health providers are regarded positively by employers and employees, and may help to reduce sickness absence rates and support sustainable return to work. These can include fast-tracked access to physiotherapy or counselling sessions.
Although it was unclear whether the interventions included in the economic model were provided at an early stage, the model suggested that providing specific interventions was cost saving. The committee noted that it is important that the potential benefits and decision to refer to occupational health are discussed and agreed between the employee and their manager to avoid it being perceived as a punitive response to absence.
The committee were aware that services such as these tend to be offered by larger employers and that people working in micro-, small- and medium-sized organisations may not have access to them. They were aware from the government policy paper on 'Improving lives – the future of work health and disability' that around 43% of employees in the UK are employed by small- or medium-sized organisations.
The committee agreed that research is needed to determine effective and cost effective ways to support people to return to work after sickness absence, in UK workplaces of all sizes, including micro-, small- and medium-sized organisations (see research recommendation 1). In addition, they agreed there is a need for research on the challenges and potential solutions for UK employers and employees in managing sickness absence and return to work in smaller organisations where access to additional services may not be readily available (see research recommendation 5).
## How the recommendations might affect practice
Larger organisations are more likely to already fund services providing early intervention opportunities, whereas micro-, small- and medium-sized organisations may not be in a position to fund external occupational health provision or provide employee assistance programmes.
Implementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity. For example, providing 'fast track' or early access to interventions may incur an additional cost. However, this may be included as part of an occupational health service that an organisation provides, as part of a proactive approach to supporting employee health and wellbeing, and this investment may help to reduce the costs of sickness absences in the longer term.
Return to recommendations
# Sustainable return to work and reducing recurrence of absence
Recommendations 1.7.1 to 1.7.2
## Why the committee made the recommendations
The committee discussed that musculoskeletal conditions and common mental health conditions are the most frequent causes of long-term sickness absence among employees. Evidence from a small number of non-UK studies in people with musculoskeletal conditions suggested that interventions to strengthen a person's physical and mental health, and to focus on reducing potential barriers in the workplace, may increase return-to-work rates.
Although the committee noted the limitations in the evidence, they agreed that for employers with occupational health access, it would be useful to have the option of arranging a therapeutic programme of graded activity or problem solving for employees who are absent for 4 or more weeks because of musculoskeletal conditions. Although the economic analysis focused only on changes in absenteeism, because of a lack of data on other outcomes, such as productivity, staff turnover and wellbeing, the committee noted that these types of interventions could be cost saving.
The committee discussed evidence which showed that the time people take to return to work after absence because of a musculoskeletal condition may be reduced if flexible adjustments are agreed between employee and employer, as part of a planned return-to-work process.
The committee heard from an occupational health expert and an expert from a mental health support service that it can be helpful for an impartial person (who may or may not be part of the organisation) to facilitate discussions between the employee and employer, to help agree adjustments that are acceptable to both. The committee noted that there may be a number of people who could fill this role, examples include people from occupational health services, occupational therapists and vocational rehabilitation consultants.
A study of people who had returned to work after absence related to mental health conditions showed a supportive monitoring and problem-solving intervention delivered over 3 months to be associated with a reduced risk of recurrent absence. Although the economic analysis only considered the impact on absenteeism, this intervention was estimated to be cost saving.
Although the evidence was limited, in that it was based on 1 low-quality study, the committee also heard from an expert who supports people with mental health conditions that have resulted in them being absent from work or struggling to remain in work. Their testimony described the use of individual support plans and supportive monitoring. Based on this evidence and their expertise, the committee noted that such interventions are considered to be good practice for people with long-term absence due to common mental health conditions.
The committee noted that although there are substantial limitations in the evidence on supporting people to return to work after absence due to musculoskeletal or mental health conditions, particularly the lack of UK-based studies, it is important to not discourage what is considered to be good practice.
The committee agreed that interventions for those with common mental health conditions should be a research priority. This group may experience recurrent and long-term sickness and there is a lack of evidence on supporting their return to work. The committee recognised that reasons why a person may take sickness absence may be complex. They therefore agreed that research studies should aim to capture the context of the sickness absence and the preferences of participants in supporting them to return to work, alongside data on whether they have been able to return to work (see research recommendation 3 and research recommendation 4).
## How the recommendations might affect practice
The recommendations made in this area reflect good practice but some may currently be more accessible to people working in larger organisations. For example, organisations may buy in occupational health services that provide access to physiotherapy, counselling or ergonomic assessment of worksites.
Not all organisations have access to such services, particularly micro-, small- and medium-sized organisations. But they may be able to access them with minimal resource implications, for example by being part of a local or sector association that subscribes to these services.
There may be resource implications if everyone returning to work after absences of 4 or more weeks because of a common mental health condition is offered a 3‑month programme of structured support.
Economic modelling indicated that such an approach could be cost saving. The committee considered that these interventions could offer value for money and in the long run could reduce their costs. In the model these were achieved through savings associated with reduced absenteeism. The committee were mindful of other potential benefits not captured in the model, such as increased productivity as a result of early or sustained return to work and reductions in the costs associated with staff turnover.
Implementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity.
Return to recommendations# Context
Absence management processes can help people return to work after long-term sickness absence, but many do not go back. Among claimants of Employment and Support Allowance who had worked in the 12 months before their claim, 45% took a period of sickness absence before they left work.
Between 2010 and 2013 there were around 960,000 long-term sickness absences a year in Britain. Stress and acute conditions are responsible for many long-term absences, followed by mental ill health, musculoskeletal injuries and back pain. Employers spend around £9 billion a year on sick pay and associated costs.
Since the NICE guideline on managing workplace sickness absence was published in 2009, there have been several changes to policy and practice designed to help people return to work and reduce the social and economic burden of long-term sickness absence from the workplace. For example, the government consultation Health is everyone's business: proposals to reduce ill health-related job loss, encourages early action by employers to support employees with a disability or long-term condition to remain in work. Since 2009, there have also been changes to legislation, including the replacement of the Disability Discrimination Act (1995) by the Equality Act 2010. In light of these, and new evidence, it was decided to update this guideline.
In 2008, Working for a healthier tomorrow - work and health in Britain (Department for Work and Pensions) challenged the perception that it is inappropriate to be in work unless 100% fit. It shifted the emphasis from what a person cannot do to what they can do and led to a move from the 'sick' to the 'fit' note. A review in the government policy paper Improving lives: the future of work, health and disability suggests that there are too many fit notes stating 'not fit for work', when people 'may be fit for work' as long as appropriate workplace adjustments are made.
The 2016 Occupational medical workforce crisis report by the All Parliamentary Group on Occupational Safety and Health noted that the recruitment of occupational health physicians has been declining since 2003. In 2011, only 38% of employees had access to occupational health services and this is less likely among smaller organisations. However, in 2019 over 99% of private sector organisations had fewer than 50 employees.
In England, 19% of long-term sickness absence is attributed to mental ill health. In 2009, the Department for Work and Pensions added employment advisers to some Improving Access to Psychological Therapies (IAPT) services. In 2019 the NHS Long Term Plan identified stable employment as a major factor in maintaining good mental health and set out plans for investing in further employment support in IAPT.
Employee assistance programmes, many of which provide counselling, are increasingly being offered as an employee benefit. In 2017 the government's Thriving at work: a review of mental health and employers proposed core mental health standards that can be implemented by organisations of all sizes, and enhanced standards for larger organisations or those that are able to do more.
Everyone aged over 16 in full-time or part-time employment (paid or unpaid), who has had a long-term sickness absence (4 or more weeks) or recurring short-term sickness absences (less than 4 weeks each) and so may be at risk of moving from short- to long-term sickness absence. Everyone aged over 16 who is unemployed and gets benefits because of a long-term condition or disability that prevents them from working.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read in conjunction with NICE's guidelines on workplace health: management practices, low back pain and sciatica in over 16s and mental wellbeing at work.\n\nThis guideline focuses on managing sickness absence among all employees, regardless of whether they have a disability or long-term condition covered by the Equality Act 2010. It should be considered alongside the legal requirements for employers in relation to health and disability, and it is not a substitute for the law or relevant codes of practice.\n\nThe recommendations in sections 1.1 and 1.3 to 1.7 are for employers, senior leadership, managers and human resources personnel.\n\nThe recommendations in section 1.2 are for those assessing and certifying fitness for work.\n\nThe recommendation in section 1.8 is for those responsible for commissioning and delivering advice and support services for people not in work and who are receiving benefits relating to a health condition or disability.\n\n# Workplace culture and policies\n\nMake health and wellbeing a core priority for the top level of management of the organisation. See the section on organisational commitment in NICE's guideline on workplace health: management practices (this section includes making health and wellbeing a core priority, ensuring the commitment of managers, and the importance of policies and of clear communication). \n\nFoster a caring and supportive culture that encourages a consistent, proactive approach to all employees' health and wellbeing. \n\nOrganisations (for example those with a small number of employees) that do not have formal policies should ensure that clear and accessible procedures for reporting and managing sickness are in place and are explained to all new and existing employees. \n\nEnsure that all employees know the workplace policies or procedures for notifying and managing sickness absence, and for return to work. Make this part of the induction process for new employees and ensure that they know the sickness absence reporting system is confidential. \n\nWhen developing workplace policies for managing sickness absence and return to work, ensure that these are part of a broader, strategically led approach to promoting employees' health and wellbeing (see recommendation 1.1.1). \n\nConsider using a confidential and accessible employee assistance programme and occupational health provider if the organisation does not already do this. \n\nMonitor and regularly review the impact of sickness absence policies and procedures to ensure that they are being implemented fairly and consistently across the organisation and that they are fit for purpose. \n\nConsider collecting non-identifiable data that can enable the sickness absence profile and changing trends to be monitored across the organisation. The data should include information on:\n\nthe duration and frequency of absence\n\nthe cause of absence (and whether work related)\n\nfactors that may be associated with sickness absence such as job role, salary band, department and location of workplace. \n\nRegularly review the data on trends in sickness absence to identify:\n\nareas in which intervention may be needed to support employees' health and wellbeing and\n\npolicies or procedures that may need to be reviewed or amended. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on workplace culture and policies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n# Assessing and certifying fitness for work\n\nThe statement of fitness for work ('fit note') should be completed by the practitioner with the most relevant recent knowledge of the person's health, reason for absence and prognosis for return to work. This can be a doctor, registered nurse, occupational therapist, pharmacist or physiotherapist. \n\nEncourage people who are assessed as not fit for work to maintain regular contact with their workplace. \n\nIf the person is likely to be absent from work for more than 4\xa0weeks, consider:\n\nreferral to health rehabilitation and support services, such as physiotherapy, counselling or occupational therapy\n\nsignposting them to other possible expert sources of vocational advice and support relevant to their condition. \n\nTake account of the fact that reasons for sickness absence can be complex. Encourage the person to:\n\nreflect on any factors in their work or personal life that may be contributing to their current absence or causing concern about returning to work and\n\nidentify any additional support they might need. \n\nBe aware that employers need information on how the employee's health condition or treatment could affect them on their return to work. Use the statement of fitness for work to provide sufficient information in clear, non‑technical language. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice,see the rationale and impact section on assessing and certifying fitness for work\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n# Statement of fitness for work\n\nWhen a statement of fitness for work ('fit note') is received indicating that someone is not fit for work, start and maintain a confidential record. This record should include:\n\nthe reason for absence, the anticipated length of absence and any recurrence of absence for the same reason and\n\nany comments from the practitioner about how the person's condition or treatment affects their capacity for work.(Also see the section on keeping in touch with people on sickness absence). \n\nTo support the person who is currently not fit for work and plan for their return to the workplace, consider:\n\ntaking into account any additional information provided (for example from an allied health professional's health and work report) about how their condition may affect their ability to do their role\n\nseeking information and advice on what support they might need, such as from an occupational health service or from other possible expert sources of vocational advice and support relevant to their condition (this may include online resources, or telephone advice from external bodies)\n\ndiscussing with them what adjustments or other support might be needed if any ongoing health needs are anticipated for when they return to work; if adjustments need approval, discuss these with decision makers to gain sign-off. \n\nWhen a statement of fitness for work indicates that a person may be fit for work, contact them as soon as possible:\n\nDiscuss what adjustments (such as flexible working, phased return, reduced hours, changes to workstations or duties) might help them return to work. Use any recommendations in the statement of fitness for work as a starting point.\n\nInvolve the employee and line managers in these discussions initially, and occupational health services if needed.\n\nHuman resources, trade unions or occupational health services (if not already participating) may also be involved, especially if the circumstances or adjustments are more complex. \n\nIf adjustments in the statement of fitness for work or requested by the employee cannot be made, explain the reasons clearly in writing to the employee. With their informed consent, send a copy to the certifying practitioner. \n\nIf a person may be fit to return to work with adjustments but those adjustments cannot be made, the person should continue to be treated as 'not fit for work', in line with the Department for Work and Pensions' guidance for employers. In such cases:\n\nAdvise the person that they should return to work only when they have sufficiently recovered and are able to perform their regular duties.\n\nDiscuss and jointly agree a plan for keeping in touch during their extended absence. Discuss any actions that may support them in making a full recovery and returning to their regular duties, and agree to regularly review these (see the section on early intervention). \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on statement of fitness for work\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n# Making workplace adjustments\n\nWhen any work adjustments have been agreed with a person returning from sickness absence:\n\nArrange additional risk assessments if needed. Guidance on these is available on the Health and Safety Executive's website.\n\nDiscuss with the returning person whether colleagues could be informed about the adjustments to help them understand the need for them. Seek the person's informed consent and, if it is given, explain the reasons why the adjustments are being made. Discuss with colleagues any concerns that they may have about the impact of adjustments. \n\nRecord any workplace adjustments agreed with the employee, including a timeframe for their implementation and how long they are expected to last, in a written return-to-work plan for the employee and their line manager. \n\nMonitor any workplace adjustments that have been put in place to see if they are meeting the needs of both the employee and employer. Review this regularly, within a timeframe agreed by the employee and line manager in the written return-to-work plan.\n\nEncourage the employee to raise any issues related to the workplace adjustments and discuss who to raise them with. This may be an independent, impartial person. If necessary, think about making changes to the return-to-work plan.\n\nEnsure that the employee is aware of other interventions that may be available to support them in their workplace (see the section on early intervention). \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on making workplace adjustments\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n# Keeping in touch with people on sickness absence\n\nEnsure that the organisation regularly keeps in touch with people who are 'not fit for work' during periods of sickness absence, including people with a chronic health condition or a progressive illness or disability covered by the Equality Act 2010. \n\nMake contact as early as possible, and within 4\xa0weeks of them starting sickness absence, depending on the circumstances. \n\nWhen contacting the employee:\n\nBe sensitive to their individual needs and circumstances.\n\nBe aware that communication style and content could affect their wellbeing and decision to return to work.\n\nEnsure that they are aware that the purpose of keeping in touch is to provide support and help them return to the workplace when they feel ready.\n\nIf an early referral to support services (for example physiotherapy, counselling or occupational therapy) is available through the organisation's occupational health provider, discuss if this may be helpful.\n\nDiscuss how they would like to be contacted in future, how frequently and by whom. If the line manager is not the most appropriate person to keep in touch, offer alternatives.\n\nProvide reassurance that anything they share about their health will be kept confidential, unless there are serious concerns for their or others' wellbeing. \n\nEnsure that members of staff responsible for keeping in touch with people on sickness absence:\n\nare aware of the need for sensitivity and discretion at all times\n\nunderstand the organisation's policies or procedures on managing sickness absence and returning to work\n\nare competent in relevant communication skills and are signposted to and encouraged to use online or other resources and advice to improve these skills. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on keeping in touch with people on sickness absence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n# Early intervention\n\nIn organisations that offer access to early interventions (such as rehabilitation, counselling or an employee assistance programme) ensure that all employees are aware of their availability, remit and confidentiality. \n\nAssure employees that all contact with the employee assistance programme is confidential. \n\nFor employees whose sickness absence is expected to continue beyond 4\xa0weeks, in organisations with access to an occupational health provider:\n\ndiscuss the possibility of a referral to occupational health for an assessment of fitness for work or\n\ndiscuss the suitability for early referral to support services; if referral is appropriate, ensure that this takes place as early as possible. \n\nIf occupational health services or an employee assistance programme are not available, encourage employees whose sickness absence is expected to continue beyond 4\xa0weeks to discuss with their GP or secondary care specialist any options for referral to support services such as physiotherapy, counselling or occupational therapy. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on early intervention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n# Sustainable return to work and reducing recurrence of absence\n\n## Sustainable return to work for people with a musculoskeletal condition\n\nFor people who have been absent for 4 or more weeks because of a musculoskeletal condition, consider interventions to help them return to work. For example:\n\nA programme of graded activity delivered by someone with appropriate training (for example, a physical or occupational therapist).\n\nProblem-solving therapy.\n\nA worksite assessment by a suitably qualified professional to review and discuss with the employee, together with a representative of the employer, the suitability of work tasks or any adjustments that could be made.\n\nA meeting between the employee and their line manager, facilitated by an impartial person, to agree the key barriers to returning to work and what modifications could be made to the work environment to overcome these. \n\n## Reducing recurrence of absence for people with a common mental health condition\n\nFor people who resume work after an absence of 4 or more weeks for a common mental health condition, consider a 3‑month structured support intervention to reduce the likelihood of a recurrence of absence. Involve the line manager in this process, which could be led by an impartial person. The intervention may include:\n\nMeeting the person to identify any issues encountered since their return to work, and exploring possible solutions and support needs.\n\nDeveloping an action plan to implement, which is agreed with the person's line manager.\n\nRegular follow-up meetings with the person and their line manager to evaluate progress. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on sustainable return to work and reducing recurrence of absence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n# People with a health condition or disability who are not currently employed\n\nCommission an integrated programme to help people receiving benefits who have a health condition or disability to enter or return to work (paid or unpaid). The programme should include a combination of interventions such as:\n\nan interview with a trained adviser to discuss the help they need to return to work\n\nvocational training (for example help producing a CV, interview training and help to find a job or a work placement)\n\na condition management component run by local health providers to help people manage their health condition\n\nsupport before and after returning to work that may include 1 or more of the following: mentoring, a job coach, occupational health support or financial advice. \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary or, for public health and social care terms, the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Common mental health condition\n\nCommon mental health conditions include conditions such as depression, generalised anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder and social anxiety disorder.\n\n## Condition management\n\nProgrammes delivered by healthcare professionals that do not treat the underlying condition, but that focus on improving the likelihood of people being able to return to, or stay in, work. These programmes may aim to improve a person's understanding of their condition, increase their confidence and improve their ability to function in the workplace, through for example, pain or stress management and building self‑esteem and confidence.\n\n## Employee assistance programme\n\nAn employer-funded programme offering confidential services such as counselling and advice on a range of work and personal issues. Although the employer may receive an indication of numbers of employees taking up the service, no personal information is shared with the employer that would enable them to identify which employees access the service or their reason for doing so.\n\n## Employment and support allowance\n\nEmployment and support allowance (ESA) is a 2‑tier system of benefits that will be replaced by the introduction of Universal Credit. All claimants who are out of work because of ill health or a disability are entitled to claim ESA (paid at the same rates as job seeker's allowance). Those deemed capable of work at some time in the future (by a medically administered 'work capability' test) are placed in a work‑related activity group. Those deemed not capable of work because of the severity of their physical or mental condition are placed in a support group with no conditions (and until April 2017 received a higher support allowance).\n\n## Graded activity\n\nGraded activity aims to increase a person's activity levels gradually using a behavioural approach. Typically, people with musculoskeletal conditions attend individually focused training sessions with a gradually increasing exercise programme.\n\n## Long-term sickness absence\n\nLong-term sickness absence is sometimes defined as an absence lasting more than 2 weeks, but for this guideline it is defined as 4 or more weeks (as per the scope of this guideline and previous NICE guidance). Recurring long-term sickness absence has been defined as more than 1\xa0episode of long-term sickness absence, with each episode lasting more than 4\xa0weeks.\n\n## Micro-, small- and medium-sized organisations\n\nOrganisations employing fewer than 250 people. Micro-sized organisations employ between 0 and 9 people, small organisations employ between 0 and 49 people and medium-sized organisations employ between 50 and 249 people.\n\n## Presenteeism\n\nInappropriately continuing to go to work despite health problems. It also describes someone's attendance at work without performing all of their usual tasks (regardless of the reason). When employees feel the need to attend work although they are not functioning fully, it can result in losses in productivity. Presenteeism can also make health problems worse.\n\n## Problem-solving therapy\n\nTherapy that involves learning or reactivating problem-solving skills.\n\n## Short-term sickness absence\n\nFor this guideline it is defined as an absence lasting up to (but less than) 4\xa0weeks. Recurring short-term sickness absence is defined as more than 1 episode of short-term sickness absence, each lasting less than 4\xa0weeks.\n\n## Wellbeing\n\nWellbeing is the subjective state of being healthy, happy, contented, comfortable and satisfied with one's quality of life.\n\n## Vocational rehabilitation\n\nHelps those who are ill, injured or who have a disability to access, maintain or return to employment or another useful occupation. It may involve liaison between healthcare and rehabilitation practitioners; management, human resources and other in‑house or external facilitators. It may result in transitional working arrangements, training, social support and modifications to tasks.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\nAs part of the 2019 update, the guideline committee made 5 additional research recommendations.\n\nFour of these relate to a UK focus on effective and cost-effective interventions to:\n\nsupport return to work after long-term sickness absence\n\nsupport return to work after recurrent short-term sickness absence\n\nreduce long-term sickness absence and support return to work in people with common mental health conditions\n\nand reduce recurrent short-term sickness absence and support return to work in people with common mental health conditions.\n\nThe other is on the challenges and potential solutions for UK employers and employees in managing sickness absence and return to work in micro-, small- and medium-sized organisations.\n\nThe committee removed 4 research recommendations from the original guideline on:\n\npreventing sickness absence\n\nevaluating interventions\n\nreturn to work interventions and programmes\n\ncost effectiveness.\n\nThe committee considered that the new research recommendations capture any research questions that still need to be addressed.\n\n# Key recommendations for research\n\n## Interventions after long-term sickness absence\n\nWhat interventions are effective and cost effective in supporting return to work, in all workplaces including micro-, small- and medium-sized organisations, after long-term sickness absence in the UK?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale sections on workplace culture and policies\xa0 and early intervention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\n## Interventions after recurrent short-term sickness absence\n\nWhat interventions are effective and cost effective in supporting return to work after recurrent short-term sickness absence in the UK?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on workplace culture and policies\xa0.x\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n## Interventions after long-term sickness absence for mental health conditions\n\nFor people with common mental health conditions, what interventions are effective and cost effective in reducing long-term sickness absence and supporting return to work in the UK?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on sustainable return to work and reducing recurrence of absence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n## Interventions after recurrent short-term sickness absence for mental health conditions\n\nFor people with common mental health conditions, what interventions are effective and cost effective in reducing recurrent short-term sickness absence and supporting return to work in the UK?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on sustainable return to work and reducing recurrence of absence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n## Challenges and potential solutions for smaller employers\n\nWhat are the challenges and potential solutions for UK employers and employees in micro-, small- and medium-sized organisations (which may not have easy access to additional services such as employee assistance programmes or occupational health services) in ensuring sickness policy is managed effectively and facilitating return to work?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on early intervention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: facilitating return to work from long-term sickness absence.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Interventions to reduce sickness absence where employees are not centrally located\n\nWhich interventions are effective and cost effective in supporting people working in organisations where employees are not centrally located to return to work after long-term sickness absence in the UK?", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Workplace culture and policies\n\nRecommendations 1.1.1 to 1.1.9\n\n## Why the committee made the recommendations\n\nEvidence from the UK showed that workplace policies on sickness absence and return to work may help to reduce uncertainty around the process of enabling return to work for employees and employers, but only if they are properly implemented. The committee agreed that it is important for all sizes of organisation to clearly communicate policies and procedures to staff.\n\nHowever, smaller organisations may not have formal policies in place. The committee agreed that in these situations it is important that all employees are aware of the procedures for reporting and managing sickness. Regularly reviewing these policies and procedures would be good practice to ensure that they are appropriately applied and fit for purpose.\n\nThe committee discussed testimony from experts in occupational health and in employment research. The expert in occupational health was asked how the occupational health service in their NHS trust had contributed to achieving and maintaining a relatively low sickness absence rate and the barriers and facilitators to doing so. The expert in employment research was asked about common and more innovative measures used by organisations to reduce sickness absence rates.\n\nThe testimony provided by the experts identified that a commitment to employee health and wellbeing, proactively and strategically led from the top levels of management, should underpin sickness absence and return-to-work policies. The committee discussed the importance of these policies being part of a wider culture that values and promotes employee health and wellbeing.\n\nThe committee discussed that inappropriately applied return-to-work policies can result in presenteeism or longer absences from work. They highlighted the importance of ensuring that everyone is treated fairly. For this reason, they thought it important to regularly review how policies are implemented across the organisation, to ensure that those who are off work or planning a return to work are treated consistently.\n\nThe focus of this guideline is on managing sickness absence among all employees, regardless of whether they have a disability or long-term condition covered by the Equality Act 2010. Although the committee were aware that organisations should also have policies and procedures in place for managing disability leave, this area is not included within the scope of this guideline. The committee noted that there are legislative requirements about health and disability for employers and that the recommendations in this guideline should be considered alongside those requirements.\n\nThere is a small amount of low-quality evidence that employers providing early access to interventions, for example through an occupational health provider or employee assistance programme, can benefit both employees and employers. There is also some similarly limited evidence that accessing interventions early may help to reduce sickness absence rates and promote a more sustainable return to work.\n\nTestimony from an expert in occupational health supported the evidence that was found on providing early access to interventions, when appropriate. Furthermore, the committee noted that guidance for employers on commissioning an occupational health service is available from the Society of Occupational Medicine. The committee discussed the limitations in the evidence and, in particular they noted that micro-, small- and medium-sized organisations are not represented in the evidence and may not have access to such services.\n\nThe committee also heard from experts, particularly the expert in occupational health, that organisations that are considered to be examples of good practice collect detailed data on trends in sickness absence according to factors such as job type and location. This detailed non-identifiable data can help the organisation target specific interventions and resources where they are most needed. It may also help to highlight any inequalities and identify policies or procedures that may need to be reviewed or amended.\n\nThe evidence seen by the committee focused almost entirely on supporting people to return to work after a period of long-term sickness absence (4 or more weeks). No evidence was found on preventing recurrent short-term sickness absence (of less than 4\xa0weeks per episode) or on preventing people moving from short-term to long-term sickness absence.\n\nDespite the lack of direct evidence the committee agreed that, in practice, interventions that were effective in supporting people to return to work after long-term sickness absence may also help to prevent recurrent short-term absences and to prevent people moving from short to long-term sickness absence. This is because they may have to overcome similar barriers and need similar support when returning to work. The recommendations therefore do not distinguish between supporting people returning from long-term or recurrent short-term sickness absences.\n\nBecause no evidence was found on preventing recurrent short-term sickness absence, the committee recommended research in this area (see research recommendation 2). They also agreed that research is needed on supporting people to return to work after long-term sickness absence in a UK context (see research recommendation 1). Most of the evidence they considered was not from the UK, but from countries with different systems for managing sickness absence. The committee therefore agreed there was a need for more evidence that was directly applicable to the UK population. The committee considered that alongside data on supporting return to work it would be helpful if studies collected data on the impact of absenteeism and presenteeism.\n\nAlthough there was no evidence on preventing the move from short-term to long-term sickness absence, the committee did not make a research recommendation in this area. This is because of the potential difficulties of identifying people with short-term sickness absence that may become long-term sickness and the feasibility of recruiting them to take part in research trials before they cross the 4‑week threshold into long-term sickness absence.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect good practice. Larger organisations are more likely to already have formal policies and procedures, but they may need to develop procedures for regularly reviewing them and how they have been implemented.\n\nThe resource implications are likely to be greater for micro-, small- and medium-sized organisations that don't have formal policies or provide access to occupational health or employee assistance programme services. Larger organisations are more likely to have these in place, but the committee heard from an expert in employment research that this may not always be the case.\n\nThe committee noted from their experience that it would be good practice for smaller organisations that do not currently have access to such services to explore where additional services (such as occupational health) may be available to provide support. This would be part of a proactive approach to promoting employee health and wellbeing. If recommendations are widely implemented, it may result in a larger number of employers having appropriate policies and procedures in place and may help to encourage the spread of good practice. Implementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity.\n\nReturn to recommendations\n\n# Assessing and certifying fitness for work\n\nRecommendations 1.2.1 to 1.2.5\n\n## Why the committee made the recommendations\n\nThere was evidence from a small number of UK studies that showed there can be challenges for GPs in completing fit notes. GPs may feel that they do not have the occupational health experience or the knowledge of the workplace needed to make suggestions about workplace adjustments.\n\nThe committee discussed that other medical practitioners were also likely to experience the same challenges and agreed that the best person to complete the fit note is the medical practitioner with the most relevant recent knowledge of the person's situation. In many cases this will be a GP, but it could also be a person's specialist in secondary care. The specialist may be able to provide more information than the GP on the anticipated effects of treatment, timeframes for rehabilitation and adjustments for when the person returns to work. September 2022: we changed the recommendation on who can complete a fit note in line with new legislation, to include registered nurses, occupational therapists, pharmacists and physiotherapists.\n\nThere was evidence from a small number of UK studies that showed it is important to avoid people becoming disconnected from work during their absence. Keeping in touch regularly with the workplace is important for building the person's confidence to return, monitoring their recovery and maintaining a focus on the goal of returning to work.\n\nThis evidence suggested and the committee agreed that the GP may be particularly well placed to refer people on long-term sickness absence to rehabilitation and support services, especially if these are not offered by the employer as part of occupational health provision. They noted that specialists may also refer people under their care to some rehabilitation services. They also noted that it may be helpful to signpost people to other possible expert sources of vocational advice and support relevant to their condition. This may include advice and support from the voluntary sector.\n\nThe committee did not specifically recommend keeping in touch regularly with the GP because this may have a resource impact that had not been assessed.\n\nThe committee noted that reasons for sickness absence can be complex and agreed that GPs primarily view their role as a patient advocate. GPs are therefore well placed to explore whether sickness absence is exacerbated by aspects of the person's job, home life (such as caring responsibilities) or workplace relationships that the person feels unable to discuss with their employer (such as poor relationships with line managers).\n\nIf the practitioner anticipates that the absence is likely to be long term (4 or more weeks), they could consider referral to rehabilitation and support services.\n\nThere is evidence from a small number of UK studies suggesting that patients believe the advice on fit notes can empower them in negotiating changes at work. But there is also evidence that employers can find fit notes unsatisfactory. In particular, employers have reported that fit notes may not give enough useful information on how the person's health condition may affect their ability to do their job. This can make employers wary of any risks associated with someone returning to work if they are not fully recovered.\n\nThe committee therefore agreed that it is important to encourage practitioners to state clearly how the person's health condition or treatment might affect them in their workplace, so that appropriate support and adjustments can be considered. However, this type of detail on the fit note needed to be added only with the person's agreement. The committee also discussed that unless the practitioner has specific knowledge about a person's workplace or role, it may be difficult for them to understand the implications of someone's condition on their ability to do their job.\n\n## How the recommendations might affect practice\n\nIf specialists certify sickness absence to employers, rather than referring them to their GP, this would free up GP appointment time and may provide more useful information for employers. However, there may then be an impact on specialists' time.\n\nThe committee agreed that it is part of the GP's role to refer people on sickness absence to rehabilitation and support services and so this should not incur an additional cost. However, there may be an additional impact on support services, such as physiotherapy and counselling.\n\nReturn to recommendations\n\n# Statement of fitness for work\n\nRecommendations 1.3.1 to 1.3.5\n\n## Why the committee made the recommendations\n\nSome UK studies showed that employers think fit notes can provide useful information to support managers in communicating with people who are absent. They can help managers understand the employee's health condition and what support they might need when they return to work. This can enable them to plan for suitable adjustments to ensure a safe and sustainable return to work.\n\nThe committee agreed that it would be good practice to start a confidential record for every absence for which a fit note is received, not just when it is anticipated that the person will be taking a long-term sickness absence. This is because it may not be immediately clear when an absence may become long term, because there may be subsequent fit notes received for the same episode of absence. In addition, keeping such records may also help to identify recurrent sickness absence.\n\nThe committee agreed it is good practice to be proactive and plan ahead how to support someone once they are ready to return to the workplace. Although there was no evidence identified on planning ahead, the committee made a recommendation encouraging employers to do so, based on good practice.\n\nThe committee were aware that there are various potential sources of expert advice available to help managers understand the effects of health conditions or treatments. These can be particularly useful if the employing organisation does not have its own occupational health adviser. This may include online information and resources that give vocational advice and specific advice relevant to the employee's particular condition.\n\nAlthough the committee had not reviewed these resources and they were conscious they may change over time, they noted that information from organisations, such as Public Health England, and some voluntary sector organisations may be helpful.\n\nThe committee noted that it is important to discuss adjustments that may be helpful with the returning employee. In many cases this discussion may involve only the employee and their line manager, and if necessary, occupational health. The evidence suggests that being able to have such a conversation may depend on a good relationship between line manager and employee.\n\nThe committee heard evidence from experts in occupational health and from a mental health support service, which showed that if relationships are difficult, or adjustments are more complex, it can be helpful to involve an impartial party to help reach an agreement.\n\nThe committee noted that recommendations for adjustments that a practitioner makes on a 'may be fit for work' note are advisory. Evidence shows that employers may have concerns about employee expectations and the possibility of conflict, if adjustments can't be accommodated. Also, the evidence suggested and the committee discussed that some GPs and patients have reported feeling undermined when their suggestions to employers are not acted on.\n\nThe committee agreed that guidance on what employers should do, if adjustments cannot be agreed, would minimise conflict. They recommended that the person should be treated as 'not fit for work' and noted the importance of maintaining contact with them. They also noted that when suggested adjustments can't be made it would be helpful to provide GPs, with the employee's informed consent, with feedback, so that they are aware of the person's continuing absence and are better informed about their particular workplace context.\n\nThe committee's recommendations on making adjustments to support people to return to work focus on all employees. But they noted that if someone has a chronic or progressive illness or disability covered by the Equality Act 2010, the employer has a legal obligation to make reasonable adjustments in the workplace.\n\nThis legal obligation applies to all employees with an illness or disability covered by the Act, not just those returning from sickness absence. But the committee noted that particular consideration may need to be given to adjustments when an employee with a disability or condition covered by the Act is returning from sickness leave, to provide them with the best possible support.\n\n## How the recommendations might affect practice\n\nLarger organisations are more likely to already have formal policies and procedures in place for making return-to-work plans.\n\nResource implications are likely to be greater for micro-, small- and medium-sized organisations, which may not have capacity to plan ahead for someone returning to work, or the capacity or resources to make adjustments to the workplace or duties. The committee noted that if an employee has a disability or a long-term condition that makes it difficult for them to do their job, organisations may find it helpful to explore whether they are eligible for funding to support making adaptations to the workplace.\n\nProviding feedback to practitioners when adjustments they have recommended cannot be accommodated would be good practice. However, the committee were aware that a mechanism for providing this feedback would need to be developed and maintained and that for some organisations, particularly micro-, small- and medium- sized organisations, this may not be sustainable.\n\nImplementing the recommendations may need resource input initially, but over time it may result in a reduction in the costs of sickness absence and improved productivity. If the resource input makes returning to work part of a proactive approach to supporting employee health and wellbeing, this investment may help to reduce the costs of sickness absences in the longer term.\n\nReturn to recommendations\n\n# Making workplace adjustments\n\nRecommendations 1.4.1 to 1.4.3\n\n## Why the committee made the recommendations\n\nThe committee were aware that it is a legal requirement for employers to carry out risk assessments to ensure a healthy and safe environment in the workplace and that guidance on these is available from the Health and Safety Executive (see Regulation 3 of the Health and Safety Executive's Management of Health and Safety at Work Regulations 1999). They discussed and agreed from their experience and expertise that it is good management practice to undertake an additional risk assessment for a person returning from sick leave and before making workplace adjustments.\n\nThere is a small amount of low-quality UK evidence to suggest that some colleagues may resent adjustments being made to the returning person's role or workload. However, other similarly limited evidence noted that other staff members can be understanding about workplace and role adjustments and help with supporting their colleagues' return to work.\n\nThe committee noted that to maintain relationships and productivity in the wider team it may be helpful to explain the reasons for the adjustments and give colleagues the opportunity to raise any concerns. It is important that this is only done after discussion with the returning person and with their informed consent.\n\nThe committee agreed that it is important to keep a written record of the adjustments that have been agreed in a written return-to-work plan. This should be based on the individual employee's needs and their role in the organisation and as such there will need to be some flexibility in terms of what the plan covers. The committee agreed it is important to regularly review the return-to-work plans to ensure that they continue to meet the person's needs as their recovery progresses and to amend them if necessary. It can also be helpful, when reviewing how the adjustments are working, to remind the person of any other interventions the employer may provide, if these are available.\n\n## How the recommendations might affect practice\n\nLarger organisations are more likely to already have formal policies and procedures in place for making return-to-work adjustments. They may need to develop additional procedures and provide resources or training for risk assessment of return-to-work plans, developing written return-to-work plans and monitoring how well workplace adjustments are working.\n\nResource implications are likely to be greater for micro-, small- and medium-sized organisations, which may not have capacity to make adjustments.\n\nThe committee noted that the capacity of organisations to provide risk assessment training may need to be considered.\n\nImplementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity.\n\nReturn to recommendations\n\n# Keeping in touch with people on sickness absence\n\nRecommendations 1.5.1 to 1.5.4\n\n## Why the committee made the recommendations\n\nEvidence from UK studies shows that keeping in touch with people who are on extended periods of sick leave can help them feel supported, valued and more confident about returning to work. The committee agreed that a positive commitment to keeping in touch should form part of the organisation's sickness absence and return-to-work policies.\n\nThe committee discussed that managers may have concerns about contacting and keeping in touch with those who are off work, and that employees may feel that this is putting additional pressure on them to return to work. Evidence from UK studies supported this discussion.\n\nThe committee also noted that if people are absent for reasons that relate to an illness or disability that is covered by the Equality Act 2010, managers may feel additional concern about the appropriateness of contacting them. These concerns may lead to those who have an illness or disability covered by the Act being disadvantaged compared with others if their employers do not contact them for fear it may be inappropriate to do so. The committee agreed that policies on keeping in touch should be followed with everyone who takes sickness absence.\n\nThe timing of initial contact should take into account the personal circumstances of the employee and their reason for, and anticipated length of, absence. In addition to making the employee feel supported, the aim is to help prevent a short-term absence becoming a long-term absence.\n\nFor this reason, the committee recommended getting in touch with the employee as soon as possible and within 4\xa0weeks. However, they were mindful of the need to keep this flexible, particularly when sickness absences may be planned or when recovery will clearly take longer than 4\xa0weeks. For example, for recovery from surgery or cancer treatments.\n\nThe committee discussed the limitations in the evidence, but noted that it has shown that relationships with managers are an important factor in people's decisions about returning to work. The committee noted that this may be particularly pertinent when there is a mental health component to the absence. It is therefore important to establish from the employee's perspective whether the line manager is the best person to keep in touch with them.\n\nThe committee noted that it is important to reassure people that anything they share about their health will remain confidential. However, they acknowledged that in circumstances when there are serious concerns for the wellbeing of the employee or others, information may have to be disclosed in order to meet an employers' duty of care, or to meet professional or legal obligations.\n\nThe evidence suggested, and the committee agreed, that the communication style of the person with responsibility for keeping in touch with the employee and the content of the communication can affect the employee's wellbeing and decisions about returning to work.\n\nFor this reason, the committee recommended that organisations should provide those with keeping in touch responsibilities access to communication skills training and encourage them to access online resources and advice to ensure that they are competent and confident in this area. Resources to help employers with this include the NHS Employers website, and Public Health England's website.\n\n## How the recommendations might affect practice\n\nMicro-, small- and medium-sized organisations may find it more difficult to offer alternatives to the line manager as a contact person for people on sickness absence. They may be less likely to have formal procedures or policies on keeping in touch with people on sickness absence.\n\nResource implications are likely to be minimal and focus mainly on communication skills training. Formal training may be more likely to be offered by larger organisations, but there are useful online resources and advice that can be used by and adapted for smaller organisations.\n\nImplementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity.\n\nReturn to recommendations\n\n# Early intervention\n\nRecommendations 1.6.1 to 1.6.4\n\n## Why the committee made the recommendations\n\nThere was a small amount of low-quality evidence from UK studies that providing free-to-access employee assistance programmes and occupational health services is regarded as good employer practice. It is valued by employees as an indication that the organisation cares about the health and wellbeing of the workforce.\n\nHowever, the evidence suggested that employees are not always aware that these services are available or what their remit is. This possible lack of awareness was discussed by the committee and also identified by the expert testimony from the occupational health expert. Particular reference was made to employee assistance programmes, for which there may be a misperception that programmes focus only on mental health and there can be stigma associated with this. In reality, they can also offer practical advice on other issues such as debt counselling.\n\nThe committee further discussed that employees may have concerns about the confidentiality of employee assistance programmes. Within this discussion the committee noted that the services provided by these programmes are confidential. They also recognised the importance of employees having information on how to access the programmes independently and without needing to ask their employer.\n\nThe committee discussed evidence and expert testimony from the occupational health expert that early access to interventions offered by occupational health providers are regarded positively by employers and employees, and may help to reduce sickness absence rates and support sustainable return to work. These can include fast-tracked access to physiotherapy or counselling sessions.\n\nAlthough it was unclear whether the interventions included in the economic model were provided at an early stage, the model suggested that providing specific interventions was cost saving. The committee noted that it is important that the potential benefits and decision to refer to occupational health are discussed and agreed between the employee and their manager to avoid it being perceived as a punitive response to absence.\n\nThe committee were aware that services such as these tend to be offered by larger employers and that people working in micro-, small- and medium-sized organisations may not have access to them. They were aware from the government policy paper on 'Improving lives – the future of work health and disability' that around 43% of employees in the UK are employed by small- or medium-sized organisations.\n\nThe committee agreed that research is needed to determine effective and cost effective ways to support people to return to work after sickness absence, in UK workplaces of all sizes, including micro-, small- and medium-sized organisations (see research recommendation 1). In addition, they agreed there is a need for research on the challenges and potential solutions for UK employers and employees in managing sickness absence and return to work in smaller organisations where access to additional services may not be readily available (see research recommendation 5).\n\n## How the recommendations might affect practice\n\nLarger organisations are more likely to already fund services providing early intervention opportunities, whereas micro-, small- and medium-sized organisations may not be in a position to fund external occupational health provision or provide employee assistance programmes.\n\nImplementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity. For example, providing 'fast track' or early access to interventions may incur an additional cost. However, this may be included as part of an occupational health service that an organisation provides, as part of a proactive approach to supporting employee health and wellbeing, and this investment may help to reduce the costs of sickness absences in the longer term.\n\nReturn to recommendations\n\n# Sustainable return to work and reducing recurrence of absence\n\nRecommendations 1.7.1 to 1.7.2\n\n## Why the committee made the recommendations\n\nThe committee discussed that musculoskeletal conditions and common mental health conditions are the most frequent causes of long-term sickness absence among employees. Evidence from a small number of non-UK studies in people with musculoskeletal conditions suggested that interventions to strengthen a person's physical and mental health, and to focus on reducing potential barriers in the workplace, may increase return-to-work rates.\n\nAlthough the committee noted the limitations in the evidence, they agreed that for employers with occupational health access, it would be useful to have the option of arranging a therapeutic programme of graded activity or problem solving for employees who are absent for 4 or more weeks because of musculoskeletal conditions. Although the economic analysis focused only on changes in absenteeism, because of a lack of data on other outcomes, such as productivity, staff turnover and wellbeing, the committee noted that these types of interventions could be cost saving.\n\nThe committee discussed evidence which showed that the time people take to return to work after absence because of a musculoskeletal condition may be reduced if flexible adjustments are agreed between employee and employer, as part of a planned return-to-work process.\n\nThe committee heard from an occupational health expert and an expert from a mental health support service that it can be helpful for an impartial person (who may or may not be part of the organisation) to facilitate discussions between the employee and employer, to help agree adjustments that are acceptable to both. The committee noted that there may be a number of people who could fill this role, examples include people from occupational health services, occupational therapists and vocational rehabilitation consultants.\n\nA study of people who had returned to work after absence related to mental health conditions showed a supportive monitoring and problem-solving intervention delivered over 3\xa0months to be associated with a reduced risk of recurrent absence. Although the economic analysis only considered the impact on absenteeism, this intervention was estimated to be cost saving.\n\nAlthough the evidence was limited, in that it was based on 1 low-quality study, the committee also heard from an expert who supports people with mental health conditions that have resulted in them being absent from work or struggling to remain in work. Their testimony described the use of individual support plans and supportive monitoring. Based on this evidence and their expertise, the committee noted that such interventions are considered to be good practice for people with long-term absence due to common mental health conditions.\n\nThe committee noted that although there are substantial limitations in the evidence on supporting people to return to work after absence due to musculoskeletal or mental health conditions, particularly the lack of UK-based studies, it is important to not discourage what is considered to be good practice.\n\nThe committee agreed that interventions for those with common mental health conditions should be a research priority. This group may experience recurrent and long-term sickness and there is a lack of evidence on supporting their return to work. The committee recognised that reasons why a person may take sickness absence may be complex. They therefore agreed that research studies should aim to capture the context of the sickness absence and the preferences of participants in supporting them to return to work, alongside data on whether they have been able to return to work (see research recommendation 3 and research recommendation 4).\n\n## How the recommendations might affect practice\n\nThe recommendations made in this area reflect good practice but some may currently be more accessible to people working in larger organisations. For example, organisations may buy in occupational health services that provide access to physiotherapy, counselling or ergonomic assessment of worksites.\n\nNot all organisations have access to such services, particularly micro-, small- and medium-sized organisations. But they may be able to access them with minimal resource implications, for example by being part of a local or sector association that subscribes to these services.\n\nThere may be resource implications if everyone returning to work after absences of 4\xa0or more weeks because of a common mental health condition is offered a 3‑month programme of structured support.\n\nEconomic modelling indicated that such an approach could be cost saving. The committee considered that these interventions could offer value for money and in the long run could reduce their costs. In the model these were achieved through savings associated with reduced absenteeism. The committee were mindful of other potential benefits not captured in the model, such as increased productivity as a result of early or sustained return to work and reductions in the costs associated with staff turnover.\n\nImplementing the recommendations may need resource input initially, but over time may result in a reduction in the costs of sickness absence and improved productivity.\n\nReturn to recommendations", 'Context': "Absence management processes can help people return to work after long-term sickness absence, but many do not go back. Among claimants of Employment and Support Allowance who had worked in the 12\xa0months before their claim, 45% took a period of sickness absence before they left work.\n\nBetween 2010 and 2013 there were around 960,000 long-term sickness absences a year in Britain. Stress and acute conditions are responsible for many long-term absences, followed by mental ill health, musculoskeletal injuries and back pain. Employers spend around £9\xa0billion a year on sick pay and associated costs.\n\nSince the NICE guideline on managing workplace sickness absence was published in 2009, there have been several changes to policy and practice designed to help people return to work and reduce the social and economic burden of long-term sickness absence from the workplace. For example, the government consultation Health is everyone's business: proposals to reduce ill health-related job loss, encourages early action by employers to support employees with a disability or long-term condition to remain in work. Since 2009, there have also been changes to legislation, including the replacement of the Disability Discrimination Act (1995) by the Equality Act 2010. In light of these, and new evidence, it was decided to update this guideline.\n\nIn 2008, Working for a healthier tomorrow - work and health in Britain (Department for Work and Pensions) challenged the perception that it is inappropriate to be in work unless 100% fit. It shifted the emphasis from what a person cannot do to what they can do and led to a move from the 'sick' to the 'fit' note. A review in the government policy paper Improving lives: the future of work, health and disability suggests that there are too many fit notes stating 'not fit for work', when people 'may be fit for work' as long as appropriate workplace adjustments are made.\n\nThe 2016 Occupational medical workforce crisis report by the All Parliamentary Group on Occupational Safety and Health noted that the recruitment of occupational health physicians has been declining since 2003. In 2011, only 38% of employees had access to occupational health services and this is less likely among smaller organisations. However, in 2019 over 99% of private sector organisations had fewer than 50 employees.\n\nIn England, 19% of long-term sickness absence is attributed to mental ill health. In 2009, the Department for Work and Pensions added employment advisers to some Improving Access to Psychological Therapies (IAPT) services. In 2019 the NHS Long Term Plan identified stable employment as a major factor in maintaining good mental health and set out plans for investing in further employment support in IAPT.\n\nEmployee assistance programmes, many of which provide counselling, are increasingly being offered as an employee benefit. In 2017 the government's Thriving at work: a review of mental health and employers proposed core mental health standards that can be implemented by organisations of all sizes, and enhanced standards for larger organisations or those that are able to do more.\n\nEveryone aged over 16 in full-time or part-time employment (paid or unpaid), who has had a long-term sickness absence (4 or more weeks) or recurring short-term sickness absences (less than 4\xa0weeks each) and so may be at risk of moving from short- to long-term sickness absence. Everyone aged over 16 who is unemployed and gets benefits because of a long-term condition or disability that prevents them from working."}
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https://www.nice.org.uk/guidance/ng146
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This guideline covers how to help people return to work after long-term sickness absence, reduce recurring sickness absence, and help prevent people moving from short-term to long-term sickness absence.
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265c46d5bf8ffdd67c386fb9181cd2ab37f403f5
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nice
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Neratinib for extended adjuvant treatment of hormone receptor-positive, HER2-positive early stage breast cancer after adjuvant trastuzumab
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Neratinib for extended adjuvant treatment of hormone receptor-positive, HER2-positive early stage breast cancer after adjuvant trastuzumab
Evidence-based recommendations on neratinib (Nerlynx) for extended adjuvant treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)‑positive early stage breast cancer in adults.
# Recommendations
Neratinib is recommended as an option for the extended adjuvant treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)‑positive early stage breast cancer in adults who completed adjuvant trastuzumab-based therapy less than 1 year ago only if:
trastuzumab is the only HER2‑directed adjuvant treatment they have had, and
if they had neoadjuvant chemotherapy-based regimens, they still had residual invasive disease in the breast or axilla following the neoadjuvant treatment, and
the company provides neratinib according to the commercial arrangement.
This recommendation is not intended to affect treatment with neratinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Trastuzumab is a HER2‑directed treatment. It can also be given in combination with another HER2‑directed treatment, pertuzumab, to reduce the risk of cancer returning after surgery in early stage cancer (adjuvant treatment). Neratinib is an option for extended adjuvant treatment in people who completed a standard course of HER2‑directed adjuvant treatment.
Clinical trial evidence shows that women who have treatment with neratinib have less risk of disease recurrence than women who have treatment with a placebo. We do not know if neratinib increases the length of time people live because the final trial results are not yet available.
The cost-effectiveness estimates are uncertain, but within the range that NICE normally considers an acceptable use of NHS resources. Therefore, neratinib is recommended if trastuzumab is the only HER2‑directed adjuvant treatment a person has had, and if they had chemotherapy-based treatment before surgery to reduce tumour size (neoadjuvant treatment) they still have signs of cancer (residual invasive disease) in tissue samples from the breast or armpit (axilla).
The clinical trial did not include people who had adjuvant pertuzumab. Also, it did not include people who had a pathological complete response (no sign of residual invasive disease in the breast or axilla) after chemotherapy-based neoadjuvant treatment, therefore these groups are not included in the recommendations.# Information about neratinib
Marketing authorisation indication
Neratinib (Nerlynx, Pierre Fabre) is indicated for 'the extended adjuvant treatment of adults with early stage hormone receptor-positive, HER2-overexpressed/amplified breast cancer and who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy'.
Dosage in the marketing authorisation
Neratinib is administered orally. The recommended dose is 240 mg neratinib, administered as 6×40-mg tablets taken once daily and continually for 1 year.
Price
£4,500 per box of 180 tablets (30 days treatment; excluding VAT; company's submission).
The company has a commercial arrangement. This makes neratinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Pierre Fabre, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
In the absence of overall-survival data, the invasive disease-free survival definition used in the ExteNET trial is suitable for decision making (issue 2, see technical report pages 10 to 11).
The mean neratinib treatment duration and the mean neratinib dose based on ExteNET is suitable for decision making (issue 5, see technical report pages 17 to 19).
Age-adjusted utilities, the ExteNET value for disease-free state, and the Lindgren et al. 2007 value for distant recurrence are suitable for decision making (issue 6, see technical report pages 20 to 23).
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 26), and took these into account in its decision making. It discussed the following issues (issues 1, 3 and 4), which were outstanding after the technical engagement stage.
# Treatment pathway
## Neratinib is an oral treatment in a new place in the pathway
NICE's guideline on early breast cancer recommends offering adjuvant trastuzumab for 1 year in combination with surgery, chemotherapy and radiotherapy as appropriate. In March 2019, NICE's technology appraisal guidance on pertuzumab for adjuvant treatment of HER2-positive early stage breast cancer recommended it, with trastuzumab and chemotherapy, for treating human epidermal growth factor receptor 2 (HER2)‑positive breast cancer in adults who have lymph node-positive disease. Neoadjuvant treatment is also an option, to reduce tumour size before surgery. NICE's technology appraisal guidance on pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer recommended it, with trastuzumab and chemotherapy, for HER2‑positive, locally advanced, inflammatory or early breast cancer at high risk of recurrence. Neratinib is an oral treatment with a marketing authorisation for the extended adjuvant treatment of adults with hormone receptor-positive, HER2‑positive early breast cancer who are less than 1 year from the completion of previous adjuvant trastuzumab-based treatment.
## It is unclear who would have neratinib in clinical practice
Since the clinical study for neratinib was done, the treatment pathway has changed. People can now have pertuzumab alongside trastuzumab for adjuvant treatment in HER2‑positive early stage breast cancer if they have lymph node-positive disease. There are no data for neratinib after combination treatment with pertuzumab for early breast cancer. The clinical experts noted that adjuvant pertuzumab treatment is not available for people with node-negative disease and that neratinib could be considered in this population. The clinical experts stated that the decision about the most suitable treatment for patients with node-positive disease would be based on clinical judgement, based on the efficacy of the appropriate treatment and the patient's preferences. The clinical experts explained that some people may prefer neratinib because it's an oral treatment. They may prefer to have adjuvant treatment with just trastuzumab as the HER2‑directed treatment administered subcutaneously, followed by extended adjuvant treatment with neratinib, because both treatments can be given at home, rather than intravenous adjuvant combination treatment with pertuzumab. However, it was noted that neratinib's high level of toxicity (see section 3.7) may mean some people have to go to hospital for diarrhoea treatment. The committee recognised that some people who did not have adjuvant pertuzumab would benefit from extended adjuvant treatment with neratinib. However, it is unclear which people would have neratinib in clinical practice.
# Clinical evidence
## ExteNET is the key trial relevant to this appraisal
ExteNET (n=2,840) is a phase 3 randomised controlled trial that compared neratinib treatment with placebo in women with HER2-positive breast cancer who had completed adjuvant trastuzumab treatment within 2 years. The company based its submission on a subgroup of women with early hormone receptor-positive cancer who were less than 1 year from completing adjuvant trastuzumab-based treatment (n=1,334). This subgroup, referred to as the 'label' population, is in line with the neratinib marketing authorisation. It showed better clinical effectiveness and fewer side effects than the whole trial. The ERG noted that ExteNET was not designed to have statistical power to detect differences between treatments within subgroups. In addition, it noted that only 80 patients were recruited in the UK and that differences in clinical effectiveness by geographical region were reported. The clinical experts suggested that the trial is generalisable to the UK population. However, they noted that clinical trials tend to recruit fitter participants, and that there may be some limitation to the trial generalisability. The committee concluded that ExteNET is the key trial relevant to this appraisal and suitable for estimating the clinical effectiveness of neratinib.
## There is no evidence for neratinib in people with a pathological complete response after neoadjuvant treatment
ExteNET did not include people who had a pathological complete response after neoadjuvant treatment. A pathological complete response means that there was no residual invasive cancer in the breast or axilla after completing neoadjuvant treatment. The committee concluded that there are no data on the clinical effectiveness of neratinib in people who had a pathological complete response after neoadjuvant treatment.
## There is no evidence for neratinib in people who have had pertuzumab treatment
ExteNET did not include people who had pertuzumab and trastuzumab as adjuvant treatment. The committee concluded that there are no data on the clinical effectiveness of extended adjuvant neratinib after adjuvant pertuzumab treatment.
## Neratinib improves invasive disease-free survival compared with placebo
Invasive disease-free survival was the primary outcome in ExteNET. The 5‑year hazard ratio for invasive disease-free survival for the whole trial was 0.73 (95% confidence interval 0.57 to 0.92). The 5‑year hazard ratio for invasive disease-free survival for the label population was 0.58 (95% CI 0.41 to 0.82). This suggests a statistically significant improvement in invasive disease-free survival for neratinib compared with placebo. Overall-survival data were collected in the trial but had not been fully analysed at the time of this appraisal, when 121 deaths had been recorded in the whole trial. The final analysis is expected after 248 deaths. Overall-survival results for the label population were not available at the time of this appraisal. The committee concluded that neratinib improves invasive disease-free survival compared with placebo in the label population. However, it is not known whether neratinib increases the length of time people live because the final trial results are not available.
# Adverse events
## Diarrhoea is severe in some people but could be managed with prophylaxis
Neratinib is associated with high rates of diarrhoea, nausea and fatigue and may require hospital visits to treat diarrhoea. In ExteNET, diarrhoea prophylaxis was not used, although people were treated for diarrhoea as needed. The company explained that if diarrhoea prophylaxis is used, diarrhoea lasts approximately 5 days. The clinical experts confirmed that diarrhoea is not an issue for all people and that it can usually be managed with prophylaxis. One clinical expert reported feedback from 2 people who have taken neratinib. One person did not have any diarrhoea, and the other had severe symptoms. It took some time to adjust the diarrhoeal treatment for this person before the symptoms diminished, but the person wanted to continue taking neratinib. The committee agreed that diarrhoea toxicity is high in some people but could be managed with prophylaxis and diarrhoeal treatments.
# Invasive disease-free survival modelling
## The company's use of general population mortality in the model is appropriate
The company developed a 5‑state Markov model to evaluate the cost effectiveness of neratinib (the states were: invasive disease-free, local recurrence, remission, distant recurrence and dead). In the absence of overall-survival data, invasive disease-free survival in the label population of ExteNET and a general population mortality rate was used to estimate overall survival. The ERG noted that death from breast cancer is only possible from the distant recurrence health state. Mortality risk for all other health states (invasive disease-free, local recurrence and remission) is based on general population mortality. The ERG said that this assumption could underestimate the cost-effectiveness results. The company explained that patients are most likely to move into the distant recurrence health state first and that no patients in ExteNET died from breast cancer without first experiencing a distant recurrence. The clinical experts and the ERG agreed that this was a reasonable assumption. The committee was satisfied that the use of the general mortality in the model was appropriate.
## It is unclear which approach to invasive disease-free survival modelling is the most appropriate
The company investigated whether neratinib's treatment effect could be modelled assuming proportional hazards between the neratinib and placebo arms of the trial. It concluded that it could, and invasive disease-free survival data in the label population were pooled and modelled together with a treatment effect as a covariate. The company chose a flexible-spline Weibull with 1 knot to model invasive disease-free survival. The ERG explained that the assumption of proportional hazards is uncertain because some of the analyses provided by the company suggested that it is not valid. The ERG assessed an overall-goodness-of-fit of the models considered by the company, and stratified models for which the proportional hazard assumption is not needed. It found that the stratified generalised gamma model provided the best overall fit for the invasive disease-free survival data and included this model in its preferred base case. In response to technical engagement the company considered the ERG's model to be a conservative approach resulting in cost-effectiveness results that are at the high end of the most plausible range. The clinical experts considered both extrapolations plausible. The committee concluded that it is unclear which approach to invasive disease-free survival modelling is the most appropriate and that both approaches could be plausible.
# Duration and type of treatment effect
## The ERG's approach is appropriate
The company assumed that the treatment effect observed in ExteNET would last beyond the trial time horizon until patients had a risk of invasive disease-free survival equal to the mortality rate in the general population. The duration of the treatment effect depends on the curve used to model invasive disease-free survival and general population mortality. The company assumed a continued effect and applied the invasive disease-free survival 5‑year hazard ratio from the ExteNET label population of 0.58 (95% CI 0.41 to 0.82) from month 62.98 (as observed 4 years after 1 year of treatment with neratinib) to month 129 (when neratinib and general population mortality hazards are the same). This continued effect is followed with an implicit taper period until month 176 (when placebo and general population mortality hazards are the same). Using the ERG's preferred method to extrapolate invasive disease-free survival, the treatment effect stops at month 140. However, the ERG assumed that the tapering starts at the end of the trial and lasts until month 140. In response to the technical engagement, the company considered the ERG's approach to modelling neratinib treatment effect and duration to be plausible, although conservative. The clinical experts considered the ERG's approach to be appropriate. The committee concluded that the ERG's approach to modelling neratinib treatment effect and duration is appropriate for decision making.
# Cost-effectiveness estimates
## The cost-effectiveness estimates are uncertain, but within the range NICE normally considers an acceptable use of NHS resources
Both the company's and ERG's preferred incremental cost-effectiveness ratios (ICERs) for people for whom trastuzumab is the only HER2-directed adjuvant treatment they have had, and who did not have a pathological complete response to neoadjuvant treatment (see section 3.4 and section 3.5) are within the range NICE normally considers an acceptable use of NHS resources. ICERs were presented as commercial in confidence to maintain the confidentiality of the proposed commercial agreement for neratinib, and therefore cannot be reported here. The committee was aware of the uncertainty associated with some of the inputs and assumptions in the model (for example, invasive disease-free survival modelling as discussed in section 3.8 and section 3.9), and the impact of the additional uncertainties as summarised in the technical report (table 2 on pages 26 to 29, and table 3 on pages 30 and 31). It considered that the most plausible ICER is unknown and could be higher or lower than the company's and ERG's preferred ICERs. However, it agreed that the most plausible ICER is unlikely to exceed the range NICE normally considers an acceptable use of NHS resources. It therefore recommended neratinib for hormone receptor-positive, HER2‑positive early breast cancer in adults who completed adjuvant trastuzumab-based treatment less than 1 year ago, only if trastuzumab was the only HER2‑directed adjuvant treatment they have had, and if their cancer did not have a pathological complete response to neoadjuvant treatment (if they had neoadjuvant chemotherapy-based regimens).
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{'Recommendations': 'Neratinib is recommended as an option for the extended adjuvant treatment of hormone receptor-positive, human epidermal growth factor receptor\xa02 (HER2)‑positive early stage breast cancer in adults who completed adjuvant trastuzumab-based therapy less than 1\xa0year ago only if:\n\ntrastuzumab is the only HER2‑directed adjuvant treatment they have had, and\n\nif they had neoadjuvant chemotherapy-based regimens, they still had residual invasive disease in the breast or axilla following the neoadjuvant treatment, and\n\nthe company provides neratinib according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with neratinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTrastuzumab is a HER2‑directed treatment. It can also be given in combination with another HER2‑directed treatment, pertuzumab, to reduce the risk of cancer returning after surgery in early stage cancer (adjuvant treatment). Neratinib is an option for extended adjuvant treatment in people who completed a standard course of HER2‑directed adjuvant treatment.\n\nClinical trial evidence shows that women who have treatment with neratinib have less risk of disease recurrence than women who have treatment with a placebo. We do not know if neratinib increases the length of time people live because the final trial results are not yet available.\n\nThe cost-effectiveness estimates are uncertain, but within the range that NICE normally considers an acceptable use of NHS resources. Therefore, neratinib is recommended if trastuzumab is the only HER2‑directed adjuvant treatment a person has had, and if they had chemotherapy-based treatment before surgery to reduce tumour size (neoadjuvant treatment) they still have signs of cancer (residual invasive disease) in tissue samples from the breast or armpit (axilla).\n\nThe clinical trial did not include people who had adjuvant pertuzumab. Also, it did not include people who had a pathological complete response (no sign of residual invasive disease in the breast or axilla) after chemotherapy-based neoadjuvant treatment, therefore these groups are not included in the recommendations.', 'Information about neratinib': "Marketing authorisation indication\n\nNeratinib (Nerlynx, Pierre Fabre) is indicated for 'the extended adjuvant treatment of adults with early stage hormone receptor-positive, HER2-overexpressed/amplified breast cancer and who are less than 1\xa0year from the completion of prior adjuvant trastuzumab-based therapy'.\n\nDosage in the marketing authorisation\n\nNeratinib is administered orally. The recommended dose is 240\xa0mg neratinib, administered as 6×40-mg tablets taken once daily and continually for 1\xa0year.\n\nPrice\n\n£4,500 per box of 180\xa0tablets (30\xa0days treatment; excluding VAT; company's submission).\n\nThe company has a commercial arrangement. This makes neratinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Pierre Fabre, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nIn the absence of overall-survival data, the invasive disease-free survival definition used in the ExteNET trial is suitable for decision making (issue\xa02, see technical report pages 10\xa0to\xa011).\n\nThe mean neratinib treatment duration and the mean neratinib dose based on ExteNET is suitable for decision making (issue\xa05, see technical report pages 17\xa0to\xa019).\n\nAge-adjusted utilities, the ExteNET value for disease-free state, and the Lindgren et al.\xa02007 value for distant recurrence are suitable for decision making (issue\xa06, see technical report pages 20\xa0to\xa023).\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa026), and took these into account in its decision making. It discussed the following issues (issues\xa01, 3 and 4), which were outstanding after the technical engagement stage.\n\n# Treatment pathway\n\n## Neratinib is an oral treatment in a new place in the pathway\n\nNICE's guideline on early breast cancer recommends offering adjuvant trastuzumab for 1\xa0year in combination with surgery, chemotherapy and radiotherapy as appropriate. In March 2019, NICE's technology appraisal guidance on pertuzumab for adjuvant treatment of HER2-positive early stage breast cancer recommended it, with trastuzumab and chemotherapy, for treating human epidermal growth factor receptor\xa02 (HER2)‑positive breast cancer in adults who have lymph node-positive disease. Neoadjuvant treatment is also an option, to reduce tumour size before surgery. NICE's technology appraisal guidance on pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer recommended it, with trastuzumab and chemotherapy, for HER2‑positive, locally advanced, inflammatory or early breast cancer at high risk of recurrence. Neratinib is an oral treatment with a marketing authorisation for the extended adjuvant treatment of adults with hormone receptor-positive, HER2‑positive early breast cancer who are less than 1\xa0year from the completion of previous adjuvant trastuzumab-based treatment.\n\n## It is unclear who would have neratinib in clinical practice\n\nSince the clinical study for neratinib was done, the treatment pathway has changed. People can now have pertuzumab alongside trastuzumab for adjuvant treatment in HER2‑positive early stage breast cancer if they have lymph node-positive disease. There are no data for neratinib after combination treatment with pertuzumab for early breast cancer. The clinical experts noted that adjuvant pertuzumab treatment is not available for people with node-negative disease and that neratinib could be considered in this population. The clinical experts stated that the decision about the most suitable treatment for patients with node-positive disease would be based on clinical judgement, based on the efficacy of the appropriate treatment and the patient's preferences. The clinical experts explained that some people may prefer neratinib because it's an oral treatment. They may prefer to have adjuvant treatment with just trastuzumab as the HER2‑directed treatment administered subcutaneously, followed by extended adjuvant treatment with neratinib, because both treatments can be given at home, rather than intravenous adjuvant combination treatment with pertuzumab. However, it was noted that neratinib's high level of toxicity (see section\xa03.7) may mean some people have to go to hospital for diarrhoea treatment. The committee recognised that some people who did not have adjuvant pertuzumab would benefit from extended adjuvant treatment with neratinib. However, it is unclear which people would have neratinib in clinical practice.\n\n# Clinical evidence\n\n## ExteNET is the key trial relevant to this appraisal\n\nExteNET (n=2,840) is a phase\xa03 randomised controlled trial that compared neratinib treatment with placebo in women with HER2-positive breast cancer who had completed adjuvant trastuzumab treatment within 2\xa0years. The company based its submission on a subgroup of women with early hormone receptor-positive cancer who were less than 1\xa0year from completing adjuvant trastuzumab-based treatment (n=1,334). This subgroup, referred to as the 'label' population, is in line with the neratinib marketing authorisation. It showed better clinical effectiveness and fewer side effects than the whole trial. The ERG noted that ExteNET was not designed to have statistical power to detect differences between treatments within subgroups. In addition, it noted that only 80\xa0patients were recruited in the UK and that differences in clinical effectiveness by geographical region were reported. The clinical experts suggested that the trial is generalisable to the UK population. However, they noted that clinical trials tend to recruit fitter participants, and that there may be some limitation to the trial generalisability. The committee concluded that ExteNET is the key trial relevant to this appraisal and suitable for estimating the clinical effectiveness of neratinib.\n\n## There is no evidence for neratinib in people with a pathological complete response after neoadjuvant treatment\n\nExteNET did not include people who had a pathological complete response after neoadjuvant treatment. A pathological complete response means that there was no residual invasive cancer in the breast or axilla after completing neoadjuvant treatment. The committee concluded that there are no data on the clinical effectiveness of neratinib in people who had a pathological complete response after neoadjuvant treatment.\n\n## There is no evidence for neratinib in people who have had pertuzumab treatment\n\nExteNET did not include people who had pertuzumab and trastuzumab as adjuvant treatment. The committee concluded that there are no data on the clinical effectiveness of extended adjuvant neratinib after adjuvant pertuzumab treatment.\n\n## Neratinib improves invasive disease-free survival compared with placebo\n\nInvasive disease-free survival was the primary outcome in ExteNET. The 5‑year hazard ratio for invasive disease-free survival for the whole trial was 0.73 (95% confidence interval [CI] 0.57 to 0.92). The 5‑year hazard ratio for invasive disease-free survival for the label population was 0.58 (95% CI 0.41 to 0.82). This suggests a statistically significant improvement in invasive disease-free survival for neratinib compared with placebo. Overall-survival data were collected in the trial but had not been fully analysed at the time of this appraisal, when 121\xa0deaths had been recorded in the whole trial. The final analysis is expected after 248\xa0deaths. Overall-survival results for the label population were not available at the time of this appraisal. The committee concluded that neratinib improves invasive disease-free survival compared with placebo in the label population. However, it is not known whether neratinib increases the length of time people live because the final trial results are not available.\n\n# Adverse events\n\n## Diarrhoea is severe in some people but could be managed with prophylaxis\n\nNeratinib is associated with high rates of diarrhoea, nausea and fatigue and may require hospital visits to treat diarrhoea. In ExteNET, diarrhoea prophylaxis was not used, although people were treated for diarrhoea as needed. The company explained that if diarrhoea prophylaxis is used, diarrhoea lasts approximately 5\xa0days. The clinical experts confirmed that diarrhoea is not an issue for all people and that it can usually be managed with prophylaxis. One clinical expert reported feedback from 2\xa0people who have taken neratinib. One person did not have any diarrhoea, and the other had severe symptoms. It took some time to adjust the diarrhoeal treatment for this person before the symptoms diminished, but the person wanted to continue taking neratinib. The committee agreed that diarrhoea toxicity is high in some people but could be managed with prophylaxis and diarrhoeal treatments.\n\n# Invasive disease-free survival modelling\n\n## The company's use of general population mortality in the model is appropriate\n\nThe company developed a 5‑state Markov model to evaluate the cost effectiveness of neratinib (the states were: invasive disease-free, local recurrence, remission, distant recurrence and dead). In the absence of overall-survival data, invasive disease-free survival in the label population of ExteNET and a general population mortality rate was used to estimate overall survival. The ERG noted that death from breast cancer is only possible from the distant recurrence health state. Mortality risk for all other health states (invasive disease-free, local recurrence and remission) is based on general population mortality. The ERG said that this assumption could underestimate the cost-effectiveness results. The company explained that patients are most likely to move into the distant recurrence health state first and that no patients in ExteNET died from breast cancer without first experiencing a distant recurrence. The clinical experts and the ERG agreed that this was a reasonable assumption. The committee was satisfied that the use of the general mortality in the model was appropriate.\n\n## It is unclear which approach to invasive disease-free survival modelling is the most appropriate\n\nThe company investigated whether neratinib's treatment effect could be modelled assuming proportional hazards between the neratinib and placebo arms of the trial. It concluded that it could, and invasive disease-free survival data in the label population were pooled and modelled together with a treatment effect as a covariate. The company chose a flexible-spline Weibull with 1\xa0knot to model invasive disease-free survival. The ERG explained that the assumption of proportional hazards is uncertain because some of the analyses provided by the company suggested that it is not valid. The ERG assessed an overall-goodness-of-fit of the models considered by the company, and stratified models for which the proportional hazard assumption is not needed. It found that the stratified generalised gamma model provided the best overall fit for the invasive disease-free survival data and included this model in its preferred base case. In response to technical engagement the company considered the ERG's model to be a conservative approach resulting in cost-effectiveness results that are at the high end of the most plausible range. The clinical experts considered both extrapolations plausible. The committee concluded that it is unclear which approach to invasive disease-free survival modelling is the most appropriate and that both approaches could be plausible.\n\n# Duration and type of treatment effect\n\n## The ERG's approach is appropriate\n\nThe company assumed that the treatment effect observed in ExteNET would last beyond the trial time horizon until patients had a risk of invasive disease-free survival equal to the mortality rate in the general population. The duration of the treatment effect depends on the curve used to model invasive disease-free survival and general population mortality. The company assumed a continued effect and applied the invasive disease-free survival 5‑year hazard ratio from the ExteNET label population of 0.58 (95% CI 0.41 to 0.82) from month\xa062.98 (as observed 4\xa0years after 1\xa0year of treatment with neratinib) to month\xa0129 (when neratinib and general population mortality hazards are the same). This continued effect is followed with an implicit taper period until month\xa0176 (when placebo and general population mortality hazards are the same). Using the ERG's preferred method to extrapolate invasive disease-free survival, the treatment effect stops at month\xa0140. However, the ERG assumed that the tapering starts at the end of the trial and lasts until month\xa0140. In response to the technical engagement, the company considered the ERG's approach to modelling neratinib treatment effect and duration to be plausible, although conservative. The clinical experts considered the ERG's approach to be appropriate. The committee concluded that the ERG's approach to modelling neratinib treatment effect and duration is appropriate for decision making.\n\n# Cost-effectiveness estimates\n\n## The cost-effectiveness estimates are uncertain, but within the range NICE normally considers an acceptable use of NHS resources\n\nBoth the company's and ERG's preferred incremental cost-effectiveness ratios (ICERs) for people for whom trastuzumab is the only HER2-directed adjuvant treatment they have had, and who did not have a pathological complete response to neoadjuvant treatment (see section\xa03.4 and section\xa03.5) are within the range NICE normally considers an acceptable use of NHS resources. ICERs were presented as commercial in confidence to maintain the confidentiality of the proposed commercial agreement for neratinib, and therefore cannot be reported here. The committee was aware of the uncertainty associated with some of the inputs and assumptions in the model (for example, invasive disease-free survival modelling as discussed in section\xa03.8 and section\xa03.9), and the impact of the additional uncertainties as summarised in the technical report (table\xa02 on pages 26\xa0to\xa029, and table\xa03 on pages 30\xa0and\xa031). It considered that the most plausible ICER is unknown and could be higher or lower than the company's and ERG's preferred ICERs. However, it agreed that the most plausible ICER is unlikely to exceed the range NICE normally considers an acceptable use of NHS resources. It therefore recommended neratinib for hormone receptor-positive, HER2‑positive early breast cancer in adults who completed adjuvant trastuzumab-based treatment less than 1\xa0year ago, only if trastuzumab was the only HER2‑directed adjuvant treatment they have had, and if their cancer did not have a pathological complete response to neoadjuvant treatment (if they had neoadjuvant chemotherapy-based regimens)."}
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https://www.nice.org.uk/guidance/ta612
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Evidence-based recommendations on neratinib (Nerlynx) for extended adjuvant treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)‑positive early stage breast cancer in adults.
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f59bed441cef4acaa7f0506dd8053e70c0730698
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nice
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Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema in phakic eyes after an inadequate response to previous therapy
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Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema in phakic eyes after an inadequate response to previous therapy
Evidence-based recommendations on fluocinolone acetonide intravitreal implant (Iluvien) for chronic diabetic macular oedema that has inadequately responded to previous therapy, in adults whose eyes have natural lenses (phakic eyes).
# Recommendations
Fluocinolone acetonide intravitreal implant is not recommended as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies in an eye with a natural lens (phakic eye).
This recommendation is not intended to affect treatment with fluocinolone acetonide intravitreal implant that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatments for untreated chronic diabetic macular oedema include laser therapy and anti-vascular endothelial growth factors (VEGFs). There are no further treatment options for eyes with a natural lens (phakic eyes).
The company submitted evidence for people with phakic eyes and symptomatic cataracts. Clinical trial evidence compares the effectiveness of fluocinolone acetonide intravitreal implant and sham in people with chronic diabetic macular oedema who already had at least 1 laser treatment. Only very few people had anti‑VEGFs before the trial and few people had phakic eyes with symptomatic cataracts. Also, non-comparative studies used to support the company's submission only include few people with phakic eyes and symptomatic cataract. No other data for this group have been identified. This makes it difficult to establish if fluocinolone acetonide intravitreal implant works better than usual care for these people, especially in the long term.
Because of the lack of clinical evidence, the cost-effectiveness estimates for fluocinolone acetonide intravitreal implant are also uncertain. Even the lowest clinically plausible cost-effectiveness estimates are substantially higher than what NICE normally considers an acceptable use of NHS resources. Therefore, fluocinolone acetonide intravitreal implant is not recommended for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies in an eye with a natural lens (phakic eye).# Information about fluocinolone acetonide intravitreal implant
Marketing authorisation indication
Fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) is indicated for 'the treatment of vision impairment associated with chronic diabetic macular oedema, (DMO) considered insufficiently responsive to available therapies'.
Dosage in the marketing authorisation
Fluocinolone acetonide intravitreal implant is administered through intravitreal injection. Each implant contains 0.19 mg of fluocinolone acetonide and releases fluocinolone acetonide for up to 36 months.
Price
£5,500 per implant (excluding VAT, BNF online, accessed June 2019).
The company has a commercial arrangement. This makes fluocinolone acetonide intravitreal implant available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Alimera Sciences and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Company's positioning in treatment pathway
## The company's proposed population is narrower than that in the NICE scope and the marketing authorisation
NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy recommends fluocinolone acetonide intravitreal implant only for eyes with an intraocular (pseudophakic) lens. In this part review, the committee considered the effectiveness of fluocinolone acetonide intravitreal implant compared with usual care in phakic eyes. The company submitted evidence for people with phakic eyes and symptomatic cataract, a population identified in NICE's guideline on the management of cataracts in adults. The committee understood that these people should be offered cataract surgery but that waiting time for cataract surgery can vary. Also, it agreed that the company's proposed population is narrower than the NICE scope and the marketing authorisation for fluocinolone acetonide intravitreal implant. The committee concluded that it is appropriate to appraise the cost effectiveness of fluocinolone acetonide intravitreal implant in phakic eyes with symptomatic cataracts compared with usual care.
# Potential new treatment option
## People with diabetic macular oedema in phakic eyes would welcome a new treatment option
Diabetic macular oedema is a common complication associated with diabetic retinopathy that can lead to loss of vision. Complications of diabetic macular oedema include cataracts and glaucoma. The patient experts explained that diabetic macular oedema can have a substantial impact on patients' and carers' quality of life. Patients and carers can experience anxiety and stress because of the chronic nature of the disease and potential sight loss. Clinical and patient experts highlighted that people with diabetic macular oedema that does not respond well enough to available therapies and who have a natural lens currently have to wait until after cataract surgery before they are offered intravitreal steroid implants. The committee recalled that waiting times for cataract surgery can vary. It was aware that, based on the recommendations in NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy, it is increasingly common for people to get cataract surgery followed immediately by fluocinolone acetonide intravitreal implant during the same procedure. Therefore, if cataract surgery waiting times were improved, the wait for fluocinolone acetonide intravitreal implant for people within the company's proposed population may also be reduced. However, the committee noted that this could not be addressed in a technology appraisal. Clinical experts confirmed that, in some cases, people continue to have anti-vascular endothelial growth factors (anti‑VEGFs), even if they do not work well. The clinical and patient experts explained that adverse events, such as cataract and increased intraocular pressure, caused by the fluocinolone acetonide intravitreal implant are manageable. The committee concluded that people with diabetic macular oedema in phakic eyes would welcome a new treatment option.
# Clinical management
## Both laser treatment and anti-VEFGs are appropriate comparators for decision making
The clinical expert explained that NHS clinical practice for treating diabetic macular oedema has changed since anti‑VEGFs were introduced. The committee was aware that most people will initially have anti‑VEGFs and that in phakic eyes they might be continued even if they do not work well. The committee understood that there is no difference between people offered laser therapy and anti‑VEGFs and that treatment choice is often guided by clinical judgement. It therefore concluded that both laser treatment and anti‑VEGFs are appropriate comparators for decision making.
# Clinical evidence
## The clinical trial does not reflect NHS clinical practice
The clinical evidence for fluocinolone acetonide intravitreal implant came from 2 phase 3 randomised sham-injection controlled trials that were analysed as 1 trial (FAME). The follow up was 36 months. FAME was carried out between 2007 and 2010 before anti‑VEGFs were introduced. Most people in the trial had previously had at least 1 laser treatment while only few had had anti‑VEGFs. Level of response to previous treatment was not an inclusion criterion of the trial. During the trial, people in both arms could have rescue treatments, such as laser therapy, anti‑VEGFs and steroids. The company presented data on rescue therapy for 2 subgroups: people with non-chronic diabetic macular oedema and people with chronic diabetic macular oedema. In the latter group, rescue therapy was more common in the sham arm than the intervention arm; rescue laser therapy (62% compared with 41%), anti‑VEGFs (15% compared with 3%) and triamcinolone (24% compared with 8%). The company did not present rescue therapy data for phakic eyes. The committee understood that most people with diabetic macular oedema will have anti‑VEGFs and that rescue therapy is not used in clinical practice. Also, in FAME, very few people had symptomatic cataract at baseline but the company positions fluocinolone acetonide intravitreal implant for people with diabetic macular oedema in phakic eyes with symptomatic cataract. Therefore, the committee concluded that FAME does not reflect NHS clinical practice, and that results from FAME may not be generalisable to people with chronic diabetic macular oedema in phakic eyes with symptomatic cataract seen in the NHS.
## The clinical evidence for people with phakic eyes with symptomatic cataract is limited because of very small numbers
Visual acuity was the primary outcome in FAME. In people with chronic diabetic macular oedema, the mean change from baseline to month 36 in best corrected visual acuity (BCVA) score was an additional 7.6 letters in the intervention arm and an additional 1.8 letters in the sham arm (p=0.004). The company explained that, in the treatment arm, the improvement was higher in the group with eyes that were phakic at baseline and became pseudophakic after cataract surgery during the study than in eyes that were pseudophakic at baseline (11 compared with 7 letters gained). However, this was not statistically significant. An improvement was also seen in both arms in the people with phakic eyes and a clinical history of cataract although the improvement was not statistically significant. The data are confidential and cannot be reported here. The clinical expert confirmed that a 5‑letter increase in BCVA is considered clinically meaningful. The committee understood that diabetic macular oedema is a disease of the retina and that phakic eyes might benefit from treatment in a similar way to pseudophakic eyes. The clinical expert also explained that treatment of diabetic macular oedema in phakic eyes might save the retina and possibly lead to better outcomes after cataract surgery. However, the committee noted that the FAME trial only included a very small number of people with a clinical history of cataract. There was no prespecified statistical analysis plan to do a subgroup analysis for people with phakic eyes with symptomatic cataract, the company's proposed population for this appraisal. The clinical expert explained that people with cataract are often excluded from clinical trials for diabetic macular oedema. Cataracts make it difficult to see the retina and to assess retinal thickness, which is a relevant clinical factor when assessing diabetic macular oedema. The committee acknowledged the difficulties of doing clinical trials in people with phakic eye and symptomatic cataract. However, it was concerned about the lack of clinical data for this population. The committee agreed that it is plausible that the fluocinolone acetonide intravitreal implant improves visual acuity compared with usual care in phakic eyes with symptomatic cataract, but that this is highly uncertain because the evidence from clinical trials was very limited. The committee concluded that there were not enough data to establish if fluocinolone acetonide intravitreal implant worked better than usual care in phakic eyes with symptomatic cataract.
## Non-comparative evidence does not reduce uncertainty in the clinical outcomes because of the extremely small number of people included
The company presented data from 2 European registry studies that were done after anti‑VEGFs were introduced as a treatment option. These studies included few people with phakic eyes and symptomatic cataract who had fluocinolone acetonide intravitreal implant on the same day as cataract surgery. The ERG identified further registry studies, but the company explained that these were inappropriate because it was difficult to identify people with phakic eyes and symptomatic cataract in these studies. The committee acknowledged that, in England, NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy limits the use of fluocinolone acetonide implant to pseudophakic eyes and therefore limits the availability of UK non-comparative data. The committee understood that there is limited non-comparative evidence for phakic eyes with symptomatic cataract, therefore it concluded that it is difficult to establish whether fluocinolone acetonide intravitreal implant works better than usual care in this group.
# The cost-effectiveness evidence
## The model structure is acceptable for decision making
The company presented a state-transition Markov model. In the model, people moved from health state to health state every 3 months and this was modelled using transition probability matrices informed by the FAME trial. The model simulated both eyes and combined them into bilateral health states. The committee concluded that the model structure was acceptable for decision making.
## The BCVA results from the model differ from the FAME results, increasing the uncertainty of what would happen in the long term or in phakic eyes with symptomatic cataracts
The company validated their model by comparing modelled BCVAs with those seen in FAME. Most model inputs came from the FAME trial with some from non-comparative studies and additional data sources. The committee noted that BCVAs from the model output and FAME trial results were very different, particularly for the sham arm of FAME. It agreed that the effectiveness data used for the usual care arm should be modelled in line with FAME results (see section 3.9). The committee noted that the model included transition probabilities derived from the full population of FAME and discussed the differences between the FAME trial population and the company's proposed population for this appraisal. The committee concluded that BCVA outcomes predicted by the model did not reflect the data seen from FAME. Further uncertainty is introduced when data are extrapolated beyond the FAME trial period of 36 months, to people who previously had anti‑VEGFs and to people with phakic eyes with symptomatic cataract.
## The net effect between the treatment arm and the sham arm should be modelled
In FAME, people in both arms could have rescue treatments which might result in improved vision. The treatment effectiveness in the FAME treatment arm captured both the effect of rescue treatments and fluocinolone acetonide intravitreal implant treatment. The improvement seen in the sham arm might be partly because of rescue therapy and partly because of placebo effect. The company included the full treatment effectiveness in the FAME treatment arm in their model but assumed no change in BCVA in the usual care arm. The company explained that this approach is taken because the sham arm of FAME does not represent current NHS clinical practice and that there is no recovery seen in usual care. Because rescue therapy was used in both arms in FAME, the ERG suggested modelling the net effect between treatment and sham arm. This accounts for the effectiveness seen in the sham arm of FAME and was included in the ERG's base-case model. It substantially increased the incremental cost-effectiveness ratio (ICER). The committee agreed that the sham arm in FAME does not represent current NHS clinical practice. However, it noted that both arms included people who had rescue therapies, and agreed that the same issue applied to the treatment arm. In response to consultation, the company presented a schematic and graphs illustrating possible visual acuity outcomes with different treatments. The committee was aware that these graphs represented theoretical outcomes from the model and FAME that it had considered at the first committee meeting. The committee concluded that modelling the net effect was more appropriate than assuming no change in BCVA for the usual care arm, although the trial data and the model outputs in relation to the trial data remained highly uncertain (see section 3.5, section 3.6 and section 3.8).
## It is reasonable to assume that people will have more than 1 implant during the first 3 years
The clinical experts explained that, in line with the summary of product characteristics, an additional fluocinolone acetonide intravitreal implant may be administered after 12 months if worsening or recurrent diabetic macular oedema results in decreased vision or an increase in retinal thickness. In their model, the company assumed an average of 1.06 implants per person over the first 3 years in line with non-comparative data from the Medisoft study. However, based on the clinical trial FAME data, the ERG estimated people with chronic diabetic macular oedema had an average of 1.3 implants over the first 3 years. Non-comparative data from the IRISS study suggested that this number is 1.13 implants over the first 3 years. The ERG included the number from the IRISS study in their base-case model. The clinical expert confirmed that some people are likely to have a second implant within the first 3 years. The committee concluded that it is reasonable to assume people may have more than 1 implant during the first 3 years and accepted the ERG's base-case model assumption but noted that this was not a key driver of the cost-effectiveness results.
## It is plausible to assume some additional gain from retreatment after 3 years
The company assumed that people who are retreated after 3 years will experience continued gain in BCVA and that this gain would be similar to the gain seen for the first implant in months 3 to 36. The ERG stated that retreatment with fluocinolone acetonide intravitreal implant at year 3 is more likely to maintain the first 3 years gain in BCVA. The clinical experts confirmed that a second implant might result in additional BCVA gains. The committee concluded that an additional gain in BCVA with a second implant after 3 years is plausible.
## About 42% of people with diabetic macular oedema in phakic eyes with symptomatic cataract might get a second implant after 3 years
Each fluocinolone acetonide intravitreal implant releases 0.2 micrograms per day over about 3 years. The clinical expert explained that people whose diabetic macular oedema responds to the implant might be offered a second implant after 3 years. The clinical expert explained that an increase of 5 letters BCVA or an improvement of retinal thickness by more than 10% is considered clinically relevant. The company estimated that about 36% of people with phakic eyes in the FAME treatment arm would have been retreated because they achieved an improvement in BCVA of 15 or more letters. In people with phakic eyes who had their cataract removed during the trial, this number was higher (42.3%). The committee concluded that about 42% of people with phakic eyes and symptomatic cataracts will be retreated and accepted the assumption in the ERG's base-case model.
## The number of monitoring visits for anti-VEGFs should be in line with registry data
Anti-VEGFs are established therapy for treating phakic eyes with symptomatic cataract. Therefore, the company included bi-monthly monitoring visits during year 1 (6 visits), 5 visits in year 2, and 4 visits in years 3, 4, 5 and 6. Data from ICE-UK suggested that people having anti-VEGFs are monitored 4 times a year. The committee discussed the frequency of anti‑VEGF injections and the need for monitoring. It agreed with the assumption in the ERG's base-case model of 8 monitoring visits in year 1 and 4 in each following year.
## It is uncertain if the treatment continues to have an effect on vision outcomes for a lifetime after treatment has stopped
In the model, the company assumed that treatment effect is maintained for a lifetime even after treatment has stopped. The committee noted from the summary of product characteristics that each fluocinolone acetonide intravitreal implant lasts about 3 years. The committee agreed that there might be a continued treatment effect after treatment has stopped but it was uncertain how long this would last. The ERG was unable to directly explore the effect of continued treatment in the model but explored this issue by adjusting the time horizon in scenario analyses. The committee concluded that it is implausible to assume the continued treatment effect would last for a lifetime.
# Health-related quality of life
## The company's preferred utility values are acceptable for decision making
The company collected quality-of-life data using the National Eye Institute Visual Function Questionnaire-25 (NEI‑VFQ‑25) during FAME. It mapped these data using a published mapping algorithm (Rentz et al. 2014) to estimate quality of life for FAME data. These quality-of-life values were then used to provide values for BCVA in the best seeing eye and the worst seeing eye. Values were weighted and smoothed to obtain final utility values. The ERG had some concerns around the health-related quality-of-life data. It noted that previous NICE appraisals within ocular diseases used the experimental lenses study by Czoski-Murray et al. (2009). The ERG provided some scenario analyses exploring the impact of different utility estimates on the cost effectiveness. The committee agreed that a disease specific instrument might be more responsive to changes in people's BCVA than the generic EQ‑5D (NICE's preferred utility instrument). The committee accepted that there are different options to capture health-related quality of life for people with diabetic macular oedema. It was aware that carers' health-related quality of life may also be affected, but that it had not been shown evidence to capture this. Overall, the committee concluded that the use of NEI‑VFG‑25 and mapping algorithm was acceptable.
# Cost-effectiveness results
## The ICERs are highly uncertain, and there is no single most plausible ICER, but all plausible ICERs exceed £30,000 per quality-adjusted life year (QALY) gained
The company's deterministic base case suggested that the ICER for the fluocinolone acetonide intravitreal implant compared with laser therapy and anti‑VEGFs combined was £2,187 per QALY gained. The committee noted that the company had not submitted new evidence or updated cost-effectiveness analyses at consultation. All analyses included the confidential commercial arrangement discount for the fluocinolone acetonide intravitreal implant. The ERG suggested several changes to the company's base-case model:
FAME sham treatment effect for usual care (see section 3.9).
Year 3 retreatment maintains vision (see section 3.11).
Number of implants is 1.13 in the first 3 years in line with the IRISS study (see section 3.10).
Increase in the percentage of responders to fluocinolone acetonide intravitreal implant (see section 3.12).
Adjustment of monitoring visits for anti-VEGFs (see section 3.13).
Minor corrections to the model structure.When considered individually, most changes only had a small effect on the ICER. Modelling the net effectiveness (see section 3.9) reduced the QALY gain substantially and had the largest effect on the ICER (ICER changed to £73,256 per QALY gained). Combining all preferred ERG changes increased the ICER to £461,000 per QALY gained. The ERG reproduced the analyses to include the confidential commercial arrangement discount for the comparators. The resulting ERG base-case ICER was substantially higher than £30,000 per QALY gained (the exact ICER is confidential and cannot be reported here). The committee accepted most of the changes the ERG made (see sections 3.9 to 3.13), including the minor structural changes.The committee discussed the additional sensitivity analyses done by the ERG and agreed that all explorations were valid, and most were clinically plausible. The committee understood that, for the ERG base case, the QALY gain for fluocinolone acetonide intravitreal implant was small, meaning the ICER changed dramatically between different clinically plausible scenarios. All were substantially higher than £30,000 per QALY gained. The ERG reproduced the sensitivity analyses to include the confidential commercial arrangement discount for the comparators. The resulting ICERs were substantially higher than £30,000 per QALY gained (the exact ICERs are confidential and cannot be reported here).The committee noted that it had considered all available evidence. The committee concluded that the cost-effectiveness estimates were very uncertain but the most plausible ICERs were all substantially over £30,000 per QALY gained. This was higher than the range normally considered a cost-effective use of NHS resources. Therefore, it did not recommend fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies if the implant is to be used in an eye with a natural lens (phakic eye).
# Innovation
## The benefits of the fluocinolone acetonide intravitreal implant are captured in the cost-effectiveness analysis
The company considered the fluocinolone acetonide intravitreal implant to be innovative. The clinical experts stated that the fluocinolone acetonide intravitreal implant would be a substantial change in treating diabetic macular oedema in phakic eyes with symptomatic cataract because the long-lasting effect reduces the need for repeated treatment and reduces treatment and follow-up burden. The committee concluded that fluocinolone acetonide intravitreal implant might be beneficial for the people with phakic eyes and symptomatic cataract but that it had not been shown evidence of any additional benefits that were not captured in the measurement of QALYs.
# Equality
## There are no equality issues relevant to the recommendation
The committee noted 2 potential equality issues raised by clinical experts. People with phakic eyes and symptomatic cataract are currently disadvantaged because they cannot have fluocinolone acetonide intravitreal implant. Some of these people continue to have anti‑VEGFs even though their diabetic macular oedema does not respond well enough. These people must wait for cataract surgery before they can have the fluocinolone acetonide intravitreal implant. It was also noted in a consultation comment that people with cataract are often older with multiple comorbidities. The committee concluded that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. It concluded that there are no equality issues relevant to the recommendation.
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{'Recommendations': "Fluocinolone acetonide intravitreal implant is not recommended as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies in an eye with a natural lens (phakic eye).\n\nThis recommendation is not intended to affect treatment with fluocinolone acetonide intravitreal implant that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatments for untreated chronic diabetic macular oedema include laser therapy and anti-vascular endothelial growth factors (VEGFs). There are no further treatment options for eyes with a natural lens (phakic eyes).\n\nThe company submitted evidence for people with phakic eyes and symptomatic cataracts. Clinical trial evidence compares the effectiveness of fluocinolone acetonide intravitreal implant and sham in people with chronic diabetic macular oedema who already had at least 1 laser treatment. Only very few people had anti‑VEGFs before the trial and few people had phakic eyes with symptomatic cataracts. Also, non-comparative studies used to support the company's submission only include few people with phakic eyes and symptomatic cataract. No other data for this group have been identified. This makes it difficult to establish if fluocinolone acetonide intravitreal implant works better than usual care for these people, especially in the long term.\n\nBecause of the lack of clinical evidence, the cost-effectiveness estimates for fluocinolone acetonide intravitreal implant are also uncertain. Even the lowest clinically plausible cost-effectiveness estimates are substantially higher than what NICE normally considers an acceptable use of NHS resources. Therefore, fluocinolone acetonide intravitreal implant is not recommended for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies in an eye with a natural lens (phakic eye).", 'Information about fluocinolone acetonide intravitreal implant': "Marketing authorisation indication\n\nFluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) is indicated for 'the treatment of vision impairment associated with chronic diabetic macular oedema, (DMO) considered insufficiently responsive to available therapies'.\n\nDosage in the marketing authorisation\n\nFluocinolone acetonide intravitreal implant is administered through intravitreal injection. Each implant contains 0.19\xa0mg of fluocinolone acetonide and releases fluocinolone acetonide for up to 36\xa0months.\n\nPrice\n\n£5,500 per implant (excluding VAT, BNF online, accessed June 2019).\n\nThe company has a commercial arrangement. This makes fluocinolone acetonide intravitreal implant available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence.", 'Committee discussion': "The appraisal committee (section 4) considered evidence submitted by Alimera Sciences and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Company's positioning in treatment pathway\n\n## The company's proposed population is narrower than that in the NICE scope and the marketing authorisation\n\nNICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy recommends fluocinolone acetonide intravitreal implant only for eyes with an intraocular (pseudophakic) lens. In this part review, the committee considered the effectiveness of fluocinolone acetonide intravitreal implant compared with usual care in phakic eyes. The company submitted evidence for people with phakic eyes and symptomatic cataract, a population identified in NICE's guideline on the management of cataracts in adults. The committee understood that these people should be offered cataract surgery but that waiting time for cataract surgery can vary. Also, it agreed that the company's proposed population is narrower than the NICE scope and the marketing authorisation for fluocinolone acetonide intravitreal implant. The committee concluded that it is appropriate to appraise the cost effectiveness of fluocinolone acetonide intravitreal implant in phakic eyes with symptomatic cataracts compared with usual care.\n\n# Potential new treatment option\n\n## People with diabetic macular oedema in phakic eyes would welcome a new treatment option\n\nDiabetic macular oedema is a common complication associated with diabetic retinopathy that can lead to loss of vision. Complications of diabetic macular oedema include cataracts and glaucoma. The patient experts explained that diabetic macular oedema can have a substantial impact on patients' and carers' quality of life. Patients and carers can experience anxiety and stress because of the chronic nature of the disease and potential sight loss. Clinical and patient experts highlighted that people with diabetic macular oedema that does not respond well enough to available therapies and who have a natural lens currently have to wait until after cataract surgery before they are offered intravitreal steroid implants. The committee recalled that waiting times for cataract surgery can vary. It was aware that, based on the recommendations in NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy, it is increasingly common for people to get cataract surgery followed immediately by fluocinolone acetonide intravitreal implant during the same procedure. Therefore, if cataract surgery waiting times were improved, the wait for fluocinolone acetonide intravitreal implant for people within the company's proposed population may also be reduced. However, the committee noted that this could not be addressed in a technology appraisal. Clinical experts confirmed that, in some cases, people continue to have anti-vascular endothelial growth factors (anti‑VEGFs), even if they do not work well. The clinical and patient experts explained that adverse events, such as cataract and increased intraocular pressure, caused by the fluocinolone acetonide intravitreal implant are manageable. The committee concluded that people with diabetic macular oedema in phakic eyes would welcome a new treatment option.\n\n# Clinical management\n\n## Both laser treatment and anti-VEFGs are appropriate comparators for decision making\n\nThe clinical expert explained that NHS clinical practice for treating diabetic macular oedema has changed since anti‑VEGFs were introduced. The committee was aware that most people will initially have anti‑VEGFs and that in phakic eyes they might be continued even if they do not work well. The committee understood that there is no difference between people offered laser therapy and anti‑VEGFs and that treatment choice is often guided by clinical judgement. It therefore concluded that both laser treatment and anti‑VEGFs are appropriate comparators for decision making.\n\n# Clinical evidence\n\n## The clinical trial does not reflect NHS clinical practice\n\nThe clinical evidence for fluocinolone acetonide intravitreal implant came from 2 phase\xa03 randomised sham-injection controlled trials that were analysed as 1\xa0trial (FAME). The follow up was 36\xa0months. FAME was carried out between 2007 and 2010 before anti‑VEGFs were introduced. Most people in the trial had previously had at least 1 laser treatment while only few had had anti‑VEGFs. Level of response to previous treatment was not an inclusion criterion of the trial. During the trial, people in both arms could have rescue treatments, such as laser therapy, anti‑VEGFs and steroids. The company presented data on rescue therapy for 2\xa0subgroups: people with non-chronic diabetic macular oedema and people with chronic diabetic macular oedema. In the latter group, rescue therapy was more common in the sham arm than the intervention arm; rescue laser therapy (62% compared with 41%), anti‑VEGFs (15% compared with 3%) and triamcinolone (24% compared with 8%). The company did not present rescue therapy data for phakic eyes. The committee understood that most people with diabetic macular oedema will have anti‑VEGFs and that rescue therapy is not used in clinical practice. Also, in FAME, very few people had symptomatic cataract at baseline but the company positions fluocinolone acetonide intravitreal implant for people with diabetic macular oedema in phakic eyes with symptomatic cataract. Therefore, the committee concluded that FAME does not reflect NHS clinical practice, and that results from FAME may not be generalisable to people with chronic diabetic macular oedema in phakic eyes with symptomatic cataract seen in the NHS.\n\n## The clinical evidence for people with phakic eyes with symptomatic cataract is limited because of very small numbers\n\nVisual acuity was the primary outcome in FAME. In people with chronic diabetic macular oedema, the mean change from baseline to month\xa036 in best corrected visual acuity (BCVA) score was an additional 7.6\xa0letters in the intervention arm and an additional 1.8\xa0letters in the sham arm (p=0.004). The company explained that, in the treatment arm, the improvement was higher in the group with eyes that were phakic at baseline and became pseudophakic after cataract surgery during the study than in eyes that were pseudophakic at baseline (11 compared with 7\xa0letters gained). However, this was not statistically significant. An improvement was also seen in both arms in the people with phakic eyes and a clinical history of cataract although the improvement was not statistically significant. The data are confidential and cannot be reported here. The clinical expert confirmed that a 5‑letter increase in BCVA is considered clinically meaningful. The committee understood that diabetic macular oedema is a disease of the retina and that phakic eyes might benefit from treatment in a similar way to pseudophakic eyes. The clinical expert also explained that treatment of diabetic macular oedema in phakic eyes might save the retina and possibly lead to better outcomes after cataract surgery. However, the committee noted that the FAME trial only included a very small number of people with a clinical history of cataract. There was no prespecified statistical analysis plan to do a subgroup analysis for people with phakic eyes with symptomatic cataract, the company's proposed population for this appraisal. The clinical expert explained that people with cataract are often excluded from clinical trials for diabetic macular oedema. Cataracts make it difficult to see the retina and to assess retinal thickness, which is a relevant clinical factor when assessing diabetic macular oedema. The committee acknowledged the difficulties of doing clinical trials in people with phakic eye and symptomatic cataract. However, it was concerned about the lack of clinical data for this population. The committee agreed that it is plausible that the fluocinolone acetonide intravitreal implant improves visual acuity compared with usual care in phakic eyes with symptomatic cataract, but that this is highly uncertain because the evidence from clinical trials was very limited. The committee concluded that there were not enough data to establish if fluocinolone acetonide intravitreal implant worked better than usual care in phakic eyes with symptomatic cataract.\n\n## Non-comparative evidence does not reduce uncertainty in the clinical outcomes because of the extremely small number of people included\n\nThe company presented data from 2 European registry studies that were done after anti‑VEGFs were introduced as a treatment option. These studies included few people with phakic eyes and symptomatic cataract who had fluocinolone acetonide intravitreal implant on the same day as cataract surgery. The ERG identified further registry studies, but the company explained that these were inappropriate because it was difficult to identify people with phakic eyes and symptomatic cataract in these studies. The committee acknowledged that, in England, NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy limits the use of fluocinolone acetonide implant to pseudophakic eyes and therefore limits the availability of UK non-comparative data. The committee understood that there is limited non-comparative evidence for phakic eyes with symptomatic cataract, therefore it concluded that it is difficult to establish whether fluocinolone acetonide intravitreal implant works better than usual care in this group.\n\n# The cost-effectiveness evidence\n\n## The model structure is acceptable for decision making\n\nThe company presented a state-transition Markov model. In the model, people moved from health state to health state every 3\xa0months and this was modelled using transition probability matrices informed by the FAME trial. The model simulated both eyes and combined them into bilateral health states. The committee concluded that the model structure was acceptable for decision making.\n\n## The BCVA results from the model differ from the FAME results, increasing the uncertainty of what would happen in the long term or in phakic eyes with symptomatic cataracts\n\nThe company validated their model by comparing modelled BCVAs with those seen in FAME. Most model inputs came from the FAME trial with some from non-comparative studies and additional data sources. The committee noted that BCVAs from the model output and FAME trial results were very different, particularly for the sham arm of FAME. It agreed that the effectiveness data used for the usual care arm should be modelled in line with FAME results (see section\xa03.9). The committee noted that the model included transition probabilities derived from the full population of FAME and discussed the differences between the FAME trial population and the company's proposed population for this appraisal. The committee concluded that BCVA outcomes predicted by the model did not reflect the data seen from FAME. Further uncertainty is introduced when data are extrapolated beyond the FAME trial period of 36\xa0months, to people who previously had anti‑VEGFs and to people with phakic eyes with symptomatic cataract.\n\n## The net effect between the treatment arm and the sham arm should be modelled\n\nIn FAME, people in both arms could have rescue treatments which might result in improved vision. The treatment effectiveness in the FAME treatment arm captured both the effect of rescue treatments and fluocinolone acetonide intravitreal implant treatment. The improvement seen in the sham arm might be partly because of rescue therapy and partly because of placebo effect. The company included the full treatment effectiveness in the FAME treatment arm in their model but assumed no change in BCVA in the usual care arm. The company explained that this approach is taken because the sham arm of FAME does not represent current NHS clinical practice and that there is no recovery seen in usual care. Because rescue therapy was used in both arms in FAME, the ERG suggested modelling the net effect between treatment and sham arm. This accounts for the effectiveness seen in the sham arm of FAME and was included in the ERG's base-case model. It substantially increased the incremental cost-effectiveness ratio (ICER). The committee agreed that the sham arm in FAME does not represent current NHS clinical practice. However, it noted that both arms included people who had rescue therapies, and agreed that the same issue applied to the treatment arm. In response to consultation, the company presented a schematic and graphs illustrating possible visual acuity outcomes with different treatments. The committee was aware that these graphs represented theoretical outcomes from the model and FAME that it had considered at the first committee meeting. The committee concluded that modelling the net effect was more appropriate than assuming no change in BCVA for the usual care arm, although the trial data and the model outputs in relation to the trial data remained highly uncertain (see section\xa03.5, section\xa03.6 and section\xa03.8).\n\n## It is reasonable to assume that people will have more than 1 implant during the first 3\xa0years\n\nThe clinical experts explained that, in line with the summary of product characteristics, an additional fluocinolone acetonide intravitreal implant may be administered after 12\xa0months if worsening or recurrent diabetic macular oedema results in decreased vision or an increase in retinal thickness. In their model, the company assumed an average of 1.06\xa0implants per person over the first 3\xa0years in line with non-comparative data from the Medisoft study. However, based on the clinical trial FAME data, the ERG estimated people with chronic diabetic macular oedema had an average of 1.3\xa0implants over the first 3\xa0years. Non-comparative data from the IRISS study suggested that this number is 1.13\xa0implants over the first 3\xa0years. The ERG included the number from the IRISS study in their base-case model. The clinical expert confirmed that some people are likely to have a second implant within the first 3\xa0years. The committee concluded that it is reasonable to assume people may have more than 1\xa0implant during the first 3\xa0years and accepted the ERG's base-case model assumption but noted that this was not a key driver of the cost-effectiveness results.\n\n## It is plausible to assume some additional gain from retreatment after 3\xa0years\n\nThe company assumed that people who are retreated after 3\xa0years will experience continued gain in BCVA and that this gain would be similar to the gain seen for the first implant in months\xa03 to 36. The ERG stated that retreatment with fluocinolone acetonide intravitreal implant at year\xa03 is more likely to maintain the first 3\xa0years gain in BCVA. The clinical experts confirmed that a second implant might result in additional BCVA gains. The committee concluded that an additional gain in BCVA with a second implant after 3\xa0years is plausible.\n\n## About 42% of people with diabetic macular oedema in phakic eyes with symptomatic cataract might get a second implant after 3\xa0years\n\nEach fluocinolone acetonide intravitreal implant releases 0.2\xa0micrograms per day over about 3\xa0years. The clinical expert explained that people whose diabetic macular oedema responds to the implant might be offered a second implant after 3\xa0years. The clinical expert explained that an increase of 5\xa0letters BCVA or an improvement of retinal thickness by more than 10% is considered clinically relevant. The company estimated that about 36% of people with phakic eyes in the FAME treatment arm would have been retreated because they achieved an improvement in BCVA of 15 or more letters. In people with phakic eyes who had their cataract removed during the trial, this number was higher (42.3%). The committee concluded that about 42% of people with phakic eyes and symptomatic cataracts will be retreated and accepted the assumption in the ERG's base-case model.\n\n## The number of monitoring visits for anti-VEGFs should be in line with registry data\n\nAnti-VEGFs are established therapy for treating phakic eyes with symptomatic cataract. Therefore, the company included bi-monthly monitoring visits during year\xa01 (6 visits), 5 visits in year\xa02, and 4 visits in years\xa03, 4, 5 and 6. Data from ICE-UK suggested that people having anti-VEGFs are monitored 4 times a year. The committee discussed the frequency of anti‑VEGF injections and the need for monitoring. It agreed with the assumption in the ERG's base-case model of 8\xa0monitoring visits in year\xa01 and 4 in each following year.\n\n## It is uncertain if the treatment continues to have an effect on vision outcomes for a lifetime after treatment has stopped\n\nIn the model, the company assumed that treatment effect is maintained for a lifetime even after treatment has stopped. The committee noted from the summary of product characteristics that each fluocinolone acetonide intravitreal implant lasts about 3\xa0years. The committee agreed that there might be a continued treatment effect after treatment has stopped but it was uncertain how long this would last. The ERG was unable to directly explore the effect of continued treatment in the model but explored this issue by adjusting the time horizon in scenario analyses. The committee concluded that it is implausible to assume the continued treatment effect would last for a lifetime.\n\n# Health-related quality of life\n\n## The company's preferred utility values are acceptable for decision making\n\nThe company collected quality-of-life data using the National Eye Institute Visual Function Questionnaire-25 (NEI‑VFQ‑25) during FAME. It mapped these data using a published mapping algorithm (Rentz et al. 2014) to estimate quality of life for FAME data. These quality-of-life values were then used to provide values for BCVA in the best seeing eye and the worst seeing eye. Values were weighted and smoothed to obtain final utility values. The ERG had some concerns around the health-related quality-of-life data. It noted that previous NICE appraisals within ocular diseases used the experimental lenses study by Czoski-Murray et al. (2009). The ERG provided some scenario analyses exploring the impact of different utility estimates on the cost effectiveness. The committee agreed that a disease specific instrument might be more responsive to changes in people's BCVA than the generic EQ‑5D (NICE's preferred utility instrument). The committee accepted that there are different options to capture health-related quality of life for people with diabetic macular oedema. It was aware that carers' health-related quality of life may also be affected, but that it had not been shown evidence to capture this. Overall, the committee concluded that the use of NEI‑VFG‑25 and mapping algorithm was acceptable.\n\n# Cost-effectiveness results\n\n## The ICERs are highly uncertain, and there is no single most plausible ICER, but all plausible ICERs exceed £30,000 per quality-adjusted life year (QALY) gained\n\nThe company's deterministic base case suggested that the ICER for the fluocinolone acetonide intravitreal implant compared with laser therapy and anti‑VEGFs combined was £2,187 per QALY gained. The committee noted that the company had not submitted new evidence or updated cost-effectiveness analyses at consultation. All analyses included the confidential commercial arrangement discount for the fluocinolone acetonide intravitreal implant. The ERG suggested several changes to the company's base-case model:\n\nFAME sham treatment effect for usual care (see section\xa03.9).\n\nYear\xa03 retreatment maintains vision (see section\xa03.11).\n\nNumber of implants is 1.13 in the first 3\xa0years in line with the IRISS study (see section\xa03.10).\n\nIncrease in the percentage of responders to fluocinolone acetonide intravitreal implant (see section\xa03.12).\n\nAdjustment of monitoring visits for anti-VEGFs (see section\xa03.13).\n\nMinor corrections to the model structure.When considered individually, most changes only had a small effect on the ICER. Modelling the net effectiveness (see section\xa03.9) reduced the QALY gain substantially and had the largest effect on the ICER (ICER changed to £73,256 per QALY gained). Combining all preferred ERG changes increased the ICER to £461,000 per QALY gained. The ERG reproduced the analyses to include the confidential commercial arrangement discount for the comparators. The resulting ERG base-case ICER was substantially higher than £30,000 per QALY gained (the exact ICER is confidential and cannot be reported here). The committee accepted most of the changes the ERG made (see sections\xa03.9 to 3.13), including the minor structural changes.The committee discussed the additional sensitivity analyses done by the ERG and agreed that all explorations were valid, and most were clinically plausible. The committee understood that, for the ERG base case, the QALY gain for fluocinolone acetonide intravitreal implant was small, meaning the ICER changed dramatically between different clinically plausible scenarios. All were substantially higher than £30,000 per QALY gained. The ERG reproduced the sensitivity analyses to include the confidential commercial arrangement discount for the comparators. The resulting ICERs were substantially higher than £30,000 per QALY gained (the exact ICERs are confidential and cannot be reported here).The committee noted that it had considered all available evidence. The committee concluded that the cost-effectiveness estimates were very uncertain but the most plausible ICERs were all substantially over £30,000 per QALY gained. This was higher than the range normally considered a cost-effective use of NHS resources. Therefore, it did not recommend fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies if the implant is to be used in an eye with a natural lens (phakic eye).\n\n# Innovation\n\n## The benefits of the fluocinolone acetonide intravitreal implant are captured in the cost-effectiveness analysis\n\nThe company considered the fluocinolone acetonide intravitreal implant to be innovative. The clinical experts stated that the fluocinolone acetonide intravitreal implant would be a substantial change in treating diabetic macular oedema in phakic eyes with symptomatic cataract because the long-lasting effect reduces the need for repeated treatment and reduces treatment and follow-up burden. The committee concluded that fluocinolone acetonide intravitreal implant might be beneficial for the people with phakic eyes and symptomatic cataract but that it had not been shown evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# Equality\n\n## There are no equality issues relevant to the recommendation\n\nThe committee noted 2 potential equality issues raised by clinical experts. People with phakic eyes and symptomatic cataract are currently disadvantaged because they cannot have fluocinolone acetonide intravitreal implant. Some of these people continue to have anti‑VEGFs even though their diabetic macular oedema does not respond well enough. These people must wait for cataract surgery before they can have the fluocinolone acetonide intravitreal implant. It was also noted in a consultation comment that people with cataract are often older with multiple comorbidities. The committee concluded that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. It concluded that there are no equality issues relevant to the recommendation."}
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https://www.nice.org.uk/guidance/ta613
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Evidence-based recommendations on fluocinolone acetonide intravitreal implant (Iluvien) for chronic diabetic macular oedema that has inadequately responded to previous therapy, in adults whose eyes have natural lenses (phakic eyes).
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1d526586a13dd6f8f57e6822638f728856a87f0d
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nice
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Point-of-care creatinine devices to assess kidney function before CT imaging with intravenous contrast
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Point-of-care creatinine devices to assess kidney function before CT imaging with intravenous contrast
Evidence-based recommendations on point-of-care creatinine devices to assess kidney function before CT imaging with intravenous contrast. The tests are ABL800 FLEX, i-STAT Alinity and StatSensor, ABL90 FLEX PLUS, Dri chem NX500, epoc Blood Analysis System, and Piccolo Xpress.
# Recommendations
Point-of-care creatinine devices ABL800 FLEX, i‑STAT Alinity and StatSensor, which calculate estimated glomerular filtration rate (eGFR), are recommended to assess kidney function to guide decisions on whether to use intravenous contrast during an outpatient CT scan in adults. They should only be used when current practice is that a recent eGFR result must be available before a person has a CT scan with intravenous contrast and if all the following apply:
a person presents for a CT scan without a recent eGFR result
the person has risk factors for acute kidney injury
clear governance structures for point-of-care testing are in place.
Take age, sex and ethnicity into account when assessing risk of acute kidney injury using a questionnaire-based tool (see section 4.13).
Point-of-care creatinine devices ABL90 FLEX PLUS, Dri‑chem NX500, epoc Blood Analysis System, and Piccolo Xpress are not recommended to assess kidney function to guide decisions on whether to use intravenous contrast during an outpatient CT scan. This is because there are insufficient data to assess their diagnostic accuracy.
Further research is recommended to:
better understand the level of risk of contrast-induced acute kidney injury (see section 5.1)
identify the most appropriate tool for identifying risk factors (see section 5.2)
monitor the effect of implementation on patient experience and efficiency in radiology departments (see section 5.3).
Why the committee made these recommendations
It's important to check whether the kidneys are working properly by measuring eGFR before a contrast-enhanced CT scan. This is because the contrast agent can cause acute kidney injury in people with low eGFR.
Normally, referrers will provide a laboratory eGFR measurement before a CT scan appointment but in cases where a person presents without a recent eGFR result, point-of-care creatinine devices can measure creatinine levels and be used to calculate eGFR rapidly. This means that people who do not have a recent eGFR result will not need to have their CT scan cancelled so that their creatinine can be measured in the laboratory. Referrers providing a laboratory eGFR measurement before a CT scan appointment remains the optimal approach, and this approach should be encouraged to avoid higher numbers of patients needing point-of-care (POC) creatinine measurement before a contrast-enhanced CT scan.
Evidence suggests that the ABL800 FLEX, i‑STAT Alinity and StatSensor all have acceptable accuracy in determining when eGFR is low (below 30 ml/min/1.73 m2). It was not possible to determine whether one is more accurate than another. Economic modelling shows that all 3 devices offer value for money to the NHS when compared with delaying scans for laboratory creatinine testing, although more people with an eGFR of less than 30 ml/min/1.73 m2 may be identified if they had laboratory testing. Using the devices can also avoid cancelling and rebooking CT scans, which is important for patients. The devices offer the most value for money when:
they are used only for people who have one or more risk factors for acute kidney injury and
cancelled CT scan appointments cannot be offered to other people.# The diagnostic tests
# Clinical need and practice
## The problem addressed
Point-of-care (POC) creatinine devices allow rapid measurement of creatinine levels and calculation of estimated glomerular filtration rate (eGFR). This can show whether the kidneys are working properly. The focus of this assessment is POC creatinine testing to assess kidney function before people have intravenous contrast for CT imaging. Intravenous iodine-based contrast agents used in CT scans can cause acute kidney injury (AKI), particularly in people who are at high risk and those with known kidney dysfunction. If a person has a low eGFR, intravenous hydration can be offered before the scan to reduce the risk of AKI. If a person does not have a recent eGFR measurement, their CT scan could be cancelled and rescheduled while a creatinine test is processed in the laboratory.
Using POC creatinine tests before outpatient contrast-enhanced CT scans in the radiology department could minimise the risk of kidney injury. It could also reduce the number of cancelled scans, which is important for patients.
## The condition
AKI covers injury to the kidneys from a number of causes; it often happens as a complication of another serious illness. If AKI is not treated promptly, levels of salts and chemicals in the body can increase, which affects the fluid balance in the body and how well other organs work.
Post-contrast AKI (PC‑AKI) is a sudden deterioration in kidney function within 48 to 72 hours of administering intravenous iodine-based contrast agent. Incidence in patients having non-emergency CT scans with intravenous contrast agent is reported to be less than 1% (Ozkok et al. 2017). Risk factors for PC‑AKI include chronic kidney disease, critical illness, contrast-enhanced imaging done as an emergency, older age, diabetes, use of nephrotoxic drugs and reduced kidney function (for example, if a person is dehydrated or has congestive heart failure). Short- and long-term mortality rates are significantly higher in patients with PC‑AKI than in patients without PC‑AKI. A history of PC‑AKI may be also be associated with development of chronic kidney disease and progression to end-stage renal disease.
## The care pathways
NICE's guideline on acute kidney injury: prevention, detection and management says that before using iodinated contrast agents for imaging, kidney function should be checked and the risk of AKI assessed. It recommends that eGFR should be measured within 3 months of using iodinated contrast agents.
The threshold for eGFR at which there is a risk of developing PC‑AKI varies across different guidelines, ranging between 30 ml/min/1.73 m2 (The Royal Australian and New Zealand College of Radiologists iodinated contrast guidelines , which have been endorsed by the Royal College of Radiologists) and 60 ml/min/1.73 m2 (Renal Association guideline on the prevention of CI-AKI in adult patients , in the Acute Kidney Injury guideline). Clinical experts suggested that people with an eGFR of less than 30 ml/min/1.73 m2 are at highest risk of developing PC‑AKI.
Guidelines recommend that adults having iodinated contrast agents at increased risk of PC‑AKI should:
be offered intravenous volume expansion
consider temporarily stopping angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
have a nephrology team discuss their care if there are contraindications to intravenous fluids.
If PC‑AKI develops, NICE's guideline on acute kidney injury recommends:
renal replacement therapy (dialysis) in some situations
loop diuretics for treating fluid overload or oedema in people waiting to have dialysis, and in people who do not need dialysis.
Children were not included in the scope of this assessment because they often have alternative imaging, such as MRI scans, rather than CT scans. In addition, different eGFR equations are used for children and adults, so studies of POC creatinine devices in adult populations may not reflect the performance of these devices in children.
# The interventions
The POC creatinine devices included in table 1 are CE marked and measure creatinine using an enzymatic method. Devices are either handheld, table-top or portable and need very small samples of whole blood from either finger-prick or venous or arterial samples. Creatinine can be measured either as one component of a panel of parameters, or as a single measurement on a test card or cartridge specific for creatinine or kidney function.
## Table 1 POC creatinine devices
Manufacturer and devices
Device format
Parameters measured
Sample volume
Analysis time
eGFR equation used
Nova Biomedical
StatSensor
Handheld
Creatinine only
microlitres
seconds
MDRD, Cockcroft-Gault, CKD-EPI, Schwartz and Counahan-Barratt
Related models: StatSensor-i, StatSensor Xpress-i. All models allow offset adjustment of results. StatSensor and StatSensor-i also allow slope adjustment.
Abbott
i‑STAT Alinity
Handheld
Multiple parameters
microlitres
minutes
MDRD and CKD-EPI
Related models: i‑STAT 1, many studies simply state 'i‑STAT'
Radiometer
ABL90 FLEX PLUS
Portable
parameters
microlitres
seconds
CKD-EPI, MDRD and Schwartz
ABL800 FLEX
Table-top
parameters
to 250 microlitres
minute
CKD-EPI and MDRD
Related models: ABL827, ABL837
Siemens Healthineers
Epoc Blood Analysis System
Handheld
parameters on 1 test card
microlitres
Less than 1 minute
CKD-EPI, MDRD and Schwartz
Abaxis
Piccolo Xpress
Table-top
Multiple parameters
microlitres
Less than 14 minutes
MDRD
Fujifilm
Dri‑chem NX500
Table-top
Multiple parameters
microlitre
minutes
Expected
Abbreviations: CKD-EPI, chronic kidney disease epidemiology; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease.
# The comparators
There were 2 comparators used in the assessment:
laboratory-based serum creatinine measurement and eGFR
clinical judgement alone (no testing).# Evidence
The diagnostics advisory committee (section 7) considered evidence on point-of-care (POC) creatinine devices to assess kidney function before CT imaging with intravenous contrast from several sources. Full details of all the evidence are in the committee papers.
# Clinical effectiveness
The external assessment group (EAG) systematically reviewed:
studies comparing the results of POC creatinine tests with laboratory-based tests to assess kidney function in any non-emergency setting
studies reporting clinical or implementation outcomes of POC creatinine tests to assess kidney function before CT imaging in a non-emergency, outpatient setting.
There were 54 studies in the review. Of those, 12 studies reported diagnostic accuracy data for estimated glomerular filtration rate (eGFR), 7 studies reported diagnostic accuracy data for serum creatinine, 50 studies presented data on correlation or measurement bias between a POC creatinine device and a laboratory reference test, and 6 studies reported data on workflow or implementation.
## Correlation and measurement bias
Results from the StatSensor studies showed wide variation in the size and direction of measurement bias. StatSensor devices can be adjusted to correct for any bias seen, to align the POC creatinine device results with those from local laboratory methods. Only 2 StatSensor studies reported using an adjustment function for measurement bias. Although potentially important measurement bias was found in some studies of i‑STAT and ABL devices, the concordance of results for these devices was generally better than for the StatSensor devices. A smaller number of studies were available on the epoc (1 study) and Piccolo Xpress (4 studies) devices.
There were 3 studies comparing different types of POC creatinine devices. Of these, 2 studies compared StatSensor, i‑STAT and ABL800 FLEX. Both studies found that the ABL800 FLEX had the strongest agreement with laboratory serum creatinine, then i‑STAT and then StatSensor. There was 1 study comparing an ABL827 device with an i‑STAT device. It concluded that creatinine results from both devices correlated well with laboratory serum creatinine.
In some studies, measurement bias increased at higher creatinine levels (lower eGFR). This could affect care decisions for people at higher risk of kidney damage.
## Diagnostic accuracy based on eGFR thresholds
There were 12 studies reporting diagnostic accuracy data on eGFR thresholds. Studies were of different devices, with some studies assessing more than one device:
i‑STAT studies
StatSensor studies
studies included a Radiometer POC device (ABL800 or ABL827)
studies assessed 3 POC devices (ABL, i‑STAT and StatSensor) and
study looked at 2 devices (ABL and i‑STAT).There were no studies of ABL90 FLEX PLUS, Dri‑chem NX500, epoc Blood Analysis System and Piccolo Xpress. The eGFR equations used in the studies varied, with only 3 studies using chronic kidney disease epidemiology (CKD-EPI). There were 3 StatSensor and 2 i‑STAT studies that used an adjustment function to correct for any measurement bias between the POC creatinine test results and laboratory test results from the study sample. Adjusted and unadjusted results were reported in all 3 StatSensor studies, but only adjusted results were presented in the 2 i‑STAT studies. Most studies used an enzymatic method as the laboratory reference, but the Jaffe method was used in 2 studies and the reference method was not reported in 1 study.
There were 6 studies at low risk across all risk of bias areas, including 2 studies of ABL800, 3 studies of i‑STAT and 3 studies of StatSensor. The other 6 studies had at least one domain at unclear or high risk of bias. Risks of bias related to:
how the adjustment function to correct for measurement bias was applied
patient selection
the use of a different modification of the diet in renal disease (MDRD) eGFR equation between the POC creatinine test and laboratory reference test
the use of a Jaffe method for the laboratory reference test (compared with an enzymatic method for the POC creatinine test).
There were low concerns about the applicability of results across all domains for only 2 studies, including 1 study of ABL800, i‑STAT and StatSensor (Snaith et al. 2018), and 1 study of i‑STAT (Snaith et al. 2019). The most common concern was the use of eGFR threshold; 3 studies used an eGFR cut-off of 60 ml/min/1.73 m2 or above. Several studies included disease-specific populations, therefore their applicability to a broader population of outpatients referred for CT scan without a recent eGFR may be limited.
The EAG quantitatively analysed the study results. The probabilities of being in each eGFR category were calculated from the number of people in each category reported by all included studies (regardless of the device assessed). The pooled probabilities of being in each of the 4 categories are in table 2. Most studies only included a few people in category 1 (eGFR less than 30 ml/min/1.73 m2) and more people in higher eGFR categories.
## Table 2 Estimated probabilities of being in each eGFR category
Category
eGFR
(ml/min/1.73 m
All data
Median
% CrI
to 29
to 0.017
to 44
to 0.064
to 59
to 0.159
-r higher
to 0.803
Abbreviations: eGFR, estimated glomerular filtration rate; CrI, credible interval.
The pooled probabilities of having a classification by a POC creatinine device in each eGFR category (k) and in each laboratory-defined eGFR category (j) are given in table 3. The i‑STAT and ABL devices have higher median probabilities of correct classification in each of the 3 lowest categories (p, p, p) compared with the StatSensor. StatSensor was particularly poor at correctly classifying category 3 (eGFR 45 to 59 ml/min/1.73 m2). However, there is considerable uncertainty in these probabilities for all devices.
## Table 3 Estimated probabilities of being classified in each eGFR category by POC creatinine device
p
StatSensor
i‑STAT
ABL (Radiometer)
Median
% CrI
Median
% CrI
Median
% CrI
p
to 0.85
to 0.94
to 0.95
p
to 0.30
to 0.18
to 0.14
p
to 0.12
to 0.18
to 0.14
p
to 0.11
to 0.16
to 0.15
p
to 0.19
to 0.21
to 0.11
p
to 0.71
to 0.87
to 0.90
p
to 0.36
to 0.21
to 0.29
p
to 0.24
to 0.06
to 0.15
p
to 0.03
to 0.05
to 0.08
p
to 0.20
to 0.17
to 0.16
p
to 0.34
to 0.88
to 0.85
p
to 0.69
to 0.13
to 0.26
p
to 0.01
to 0.01
to 0.01
p
to 0.01
to 0.02
to 0.01
p
to 0.08
to 0.10
to 0.01
p
to 0.95
to 0.93
to 0.99
eGFR categories (ml/min/1.73 m2): 1=0 to 29; 2=30 to 44, 3=5 to 59; 4=60 or higher.
Abbreviation: CrI, credible interval.
Additional analyses were done to assess the effect of removing studies with limited applicability to clinical practice in the NHS. The pooled probabilities from these analyses were used in scenario analyses in the economic model:
StatSensor devices allow a user-specified adjustment if systematic measurement bias is identified. An additional analysis including the adjusted data reported by Korpi-Steiner et al. (2009) and Shephard et al. (2010) was done. The Inoue et al. (2017) study was not included in this analysis because the reported adjustment could not be replicated in NHS practice.
Only 2 studies used the CKD-EPI equation to calculate eGFR, all others used the MDRD equation. Of these studies, one included StatSensor, i‑STAT and ABL800 FLEX devices (Snaith et al. 2018) and the other only included an i‑STAT device (Snaith et al. 2019). An additional analysis using only the data in these 2 studies was done.
## Clinical, workflow or implementation outcomes
There were 6 studies reporting a relevant outcome after using a POC creatinine device. The results showed variation in practice in both the proportions of patients who do not have a recent eGFR result and in the management decisions when a POC creatinine device shows an abnormal eGFR. For example, the proportion of people offered scans with or without contrast, or offered a reduced dose of contrast. Also, many of the studies were done several years ago so the value of their results is limited because eGFR thresholds for defining an abnormal result have decreased over time. No data were available on clinical outcomes such as need for renal replacement therapy or hospital admissions.
# Cost effectiveness
The EAG identified existing studies on the cost effectiveness of POC creatinine tests in an outpatient non-emergency secondary care setting, to assess kidney function before contrast-enhanced CT imaging. Because only a single cost-consequence analysis was found, provided as an academic-in-confidence manuscript, the EAG also constructed a de novo economic model to assess the cost effectiveness of POC creatinine tests.
## Model structure
The model assessed a cohort of outpatients presenting for a non-emergency contrast-enhanced CT scan without a recent eGFR measurement. Costs were presented from the perspective of the NHS and personal social services and were reported in UK pounds at 2018 prices. Outcomes after the first year were discounted at a rate of 3.5% per year. Most costs happened in the first year and were therefore not discounted.
The model used a decision tree cohort approach to estimate the costs and health outcomes of the different testing and treatment strategies. The model captured:
true eGFR status (less than 30 ml/min/1.73 m2 or 30 ml/min/1.73 m2 and above)
how eGFR status is classified by different testing strategies, using the eGFR cut-off value of 30 ml/min/1.73 m2 and probabilities conditional on true eGFR status
any actions to reduce post-contrast acute kidney injury (PC‑AKI) risk in patients with eGFR below the cut-off value (correct or incorrect eGFR)
the subsequent risk of PC‑AKI (depends on eGFR status and any actions to reduce PC‑AKI risk)
the risk of renal replacement therapy (depends on whether a patient had a PC‑AKI).
The model assessed 6 strategies to identify and manage treatment for patients with an eGFR less than 30 ml/min/1.73 m2:
laboratory testing only
risk factor screening with POC creatinine testing
risk factor screening with laboratory testing
risk factor screening with POC creatinine testing and laboratory testing
POC creatinine testing only
POC creatinine testing with laboratory testing.For strategies with sequential tests, only people who have a test result of eGFR less than 30 ml/min/1.73 m2 would go on to receive the next test in the sequence.
For each strategy that includes POC creatinine testing, the model considered separate strategies for each of the POC devices, to give 14 alternative testing strategies. The 3 devices considered in the model were i‑STAT Alinity, ABL800 FLEX and StatSensor because only these had sufficient data available to calculate classification probabilities.
## Model inputs
Population characteristics, including the probability of a patient being in 1 of 4 eGFR categories, are presented in table 4. The proportion of people attending a CT scan appointment without a recent eGFR measurement was used to estimate the throughput of POC creatinine devices.
## Table 4 Population parameters used in the model
Parameter
Input
Source
Probability of eGFR
Below 30 ml/min/1.73 m2: 0.006
to 45 ml/min/1.73 m2: 0.063
to 60 ml/min/1.73 m2: 0.154
ml/min/1.73 m2 or higher:0.777
Gamma distribution fitted to Mid Yorkshire NHS trust data
Age and proportion of men
years, 51.7%
Snaith et al. (2019)
% missing eGFR
Cope et al. (2017)
Patients per site
per month
Mid Yorkshire NHS trust data
Abbreviation: eGFR, estimated glomerular filtration rate.
The diagnostic accuracy data used for each of the tests included in the model are in table 5. The cut-off used to define a positive result is eGFR less than 30 ml/min/1.73 m2. The sensitivity of the tests is equivalent to the probability that a person with eGFR less than 30 ml/min/1.73 m2 is correctly categorised as having eGFR less than 30 ml/min/1.73 m2. The specificity of the POC creatinine devices was calculated by combining information on the distribution of population eGFR with the probability of having a classification of eGFR less than 30 ml/min/1.73 m2 for a given true eGFR category (a weighted average).
## Table 5 Diagnostic accuracy data
Test
Input
Source
Lab test
Sensitivity: 100%
Specificity: 100%
Assumption
i‑STAT Alinity
Sensitivity: 84.1%
Specificity: 98.9%
Evidence synthesis of point-of-care diagnostic accuracy – main analysis
ABL80 FLEX
Sensitivity: 86.1%
Specificity: 99.2%
StatSensor
Sensitivity: 73.9%
Specificity: 99.1%
Risk factor questionnaire
Sensitivity: 100%
Specificity: 65.2%
Too et al. (2015)
In the base-case analysis, an odds ratio of 0.97 (95% confidence interval 0.52 to 1.9) for the effect of preventative intravenous hydration was used for patients with an eGFR below 30 ml/min/1.73 m2 (Ahmed et al. 2018). It was assumed there would be no effect of intravenous hydration on risk for patients with an eGFR above 30 ml/min/1.73 m2 (AMACING trial). A scenario analysis was done using the lower bound of the odds ratio (0.52), implying a greater protective effect of intravenous hydration compared with the base-case analysis.
A fixed effects meta-analysis of 3 studies (Hinson et al. 2017; Davenport et al. 2013; McDonald et al. 2014) suggested no effect of contrast on PC‑AKI risk (odds ratio 0.98; 95% CI 0.88 to 1.08). It was therefore assumed in the base case that there was no effect of contrast on the risk of PC‑AKI. A scenario analysis exploring a greater risk of PC‑AKI in people with an eGFR of less than 30 ml/min/1.73 m2 was done.
The probability of having AKI after contrast for people with an eGFR of less than 30 ml/min/1.73 m2 or 30 ml/min/1.73 m2 and above depending on whether they had intravenous hydration or not is shown in table 6.
## Table 6 Probability of AKI after contrast
eGFR (ml/min/1.73 m
and hydration
Probability of AKI
Source
eGFR below 30 and IV hydration
Park et al. (2016)
eGFR below 30 and no IV hydration
Park et al. (2010), Ahmed et al. (2018)
eGFR 30 and above with IV hydration
Park et al. (2016)
eGFR 30 and above with no IV hydration
Assumption
Abbreviations: AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; IV, intravenous.
After having a CT scan, the probability that people who did not develop AKI after contrast needed renal replacement therapy was 0.014 and for people who did develop AKI after contrast was 0.111.
The model did not consider the effect of a delay in the planned CT scan on patient outcomes because of any change in their underlying condition during the waiting period.
It was assumed that 94.5% of people were alive 6 months after they had the CT scan, based on data reported in Park et al. (2016). The health-related quality-of-life data used in the base case are shown in table 7. No disutility from PC‑AKI or intravenous hydration was included in the model.
## Table 7 Health-related quality of life
Parameter
Value (QALYs)
Source
HRQoL adjusted life expectancy
Calculated from ONS mortality data and Ara and Brazier, 2010 general population utility equation
QALY loss from RRT
Wyld et al. (2012), and assuming 3 months of RRT
QALY loss from anxiety caused by delays
Assumption
Abbreviations: HRQoL, health-related quality of life; QALY, quality-adjusted life year; ONS, Office for National Statistics; RRT, renal replacement therapy.
Costs were calculated for each POC creatinine test, laboratory test, CT scan, intravenous hydration and for associated adverse events. The costs used in the model are shown in table 8. It was estimated that 92.6 patients per month would have a POC creatinine test. Risk factor screening before a POC creatinine test resulted in an estimated 32.6 patients per month having a POC test.
## Table 8 Costs used in the model
Parameter
Value
Source
Laboratory test
NHS reference costs 2017/18
Risk factor screening
Lederman et al. (2010), NHS reference costs 2017/18
i‑STAT Alinity without risk factor screening
Calculated from company data
ABL800 FLEX without risk factor screening
Calculated from company data
StatSensor without risk factor screening
Calculated from company data
i‑STAT Alinity with risk factor screening
Calculated from company data
ABL800 FLEX with risk factor screening
Calculated from company data
StatSensor with risk factor screening
Calculated from company data
Contrast-enhanced CT scan
NHS reference costs 2017/18
CT scan cancellation
NHS reference costs 2017/18, assumed to be the cost of an unenhanced CT scan
Intravenous hydration
NHS reference costs 2017/18
Adverse events from intravenous hydration
Nijssen et al. (2017), NHS reference costs 2017/18
Renal medicine follow up if test positive (from last test in sequence)
NHS reference costs 2017/18
Renal replacement therapy
NHS reference costs 2017/18; assuming 3 sessions per week over 3 months
## Base-case assumptions
The following assumptions were applied in the base-case analysis:
The laboratory test would have perfect diagnostic accuracy (100% sensitivity and specificity).
Risk factor screening in the model would be done with a generic risk factor questionnaire.
All patients having a laboratory test would have their CT scan cancelled and rebooked.
A positive test result at the last step of the testing sequence resulted in the scan being cancelled and rebooked with intravenous hydration and contrast-enhanced CT scan.
Adverse events from intravenous hydration were associated with costs but no health-related quality-of-life loss.
Mortality in the model was the same for all patients regardless of PC‑AKI status.
Mortality was independent of eGFR levels and PC‑AKI.
Renal replacement therapy consisted of haemodialysis.
## Base-case results
Deterministic and probabilistic results were presented as net monetary benefit and net health benefit using a maximum acceptable incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained. Incremental net benefit was calculated for each strategy compared with laboratory testing. A fully incremental analysis was also done, but because the incremental cost and QALY differences between the strategies were so small, the ICERs are of limited use. This is because they are very sensitive to extremely small differences in the QALYs. If pairwise ICERs had been calculated, all strategies that include POC creatinine devices would cost less and be less effective than the strategy of laboratory testing for all. Full results of the base case are shown in tables 9 and 10. In general:
Strategies that combine risk factor screening with POC creatinine testing and laboratory testing result in higher net benefit than other types of strategies, because they have a high positive predictive value. This avoids unnecessarily offering people who have false positive results intravenous hydration, which is associated with costs including cancelling and rebooking CT scans, giving intravenous hydration, treating intravenous hydration adverse events and patient follow up.
Strategies that combine risk factor screening with POC creatinine testing, without confirmatory laboratory testing, are the next highest ranking. These have lower overall specificity and give more false positive results, which are associated with increased costs from unnecessary management for patients whose results were misclassified as eGFR less than 30 ml/min/1.73 m2 (cancelling and rebooking CT scans, giving intravenous hydration, treating intravenous hydration adverse events and patient follow up).
Strategies with POC creatinine testing that do not use risk factor screening have lower average net benefit than POC creatinine test strategies that do, because of the higher costs of testing when all patients have POC creatinine testing.
The strategies using POC creatinine in isolation are the lowest ranking strategies involving POC creatinine testing, because they misclassify more patients' results as false positives and all patients incur the cost of POC testing.
Laboratory testing alone and risk factor screening then laboratory testing are the lowest ranking strategies. Although they have the highest QALY gains because they give no false positives or false negatives, they are associated with the highest costs, because of cancellation, rebooking and managing treatment for people who test positive.
## Table 9 Base-case probabilistic cost-effectiveness results – net benefit per patient presenting without a recent eGFR
## Table 10 Base-case cost-effectiveness deterministic results – full incremental analysis per patient presenting without a recent eGFR
The strategy with the highest incremental net benefit was strategy 6 (risk factor screening plus i‑STAT Alinity plus laboratory testing). In the probabilistic sensitivity analysis, this strategy had the highest probability of being the most cost effective (79.3% for maximum acceptable ICERs of £20,000 and £30,000 per QALY gained). It was also the least costly of all strategies compared, but gave fewer QALYs than most other strategies. The corresponding strategy with StatSensor, strategy 8, only had a marginally smaller average incremental net benefit (£87.11 compared with £87.42 for strategy 6). In the probabilistic sensitivity analysis, the probability of this strategy being the most cost effective at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained was 20.7%. Although ABL800 FLEX has the best diagnostic accuracy, strategies including testing with ABL800 FLEX have consistently lower net benefit than corresponding strategies with i‑STAT Alinity and StatSensor because of the higher costs of testing with this device.
The fully incremental ICER analysis showed that most strategies were dominated or extendedly dominated by strategy 6. Strategy 5 (risk factor screening plus laboratory testing) had an ICER of £3.61 billion per QALY gained compared with strategy 6.
## Analysis of alternative scenarios
Several scenario analyses were explored; results from most of the analyses were robust to changes in the assumptions. Some analyses caused strategy 8 (risk factor screening plus StatSensor plus laboratory testing) to become more cost effective than strategy 6 (risk factor screening plus i‑STAT Alinity plus laboratory testing). This was generally because of changes to the assumptions about the diagnostic accuracy and the costs of the POC creatinine tests. The scenario analysis in which there were no delays to CT scanning from laboratory testing with or without intravenous hydration resulted in strategy 5 (risk factor screening plus laboratory testing) and strategy 1 (laboratory testing) being more cost effective than strategies involving POC creatinine devices.
The base-case analysis was also replicated, adding 2 new strategies:
a 'no testing' strategy when all patients had a contrast-enhanced CT scan without testing for risk of PC‑AKI
a 'no testing' strategy combined with a greater reduction in risk of PC‑AKI from intravenous hydration.Both these strategies were associated with higher net benefit than other strategies included in the base-case analysis. That is, the no testing strategies were both less effective and cheaper than all other strategies.
An additional scenario analysis was done to consider the effect on the results if there was a higher risk of PC‑AKI than in the base case; the risk from contrast agent was increased and the protective effect of intravenous hydration was increased to give an absolute risk difference with and without hydration of 10.3%. The results of this analysis were consistent with the base case.# Committee discussion
# Current practice
## The safety of contrast agents has improved over time, but they may still increase the risk of acute kidney injury in some people
Historically contrast agents were much more toxic than those used in current practice, with side effects including kidney damage. Clinical experts noted that the risk of developing acute kidney injury (AKI) from contrast agents currently used in the NHS is thought to be very low, especially in people with an estimated glomerular filtration rate (eGFR) of 30 ml/min/1.73 m2 and above. However, they noted that there is some concern about the risk of post-contrast AKI (PC‑AKI) for people with an eGFR of less than 30 ml/min/1.73 m2, especially if they have other risk factors for kidney disease. Although end-stage renal disease after PC‑AKI is extremely rare, transient rises in creatinine (decreases in eGFR) can have clinical effects and increase mortality, especially if there are repeated rises. Patient experts noted that when a contrast-enhanced CT scan does lead to substantial kidney damage, the effect on a person's quality of life can be considerable. The committee concluded that the risk of PC‑AKI is very low for most people, but there may be a higher risk if eGFR is less than 30 ml/min/1.73 m2.
## NHS clinical practice varies on whether an eGFR result is needed for everyone having a contrast-enhanced CT scan
NICE's guideline on acute kidney injury recommends that the risk of AKI should be assessed before offering iodinated contrast agents to adults for emergency or non‑emergency imaging, and that increased risk is associated with an eGFR less than 40 ml/min/1.73 m2. However, the Royal Australian and New Zealand College of Radiologists iodinated contrast guidelines, which have been endorsed by the Royal College of Radiologists, recommend that an eGFR is only needed before offering iodinated contrast agents if there are risk factors for AKI. The committee noted that these 2 approaches have resulted in variation in clinical practice in the NHS. Some trusts need a recent eGFR result from all patients before doing a contrast-enhanced CT scan. Other trusts will do a contrast-enhanced CT scan without a recent eGFR result if there is a low risk of AKI. The definition of 'recent' may vary between 3 and 12 months in practice.
# Clinical effectiveness
## The diagnostic accuracy of the point-of-care creatinine devices is acceptable, but there is uncertainty, particularly for StatSensor
The evidence showed that the 3 devices with diagnostic accuracy data (ABL800 FLEX, i‑STAT Alinity and StatSensor) perform reasonably well in classifying eGFR into the correct categories. The committee noted that measuring creatinine using the point-of-care (POC) creatinine devices is not as accurate as laboratory measurement. Therefore, there would be some false positive results (incorrectly categorised as eGFR below 30 ml/min/1.73 m2; people would have intravenous hydration unnecessarily) and false negative results (incorrectly categorised as an eGFR of 30 ml/min/1.73 m2 and above; people would miss out on intravenous hydration). However, the number of these would be small. A clinical expert explained that the tests are more accurate at high levels of creatinine (low eGFR values), which is when clinical decision making is the most critical. StatSensor appeared to be less accurate than the other 2 devices, but the committee noted that the 95% credible intervals for sensitivity for the different devices overlapped. This means that the sensitivity of StatSensor could be as good as the other devices. The committee acknowledged that the laboratory reference standard used to calculate diagnostic accuracy for the POC creatinine devices was assumed to be 100% accurate, which is probably not the case. It also noted that the studies would have been done under controlled conditions and that the devices may not perform as well in clinical practice. The committee concluded that there was some uncertainty about whether ABL800 FLEX, i‑STAT Alinity and StatSensor can correctly categorise eGFR, but in general, the accuracy of the devices was acceptable.
## Further research in people with an eGFR of less than 30 ml/min/1.73 m2 would be helpful
The diagnostic accuracy studies included very few people with an eGFR less than 30 ml/min/1.73 m2. The committee noted that although this could affect the confidence placed on sensitivity calculations, it does reflect clinical practice because most people present for an outpatient CT scan with an eGFR of 30 ml/min/1.73 m2 and above. The committee concluded that further research in a population with eGFR less than 30 ml/min/1.73 m2 would be beneficial (see section 5.1).
## There is no evidence on rates of cancelled CT scans, PC‑AKI and patient experience
The value of the POC creatinine devices is that they prevent the cancellation and rebooking of CT scans, reduce PC‑AKI and improve the experience for patients attending for a CT scan by allowing same day assessment and decisions. The committee noted that there was no evidence on these outcomes and encouraged further research incorporating them (see section 5.3).
# Cost effectiveness
## The structure, inputs and assumptions used in the model are appropriate
The model only included people who present for an outpatient CT scan without a recent (within 3 months) eGFR result; it did not assess strategies for increasing the number of people who present for their CT scan with a recent eGFR result. The committee considered that the structure, inputs and assumptions used in the model were appropriate. It noted that the external assessment group (EAG) was unable to include the effect of delaying a planned CT scan on clinical outcomes relating to the underlying condition during a wait for a rescheduled scan. This was because there are many different reasons for having a CT scan and the effect of them all could not be quantified. The committee also noted that costs for training and laboratory governance of the POC creatinine devices were not included. A clinical expert explained that laboratory governance costs can vary considerably between trusts, depending on how much POC testing is already done across the trust and whether IT connectivity is already in place. The EAG estimated that annual implementation and governance costs would have to be over £80,000 to change conclusions from the economic model. Clinical experts agreed that these costs would be much lower than this and therefore concluded that the model analyses were acceptable for decision making.
## The strategy of 'no testing' is not an appropriate comparator for the model
The testing strategy in which people presenting for a CT scan without a recent eGFR had no further testing and had a contrast-enhanced scan without intravenous hydration resulted in the highest net benefit. The committee considered however, that no testing for anybody, regardless of whether risk factors were present, and giving contrast agent to all without intravenous hydration was not an appropriate comparator in the model. This was because it is not in line with national and international guidelines, which recommend assessing the risk of AKI because, although rare, when PC‑AKI does occur the consequences for an individual are substantial (see section4.1).
## The different testing strategies result in similar QALYs
The differences in quality-adjusted life years (QALYs) between the different testing strategies assessed were extremely small. The strategy in which all people presenting for a CT scan without a recent eGFR would have a laboratory test was associated with more QALYs than the strategies involving a POC creatinine device. The EAG explained that this was because the number of false negative test results (that is, when true eGFR is less than 30 ml/min/1.73 m2 but the test suggests an eGFR of 30 ml/min/1.73 m2 and above) is higher for strategies including POC creatinine devices than for the laboratory test (which is assumed to have 100% sensitivity). However, the QALY gain from appropriately managing treatment for people who have an eGFR of less than 30 ml/min/1.73 m2 is very small. The committee concluded that overall the clinical effectiveness is very similar across the different strategies. But it noted that the effect on quality of life for the small number of people who do develop kidney damage after a contrast-enhanced scan can be considerable (see section 4.1).
## The ABL800 FLEX has a higher cost per test than the i‑STAT Alinity and StatSensor
In the model, the POC creatinine devices were assumed to be used only for measuring creatinine and calculating eGFR, but the committee noted that some of the devices have multiple uses. For example, the ABL800 FLEX can measure 18 analytes, but test costs were not apportioned to other uses. Therefore, the cost per test for ABL800 FLEX was higher than for the i‑STAT Alinity and StatSensor. This led to strategies including ABL800 FLEX having lower net benefit than strategies involving i‑STAT Alinity or StatSensor. The committee noted that, depending on the setting of the radiology department, an ABL800 FLEX could also be used by different departments, which would reduce the cost per test because the throughput would be higher.
## The opportunity cost of cancelling CT scans is a key factor influencing model results
In the model, if a scan was cancelled and rebooked because of a positive POC creatinine test result or the need for a laboratory test, then a cost of £87.92 (equal to the cost of an unenhanced scan) was included. The committee noted that this assumes that the cancelled CT scan appointment cannot be filled. Clinical experts explained that in radiology departments that do both acute (emergency and inpatients) and elective (outpatient) CT scans these cancelled appointments would be filled by other patients waiting for CT scans. However, if the radiology department only does elective CT scans, for example a mobile clinic, then the cancelled appointment is unlikely to be filled and the cost assigned to a cancelled scan is appropriate. The committee also considered that using an unenhanced CT reference cost as a proxy for the rebooked CT scan could overestimate the opportunity cost because the cost of cancellation would already be accounted for in the fully absorbed reference cost. The committee noted that a scenario analysis of the model was run in which no CT scans were cancelled because of a laboratory test. The results of this analysis showed that the strategies of laboratory testing for all or risk factor screening followed by laboratory testing were the most cost effective. However, in the scenario in which 25% of CT scans were cancelled because of a laboratory test, laboratory testing for all returned to being the least cost-effective strategy. The committee acknowledged that cancelled CT scans are not only an opportunity cost for the NHS, but would not be good for patients, who would have to return to the hospital for a rebooked CT scan. The committee concluded that there was uncertainty in the opportunity cost associated with cancelling CT scans and therefore in the optimal strategy.
## Risk factor screening is an appropriate first step for people presenting for a CT scan without a recent eGFR result
Strategies in which risk factor screening was done first followed by a POC creatinine test for people who were identified as having at least one risk factor were more cost effective than strategies in which POC creatinine testing was done for all people presenting for a CT scan without an eGFR. The committee noted that including risk factor screening as a first step reduced the number of POC creatinine tests that would be done, which reduced the overall cost of testing. In the model, risk factor screening was assumed to be done with a generic risk factor questionnaire that had 100% sensitivity and 65.2% specificity. The committee agreed that risk factor screening should identify people at higher risk of AKI. But it noted that defined questionnaires had not been assessed, although risk factors are clearly stated in national and international guidelines. The committee concluded that risk factor screening is likely to be an appropriate first step for people presenting for a CT scan without an eGFR, but that further research should be done to develop a suitable risk tool or validate an existing risk tool for use in the NHS (see section 5.2).
## Test strategies that include laboratory confirmation of a positive result from a POC device would not be good for patients
The strategies with the highest net benefit in the model were those that combined risk factor screening, a POC creatinine test for all people identified as having at least one risk factor, and a final confirmatory laboratory test for people who have a positive test result from a POC device. A confirmatory laboratory test would result in the CT scan being cancelled and rebooked. In practice this often means that the referral for CT would be cancelled, resulting in another referral having to be made for the patient. A patient expert explained that cancelling a CT scan would not be good for patients and their carers because it would take time to go for a blood test, wait for another referral and return to the hospital for the rebooked CT scan. This may also be associated with travel expenses, time off work, and anxiety about the scan and the underlying clinical condition, most of which were not captured in the model. The committee noted that people with a true eGFR of 30 ml/min/1.73 m2 and above who are identified as having an eGFR of less than 30 ml/min/1.73 m2 using a POC creatinine device (false positive) would have intravenous hydration unnecessarily, which is associated with additional cost, but not with a QALY loss. It therefore concluded that although a strategy with a confirmatory laboratory test is slightly cheaper, it should not be considered further because of the negative experience for patients and their carers of cancelling the CT scan, going for a blood test and returning for the rescheduled CT scan.
## POC creatinine devices could have a greater benefit for some people
Men, people over the age of 60, and those of African-Caribbean, African or South Asian family origin are at higher risk of kidney disease than others. The committee noted that people of these family origins are not often included in research studies, but the availability of POC creatinine devices could have a greater benefit for them than for the rest of the population. This is because in some trusts if a person is at low risk of PC‑AKI, eGFR would not be measured before a contrast-enhanced CT scan (see section 4.2). Men, people over the age of 60, and those of African-Caribbean, African or South Asian family origin thought to be at low risk of PC‑AKI based on clinical factors may still have a higher risk than other people.
## POC creatinine devices are likely to be a cost-effective use of NHS resources and improve patient experience in some situations
The committee concluded that using POC creatinine devices to guide the use of contrast in outpatient CT scans is likely to be cost effective and improve patient experience if current protocols need all outpatients to have a recent eGFR result before a contrast-enhanced CT scan can be done (see section 4.2). The committee agreed that the most appropriate testing strategy was to use a risk factor screening questionnaire and then a POC creatinine device to test people with one or more risk factors (see section 4.11), without laboratory confirmation of positive test results (eGFR less than 30 ml/min/1.73 m2; see section 4.12). It acknowledged that:
POC creatinine test results should not be used to make decisions about care other than the decision to give contrast agent because of their lower accuracy than laboratory creatinine measurement.
POC creatinine testing should be set up and run as a collaboration between the radiology department and the pathology laboratory.
POC creatinine testing should only be done when clear laboratory governance structures for point-of-care testing are in place.
## Optimal care is for the referrer to provide a recent eGFR measurement and for all patients to receive diagnostic imaging
The committee noted that a risk of PC‑AKI should not prevent diagnostic images being taken to inform treatment decisions. All patients in whom contrast-enhanced CT imaging is indicated should get a form of imaging that enables access to treatment they might need. The committee acknowledged that POC creatinine devices are less accurate than laboratory creatinine testing. Therefore, patients who arrive at a CT scan appointment with a recent eGFR result are most likely to have appropriate management of their condition. The committee noted that these patients were not included in the economic model, but that a scenario in which all referrers provide an eGFR measurement before a CT scan appointment is likely to be the optimal approach, and that this approach should be encouraged to avoid higher numbers of patients needing POC creatinine measurement before a contrast-enhanced CT scan.# Recommendations for further research
The committee recommended further research on the incidence and effect of post-contrast acute kidney injury (PC‑AKI) in people with eGFR less than 30 ml/min/1.73 m2.
The committee recommended that a suitable risk factor screening tool for identifying risk of PC‑AKI for use across the NHS in people presenting for an outpatient CT scan with contrast agent is developed or an existing tool is validated.
The committee recommended studies to collect data on the rates of cancelled CT scans, whether cancelled appointments are filled and the effect on patients' experience before and after the introduction of point-of-care (POC) creatinine devices to radiology departments.
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{'Recommendations': "Point-of-care creatinine devices ABL800 FLEX, i‑STAT Alinity and StatSensor, which calculate estimated glomerular filtration rate (eGFR), are recommended to assess kidney function to guide decisions on whether to use intravenous contrast during an outpatient CT scan in adults. They should only be used when current practice is that a recent eGFR result must be available before a person has a CT scan with intravenous contrast and if all the following apply:\n\na person presents for a CT scan without a recent eGFR result\n\nthe person has risk factors for acute kidney injury\n\nclear governance structures for point-of-care testing are in place.\n\nTake age, sex and ethnicity into account when assessing risk of acute kidney injury using a questionnaire-based tool (see section\xa04.13).\n\nPoint-of-care creatinine devices ABL90 FLEX PLUS, Dri‑chem NX500, epoc Blood Analysis System, and Piccolo Xpress are not recommended to assess kidney function to guide decisions on whether to use intravenous contrast during an outpatient CT scan. This is because there are insufficient data to assess their diagnostic accuracy.\n\nFurther research is recommended to:\n\nbetter understand the level of risk of contrast-induced acute kidney injury (see section\xa05.1)\n\nidentify the most appropriate tool for identifying risk factors (see section\xa05.2)\n\nmonitor the effect of implementation on patient experience and efficiency in radiology departments (see section\xa05.3).\n\nWhy the committee made these recommendations\n\nIt's important to check whether the kidneys are working properly by measuring eGFR before a contrast-enhanced CT scan. This is because the contrast agent can cause acute kidney injury in people with low eGFR.\n\nNormally, referrers will provide a laboratory eGFR measurement before a CT scan appointment but in cases where a person presents without a recent eGFR result, point-of-care creatinine devices can measure creatinine levels and be used to calculate eGFR rapidly. This means that people who do not have a recent eGFR result will not need to have their CT scan cancelled so that their creatinine can be measured in the laboratory. Referrers providing a laboratory eGFR measurement before a CT scan appointment remains the optimal approach, and this approach should be encouraged to avoid higher numbers of patients needing point-of-care (POC) creatinine measurement before a contrast-enhanced CT scan.\n\nEvidence suggests that the ABL800 FLEX, i‑STAT Alinity and StatSensor all have acceptable accuracy in determining when eGFR is low (below 30\xa0ml/min/1.73\xa0m2). It was not possible to determine whether one is more accurate than another. Economic modelling shows that all 3\xa0devices offer value for money to the NHS when compared with delaying scans for laboratory creatinine testing, although more people with an eGFR of less than 30\xa0ml/min/1.73\xa0m2 may be identified if they had laboratory testing. Using the devices can also avoid cancelling and rebooking CT scans, which is important for patients. The devices offer the most value for money when:\n\nthey are used only for people who have one\xa0or more risk factors for acute kidney injury and\n\ncancelled CT scan appointments cannot be offered to other people.", 'The diagnostic tests': "# Clinical need and practice\n\n## The problem addressed\n\nPoint-of-care (POC) creatinine devices allow rapid measurement of creatinine levels and calculation of estimated glomerular filtration rate (eGFR). This can show whether the kidneys are working properly. The focus of this assessment is POC creatinine testing to assess kidney function before people have intravenous contrast for CT imaging. Intravenous iodine-based contrast agents used in CT scans can cause acute kidney injury (AKI), particularly in people who are at high risk and those with known kidney dysfunction. If a person has a low eGFR, intravenous hydration can be offered before the scan to reduce the risk of AKI. If a person does not have a recent eGFR measurement, their CT scan could be cancelled and rescheduled while a creatinine test is processed in the laboratory.\n\nUsing POC creatinine tests before outpatient contrast-enhanced CT scans in the radiology department could minimise the risk of kidney injury. It could also reduce the number of cancelled scans, which is important for patients.\n\n## The condition\n\nAKI covers injury to the kidneys from a number of causes; it often happens as a complication of another serious illness. If AKI is not treated promptly, levels of salts and chemicals in the body can increase, which affects the fluid balance in the body and how well other organs work.\n\nPost-contrast AKI (PC‑AKI) is a sudden deterioration in kidney function within 48\xa0to 72\xa0hours of administering intravenous iodine-based contrast agent. Incidence in patients having non-emergency CT scans with intravenous contrast agent is reported to be less than 1% (Ozkok et\xa0al. 2017). Risk factors for PC‑AKI include chronic kidney disease, critical illness, contrast-enhanced imaging done as an emergency, older age, diabetes, use of nephrotoxic drugs and reduced kidney function (for example, if a person is dehydrated or has congestive heart failure). Short- and long-term mortality rates are significantly higher in patients with PC‑AKI than in patients without PC‑AKI. A history of PC‑AKI may be also be associated with development of chronic kidney disease and progression to end-stage renal disease.\n\n## The care pathways\n\nNICE's guideline on acute kidney injury: prevention, detection and management says that before using iodinated contrast agents for imaging, kidney function should be checked and the risk of AKI assessed. It recommends that eGFR should be measured within 3\xa0months of using iodinated contrast agents.\n\nThe threshold for eGFR at which there is a risk of developing PC‑AKI varies across different guidelines, ranging between 30\xa0ml/min/1.73\xa0m2 (The Royal Australian and New Zealand College of Radiologists iodinated contrast guidelines , which have been endorsed by the Royal College of Radiologists) and 60\xa0ml/min/1.73\xa0m2 (Renal Association guideline on the prevention of CI-AKI in adult patients , in the Acute Kidney Injury guideline). Clinical experts suggested that people with an eGFR of less than 30\xa0ml/min/1.73\xa0m2 are at highest risk of developing PC‑AKI.\n\nGuidelines recommend that adults having iodinated contrast agents at increased risk of PC‑AKI should:\n\nbe offered intravenous volume expansion\n\nconsider temporarily stopping angiotensin-converting enzyme inhibitors and angiotensin receptor blockers\n\nhave a nephrology team discuss their care if there are contraindications to intravenous fluids.\n\nIf PC‑AKI develops, NICE's guideline on acute kidney injury recommends:\n\nrenal replacement therapy (dialysis) in some situations\n\nloop diuretics for treating fluid overload or oedema in people waiting to have dialysis, and in people who do not need dialysis.\n\nChildren were not included in the scope of this assessment because they often have alternative imaging, such as MRI scans, rather than CT scans. In addition, different eGFR equations are used for children and adults, so studies of POC creatinine devices in adult populations may not reflect the performance of these devices in children.\n\n# The interventions\n\nThe POC creatinine devices included in table\xa01 are CE marked and measure creatinine using an enzymatic method. Devices are either handheld, table-top or portable and need very small samples of whole blood from either finger-prick or venous or arterial samples. Creatinine can be measured either as one\xa0component of a panel of parameters, or as a single measurement on a test card or cartridge specific for creatinine or kidney function.\n\n## Table 1 POC creatinine devices\n\nManufacturer and devices\n\nDevice format\n\nParameters measured\n\nSample volume\n\nAnalysis time\n\neGFR equation used\n\nNova Biomedical\n\nStatSensor\n\nHandheld\n\nCreatinine only\n\nmicrolitres\n\nseconds\n\nMDRD, Cockcroft-Gault, CKD-EPI, Schwartz and Counahan-Barratt\n\nRelated models: StatSensor-i, StatSensor Xpress-i. All models allow offset adjustment of results. StatSensor and StatSensor-i also allow slope adjustment.\n\nAbbott\n\ni‑STAT Alinity\n\nHandheld\n\nMultiple parameters\n\nmicrolitres\n\nminutes\n\nMDRD and CKD-EPI\n\nRelated models: i‑STAT 1, many studies simply state 'i‑STAT'\n\nRadiometer\n\nABL90 FLEX PLUS\n\nPortable\n\nparameters\n\nmicrolitres\n\nseconds\n\nCKD-EPI, MDRD and Schwartz\n\nABL800 FLEX\n\nTable-top\n\nparameters\n\nto\xa0250 microlitres\n\nminute\n\nCKD-EPI and MDRD\n\nRelated models: ABL827, ABL837\n\nSiemens Healthineers\n\nEpoc Blood Analysis System\n\nHandheld\n\nparameters on 1\xa0test card\n\nmicrolitres\n\nLess than 1\xa0minute\n\nCKD-EPI, MDRD and Schwartz\n\nAbaxis\n\nPiccolo Xpress\n\nTable-top\n\nMultiple parameters\n\nmicrolitres\n\nLess than 14\xa0minutes\n\nMDRD\n\nFujifilm\n\nDri‑chem NX500\n\nTable-top\n\nMultiple parameters\n\nmicrolitre\n\nminutes\n\nExpected\n\nAbbreviations: CKD-EPI, chronic kidney disease epidemiology; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease.\n\n# The comparators\n\nThere were 2\xa0comparators used in the assessment:\n\nlaboratory-based serum creatinine measurement and eGFR\n\nclinical judgement alone (no testing).", 'Evidence': "The diagnostics advisory committee (section\xa07) considered evidence on point-of-care (POC) creatinine devices to assess kidney function before CT imaging with intravenous contrast from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) systematically reviewed:\n\nstudies comparing the results of POC creatinine tests with laboratory-based tests to assess kidney function in any non-emergency setting\n\nstudies reporting clinical or implementation outcomes of POC creatinine tests to assess kidney function before CT imaging in a non-emergency, outpatient setting.\n\nThere were 54\xa0studies in the review. Of those, 12\xa0studies reported diagnostic accuracy data for estimated glomerular filtration rate (eGFR), 7\xa0studies reported diagnostic accuracy data for serum creatinine, 50\xa0studies presented data on correlation or measurement bias between a POC creatinine device and a laboratory reference test, and 6\xa0studies reported data on workflow or implementation.\n\n## Correlation and measurement bias\n\nResults from the StatSensor studies showed wide variation in the size and direction of measurement bias. StatSensor devices can be adjusted to correct for any bias seen, to align the POC creatinine device results with those from local laboratory methods. Only 2\xa0StatSensor studies reported using an adjustment function for measurement bias. Although potentially important measurement bias was found in some studies of i‑STAT and ABL devices, the concordance of results for these devices was generally better than for the StatSensor devices. A smaller number of studies were available on the epoc (1\xa0study) and Piccolo Xpress (4\xa0studies) devices.\n\nThere were 3\xa0studies comparing different types of POC creatinine devices. Of these, 2\xa0studies compared StatSensor, i‑STAT and ABL800 FLEX. Both studies found that the ABL800 FLEX had the strongest agreement with laboratory serum creatinine, then i‑STAT and then StatSensor. There was 1\xa0study comparing an ABL827 device with an i‑STAT device. It concluded that creatinine results from both devices correlated well with laboratory serum creatinine.\n\nIn some studies, measurement bias increased at higher creatinine levels (lower eGFR). This could affect care decisions for people at higher risk of kidney damage.\n\n## Diagnostic accuracy based on eGFR thresholds\n\nThere were 12\xa0studies reporting diagnostic accuracy data on eGFR thresholds. Studies were of different devices, with some studies assessing more than one device:\n\ni‑STAT studies\n\nStatSensor studies\n\nstudies included a Radiometer POC device (ABL800 or ABL827)\n\nstudies assessed 3\xa0POC devices (ABL, i‑STAT and StatSensor) and\n\nstudy looked at 2\xa0devices (ABL and i‑STAT).There were no studies of ABL90 FLEX PLUS, Dri‑chem NX500, epoc Blood Analysis System and Piccolo Xpress. The eGFR equations used in the studies varied, with only 3\xa0studies using chronic kidney disease epidemiology (CKD-EPI). There were 3\xa0StatSensor and 2\xa0i‑STAT studies that used an adjustment function to correct for any measurement bias between the POC creatinine test results and laboratory test results from the study sample. Adjusted and unadjusted results were reported in all 3\xa0StatSensor studies, but only adjusted results were presented in the 2\xa0i‑STAT studies. Most studies used an enzymatic method as the laboratory reference, but the Jaffe method was used in 2\xa0studies and the reference method was not reported in 1\xa0study.\n\nThere were 6\xa0studies at low risk across all risk of bias areas, including 2\xa0studies of ABL800, 3\xa0studies of i‑STAT and 3\xa0studies of StatSensor. The other 6\xa0studies had at least one domain at unclear or high risk of bias. Risks of bias related to:\n\nhow the adjustment function to correct for measurement bias was applied\n\npatient selection\n\nthe use of a different modification of the diet in renal disease (MDRD) eGFR equation between the POC creatinine test and laboratory reference test\n\nthe use of a Jaffe method for the laboratory reference test (compared with an enzymatic method for the POC creatinine test).\n\nThere were low concerns about the applicability of results across all domains for only 2\xa0studies, including 1\xa0study of ABL800, i‑STAT and StatSensor (Snaith et\xa0al. 2018), and 1\xa0study of i‑STAT (Snaith et\xa0al. 2019). The most common concern was the use of eGFR threshold; 3\xa0studies used an eGFR cut-off of 60\xa0ml/min/1.73\xa0m2 or above. Several studies included disease-specific populations, therefore their applicability to a broader population of outpatients referred for CT scan without a recent eGFR may be limited.\n\nThe EAG quantitatively analysed the study results. The probabilities of being in each eGFR category were calculated from the number of people in each category reported by all included studies (regardless of the device assessed). The pooled probabilities of being in each of the 4\xa0categories are in table\xa02. Most studies only included a few people in category\xa01 (eGFR less than 30\xa0ml/min/1.73\xa0m2) and more people in higher eGFR categories.\n\n## Table 2 Estimated probabilities of being in each eGFR category\n\nCategory\n\neGFR\n\n(ml/min/1.73\xa0m\n \n \n 2\n \n )\n\nAll data\n\nMedian\n\n% CrI\n\n\n\nto 29\n\n\n\nto 0.017\n\n\n\nto 44\n\n\n\nto 0.064\n\n\n\nto 59\n\n\n\nto 0.159\n\n\n\nor higher\n\n\n\nto 0.803\n\nAbbreviations: eGFR, estimated glomerular filtration rate; CrI, credible interval.\n\nThe pooled probabilities of having a classification by a POC creatinine device in each eGFR category (k) and in each laboratory-defined eGFR category (j) are given in table\xa03. The i‑STAT and ABL devices have higher median probabilities of correct classification in each of the 3\xa0lowest categories (p[1,1], p[2,2], p[3,3]) compared with the StatSensor. StatSensor was particularly poor at correctly classifying category\xa03 (eGFR 45\xa0to 59\xa0ml/min/1.73\xa0m2). However, there is considerable uncertainty in these probabilities for all devices.\n\n## Table 3 Estimated probabilities of being classified in each eGFR category by POC creatinine device\n\np[j,k]\n\nStatSensor\n\ni‑STAT\n\nABL (Radiometer)\n\nMedian\n\n% CrI\n\nMedian\n\n% CrI\n\nMedian\n\n% CrI\n\np[1,1]\n\n\n\nto 0.85\n\n\n\nto 0.94\n\n\n\nto 0.95\n\np[1,2]\n\n\n\nto 0.30\n\n\n\nto 0.18\n\n\n\nto 0.14\n\np[1,3]\n\n\n\nto 0.12\n\n\n\nto 0.18\n\n\n\nto 0.14\n\np[1,4]\n\n\n\nto 0.11\n\n\n\nto 0.16\n\n\n\nto 0.15\n\np[2,1]\n\n\n\nto 0.19\n\n\n\nto 0.21\n\n\n\nto 0.11\n\np[2,2]\n\n\n\nto 0.71\n\n\n\nto 0.87\n\n\n\nto 0.90\n\np[2,3]\n\n\n\nto 0.36\n\n\n\nto 0.21\n\n\n\nto 0.29\n\np[2,4]\n\n\n\nto 0.24\n\n\n\nto 0.06\n\n\n\nto 0.15\n\np[3,1]\n\n\n\nto 0.03\n\n\n\nto 0.05\n\n\n\nto 0.08\n\np[3,2]\n\n\n\nto 0.20\n\n\n\nto 0.17\n\n\n\nto 0.16\n\np[3,3]\n\n\n\nto 0.34\n\n\n\nto 0.88\n\n\n\nto 0.85\n\np[3,4]\n\n\n\nto 0.69\n\n\n\nto 0.13\n\n\n\nto 0.26\n\np[4,1]\n\n\n\nto 0.01\n\n\n\nto 0.01\n\n\n\nto 0.01\n\np[4,2]\n\n\n\nto 0.01\n\n\n\nto 0.02\n\n\n\nto 0.01\n\np[4,3]\n\n\n\nto 0.08\n\n\n\nto 0.10\n\n\n\nto 0.01\n\np[4,4]\n\n\n\nto 0.95\n\n\n\nto 0.93\n\n\n\nto 0.99\n\neGFR categories (ml/min/1.73\xa0m2): 1=0 to 29; 2=30 to 44, 3=5 to 59; 4=60 or higher.\n\nAbbreviation: CrI, credible interval.\n\nAdditional analyses were done to assess the effect of removing studies with limited applicability to clinical practice in the NHS. The pooled probabilities from these analyses were used in scenario analyses in the economic model:\n\nStatSensor devices allow a user-specified adjustment if systematic measurement bias is identified. An additional analysis including the adjusted data reported by Korpi-Steiner et\xa0al. (2009) and Shephard et\xa0al. (2010) was done. The Inoue et\xa0al. (2017) study was not included in this analysis because the reported adjustment could not be replicated in NHS practice.\n\nOnly 2\xa0studies used the CKD-EPI equation to calculate eGFR, all others used the MDRD equation. Of these studies, one included StatSensor, i‑STAT and ABL800 FLEX devices (Snaith et\xa0al. 2018) and the other only included an i‑STAT device (Snaith et\xa0al. 2019). An additional analysis using only the data in these 2\xa0studies was done.\n\n## Clinical, workflow or implementation outcomes\n\nThere were 6\xa0studies reporting a relevant outcome after using a POC creatinine device. The results showed variation in practice in both the proportions of patients who do not have a recent eGFR result and in the management decisions when a POC creatinine device shows an abnormal eGFR. For example, the proportion of people offered scans with or without contrast, or offered a reduced dose of contrast. Also, many of the studies were done several years ago so the value of their results is limited because eGFR thresholds for defining an abnormal result have decreased over time. No data were available on clinical outcomes such as need for renal replacement therapy or hospital admissions.\n\n# Cost effectiveness\n\nThe EAG identified existing studies on the cost effectiveness of POC creatinine tests in an outpatient non-emergency secondary care setting, to assess kidney function before contrast-enhanced CT imaging. Because only a single cost-consequence analysis was found, provided as an academic-in-confidence manuscript, the EAG also constructed a de novo economic model to assess the cost effectiveness of POC creatinine tests.\n\n## Model structure\n\nThe model assessed a cohort of outpatients presenting for a non-emergency contrast-enhanced CT scan without a recent eGFR measurement. Costs were presented from the perspective of the NHS and personal social services and were reported in UK pounds at 2018 prices. Outcomes after the first year were discounted at a rate of 3.5% per year. Most costs happened in the first year and were therefore not discounted.\n\nThe model used a decision tree cohort approach to estimate the costs and health outcomes of the different testing and treatment strategies. The model captured:\n\ntrue eGFR status (less than 30\xa0ml/min/1.73\xa0m2 or 30\xa0ml/min/1.73\xa0m2 and above)\n\nhow eGFR status is classified by different testing strategies, using the eGFR cut-off value of 30\xa0ml/min/1.73\xa0m2 and probabilities conditional on true eGFR status\n\nany actions to reduce post-contrast acute kidney injury (PC‑AKI) risk in patients with eGFR below the cut-off value (correct or incorrect eGFR)\n\nthe subsequent risk of PC‑AKI (depends on eGFR status and any actions to reduce PC‑AKI risk)\n\nthe risk of renal replacement therapy (depends on whether a patient had a PC‑AKI).\n\nThe model assessed 6\xa0strategies to identify and manage treatment for patients with an eGFR less than 30\xa0ml/min/1.73\xa0m2:\n\nlaboratory testing only\n\nrisk factor screening with POC creatinine testing\n\nrisk factor screening with laboratory testing\n\nrisk factor screening with POC creatinine testing and laboratory testing\n\nPOC creatinine testing only\n\nPOC creatinine testing with laboratory testing.For strategies with sequential tests, only people who have a test result of eGFR less than 30\xa0ml/min/1.73\xa0m2 would go on to receive the next test in the sequence.\n\nFor each strategy that includes POC creatinine testing, the model considered separate strategies for each of the POC devices, to give 14\xa0alternative testing strategies. The 3\xa0devices considered in the model were i‑STAT Alinity, ABL800 FLEX and StatSensor because only these had sufficient data available to calculate classification probabilities.\n\n## Model inputs\n\nPopulation characteristics, including the probability of a patient being in 1\xa0of 4\xa0eGFR categories, are presented in table\xa04. The proportion of people attending a CT scan appointment without a recent eGFR measurement was used to estimate the throughput of POC creatinine devices.\n\n## Table 4 Population parameters used in the model\n\nParameter\n\nInput\n\nSource\n\nProbability of eGFR\n\nBelow 30\xa0ml/min/1.73\xa0m2: 0.006\n\nto 45\xa0ml/min/1.73\xa0m2: 0.063\n\nto 60\xa0ml/min/1.73\xa0m2: 0.154\n\nml/min/1.73\xa0m2 or higher:0.777\n\nGamma distribution fitted to Mid Yorkshire NHS trust data\n\nAge and proportion of men\n\nyears, 51.7%\n\nSnaith et\xa0al. (2019)\n\n% missing eGFR\n\n%\n\nCope et\xa0al. (2017)\n\nPatients per site\n\nper month\n\nMid Yorkshire NHS trust data\n\nAbbreviation: eGFR, estimated glomerular filtration rate.\n\nThe diagnostic accuracy data used for each of the tests included in the model are in table\xa05. The cut-off used to define a positive result is eGFR less than 30\xa0ml/min/1.73\xa0m2. The sensitivity of the tests is equivalent to the probability that a person with eGFR less than 30\xa0ml/min/1.73\xa0m2 is correctly categorised as having eGFR less than 30\xa0ml/min/1.73\xa0m2. The specificity of the POC creatinine devices was calculated by combining information on the distribution of population eGFR with the probability of having a classification of eGFR less than 30\xa0ml/min/1.73\xa0m2 for a given true eGFR category (a weighted average).\n\n## Table 5 Diagnostic accuracy data\n\nTest\n\nInput\n\nSource\n\nLab test\n\nSensitivity: 100%\n\nSpecificity: 100%\n\nAssumption\n\ni‑STAT Alinity\n\nSensitivity: 84.1%\n\nSpecificity: 98.9%\n\nEvidence synthesis of point-of-care diagnostic accuracy – main analysis\n\nABL80 FLEX\n\nSensitivity: 86.1%\n\nSpecificity: 99.2%\n\nStatSensor\n\nSensitivity: 73.9%\n\nSpecificity: 99.1%\n\nRisk factor questionnaire\n\nSensitivity: 100%\n\nSpecificity: 65.2%\n\nToo et\xa0al. (2015)\n\nIn the base-case analysis, an odds ratio of 0.97 (95% confidence interval [CI] 0.52 to 1.9) for the effect of preventative intravenous hydration was used for patients with an eGFR below 30\xa0ml/min/1.73\xa0m2 (Ahmed et\xa0al. 2018). It was assumed there would be no effect of intravenous hydration on risk for patients with an eGFR above 30\xa0ml/min/1.73\xa0m2 (AMACING trial). A scenario analysis was done using the lower bound of the odds ratio (0.52), implying a greater protective effect of intravenous hydration compared with the base-case analysis.\n\nA fixed effects meta-analysis of 3\xa0studies (Hinson et\xa0al. 2017; Davenport et\xa0al. 2013; McDonald et\xa0al. 2014) suggested no effect of contrast on PC‑AKI risk (odds ratio [OR] 0.98; 95% CI 0.88 to 1.08). It was therefore assumed in the base case that there was no effect of contrast on the risk of PC‑AKI. A scenario analysis exploring a greater risk of PC‑AKI in people with an eGFR of less than 30\xa0ml/min/1.73\xa0m2 was done.\n\nThe probability of having AKI after contrast for people with an eGFR of less than 30\xa0ml/min/1.73\xa0m2 or 30\xa0ml/min/1.73\xa0m2 and above depending on whether they had intravenous hydration or not is shown in table\xa06.\n\n## Table 6 Probability of AKI after contrast\n\neGFR (ml/min/1.73\xa0m\n \n 2\n \n )\n and hydration\n\nProbability of AKI\n\nSource\n\neGFR below 30 and IV hydration\n\n%\n\nPark et\xa0al. (2016)\n\neGFR below 30 and no IV hydration\n\n%\n\nPark et\xa0al. (2010), Ahmed et\xa0al. (2018)\n\neGFR 30 and above with IV hydration\n\n%\n\nPark et\xa0al. (2016)\n\neGFR 30 and above with no IV hydration\n\n%\n\nAssumption\n\nAbbreviations: AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; IV, intravenous.\n\nAfter having a CT scan, the probability that people who did not develop AKI after contrast needed renal replacement therapy was 0.014 and for people who did develop AKI after contrast was 0.111.\n\nThe model did not consider the effect of a delay in the planned CT scan on patient outcomes because of any change in their underlying condition during the waiting period.\n\nIt was assumed that 94.5% of people were alive 6\xa0months after they had the CT scan, based on data reported in Park et\xa0al. (2016). The health-related quality-of-life data used in the base case are shown in table\xa07. No disutility from PC‑AKI or intravenous hydration was included in the model.\n\n## Table 7 Health-related quality of life\n\nParameter\n\nValue (QALYs)\n\nSource\n\nHRQoL adjusted life expectancy\n\n\n\nCalculated from ONS mortality data and Ara and Brazier, 2010 general population utility equation\n\nQALY loss from RRT\n\n−0.0275\n\nWyld et\xa0al. (2012), and assuming 3\xa0months of RRT\n\nQALY loss from anxiety caused by delays\n\n\n\nAssumption\n\nAbbreviations: HRQoL, health-related quality of life; QALY, quality-adjusted life year; ONS, Office for National Statistics; RRT, renal replacement therapy.\n\nCosts were calculated for each POC creatinine test, laboratory test, CT scan, intravenous hydration and for associated adverse events. The costs used in the model are shown in table\xa08. It was estimated that 92.6\xa0patients per month would have a POC creatinine test. Risk factor screening before a POC creatinine test resulted in an estimated 32.6\xa0patients per month having a POC test.\n\n## Table 8 Costs used in the model\n\nParameter\n\nValue\n\nSource\n\nLaboratory test\n\n£3.31\n\nNHS reference costs 2017/18\n\nRisk factor screening\n\n£1.11\n\nLederman et\xa0al. (2010), NHS reference costs 2017/18\n\ni‑STAT Alinity without risk factor screening\n\n£8.85\n\nCalculated from company data\n\nABL800 FLEX without risk factor screening\n\n£15.73\n\nCalculated from company data\n\nStatSensor without risk factor screening\n\n£8.52\n\nCalculated from company data\n\ni‑STAT Alinity with risk factor screening\n\n£11.96\n\nCalculated from company data\n\nABL800 FLEX with risk factor screening\n\n£36.36\n\nCalculated from company data\n\nStatSensor with risk factor screening\n\n£14.25\n\nCalculated from company data\n\nContrast-enhanced CT scan\n\n£111.65\n\nNHS reference costs 2017/18\n\nCT scan cancellation\n\n£87.92\n\nNHS reference costs 2017/18, assumed to be the cost of an unenhanced CT scan\n\nIntravenous hydration\n\n£340.89\n\nNHS reference costs 2017/18\n\nAdverse events from intravenous hydration\n\n£32.76\n\nNijssen et\xa0al. (2017), NHS reference costs 2017/18\n\nRenal medicine follow up if test positive (from last test in sequence)\n\n£186.49\n\nNHS reference costs 2017/18\n\nRenal replacement therapy\n\n£9,758\n\nNHS reference costs 2017/18; assuming 3\xa0sessions per week over 3\xa0months\n\n## Base-case assumptions\n\nThe following assumptions were applied in the base-case analysis:\n\nThe laboratory test would have perfect diagnostic accuracy (100% sensitivity and specificity).\n\nRisk factor screening in the model would be done with a generic risk factor questionnaire.\n\nAll patients having a laboratory test would have their CT scan cancelled and rebooked.\n\nA positive test result at the last step of the testing sequence resulted in the scan being cancelled and rebooked with intravenous hydration and contrast-enhanced CT scan.\n\nAdverse events from intravenous hydration were associated with costs but no health-related quality-of-life loss.\n\nMortality in the model was the same for all patients regardless of PC‑AKI status.\n\nMortality was independent of eGFR levels and PC‑AKI.\n\nRenal replacement therapy consisted of haemodialysis.\n\n## Base-case results\n\nDeterministic and probabilistic results were presented as net monetary benefit and net health benefit using a maximum acceptable incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained. Incremental net benefit was calculated for each strategy compared with laboratory testing. A fully incremental analysis was also done, but because the incremental cost and QALY differences between the strategies were so small, the ICERs are of limited use. This is because they are very sensitive to extremely small differences in the QALYs. If pairwise ICERs had been calculated, all strategies that include POC creatinine devices would cost less and be less effective than the strategy of laboratory testing for all. Full results of the base case are shown in tables\xa09 and\xa010. In general:\n\nStrategies that combine risk factor screening with POC creatinine testing and laboratory testing result in higher net benefit than other types of strategies, because they have a high positive predictive value. This avoids unnecessarily offering people who have false positive results intravenous hydration, which is associated with costs including cancelling and rebooking CT scans, giving intravenous hydration, treating intravenous hydration adverse events and patient follow up.\n\nStrategies that combine risk factor screening with POC creatinine testing, without confirmatory laboratory testing, are the next highest ranking. These have lower overall specificity and give more false positive results, which are associated with increased costs from unnecessary management for patients whose results were misclassified as eGFR less than 30\xa0ml/min/1.73\xa0m2 (cancelling and rebooking CT scans, giving intravenous hydration, treating intravenous hydration adverse events and patient follow up).\n\nStrategies with POC creatinine testing that do not use risk factor screening have lower average net benefit than POC creatinine test strategies that do, because of the higher costs of testing when all patients have POC creatinine testing.\n\nThe strategies using POC creatinine in isolation are the lowest ranking strategies involving POC creatinine testing, because they misclassify more patients' results as false positives and all patients incur the cost of POC testing.\n\nLaboratory testing alone and risk factor screening then laboratory testing are the lowest ranking strategies. Although they have the highest QALY gains because they give no false positives or false negatives, they are associated with the highest costs, because of cancellation, rebooking and managing treatment for people who test positive.\n\n## Table 9 Base-case probabilistic cost-effectiveness results – net benefit per patient presenting without a recent eGFR\n\n## Table 10 Base-case cost-effectiveness deterministic results – full incremental analysis per patient presenting without a recent eGFR\n\nThe strategy with the highest incremental net benefit was strategy\xa06 (risk factor screening plus i‑STAT Alinity plus laboratory testing). In the probabilistic sensitivity analysis, this strategy had the highest probability of being the most cost effective (79.3% for maximum acceptable ICERs of £20,000 and £30,000 per QALY gained). It was also the least costly of all strategies compared, but gave fewer QALYs than most other strategies. The corresponding strategy with StatSensor, strategy\xa08, only had a marginally smaller average incremental net benefit (£87.11 compared with £87.42 for strategy\xa06). In the probabilistic sensitivity analysis, the probability of this strategy being the most cost effective at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained was 20.7%. Although ABL800 FLEX has the best diagnostic accuracy, strategies including testing with ABL800 FLEX have consistently lower net benefit than corresponding strategies with i‑STAT Alinity and StatSensor because of the higher costs of testing with this device.\n\nThe fully incremental ICER analysis showed that most strategies were dominated or extendedly dominated by strategy\xa06. Strategy\xa05 (risk factor screening plus laboratory testing) had an ICER of £3.61 billion per QALY gained compared with strategy\xa06.\n\n## Analysis of alternative scenarios\n\nSeveral scenario analyses were explored; results from most of the analyses were robust to changes in the assumptions. Some analyses caused strategy\xa08 (risk factor screening plus StatSensor plus laboratory testing) to become more cost effective than strategy\xa06 (risk factor screening plus i‑STAT Alinity plus laboratory testing). This was generally because of changes to the assumptions about the diagnostic accuracy and the costs of the POC creatinine tests. The scenario analysis in which there were no delays to CT scanning from laboratory testing with or without intravenous hydration resulted in strategy\xa05 (risk factor screening plus laboratory testing) and strategy\xa01 (laboratory testing) being more cost effective than strategies involving POC creatinine devices.\n\nThe base-case analysis was also replicated, adding 2\xa0new strategies:\n\na 'no testing' strategy when all patients had a contrast-enhanced CT scan without testing for risk of PC‑AKI\n\na 'no testing' strategy combined with a greater reduction in risk of PC‑AKI from intravenous hydration.Both these strategies were associated with higher net benefit than other strategies included in the base-case analysis. That is, the no testing strategies were both less effective and cheaper than all other strategies.\n\nAn additional scenario analysis was done to consider the effect on the results if there was a higher risk of PC‑AKI than in the base case; the risk from contrast agent was increased and the protective effect of intravenous hydration was increased to give an absolute risk difference with and without hydration of 10.3%. The results of this analysis were consistent with the base case.", 'Committee discussion': "# Current practice\n\n## The safety of contrast agents has improved over time, but they may still increase the risk of acute kidney injury in some people\n\nHistorically contrast agents were much more toxic than those used in current practice, with side effects including kidney damage. Clinical experts noted that the risk of developing acute kidney injury (AKI) from contrast agents currently used in the NHS is thought to be very low, especially in people with an estimated glomerular filtration rate (eGFR) of 30\xa0ml/min/1.73\xa0m2 and above. However, they noted that there is some concern about the risk of post-contrast AKI (PC‑AKI) for people with an eGFR of less than 30\xa0ml/min/1.73\xa0m2, especially if they have other risk factors for kidney disease. Although end-stage renal disease after PC‑AKI is extremely rare, transient rises in creatinine (decreases in eGFR) can have clinical effects and increase mortality, especially if there are repeated rises. Patient experts noted that when a contrast-enhanced CT scan does lead to substantial kidney damage, the effect on a person's quality of life can be considerable. The committee concluded that the risk of PC‑AKI is very low for most people, but there may be a higher risk if eGFR is less than 30\xa0ml/min/1.73\xa0m2.\n\n## NHS clinical practice varies on whether an eGFR result is needed for everyone having a contrast-enhanced CT scan\n\nNICE's guideline on acute kidney injury recommends that the risk of AKI should be assessed before offering iodinated contrast agents to adults for emergency or non‑emergency imaging, and that increased risk is associated with an eGFR less than 40\xa0ml/min/1.73\xa0m2. However, the Royal Australian and New Zealand College of Radiologists iodinated contrast guidelines, which have been endorsed by the Royal College of Radiologists, recommend that an eGFR is only needed before offering iodinated contrast agents if there are risk factors for AKI. The committee noted that these 2\xa0approaches have resulted in variation in clinical practice in the NHS. Some trusts need a recent eGFR result from all patients before doing a contrast-enhanced CT scan. Other trusts will do a contrast-enhanced CT scan without a recent eGFR result if there is a low risk of AKI. The definition of 'recent' may vary between 3\xa0and 12\xa0months in practice.\n\n# Clinical effectiveness\n\n## The diagnostic accuracy of the point-of-care creatinine devices is acceptable, but there is uncertainty, particularly for StatSensor\n\nThe evidence showed that the 3\xa0devices with diagnostic accuracy data (ABL800 FLEX, i‑STAT Alinity and StatSensor) perform reasonably well in classifying eGFR into the correct categories. The committee noted that measuring creatinine using the point-of-care (POC) creatinine devices is not as accurate as laboratory measurement. Therefore, there would be some false positive results (incorrectly categorised as eGFR below 30\xa0ml/min/1.73\xa0m2; people would have intravenous hydration unnecessarily) and false negative results (incorrectly categorised as an eGFR of 30\xa0ml/min/1.73\xa0m2 and above; people would miss out on intravenous hydration). However, the number of these would be small. A clinical expert explained that the tests are more accurate at high levels of creatinine (low eGFR values), which is when clinical decision making is the most critical. StatSensor appeared to be less accurate than the other 2\xa0devices, but the committee noted that the 95% credible intervals for sensitivity for the different devices overlapped. This means that the sensitivity of StatSensor could be as good as the other devices. The committee acknowledged that the laboratory reference standard used to calculate diagnostic accuracy for the POC creatinine devices was assumed to be 100% accurate, which is probably not the case. It also noted that the studies would have been done under controlled conditions and that the devices may not perform as well in clinical practice. The committee concluded that there was some uncertainty about whether ABL800 FLEX, i‑STAT Alinity and StatSensor can correctly categorise eGFR, but in general, the accuracy of the devices was acceptable.\n\n## Further research in people with an eGFR of less than 30\xa0ml/min/1.73\xa0m2 would be helpful\n\nThe diagnostic accuracy studies included very few people with an eGFR less than 30\xa0ml/min/1.73\xa0m2. The committee noted that although this could affect the confidence placed on sensitivity calculations, it does reflect clinical practice because most people present for an outpatient CT scan with an eGFR of 30\xa0ml/min/1.73\xa0m2 and above. The committee concluded that further research in a population with eGFR less than 30\xa0ml/min/1.73\xa0m2 would be beneficial (see section\xa05.1).\n\n## There is no evidence on rates of cancelled CT scans, PC‑AKI and patient experience\n\nThe value of the POC creatinine devices is that they prevent the cancellation and rebooking of CT scans, reduce PC‑AKI and improve the experience for patients attending for a CT scan by allowing same day assessment and decisions. The committee noted that there was no evidence on these outcomes and encouraged further research incorporating them (see section\xa05.3).\n\n# Cost effectiveness\n\n## The structure, inputs and assumptions used in the model are appropriate\n\nThe model only included people who present for an outpatient CT scan without a recent (within 3\xa0months) eGFR result; it did not assess strategies for increasing the number of people who present for their CT scan with a recent eGFR result. The committee considered that the structure, inputs and assumptions used in the model were appropriate. It noted that the external assessment group (EAG) was unable to include the effect of delaying a planned CT scan on clinical outcomes relating to the underlying condition during a wait for a rescheduled scan. This was because there are many different reasons for having a CT scan and the effect of them all could not be quantified. The committee also noted that costs for training and laboratory governance of the POC creatinine devices were not included. A clinical expert explained that laboratory governance costs can vary considerably between trusts, depending on how much POC testing is already done across the trust and whether IT connectivity is already in place. The EAG estimated that annual implementation and governance costs would have to be over £80,000 to change conclusions from the economic model. Clinical experts agreed that these costs would be much lower than this and therefore concluded that the model analyses were acceptable for decision making.\n\n## The strategy of 'no testing' is not an appropriate comparator for the model\n\nThe testing strategy in which people presenting for a CT scan without a recent eGFR had no further testing and had a contrast-enhanced scan without intravenous hydration resulted in the highest net benefit. The committee considered however, that no testing for anybody, regardless of whether risk factors were present, and giving contrast agent to all without intravenous hydration was not an appropriate comparator in the model. This was because it is not in line with national and international guidelines, which recommend assessing the risk of AKI because, although rare, when PC‑AKI does occur the consequences for an individual are substantial (see section4.1).\n\n## The different testing strategies result in similar QALYs\n\nThe differences in quality-adjusted life years (QALYs) between the different testing strategies assessed were extremely small. The strategy in which all people presenting for a CT scan without a recent eGFR would have a laboratory test was associated with more QALYs than the strategies involving a POC creatinine device. The EAG explained that this was because the number of false negative test results (that is, when true eGFR is less than 30\xa0ml/min/1.73\xa0m2 but the test suggests an eGFR of 30\xa0ml/min/1.73\xa0m2 and above) is higher for strategies including POC creatinine devices than for the laboratory test (which is assumed to have 100% sensitivity). However, the QALY gain from appropriately managing treatment for people who have an eGFR of less than 30\xa0ml/min/1.73\xa0m2 is very small. The committee concluded that overall the clinical effectiveness is very similar across the different strategies. But it noted that the effect on quality of life for the small number of people who do develop kidney damage after a contrast-enhanced scan can be considerable (see section\xa04.1).\n\n## The ABL800 FLEX has a higher cost per test than the i‑STAT Alinity and StatSensor\n\nIn the model, the POC creatinine devices were assumed to be used only for measuring creatinine and calculating eGFR, but the committee noted that some of the devices have multiple uses. For example, the ABL800 FLEX can measure 18\xa0analytes, but test costs were not apportioned to other uses. Therefore, the cost per test for ABL800 FLEX was higher than for the i‑STAT Alinity and StatSensor. This led to strategies including ABL800 FLEX having lower net benefit than strategies involving i‑STAT Alinity or StatSensor. The committee noted that, depending on the setting of the radiology department, an ABL800 FLEX could also be used by different departments, which would reduce the cost per test because the throughput would be higher.\n\n## The opportunity cost of cancelling CT scans is a key factor influencing model results\n\nIn the model, if a scan was cancelled and rebooked because of a positive POC creatinine test result or the need for a laboratory test, then a cost of £87.92 (equal to the cost of an unenhanced scan) was included. The committee noted that this assumes that the cancelled CT scan appointment cannot be filled. Clinical experts explained that in radiology departments that do both acute (emergency and inpatients) and elective (outpatient) CT scans these cancelled appointments would be filled by other patients waiting for CT scans. However, if the radiology department only does elective CT scans, for example a mobile clinic, then the cancelled appointment is unlikely to be filled and the cost assigned to a cancelled scan is appropriate. The committee also considered that using an unenhanced CT reference cost as a proxy for the rebooked CT scan could overestimate the opportunity cost because the cost of cancellation would already be accounted for in the fully absorbed reference cost. The committee noted that a scenario analysis of the model was run in which no CT scans were cancelled because of a laboratory test. The results of this analysis showed that the strategies of laboratory testing for all or risk factor screening followed by laboratory testing were the most cost effective. However, in the scenario in which 25% of CT scans were cancelled because of a laboratory test, laboratory testing for all returned to being the least cost-effective strategy. The committee acknowledged that cancelled CT scans are not only an opportunity cost for the NHS, but would not be good for patients, who would have to return to the hospital for a rebooked CT scan. The committee concluded that there was uncertainty in the opportunity cost associated with cancelling CT scans and therefore in the optimal strategy.\n\n## Risk factor screening is an appropriate first step for people presenting for a CT scan without a recent eGFR result\n\nStrategies in which risk factor screening was done first followed by a POC creatinine test for people who were identified as having at least one risk factor were more cost effective than strategies in which POC creatinine testing was done for all people presenting for a CT scan without an eGFR. The committee noted that including risk factor screening as a first step reduced the number of POC creatinine tests that would be done, which reduced the overall cost of testing. In the model, risk factor screening was assumed to be done with a generic risk factor questionnaire that had 100% sensitivity and 65.2% specificity. The committee agreed that risk factor screening should identify people at higher risk of AKI. But it noted that defined questionnaires had not been assessed, although risk factors are clearly stated in national and international guidelines. The committee concluded that risk factor screening is likely to be an appropriate first step for people presenting for a CT scan without an eGFR, but that further research should be done to develop a suitable risk tool or validate an existing risk tool for use in the NHS (see section\xa05.2).\n\n## Test strategies that include laboratory confirmation of a positive result from a POC device would not be good for patients\n\nThe strategies with the highest net benefit in the model were those that combined risk factor screening, a POC creatinine test for all people identified as having at least one risk factor, and a final confirmatory laboratory test for people who have a positive test result from a POC device. A confirmatory laboratory test would result in the CT scan being cancelled and rebooked. In practice this often means that the referral for CT would be cancelled, resulting in another referral having to be made for the patient. A patient expert explained that cancelling a CT scan would not be good for patients and their carers because it would take time to go for a blood test, wait for another referral and return to the hospital for the rebooked CT scan. This may also be associated with travel expenses, time off work, and anxiety about the scan and the underlying clinical condition, most of which were not captured in the model. The committee noted that people with a true eGFR of 30\xa0ml/min/1.73\xa0m2 and above who are identified as having an eGFR of less than 30\xa0ml/min/1.73\xa0m2 using a POC creatinine device (false positive) would have intravenous hydration unnecessarily, which is associated with additional cost, but not with a QALY loss. It therefore concluded that although a strategy with a confirmatory laboratory test is slightly cheaper, it should not be considered further because of the negative experience for patients and their carers of cancelling the CT scan, going for a blood test and returning for the rescheduled CT scan.\n\n## POC creatinine devices could have a greater benefit for some people\n\nMen, people over the age of 60, and those of African-Caribbean, African or South Asian family origin are at higher risk of kidney disease than others. The committee noted that people of these family origins are not often included in research studies, but the availability of POC creatinine devices could have a greater benefit for them than for the rest of the population. This is because in some trusts if a person is at low risk of PC‑AKI, eGFR would not be measured before a contrast-enhanced CT scan (see section\xa04.2). Men, people over the age of 60, and those of African-Caribbean, African or South Asian family origin thought to be at low risk of PC‑AKI based on clinical factors may still have a higher risk than other people.\n\n## POC creatinine devices are likely to be a cost-effective use of NHS resources and improve patient experience in some situations\n\nThe committee concluded that using POC creatinine devices to guide the use of contrast in outpatient CT scans is likely to be cost effective and improve patient experience if current protocols need all outpatients to have a recent eGFR result before a contrast-enhanced CT scan can be done (see section\xa04.2). The committee agreed that the most appropriate testing strategy was to use a risk factor screening questionnaire and then a POC creatinine device to test people with one or more risk factors (see section\xa04.11), without laboratory confirmation of positive test results (eGFR less than 30\xa0ml/min/1.73\xa0m2; see section\xa04.12). It acknowledged that:\n\nPOC creatinine test results should not be used to make decisions about care other than the decision to give contrast agent because of their lower accuracy than laboratory creatinine measurement.\n\nPOC creatinine testing should be set up and run as a collaboration between the radiology department and the pathology laboratory.\n\nPOC creatinine testing should only be done when clear laboratory governance structures for point-of-care testing are in place.\n\n## Optimal care is for the referrer to provide a recent eGFR measurement and for all patients to receive diagnostic imaging\n\nThe committee noted that a risk of PC‑AKI should not prevent diagnostic images being taken to inform treatment decisions. All patients in whom contrast-enhanced CT imaging is indicated should get a form of imaging that enables access to treatment they might need. The committee acknowledged that POC creatinine devices are less accurate than laboratory creatinine testing. Therefore, patients who arrive at a CT scan appointment with a recent eGFR result are most likely to have appropriate management of their condition. The committee noted that these patients were not included in the economic model, but that a scenario in which all referrers provide an eGFR measurement before a CT scan appointment is likely to be the optimal approach, and that this approach should be encouraged to avoid higher numbers of patients needing POC creatinine measurement before a contrast-enhanced CT scan.", 'Recommendations for further research': "The committee recommended further research on the incidence and effect of post-contrast acute kidney injury (PC‑AKI) in people with eGFR less than 30\xa0ml/min/1.73\xa0m2.\n\nThe committee recommended that a suitable risk factor screening tool for identifying risk of PC‑AKI for use across the NHS in people presenting for an outpatient CT scan with contrast agent is developed or an existing tool is validated.\n\nThe committee recommended studies to collect data on the rates of cancelled CT scans, whether cancelled appointments are filled and the effect on patients' experience before and after the introduction of point-of-care (POC) creatinine devices to radiology departments."}
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https://www.nice.org.uk/guidance/dg37
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Evidence-based recommendations on point-of-care creatinine devices to assess kidney function before CT imaging with intravenous contrast. The tests are ABL800 FLEX, i-STAT Alinity and StatSensor, ABL90 FLEX PLUS, Dri chem NX500, epoc Blood Analysis System, and Piccolo Xpress.
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474f9f4e095594d16960ae252f8beee812b4001d
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nice
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Rapid tests for group A streptococcal infections in people with a sore throat
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Rapid tests for group A streptococcal infections in people with a sore throat
Evidence-based recommendations on rapid tests for group A streptococcal infections in people aged 5 and over with a sore throat.
# Recommendations
This guidance covers using rapid tests for group A streptococcal (strep A) infections in people aged 5 and over with a sore throat.
For children under 5, assessment is described in NICE's guideline on fever in under 5s: assessment and initial management.
People who are at higher risk of complications, for example women who are pregnant or who have just had a baby, or people who are immunocompromised, should be offered antibiotics in line with NICE's guideline on antimicrobial prescribing for acute sore throat.
This guidance also does not cover using the rapid tests:
for people presenting with scarlet fever. Scarlet fever is a notifiable condition; its diagnosis and management is covered in guidance from Public Health England
to help manage outbreaks of strep A infections because this is different to using the tests for people presenting to healthcare providers with an uncomplicated sore throat.
Rapid tests for strep A infections are not recommended for routine adoption for people with a sore throat. This is because their effect on improving antimicrobial prescribing and stewardship, and on patient outcomes, as compared with clinical scoring tools alone, is likely to be limited. Therefore, they are unlikely to be a cost-effective use of NHS resources.
Why the committee made these recommendations
Unnecessary use of antibiotics can contribute to antimicrobial resistance, which is a public health concern. NICE's guideline on antimicrobial prescribing for acute sore throat aims to limit antibiotic use and reduce antimicrobial resistance. It advises that sore throat is self-limiting and so, in people who are otherwise healthy, antibiotics are usually not needed regardless of the cause (bacterial or viral). So, it is uncertain whether there is a clinical need for rapid testing for strep A infections in the people covered by this guidance. Also, the diagnostic accuracy of the tests in routine clinical practice is uncertain and likely to be highly variable. There is no evidence to suggest that using the rapid tests could reduce antibiotic prescribing or improve clinical outcomes for people with a sore throat, as compared with clinical scoring tools alone.
The economic modelling predicts a reduction in antibiotic use with the rapid tests, but this is based on uncertain evidence, and it is therefore unclear if it would be replicated in NHS practice. The introduction of the guideline on antimicrobial prescribing for acute sore throat may, on its own, substantially reduce antibiotic prescribing. There is also uncertainty about whether confirming a bacterial infection by rapid testing could lead to changes in patient and clinical behaviour that result in increased antibiotic prescribing when antibiotics would not usually be prescribed.
The predicted reduction in antibiotic use is included in the cost-effectiveness analyses for using rapid tests in people with a sore throat but the resulting incremental cost-effectiveness ratios (ICERs) are much higher than what NICE usually considers acceptable. There is no evidence on the wider benefits of using the tests on antimicrobial stewardship and onward transmission rates. So these potential benefits are not considered in the modelling. However, it is unlikely that the effect of capturing these wider benefits would reduce the ICERs to the extent that these tests would be considered a cost-effective use of NHS resources. The uncertainty and likely minimal effect the rapid tests would have on reducing antibiotic use also means that there are likely to be limited or no wider benefits. Therefore, the rapid tests are not recommended.# The diagnostic tests
# Clinical need and practice
Sore throat is usually a self-limiting condition that lasts about a week. In most cases it is caused by a virus but, in a few people, sore throat is caused by bacterial infection, usually group A streptococcus (strep A). Sore throat usually does not need antibiotic treatment, regardless of the cause (viral or bacterial). Most people get better without antibiotics and withholding antibiotics rarely leads to complications.
Unnecessary use of antibiotics can contribute to antimicrobial resistance. This is microorganisms' ability to withstand antimicrobial treatments such as antibiotics (that is, the antimicrobial treatments become ineffective). Addressing antimicrobial resistance is one of the key NHS priorities, described in the NHS 5‑year plan for how the UK will contribute to containing and controlling antimicrobial resistance by 2040.
NICE's guideline on antimicrobial prescribing for acute sore throat was developed to help limit antibiotic use and reduce antimicrobial resistance. The guidance advises that sore throat is self-limiting. Also, it recommends using clinical scoring criteria such as Centor or FeverPAIN to help identify people who are more or most likely to benefit from an antibiotic. However, the guidance does not cover the potential use of rapid tests for strep A to increase diagnostic confidence of strep A infection and guide antimicrobial prescribing.
The purpose of this assessment is to evaluate the clinical and cost effectiveness of using rapid tests to detect strep A infection in people with a sore throat aged 5 and over, to help appropriate prescribing of antibiotics. These tests are only intended for people who are identified as more or most likely to benefit from antibiotics by clinical scoring tools such as FeverPAIN or Centor.
# The condition
Sore throat is characterised by inflammation of the pharynx (pharyngitis) or inflammation of the tonsils (tonsillitis). Symptoms of a sore throat include pain in the throat, fever and a headache. Other symptoms could also include nausea, vomiting, abdominal pain, muscle pain, and rashes.
The most common cause of bacterial infection is strep A, accounting for about 80% of bacterial infections. The remaining 20% of bacterial infections are usually caused by group C and G streptococcus. Strep A throat infections are more common in children than adults and the incidence of strep A infections is highest in winter and spring.
Most cases of strep A infection resolve without complications. However, rarely complications can develop, such as rheumatic fever (affecting the heart), post-streptococcal glomerulonephritis (affecting the kidneys), or necrotising fasciitis (a severe infection of soft tissue). Strep A can also cause scarlet fever and invasive group A strep infections. Invasive group A strep infections happen when the bacteria move from the throat into other parts of the body. This can lead to sepsis or streptococcal toxic shock syndrome. The risk of invasive group A strep infections is usually very low, but is higher in older people (aged over 75 years), in whom the risk of associated mortality is also higher.
# The care pathway
The care pathway for assessing and treating a sore throat is outlined in NICE's guideline on antimicrobial prescribing for acute sore throat. Healthcare professionals should advise people with a sore throat that it usually gets better without treatment, and explain self-care measures.
Antibiotic prescribing for sore throat should be guided by the FeverPAIN or Centor clinical risk scoring tools, unless the patient is systemically very unwell, has symptoms and signs of a more serious illness or condition, or is at high risk of complications.
People with a FeverPAIN score of 0 or 1, or a Centor score of 0, 1 and 2 are unlikely to benefit from an antibiotic. They should be offered advice on self-care without an antibiotic prescription.
People with a FeverPAIN score of 2 or 3 might benefit from an antibiotic. They may be offered advice on self-care or a back‑up antibiotic prescription (to use if symptoms do not start to improve within 3 to 5 days or worsen rapidly or significantly at any time).
People with a FeverPAIN score of 4 or 5, or a Centor score of 3 or 4 are most likely to benefit from an antibiotic. For these people either an immediate or a back-up antibiotic prescription should be considered. This should take into account the risk of possible complications of untreated strep A and of possible adverse effects of antibiotics.
The purpose of the rapid tests is to increase diagnostic confidence of a suspected strep A infection and guide antimicrobial prescribing decisions. The tests are for people identified as more or most likely to benefit from antibiotics by clinical scoring tools. They have a faster turnaround time than laboratory culture of throat swabs. This could allow a prescribing decision in the initial consultation (but some tests might need confirmation of negative test results by laboratory culture). This may contribute to improved antimicrobial stewardship. The tests are suitable for all settings where patients present with an acute sore throat. This includes both primary and secondary care, and community pharmacies.
# The interventions
The assessment included 21 rapid tests for strep A, of which 17 tests use immunoassay detection methods (rapid antigen detection tests) and 4 use molecular methods (polymerase chain reaction or isothermal nucleic acid amplification).
## Rapid antigen detection tests
Of the rapid antigen detection tests, 16 use lateral flow (immunochromatographic and immunofluorescence) technology and 1 test (QuikRead Go Strep A test) is a turbidimetric immunoassay (see table 1). Depending on the technology, the results of the lateral flow tests are read by visual inspection or by using a test reader device.
Several manufacturers recommend that negative rapid antigen detection test results are confirmed by microbiological culture of a throat swab.
## Table 1 Summary of rapid antigen detection tests
Product (manufacturer)
Test format
Limit of detection
Time to result
a
(minutes)
Results
Confirmation of negative result?
Clearview exact Strep A cassette (Abbott)b
Cassette
×104 organisms/test
Qualitative
Yes
Clearview exact Strep A dipstick (Abbott)c
Test strip
×104 organisms/test
Qualitative
Yes
BD Veritor plus system group A Strep (Becton Dickinson)
Cassette
×105 to 5×104 CFU/ml
Qualitative
Yes
Strep A rapid test (Biopanda reagents)
Cassette
E+05 organisms/swab
Qualitative
Yes
Strep A rapid test (Biopanda reagents)
Test strip
E+05 organisms/swab
Qualitative
Yes
NADAL Strep A (nal von minden GmbH)
Test strip
×105 organisms/swab
Qualitative
No
NADAL Strep A (nal von minden GmbH)
Cassette
×105 organisms/swab
Qualitative
No
NADAL Strep A plus (nal von minden GmbH)
Cassette
×105 organisms/swab
Qualitative
No
NADAL Strep A plus (nal von minden GmbH)
Test strip
×105 organisms/swab
Qualitative
No
NADAL Strep A scan test (nal von minden GmbH)d
Cassette
×105 organisms/swab
Qualitative
No
OSOM Strep A test (Sekisui diagnostics)
Test strip
Not known
Qualitative
Yes
QuikRead Go Strep A test kit (Orion Diagnostica)e
N/A
×104 CFU/swab
Less than 7
Qualitative
Not known
Alere TestPack Plus Strep A (Abbott)
Cassette
Not known
Qualitative
Yes (if symptoms persist)
Bionexia Strep A plus (Biomerieux)
Cassette
×104 organisms/swab
Qualitative
Not known
Bionexia Strep A dipstick (Biomerieux)
Test strip
Not known
Qualitative
Not known
Biosynex Strep A (Biosynex)
Cassette
×105 bacteria/swab
Qualitative
Not known
Sofia Strep A FIA (Quidel)f
Cassette
×104 to 9.24×103 CFU/test
to 6
Qualitative
Yes
Abbreviations: CFU, colony forming units; N/A, not applicable.
a Read time (does not include sample preparation time).
b Replaced by Clearview Strep A cassette 2.
c Replaced by Clearview Strep A dipstick 2.
d Needs BD Veritor Plus analyser.
e Needs QuikRead go instrument.
f Needs Sofia analyser.
## Molecular tests
Of the molecular tests, 2 use isothermal nucleic acid amplification (Alere i Strep A and Alere i Strep A 2 tests) and 2 use PCR (Cobas Strep A assay and Xpert Xpress Strep A); see table 2.
## Table 2 Summary of molecular tests for rapid strep A detection
Product
Analyser
Limit of detection
Time to result (minutes)
Result
Confirmation of negative result?
Alere i Strep A (Abbott)2
Alere i instrument
to 42 CFU/ml
Less than 8
Qualitative
Yes
Alere i Strep A 2 (Abbott)3
Alere i instrument
Not known
Less than 6
Qualitative
No
Cobas Strep A assay (Roche Diagnostics)
Cobas Liat analyser
to 10 CFU/ml
Less than 15
Qualitative
No
Xpert Xpress Strep A (Cepheid)
GeneXpert system
Not known
-r more
Not known
Not known
Abbreviation: CFU, colony forming units.
Read time (does not include sample preparation time).
Replaced by ID NOW Strep A 2 test.
Rebranded to ID NOW Strep A 2.
# The comparator
Antibiotic prescribing decisions using clinical judgement and a clinical scoring tool such as FeverPAIN or Centor, outlined in section 2.9.
# Reference standard
The reference standard for assessing the accuracy of the rapid strep A tests is microbiological culture of throat swabs.
The reference standard is unlikely to be 100% accurate. Its accuracy may depend on the culture media and swabbing technique used to collect the sample.# Evidence
The diagnostics advisory committee (section 7) considered evidence on rapid tests for group A streptococcal infections (strep A) in people with a sore throat from several sources. Full details of the evidence are in the committee papers.
# Clinical effectiveness
The external assessment group (EAG) did a systematic review to identify evidence on the clinical effectiveness of rapid tests for detecting strep A infection in people with a sore throat. Evidence on the following outcomes was of interest:
diagnostic performance
effect on prescribing behaviours and clinical outcomes
contribution to antimicrobial stewardship and onward transmission of infection.
The EAG found 38 studies that met the inclusion criteria:
studies reported test accuracy data, 12 reported antibiotic prescribing behaviours (9 studies reported both outcomes), and none reported clinical outcomes such as morbidity, mortality or onward transmission rate.
studies were reported in peer-reviewed journals (full-text articles), 3 in conference abstracts, 4 in Food and Drug Administration (FDA) documents and 5 in unpublished manufacturers' data.
Across studies, the prevalence of strep A ranged from 15% to 49%. There were no clear demographic or clinical patterns accounting for this variation, and no identified differences between primary and secondary care settings.
Populations in most studies did not fit the scope for this assessment. Only 2 studies included people with a Centor score of 3 or more, or FeverPAIN score of 4 or more; the people who would have a rapid test in current practice. Both studies reported antibiotic prescribing behaviours only. There were 2 test accuracy studies that reported outcomes separately by Centor score. All other studies enrolled people with lower clinical scores than those in the scope, or did not use clinical scores as an inclusion criterion.
The relevant subgroups in the review included children (aged 5 to 14), adults (aged 15 to 75) and older people (aged over 75). However, age group definitions varied between studies. Only 2 studies met the age criterion for children and 2 studies met the age criterion for adults defined in the topic scope. There were no studies reporting data for the older population (aged over 75).
The quality of all 26 published accuracy studies was assessed using QUADAS‑2 criteria. All studies were considered at high risk of bias in at least 1 domain, and 13 studies were considered at high risk of bias in 2 or more domains. Studies reported in FDA documents or unpublished manufacturer data could not be quality assessed because of the lack of information. The main applicability issue was related to not using clinical scoring tools, described in section 3.4.
Of studies reporting antibiotic prescribing behaviours, the methodological quality of the 3 randomised controlled trials was fair, as assessed by the Cochrane risk of bias tool. No domains were considered at high risk of bias but 1 to 3 domains per study had unclear risk of bias. Of 9 cohort studies, 3 assessed hypothetical prescribing behaviours according to the prescribing guidelines and were not quality assessed. The remaining 6 cohort studies were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for analytical cross-sectional studies. There was 1 study with unclear risk of bias in 1 domain, and 5 studies were at high risk of bias in 1 or more domains.
## Evidence on diagnostic performance of rapid tests for strep A infections
Only 2 studies reported the diagnostic accuracy of the rapid tests in people who are more (FeverPAIN score of 2 or 3), or most (Centor score of 3 or 4, or a FeverPAIN score of 3 or 4) likely to benefit from antibiotics. Accuracy data from these 2 studies is in table 3.
## Table 3 Diagnostic accuracy of rapid tests in people who are more or most likely to benefit from antibiotics
Citation
Test
Population
Setting
Centor threshold
Sensitivity (95% confidence interval) %
Specificity (95% confidence interval) %
Humair et al. (2006)
Alere TestPack Plus Strep A
Adults with a Centor score of 2 or more
Primary care in Switzerland
Centor 3 or more
% (89% to 98%)
% (88% to 98%)
Centor 2
% (63% to 92%)
% (91% to 99%)
Llor et al. (2011)
OSOM Strep A
Adults with a Centor score of 1 or more
Primary care in Spain
Centor 3 or more
% (76% to 98%)
% (89% to 99%)
Centor 1 or 2
% (55% to 98%)
% (87% to 96%)
Most studies included either all patients with acute sore throat, without using the clinical scoring tools, or used these tools at a lower threshold than in UK practice. Across these studies (any population or healthcare setting), accuracy data were available for 18 of 21 tests:
There were no accuracy data for 3 tests: Strep A Rapid Test Strip (Biopanda), Biosynex Strep A Cassette test, and Bionexia Strep A Plus Cassette test.
Accuracy estimates for 8 tests (Strep A rapid test cassette , 5 NADAL Strep A tests, Alere i Strep A 2 tests and Xpert Xpress Strep A test) were only available from unpublished manufacturer data or FDA reports.
Only 5 tests had data from 2 or more published studies (BD Veritor Plus System, GuickRead Go Strep A Kit, Alere i Strep A, OSOM Strep A Strip, Alere TestPack Plus Cassette). Meta-analysis was possible for these tests.
Across studies, there was a wide variation in sensitivity (67.9% to 100%), and specificity (73.3% to 100%) of the rapid tests. There was a wide variation in accuracy estimates even for the same test. For example, the sensitivity of the Alere TestPack Plus cassette ranged from 73% (95% confidence interval 45% to 92%) to 96% (95% CI 91% to 99%). Its specificity ranged from 86% (95% CI 81% to 91%) to 100% (95% CI 96% to 100%) across 10 studies. Data from the manufacturer and FDA submissions consistently provided higher estimates of sensitivity and specificity than peer-reviewed studies.
Head-to-head comparison of the diagnostic accuracy of different tests was only reported in 4 studies. These studies suggested there is some variation in accuracy between tests. Because of the large degree of inter-study variability, it was not possible to compare the relative accuracy of different tests across different studies.
There were 3 studies that enrolled both adults and children, with separate accuracy data for each age group, allowing for a within-study comparison. These studies showed no clear trends in the diagnostic accuracy of the rapid tests between different age groups. In addition, there were 7 studies that enrolled adults only and 10 studies that enrolled children only. All other studies enrolled a mixed population of adults and children or did not report the age group.
No studies compared the diagnostic accuracy of the rapid tests in different healthcare settings. A total of 10 studies were done in primary care and 14 in secondary care; healthcare setting was not reported in the remaining studies. There were no studies done in a pharmacy setting.
Conflicting results between the rapid tests and microbiological culture of throat swabs were resolved using polymerase chain reaction (PCR) in 4 studies. A large proportion of conflicting results (both false positive and false negative) tested positive with PCR. This suggests that the reference standard used in this assessment is not 100% accurate, and may be under or overestimating the accuracy of rapid tests.
Rapid test failure rates were generally low, as reported in 5 studies:
Alere i Strep A: 0% and 2.8% (2 studies).
Alere TestPack Plus Strep A: 0.3% and 1.3% (2 studies).
Sofia Strep A FIA: 4.7% (1 study).The EAG noted that these differences could be because of environmental factors such as staff training rather than issues with the tests.
## Evidence on antibiotic prescribing behaviour
The 3 randomised controlled trials reporting on antibiotic prescribing showed a decrease in antibiotic prescribing with the rapid tests:
In a UK study of adults and children aged 3 years or more with acute sore throat in primary care (Little et al. 2013), the rate of immediate prescribing was 10% (21 of 207 patients) in the control (delayed antibiotic) group, 16% (33 of 211 patients) in the clinical scoring tool (FeverPAIN) group, and 18% (38 of 213 patients) in the FeverPAIN plus rapid strep A (Alere TestPack Plus Strep A) test group. The rate of delayed prescribing was 79%, 41% and 23%, respectively. The rate of immediate or delayed prescriptions was lower with the rapid strep A test compared with the clinical scoring group, but the reported use of antibiotics was comparable between the groups (35% and 37% respectively, compared with 46% in the control group). Data on reported antibiotic use were only available for 80% of enrolled patients so should be interpreted with caution.
In a Spanish study of adults in primary care (Llor et al. 2011), 44% of people who had the OSOM Strep A test as well as the Centor tool had an antibiotic prescription, compared with 64% of people in the Centor only group.
In a Canadian study of adults in primary care (Worrall et al. 2007), antibiotics were prescribed for 58% of patients in the control group (usual care), 55% of people in the sore throat decision rules group (STDR; modified Centor), 27% of people in the rapid test group (Clearview Exact Strep A), and 38% of patients in the STDR plus rapid test group.
The before-and-after study by Bird et al. (2018) assessed antibiotic prescribing rates before and after introducing the McIsaac clinical scoring tool and a rapid strep A test (Bionexia Strep A) in a UK paediatric emergency department. After introducing this strategy, antibiotic prescribing rates decreased from 79% at baseline (October to November 2014) to 24% in the first year (August to November 2015) and 28% in the second year (September to November 2016). However, random annual fluctuations and seasonality could have confounded the results.
# Cost effectiveness
## Systematic review of cost-effectiveness evidence
The EAG found 3 cost-effectiveness studies for the rapid strep A tests. However, 2 of these studies only reported cost per person and did not report enough information for full data extraction and their quality appraisal. The economic evaluation by Little et al. (2014) was considered high quality according to the consolidated health-economic evaluation reporting standards checklist.
Little et al. (2014) did an economic analysis alongside a randomised controlled trial (reported in Little et al. 2013). The trial was based in UK primary care clinics, and included both adults and children aged 3 years or more with acute sore throat. Patients were randomised to targeted antibiotic use according to:
delayed prescribing
FeverPAIN clinical scoring tool
rapid strep A test (Alere TestPack Plus Strep A; used with FeverPAIN tool).
The economic analysis was from the NHS perspective and the time horizon was short (14 and 28 days), so long-term effects were not captured. The analysis included a cost-effectiveness analysis (cost per change in symptom severity) and a cost–utility analysis (cost per quality-adjusted life year ). QALYs were calculated using the mean EQ-5D scores from the 14‑day diary records, and were adjusted for differences in baseline characteristics.
In the cost–utility analysis, the delayed prescribing group was dominated by the FeverPAIN group for both time frames. The incremental cost-effectiveness ratio (ICER) for the rapid test compared with FeverPAIN was £74,286 per QALY gained for the 14‑day time frame and £24,528 per QALY gained for the 28‑day time frame. At £30,000 per QALY gained, the probabilities of each strategy being cost effective were 28%, 38% and 35% for delayed prescribing, FeverPAIN clinical score and the rapid test, respectively, for the 28‑day time frame.
## Economic analysis
The study by Little et al. (2014) included only 1 of the 21 rapid tests relevant to this assessment. Also, it only considered a primary care setting, and did not assess adults and children separately. Therefore, the EAG constructed 4 de novo economic models to assess the cost effectiveness of all relevant rapid tests in people with acute sore throat:
adults in primary care
adults in secondary care
children in primary care
children in secondary care.
Economic assessment for older people or for the pharmacy setting was not possible because of the lack of evidence.
A decision tree was created to simulate the potential care pathways associated with using rapid tests and clinical scoring tools, compared with using clinical scoring tools only (current practice), in people with acute sore throat.
The economic analysis was from the UK NHS and personal social services perspective. A 1‑year time horizon was used to see the effect of rare but serious complications of strep A infection on costs and outcomes (a shorter time frame of 14 days was used in sensitivity analyses). No discounting was applied to costs and benefits because of the short time horizon. Because of the lack of published data, the models did not consider wider public health benefits such as the potential effect on antimicrobial stewardship or onward transmission rates.
A prevalence of 22.6% was used for adults, based on the study by Little et al. (2014). The study enrolled patients aged 3 years or older in UK primary care. For children, an estimate of 30.2% was assumed, based on the median of 3 non-UK studies of children in primary care.
The accuracy estimates for the Centor clinical scoring tool were taken from the meta-analysis by Aalbers et al. (2011). It focused on Centor to predict strep A pharyngitis in adults (15 years or older) in primary care. At the Centor threshold of 3 or more, the sensitivity was estimated as 49% (95% CI 38% to 60%), and specificity as 82% (95% CI 72% to 88%). There were no studies reporting the accuracy of the FeverPAIN clinical scoring tool so it could not be modelled.
The accuracy estimates for the rapid strep A tests were from the systematic literature review done by the EAG. The sensitivity of the rapid tests ranged from 68% to 100%, and the specificity from 79% to 100% (see table 4 and table 5). The estimates of accuracy based on unpublished manufacturers' data or FDA reports were consistently higher than the estimates from the published peer-reviewed studies. Therefore, the economic models based solely on manufacturers' test accuracy data should be interpreted with caution.
## Table 4 Test accuracy data used in the economic model for adults in primary care
Test name (manufacturer)
Sensitivity (95% confidence interval) %
Specificity (95% confidence interval) %
Data source
Clearview Exact Strep A cassette (Abbott)
(54 to 80)
(92 to 97)
abstract
Clearview Exact Strep A dipstick (Abbott)
(54 to 80)
(92 to 97)
abstract
BD Veritor Plus system group A Strep Assay cassette (Becton Dickinson)
(67 to 87)
(86 to 93)
published studies
Strep A rapid test cassette (Biopanda Reagents)
(90 to 98)
(96 to 99)
unpublished study1
Strep A rapid test dipstick (Biopanda Reagents)
(90 to 98)
(96 to 99)
No data2
NADAL Strep A test strip (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
NADAL Strep A cassette (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
NADAL Strep A plus cassette (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
NADAL Strep A plus test strip (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
NADAL Strep A scan test cassette (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
OSOM Strep A test strip (Sekisui Diagnostics)
(76 to 98)
(89 to 99)
published studies
QuikRead Go Strep A test kit (Orion Diagnostica)
(85 to 100)
(60 to 92)
published study
Alere TestPack Plus Strep A cassette (Abbott)
(89 to 98)
(88 to 98)
published study
Bionexia Strep A plus cassette (Biomerieux)
No data
Bionexia Strep A dipstick test strip (Biomerieux)
(74 to 92)
(84 to 95)
abstract
Biosynex Strep A cassette (Biosynex)
No data
Sofia Strep A FIA (Quidel)
(81 to 89)
(93 to 97)
published study
Alere i Strep A (Abbott)3
(74 to 100)
(92 to 99)
published study
Alere i Strep A 2 (Abbott)4
(96 to 100)
(91 to 95)
FDA Report
Cobas Strep A assay on Liat system (Roche Diagnostics)
(93 to 100)
(90 to 96)
published study
Xpert Xpress Strep A (Cepheid)
(99 to 100)
(92 to 96)
unpublished study1 and 1 FDA report
Unpublished manufacturer data.
Assumed the same accuracy as the cassette version of the test.
Replaced by ID NOW Strep A.
Rebranded to ID NOW Strep A 2.
## Table 5 Test accuracy data used in the economic model for children in primary care
Test name (manufacturer)
Sensitivity (95% confidence interval) %
Specificity (95% confidence interval) %
Data source
Clearview Exact Strep A cassette (Abbott)
(54 to 80)
(92 to 97)
abstract
Clearview Exact Strep A dipstick (Abbott)
(54 to 80)
(92 to 97)
abstract
BD Veritor Plus system group A Strep Assay cassette (Becton Dickinson)
(61 to 88)
(89 to 97)
published study
Strep A rapid test cassette (Biopanda Reagents)
(90 to 98)
(96 to 99)
unpublished study1
Strep A rapid test dipstick (Biopanda Reagents)
(90 to 98)
(96 to 99)
No data2
NADAL Strep A test strip (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
NADAL Strep A cassette (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
NADAL Strep A plus cassette (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
NADAL Strep A plus test strip (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
NADAL Strep A scan test cassette (nal von minden GmbH)
(92 to 100)
(94 to 99)
unpublished study1
OSOM Strep A test strip (Sekisui Diagnostics)
(89 to 98)
(91 to 98)
published study
QuikRead Go Strep A test kit (Orion Diagnostica)
(56 to 94)
(72 to 99)
published study
Alere TestPack Plus Strep A cassette (Abbott)
(79 to 91)
(97 to 100)
published study
Bionexia Strep A plus cassette (Biomerieux)
No data
Bionexia Strep A dipstick test strip (Biomerieux)
(74 to 92)
(84 to 95)
abstract
Biosynex Strep A cassette (Biosynex)
No data
Sofia Strep A FIA (Quidel)
(81 to 89)
(93 to 97)
published study
Alere i Strep A (Abbott)3
(95 to 100)
(89 to 100)
published studies
Alere i Strep A 2 (Abbott)4
(96 to 100)
(91 to 95)
FDA Report
Cobas Strep A assay on Liat system (Roche Diagnostics)
(93 to 100)
(90 to 96)
published study
Xpert Xpress Strep A (Cepheid)
(99 to 100)
(92 to 96)
unpublished study1 and 1 FDA report
Unpublished manufacturer data.
Assumed the same accuracy as the cassette version of the test.
Replaced by ID NOW Strep A.
Rebranded to ID NOW Strep A 2.
Treatment-related probabilities and complication rates used in the models are in table 6.
## Table 6 Treatment-related probabilities and complication rates
Description of parameter
Mean
Standard error
GP practice
Proportion attending repeat GP consultation following group A streptococcal infection
Antibiotic prescribing probabilities
Probability of immediate prescription if Centor score is 3 or higher, or positive test
Probability of delayed prescription if Centor score is below 3 (current practice arm)
Probability of delayed prescription if negative test (intervention arm)
Probability of antibiotics used given delayed prescription
Probability of antibiotics used given immediate prescription
Complication rates following group A streptococcal infection
Probability of complication if antibiotics given (treated infection)
Probability of complications if no antibiotics given (untreated infection)
Proportion of complications that are non-suppurative (that is, rheumatic fever)
Adverse effects of penicillin
Penicillin-induced rash
Penicillin-induced anaphylaxis
Standard error derived assuming upper and lower bound equal to 10% of the mean estimate.
The health impact of each pathway was expressed in QALYs. These were calculated by subtracting the disutilities associated with treated and untreated strep A infection, complications of strep A infection and adverse effects of penicillin (see table 7) over 1 year from the mean baseline utilities. The mean baseline utilities in the models were based on a general UK population: 0.863 for adults and 0.94 for people under 25 years (Kind et al. 1998). The latter is the closest age group to children and therefore was used as a baseline utility in the children's models. Mean disutilities were based on published literature (Neuner et al. 2003; reported as quality-adjusted life days), by converting quality-adjusted life days to utility decrements.
## Table 7 Utility decrements associated with strep A infection and complications
Mean quality-adjusted life days lost
Mean utility decrement used in the models
Standard error
Utility decrement associated with strep A infections
Untreated infection
Treated infection
Utility decrement associated with strep A infection complications
Peritonsillar abscess
Rheumatic fever
Utility decrement associated with adverse effects of penicillin
Penicillin-induced anaphylaxis
Penicillin-induced rash
Calculated by converting quality-adjusted life days to utilities.
Standard error derived assuming upper and lower bound equal to 10% of the mean estimate.
Costs were calculated using 2017/18 prices. The total costs for each strategy (current practice and rapid tests) include GP consultations, antimicrobial therapy, and managing strep A infection-related complications and adverse effects of penicillin (see table 8).
## Table 8 Treatment costs (2017/18 price year)
Treatment costs
Mean
Standard error
Source
Antibiotics (phenoxymethylpenicillin 250 mg, 28‑tablet pack)
BNF 72 (2017)
Pain relief (paracetamol 500 mg, 32-tablet pack)
BNF 72 (2017)
GP consultation (9.22 minutes)
Personal social services research unit costs 2017
Treatment costs, penicillin-induced rash (switch to erythromycin 500 mg)
BNF 72 (2017)
Treatment costs, penicillin-induced anaphylaxis1
Derived from Hex et al. 2017
Treatment costs, abscess (tonsillectomy)
NHS reference costs
Treatment costs, acute rheumatic fever
NHS reference costs
Based on expert opinion, costs of penicillin-induced anaphylaxis were assumed to be equivalent to the initial cost of treating sepsis, as derived from Hex et al. 2017.
Cost data were available for 14 of the 21 rapid tests in this assessment (see table 9). The cost of testing also accounted for:
Additional GP time needed to process the test, ranging from 5 to 12 minutes depending on the test.
Apportioned cost of analyser or test cassette reader (that is, cost of analyser or reader adjusted for its average life span and the average number of samples analysed).
Cost of the microbiological culture of throat swabs (£8 per sample) to confirm negative test results, when needed.
## Table 9 Test costs
Test ID
Test name
Cost
Test process time
Throat culture
Clearview Exact Strep A cassette (Abbott)
Yes
Clearview Exact Strep A dipstick (Abbott)
Yes
BD Veritor Plus system group A Strep Assay cassette (Becton Dickinson)
Not known
Strep A rapid test cassette (Biopanda Reagents)
Yes
Strep A rapid test dipstick (Biopanda Reagents)
Yes
NADAL Strep A test strip (nal von minden GmbH)
No
NADAL Strep A cassette (nal von minden GmbH)
No
NADAL Strep A plus cassette (nal von minden GmbH)
No
NADAL Strep A plus test strip (nal von minden GmbH)
No
NADAL Strep A scan test cassette (nal von minden GmbH)
No
OSOM Strep A test strip (Sekisui Diagnostics)
Not known
QuikRead Go Strep A test kit (Orion Diagnostica)
Assumed yes3
Alere TestPack Plus Strep A cassette (Abbott)
Assumed no4
Bionexia Strep A plus cassette (Biomerieux)
Not known
Bionexia Strep A dipstick (Biomerieux)
Not known
Biosynex Strep A cassette (Biosynex)
Not known
Sofia Strep A FIA (Quidel)
Not known
Alere i Strep A (Abbott)5
Not known
Alere i Strep A 2 (Abbott)6
No
Cobas Strep A assay on Liat system (Roche Diagnostics)
No
Xpert Xpress Strep A (Cepheid)
Assumed yes2
Includes apportioned cost of analyser or test cassette reader (that is, cost of analyser or reader adjusted for its average life span and the average number of samples analysed), when relevant.
Confirmatory microbiological culture of throat swabs for negative results of rapid tests is needed, as specified in the information for use documents.
Not known whether confirmatory test is needed, assumed that it is.
Confirmatory testing warranted only if symptoms persist.
This test has been replaced by ID NOW Strep A 2 test.
Rebranded to ID NOW Strep A 2.
Average test selling price based on volume-based discounts (submitted by company during consultation; does not include apportioned analyser cost).
Based on the list price provided by the company and EAG's assumptions.
The model was created for adults in primary care and then adapted for children and secondary care:
In current practice, antibiotic prescribing (immediate, delayed or no prescribing) is based on the Centor score.
In the rapid test cohort, people with a Centor score of 3 or more are offered the rapid test. Antibiotic prescribing decisions (immediate, delayed or no prescribing) are based on the test results.
Of people offered delayed prescription, 46% use their prescription.
There are 1.3% to 1.5% of people with strep A infection who develop complications, depending on whether or not they had antibiotics.
People who take antibiotics are at risk of penicillin-related adverse effects (2% have penicillin-induced rash and 0.01% have penicillin-induced anaphylaxis).
When recommended by manufacturers, negative results for rapid strep A tests were followed up with a microbiological culture or throat swabs to confirm the results.
The model for adults in secondary care was adapted from the adult primary care model by excluding the cost of the initial GP consultation. Also, it was assumed that all rapid tests could be done in the standard time allocated for secondary care appointments. The accuracy of rapid tests was assumed to be the same as in primary care (because of the lack of specific data in secondary care) except for 3 tests for which the sensitivity estimates from secondary care were available: OSOM Strep A test (94%), QuikRead Go Strep A test kit (87%) and the Alere TestPack Plus Strep A (90%). All other assumptions and inputs are the same as in the primary care model.
The model for children in primary care was adapted from the corresponding adult model by adjusting the prevalence of strep A infections from 22.6% to 30.2%, and using the accuracy estimates from studies in children whenever these were available (see table 5). The costs of treating peritonsillar abscess and related complications in children were assumed to be lower than in adults (£1,420.50 compared with £1,571.28), based on the NHS reference costs for both age groups.
The test accuracy data for children in secondary care were assumed to be the same as in primary care (because of the lack of specific data in secondary care), except for 3 tests for which the accuracy estimates from secondary care were available: OSOM Strep A test (test strip; sensitivity: 94%, specificity: 97%), QuikRead Go Strep A test kit (sensitivity: 87%, specificity: 78%), and Alere TestPack Plus Strep A (sensitivity: 77%, specificity: 97%).
## Economic analysis results
In the base-case adult primary care model, current practice dominated (that is, current practice was more effective and cheaper than the testing strategy) 2 tests: the Clearview Exact Strep A cassette and dipstick. The ICERs for the remaining 12 tests ranged from £1,353,677 to £6,059,081 per QALY gained, compared with current practice (see table 10). Costs and QALYs were multiplied by 1,000 because of the very small incremental QALYs.
The results of the base-case adult secondary care model were in line with the results of the adult primary care model, but the ICERs were much lower (see table 11).
In both models for children, current practice dominated 4 tests: the Clearview Exact Strep A cassette and dipstick, QuikRead Go Strep A test kit and Alere TestPack Plus Strep A cassette (see table 11). In the children's primary care model, the ICERs for the remaining 10 tests ranged from £1,762,306 to £7,893,857 per QALY gained, compared with current practice. In the children's secondary care model, the ICERs for the remaining 10 tests ranged from £65,122 to £5,723,279 per QALY gained, compared with current practice.
## Table 10 Base-case cost-effectiveness results: adult primary care model
Test
Mean costs
Mean quality-adjusted life years
Incremental costs
Incremental quality-adjusted life years
Incremental cost-effectiveness ratio versus current practice
Current practice2
Clearview Exact Strep A cassette (Abbott)3
Dominated
Clearview Exact Strep A dipstick (Abbott)3
Dominated
Strep A rapid test cassette (Biopanda Reagents)4
Strep A rapid test dipstick (Biopanda Reagents)4,5
NADAL Strep A test strip (nal von minden GmbH)4
NADAL Strep A cassette (nal von minden GmbH)4
NADAL Strep A plus cassette (nal von minden GmbH)4
NADAL Strep A plus test strip (nal von minden GmbH)4
NADAL Strep A scan test cassette (nal von minden GmbH)4
QuikRead Go Strep A test kit (Orion Diagnostica)
Alere TestPack Plus Strep A cassette (Abbott)
Alere i Strep A 2 (Abbott)4,6
Cobas Strep A assay on Liat system (Roche Diagnostics)7
Xpert Xpress Strep A (Cepheid)4
Notes: Cost-effectiveness analyses were not done for 7 tests that had no cost data (Bionexia Strep A plus cassette and Biosynex Strep A cassette had neither costs nor accuracy data available).
Per 1,000 individuals.
Clinical scoring based on Centor 3 or higher plus clinical assessment.
Based on the accuracy data presented in a conference abstract only.
Based on the accuracy data from the FDA or manufacturer's data.
Assumed equal accuracy to the cassette version of this test.
Rebranded to ID NOW Strep A 2.
Based on average selling price submitted by the company during consultation (based on volume-based discounts; without including apportioned analyser costs).
## Table 11 Base-case cost-effectiveness results: other models
Test
Incremental cost-effectiveness ratio versus current practice
Adults secondary care
Children primary care
Children secondary care
Current practice2
Clearview Exact Strep A cassette (Abbott)3
Dominated
Dominated
Dominated
Clearview Exact Strep A dipstick (Abbott)3
Dominated
Dominated
Dominated
Strep A rapid test cassette (Biopanda Reagents)4
Strep A rapid test dipstick (Biopanda Reagents)4,5
NADAL Strep A test strip (nal von minden GmbH)4
NADAL Strep A cassette (nal von minden GmbH)4
NADAL Strep A plus cassette (nal von minden GmbH)4
NADAL Strep A plus test strip (nal von minden GmbH)4
NADAL Strep A scan test cassette (nal von minden GmbH)4
QuikRead Go Strep A test kit (Orion Diagnostica)
Dominated
Dominated
Alere TestPack Plus Strep A cassette (Abbott)
Dominated
Dominated
Alere i Strep A 2 (Abbott)4,6
Cobas Strep A assay on Liat system (Roche Diagnostics)7
Xpert Xpress Strep A (Cepheid)4
Notes: Cost-effectiveness analyses were not done for 7 tests that had no cost data (Bionexia Strep A plus cassette and Biosynex Strep A cassette had neither costs nor accuracy data available).
Per 1,000 individuals.
Clinical scoring based on Centor 3 or higher plus clinical assessment.
Based on the accuracy data presented in a conference abstract only.
Based on the accuracy data from the FDA or manufacturer's data.
Assumed equal accuracy to the cassette version of this test.
Rebranded to ID NOW Strep A 2.
Based on average selling price submitted by the company during consultation (based on volume-based discounts; without including apportioned analyser costs).
The results of the probabilistic sensitivity analysis mirrored the results of the deterministic base-case analysis in all models.
The probability of a rapid test being cost effective was 0 in all 4 models, regardless of the rapid test used.
A range of scenario analyses was done. For the adult primary care model, none produced ICERs that were around or below £30,000 per QALY gained, compared with current practice.
For the adult secondary care model, changing the rate of penicillin-induced anaphylaxis from 0.01% (Neuner et al. 2003) to 0.64% (Van Howe and Kusnier 2006), resulted in 6 rapid tests dominating current practice (that is, testing was cheaper and more effective than current practice). These were the 5 NADAL tests and Alere TestPack Plus Strep A. The ICERs for 4 tests (2 Clearview Exact Strep A tests and 2 Strep A rapid tests from Biopanda) decreased to around or below £30,000 per QALY gained, compared with current practice.
In addition, for the adult secondary care model, the ICERs for the 5 NADAL tests decreased to around or below £30,000 per QALY gained, compared with current practice, for the following assumptions:
changing the Centor threshold for starting antibiotics and testing to 2 or more (ICERs: £30,230 to £69,690 per QALY gained)
changing the Centor threshold for starting antibiotics and testing to 1 or more (ICERs: £22,220 to £56,190 per QALY gained)
lowering the prevalence of strep A infection to 10% (ICERs: £20,628 to £53,506 per QALY gained)
doubling the rate of penicillin-related rash to 4% (ICERs: £8,913 to £32,557 per QALY gained)
doubling the utility decrement of penicillin-induced rash (ICERs: £21,309 to £44,953 per QALY gained).
For the children's primary care model, no scenario analyses produced ICERs that were around or below £30,000 per QALY gained.
The scenario analyses for the children's secondary care model largely mirrored scenario analyses for the adult secondary care model, except that changing Centor threshold for starting antibiotics and testing to a score of 2 or more had no major effect on the ICERs.
In addition, several analyses favoured testing strategies, and all or some of the tests dominated by current practice in base-case analyses were no longer dominated. However, the ICERs were around or above £100,000 per QALY gained:
doubling the complication rate of treated strep A infection to 2.6%
halving the complication rate of untreated strep A infection to 0.75% (children's primary care model only)
halving the utility decrement of untreated strep A infection
doubling the utility decrement of treated strep A infection
changing the accuracy estimates to the lower confidence limits for both the rapid test and Centor clinical scoring tool (children's primary care model only).
Several scenario analyses favoured current practice. In all 4 models, doubling the utility decrement associated with untreated strep A infection resulted in an additional 2 to 4 tests being dominated by current practice, compared with base-case results. These tests were the Strep A rapid test cassette and the test strip from Biopanda (all models), the Alere TestPack Plus Strep A cassette (adult primary and secondary care models) and the QuikRead Go Strep A test kit (adult secondary care model). In the adult secondary care model, the following assumptions also resulted in additional tests being dominated by current practice:
increasing the prevalence rate to 35.9%
halving the complication rate of treated strep A infection to 0.65%
doubling the complication rate of untreated strep A infection to 3%
halving the rate of penicillin-related rash to 1%
halving the utility decrement of treated strep A infection
halving the utility decrement of penicillin-induced rash
doubling the utility decrement of an abscess.# Committee discussion
# Clinical need and practice
## Antimicrobial resistance is a growing public health concern
A clinical expert explained concerns about the global increase in bacteria developing resistance to antibiotics (antimicrobial resistance). Data from the UK's 5-year action plan for antimicrobial resistance 2019 to 2024 estimate that 700,000 people die every year globally because of infections caused by resistant strains of bacteria and this number will increase if no action is taken. The report notes that no new classes of antibiotics have been developed since the 1980s. Tackling antimicrobial resistance has been one of the key UK public health priorities for several years, and the use of antibiotics is gradually reducing. From 2014 to 2017, antibiotic use decreased by 7.3%, from 23.4 to 21.7 defined daily doses per 1,000 inhabitants per day. A key aim of the UK's 5‑year action plan for antimicrobial resistance is to implement diagnostic tests that can guide antimicrobial prescribing decisions. The committee noted that rapid tests for group A streptococcal infections (strep A) have been promoted for this purpose.
## Sore throat is usually a self-limiting condition and clinical need for the rapid tests is unclear
A clinical expert explained that sore throat is a common condition that is usually self-limiting, that is, it usually resolves without any antibiotic treatment. Usually a sore throat is caused by a virus and so treatment with antibiotics is not needed. The committee was aware of NICE's guideline on antimicrobial prescribing for acute sore throat. This highlights that treatment with antibiotics only reduces symptom duration by around 16 hours. However, the committee noted that this guideline covers all bacterial infections of the throat, and it was not clear what the treatment effect of antibiotics would be in people with a confirmed strep A infection. Antibiotics could reduce the risk of some complications of strep A, but these are usually either very rare or not serious. The committee heard that antibiotics are often prescribed because of perceived clinical need or patient and carers' expectations to have treatment. Clinical experts explained that NICE's guideline on antimicrobial prescribing for acute sore throat focuses on measures of self-care and advises that antibiotics should only be considered for people who are most likely to benefit from them. Delayed prescribing is an option for most people who need antibiotics; that is, when antibiotics are only dispensed if symptoms do not improve within a few days of the person visiting their GP. Full implementation of this guideline is anticipated to reduce the use of antibiotics in people with a sore throat. Patients may be reassured by a discussion that highlights the likelihood of a sore throat becoming more severe balanced with the risk associated with taking antibiotics. The committee concluded that, in people who are otherwise healthy, antibiotics are usually not needed for a sore throat. Therefore, the clinical need for rapid testing for strep A infections is unclear.
## People with a sore throat may have different testing needs and preferences
A patient expert explained about the needs of patients and carers when they are seeking medical advice for a sore throat, and making a decision about whether to have antibiotics or whether to self-care. Patients would value information on what the results of the rapid strep A tests mean, how reliable they are, what the test involves and whether this information influences a treatment decision. The patient expert noted that it could be more difficult to explain the test procedure or take a throat swab in younger children and in people with cognitive impairment or learning difficulties. Therefore, this could be challenging to do routinely in a standard appointment. They noted that some people with sore throat may appreciate point-of-care testing and almost immediate results, whereas others may prefer the samples being sent for laboratory processing because this may be seen as more reliable. The committee concluded that patients and carers seeking advice for sore throat may have different testing needs and preferences, and treatment expectations.
# Clinical effectiveness
## Most accuracy studies are not applicable to NHS practice
The committee discussed the available data on the diagnostic accuracy of the rapid tests for strep A in people with a sore throat. It noted that although 26 accuracy studies were identified by the external assessment group (EAG), most included a broad population and only 2 reported data separately for people with a high clinical score (Centor score of 3 or more). The rapid tests for strep A are most likely to be useful for people with a high clinical score. The committee noted that the prevalence of strep A is higher in people with high clinical scores than in people with low clinical scores or in an unselected population of people with a sore throat. Therefore, it concluded that studies in unselected populations or populations with lower clinical scores may not be applicable to NHS practice.
## The accuracy of the rapid tests in routine clinical practice is uncertain and likely to be very variable
The committee discussed the accuracy data available for each of the tests. It noted that no data were available for 3 of the tests (Strep A Rapid Test Strip from Biopanda, Biosynex Strep A Cassette test, and Bionexia Strep A Plus Cassette test). The EAG highlighted the high level of uncertainty in the estimates of rapid test accuracy because of the limited evidence available and the high variability between the studies. The committee noted that some tests only had accuracy data from studies done under ideal conditions (such as in unpublished manufacturer studies), which are unlikely to be repeatable in routine clinical practice. This is because the rapid tests' performance is linked to the quality of sampling and processing the sample. A clinical expert commented that positive test results are usually correct, but negative results could be related to absence of strep A infection, poor test sensitivity, or poor sampling technique. The committee also noted the imperfect accuracy of the reference standard (microbiological culture of throat swabs), which is subject to similar limitations. Laboratory polymerase chain reaction (PCR) tests have higher sensitivity than microbiological culture of throat swabs, but the clinical significance of this is unclear. For example, laboratory PCR tests could detect strep A carriers rather than infection, resulting in false positive results. The committee noted that the imperfect reference standard could under- or overestimate the accuracy of the rapid tests but that the size of either bias was not known. Overall, the committee concluded that the performance of the rapid tests in routine clinical practice is uncertain and difficult to predict, and is likely to vary from practice to practice.
## Rapid tests (used with clinical scoring tools) are unlikely to improve clinical outcomes compared with the use of clinical scoring tools alone
The committee reviewed the available evidence on the clinical effectiveness of using the rapid tests for people with suspected strep A throat infections. There was no evidence available on clinical outcomes such as morbidity, mortality, or onward transmission rate. The committee noted that severe complications of strep A are rare and there is no evidence to suggest that the rapid tests would reduce the risk of them happening. There were only 3 randomised controlled trials that reported antibiotic prescribing behaviours with or without rapid testing. The committee discussed the study by Little et al. (2013), done in UK primary care. The rate of delayed prescribing was lower in the rapid test group (23%) compared with the clinical score only group (43%). However, the reported use of antibiotics appeared similar in both groups (35% and 37%, respectively) and the level of immediate prescribing was also similar in both groups (18% and 16%, respectively). The EAG explained that data on reported antibiotic use were only available for 80% of enrolled patients so should be interpreted with caution. Also, a clinical expert commented that symptom severity and time to symptom resolution were comparable between these 2 groups (although the 2 groups were not formally tested for a difference). The committee concluded that the clinical benefit of the rapid tests was uncertain. The only study (Little et al. 2013) providing some evidence on this suggested there may be no benefit of rapid testing (used with the clinical scoring tool), compared with the use of clinical scoring tools alone.
# Cost effectiveness
## There is no evidence to assess the cost effectiveness of the rapid tests in pharmacies
The committee was aware that the rapid tests may be available in some community pharmacies. The EAG found no evidence on the diagnostic or clinical utility of rapid test accuracy when used in pharmacies, and therefore could not model this. Also, the committee noted that FeverPAIN had not been validated for use in pharmacies and that staff might need training to use clinical scoring tools. The committee concluded that it was not possible to assess the cost effectiveness of rapid tests for use in pharmacies.
## The accuracy inputs for the rapid tests are highly uncertain
The committee noted that test accuracy inputs for 9 of 14 rapid tests for which cost-effectiveness analysis was possible were from unpublished manufacturer data. This is likely to overestimate the accuracy of tests in routine clinical practice. Most accuracy estimates were from studies that were not applicable to NHS practice (see sections 4.4 and 4.5) because they did not use the tests with clinical scoring tools, or included unselected populations who did not necessarily have high scores from clinical scoring tools. The committee therefore concluded that the incremental cost-effectiveness ratios (ICERs) produced by the models were highly uncertain because of bias in the data used to model the accuracy of the rapid tests.
## The costs of using the tests in routine practice are likely to be underestimated in the models
The committee discussed the estimated costs of the tests and of the staff time for running the tests in the models. It raised concerns about the Xpert Xpress Strep A test cost, which was much lower than the costs of the other 3 molecular tests. The EAG explained that the test costs also included analyser or test cassette reader costs (when this equipment is needed). For all tests except Xpert Xpress Strep A, it was assumed that 2 tests per day would be done in a medium-sized GP practice, based on expert opinion. For the Xpert Xpress Strep A test, it was assumed that 28 tests per day would be run, resulting in a lower cost per test and therefore more favourable ICERs. The committee noted that an updated price for the Cobas Strep A assay was submitted by the company during consultation. It understood this to be an average selling price, based on volume-based discounts; the range associated with the average selling price was not provided to NICE. The updated test cost did not change the conclusions of the analyses. Also, the committee noted that the updated cost did not include analyser costs. Therefore, the incremental costs associated with this test are likely to have been underestimated. Clinical experts commented that the time to process the rapid tests in routine clinical practice was likely underestimated in the models. They explained that the time included appeared to account only for the time for the test read-out, and not for the time needed to prepare the test and take the throat swab. The total time necessary to run the test would depend on the experience of the healthcare professional doing the test. This could vary considerably between practices depending on their set-up for point-of-care testing. The time needed to take the throat swab might also be longer for certain populations, for example younger children. The committee concluded that including a more realistic estimate of test processing time would further increase the costs and ICERs for the rapid tests.
## Penicillin-induced anaphylaxis is very rare
The committee considered the adverse events in the models and noted that the rate of penicillin-induced anaphylaxis had a big effect on the ICERs in scenario analyses. Clinical experts advised that the rate of penicillin-related anaphylaxis, when penicillin is taken orally, is very low (about 1 in a million). Therefore, the rate assumed in the base-case scenario (0.01%) is more appropriate than the rate assumed in the scenario analyses (0.64%), but could even overestimate the rate of penicillin-related anaphylaxis in the UK. Clinical experts also noted that the costs of sepsis are not generalisable to the treatment costs of penicillin-induced anaphylaxis, as had been assumed by the EAG. The committee concluded that penicillin-induced anaphylaxis is rare, and that the results of the scenario analyses which included a higher rate were unrealistic.
## The models predict a decrease in antibiotic use, but this might not be replicated in NHS practice
The committee recalled that one of the suggested benefits of the tests was providing a more targeted approach to antibiotic prescribing (see section 4.1). It discussed the antibiotic use predicted by the models for both current practice and for the rapid tests (used with clinical scoring tools). The models predicted a 10% to 15% decrease in the absolute rate of antibiotic use with rapid tests, compared with current practice. This was based on predicted treatment decisions related to the Centor score or the rapid test results (see table 6). The committee questioned the external validity of this prediction because the study by Little et al. (2013) suggested similar antibiotic use between people who had the rapid test (with the clinical scoring tool), or the clinical scoring tool only (see section 4.6). It also recalled that the recent publication of NICE's guideline on antimicrobial prescribing for acute sore throat is expected to reduce antibiotic prescribing in sore throat further (see section 4.2). This could result in the tests having the potential to increase antibiotic prescribing. Clinical experts also advised that the FeverPAIN clinical scoring tool is more discriminative for strep A than the Centor tool. Therefore, the potential clinical benefits of the rapid tests compared with FeverPAIN could be even lower. The committee concluded that the predicted decrease in antibiotic use associated with the rapid tests might not be replicated in NHS practice.
## The models do not account for all complications of strep A, but this is appropriate because they are very rare
The committee noted that the models do not capture all complications of strep A and discussed the effect of excluding those that are more serious. Clinical experts advised that the risk of serious complications, such as invasive strep A or sepsis, is very low and therefore unlikely to have a major effect on the modelling results. The rates of invasive strep A appear to have been increasing in the UK in recent years, but are still very low considering the high number of people presenting with a sore throat. The rate of serious complications is higher in people over 75 years, and the risk of associated mortality is higher for these people. Therefore, modelling serious complications could be important. However, modelling the use of rapid tests for people over 75 was not possible because of the lack of data for the models. The committee also discussed that the models did not capture the risk of scarlet fever, although they acknowledged that this was a possible complication in children presenting early with a sore throat. Scarlet fever is more likely in children than adults. The rates of scarlet fever appear to have been increasing in the UK in recent years but are still low considering the total number of children presenting with a sore throat. For the children and adult models, the committee concluded that excluding the more severe complications was unlikely to have had a big effect on the results.
## Wider public health benefits are not captured in the models
The committee noted that the wider public health benefits of the rapid tests, such as contribution to antimicrobial stewardship or effect on onward transmission rate, were not captured in the models. The committee discussed the risk of onward transmission of untreated strep A infection to other household members, particularly the risk of onward transmission leading to invasive strep A infection. It noted that although this risk exists, it is very small. The risk of onward transmission could be higher during an outbreak, for example, in a care home. However, using the tests during an outbreak was outside the scope of this assessment. The committee also noted that currently the effect on public health (health effects and costs) of reduced antibiotic use has not been quantified. The modelling predicted a 10% to 15% reduction in the absolute rate of antibiotic use with the rapid tests (with clinical scoring tools), compared with using clinical scoring tools only. However, this had minimal effect on the total cost of the pathway because penicillin costs are very low. The only differences in costs and quality-adjusted life years (QALYs) related to antibiotic prescribing were those of managing less severe strep A complications and side effects of penicillin. The committee discussed that although bacterial resistance to penicillin is not thought to be as great a problem as resistance to other classes of antibiotics such as macrolides (for example, erythromycin) or cephalosporins, there is very limited evidence to quantify this. Therefore, further research on the contribution of different classes of antibiotics to antimicrobial resistance, and to quantify the wider effect of antimicrobial stewardship, is needed (see section 5.1). The committee concluded that this evidence will be important for developing tests to improve prescribing decisions, which have the greatest effect on reducing antimicrobial resistance.
## The rapid tests for strep A are unlikely to be a cost-effective use of NHS resources
The modelling predicted very small incremental costs and even smaller incremental QALYs. This resulted in ICERs between £1 million and £6 million per QALY gained, compared with current clinical practice, for most rapid tests (adult primary care model). These ICERs are far higher than those normally considered to be a cost-effective use of NHS resources and are based on the modelling predicting a decrease in antibiotic use that may not be replicated in NHS practice (see section 4.11). The committee noted that there is uncertainty about the model inputs and the most plausible ICERs. However, all sensitivity analyses suggested that the rapid tests are unlikely to be a cost-effective use of NHS resources. Also, the magnitude of any uncaptured benefit is not likely to be sufficient to change the interpretation of the results. The committee recalled the uncertain clinical role of the rapid tests in the context of NICE's recent guidance on antimicrobial prescribing for acute sore throat. The guidance advises that sore throat is self-limiting, and so in people who are otherwise healthy, antibiotics are usually not needed. The committee noted that the diagnostic accuracy of the tests in routine clinical practice is uncertain and likely to be highly variable. Also, there was no evidence to suggest that the rapid tests could reduce the rate of antibiotic prescribing or improve clinical outcomes in people with a sore throat. Therefore, the committee concluded that the most plausible ICERs for the rapid tests were too high, and their effect on wider public health benefits too uncertain (see section 4.13), to recommend routine adoption.# Recommendations for further research
The committee recommended that further research is needed to measure the wider effects on public health and the costs of antimicrobial stewardship associated with different classes of antibiotics used in different healthcare settings. This will help to inform the development of technologies to guide more targeted use of antibiotics and wider UK antimicrobial resistance policy.
|
{'Recommendations': "This guidance covers using rapid tests for group\xa0A streptococcal (strep\xa0A) infections in people aged\xa05 and over with a sore throat.\n\nFor children under\xa05, assessment is described in NICE's guideline on fever in under 5s: assessment and initial management.\n\nPeople who are at higher risk of complications, for example women who are pregnant or who have just had a baby, or people who are immunocompromised, should be offered antibiotics in line with NICE's guideline on antimicrobial prescribing for acute sore throat.\n\nThis guidance also does not cover using the rapid tests:\n\nfor people presenting with scarlet fever. Scarlet fever is a notifiable condition; its diagnosis and management is covered in guidance from Public Health England\n\nto help manage outbreaks of strep\xa0A infections because this is different to using the tests for people presenting to healthcare providers with an uncomplicated sore throat.\n\nRapid tests for strep\xa0A infections are not recommended for routine adoption for people with a sore throat. This is because their effect on improving antimicrobial prescribing and stewardship, and on patient outcomes, as compared with clinical scoring tools alone, is likely to be limited. Therefore, they are unlikely to be a cost-effective use of NHS resources.\n\nWhy the committee made these recommendations\n\nUnnecessary use of antibiotics can contribute to antimicrobial resistance, which is a public health concern. NICE's guideline on antimicrobial prescribing for acute sore throat aims to limit antibiotic use and reduce antimicrobial resistance. It advises that sore throat is self-limiting and so, in people who are otherwise healthy, antibiotics are usually not needed regardless of the cause (bacterial or viral). So, it is uncertain whether there is a clinical need for rapid testing for strep\xa0A infections in the people covered by this guidance. Also, the diagnostic accuracy of the tests in routine clinical practice is uncertain and likely to be highly variable. There is no evidence to suggest that using the rapid tests could reduce antibiotic prescribing or improve clinical outcomes for people with a sore throat, as compared with clinical scoring tools alone.\n\nThe economic modelling predicts a reduction in antibiotic use with the rapid tests, but this is based on uncertain evidence, and it is therefore unclear if it would be replicated in NHS practice. The introduction of the guideline on antimicrobial prescribing for acute sore throat may, on its own, substantially reduce antibiotic prescribing. There is also uncertainty about whether confirming a bacterial infection by rapid testing could lead to changes in patient and clinical behaviour that result in increased antibiotic prescribing when antibiotics would not usually be prescribed.\n\nThe predicted reduction in antibiotic use is included in the cost-effectiveness analyses for using rapid tests in people with a sore throat but the resulting incremental cost-effectiveness ratios (ICERs) are much higher than what NICE usually considers acceptable. There is no evidence on the wider benefits of using the tests on antimicrobial stewardship and onward transmission rates. So these potential benefits are not considered in the modelling. However, it is unlikely that the effect of capturing these wider benefits would reduce the ICERs to the extent that these tests would be considered a cost-effective use of NHS resources. The uncertainty and likely minimal effect the rapid tests would have on reducing antibiotic use also means that there are likely to be limited or no wider benefits. Therefore, the rapid tests are not recommended.", 'The diagnostic tests': "# Clinical need and practice\n\nSore throat is usually a self-limiting condition that lasts about a week. In most cases it is caused by a virus but, in a few people, sore throat is caused by bacterial infection, usually group\xa0A streptococcus (strep\xa0A). Sore throat usually does not need antibiotic treatment, regardless of the cause (viral or bacterial). Most people get better without antibiotics and withholding antibiotics rarely leads to complications.\n\nUnnecessary use of antibiotics can contribute to antimicrobial resistance. This is microorganisms' ability to withstand antimicrobial treatments such as antibiotics (that is, the antimicrobial treatments become ineffective). Addressing antimicrobial resistance is one of the key NHS priorities, described in the NHS 5‑year plan for how the UK will contribute to containing and controlling antimicrobial resistance by 2040.\n\nNICE's guideline on antimicrobial prescribing for acute sore throat was developed to help limit antibiotic use and reduce antimicrobial resistance. The guidance advises that sore throat is self-limiting. Also, it recommends using clinical scoring criteria such as Centor or FeverPAIN to help identify people who are more or most likely to benefit from an antibiotic. However, the guidance does not cover the potential use of rapid tests for strep\xa0A to increase diagnostic confidence of strep\xa0A infection and guide antimicrobial prescribing.\n\nThe purpose of this assessment is to evaluate the clinical and cost effectiveness of using rapid tests to detect strep\xa0A infection in people with a sore throat aged\xa05 and over, to help appropriate prescribing of antibiotics. These tests are only intended for people who are identified as more or most likely to benefit from antibiotics by clinical scoring tools such as FeverPAIN or Centor.\n\n# The condition\n\nSore throat is characterised by inflammation of the pharynx (pharyngitis) or inflammation of the tonsils (tonsillitis). Symptoms of a sore throat include pain in the throat, fever and a headache. Other symptoms could also include nausea, vomiting, abdominal pain, muscle pain, and rashes.\n\nThe most common cause of bacterial infection is strep\xa0A, accounting for about 80% of bacterial infections. The remaining 20% of bacterial infections are usually caused by group\xa0C and\xa0G streptococcus. Strep\xa0A throat infections are more common in children than adults and the incidence of strep\xa0A infections is highest in winter and spring.\n\nMost cases of strep\xa0A infection resolve without complications. However, rarely complications can develop, such as rheumatic fever (affecting the heart), post-streptococcal glomerulonephritis (affecting the kidneys), or necrotising fasciitis (a severe infection of soft tissue). Strep\xa0A can also cause scarlet fever and invasive group\xa0A strep infections. Invasive group\xa0A strep infections happen when the bacteria move from the throat into other parts of the body. This can lead to sepsis or streptococcal toxic shock syndrome. The risk of invasive group\xa0A strep infections is usually very low, but is higher in older people (aged over 75\xa0years), in whom the risk of associated mortality is also higher.\n\n# The care pathway\n\nThe care pathway for assessing and treating a sore throat is outlined in NICE's guideline on antimicrobial prescribing for acute sore throat. Healthcare professionals should advise people with a sore throat that it usually gets better without treatment, and explain self-care measures.\n\nAntibiotic prescribing for sore throat should be guided by the FeverPAIN or Centor clinical risk scoring tools, unless the patient is systemically very unwell, has symptoms and signs of a more serious illness or condition, or is at high risk of complications.\n\nPeople with a FeverPAIN score of 0\xa0or\xa01, or a Centor score of 0,\xa01 and\xa02 are unlikely to benefit from an antibiotic. They should be offered advice on self-care without an antibiotic prescription.\n\nPeople with a FeverPAIN score of 2\xa0or\xa03 might benefit from an antibiotic. They may be offered advice on self-care or a back‑up antibiotic prescription (to use if symptoms do not start to improve within 3\xa0to 5\xa0days or worsen rapidly or significantly at any time).\n\nPeople with a FeverPAIN score of 4\xa0or\xa05, or a Centor score of 3\xa0or\xa04 are most likely to benefit from an antibiotic. For these people either an immediate or a back-up antibiotic prescription should be considered. This should take into account the risk of possible complications of untreated strep\xa0A and of possible adverse effects of antibiotics.\n\nThe purpose of the rapid tests is to increase diagnostic confidence of a suspected strep\xa0A infection and guide antimicrobial prescribing decisions. The tests are for people identified as more or most likely to benefit from antibiotics by clinical scoring tools. They have a faster turnaround time than laboratory culture of throat swabs. This could allow a prescribing decision in the initial consultation (but some tests might need confirmation of negative test results by laboratory culture). This may contribute to improved antimicrobial stewardship. The tests are suitable for all settings where patients present with an acute sore throat. This includes both primary and secondary care, and community pharmacies.\n\n# The interventions\n\nThe assessment included 21\xa0rapid tests for strep\xa0A, of which 17\xa0tests use immunoassay detection methods (rapid antigen detection tests) and 4\xa0use molecular methods (polymerase chain reaction [PCR] or isothermal nucleic acid amplification).\n\n## Rapid antigen detection tests\n\nOf the rapid antigen detection tests, 16\xa0use lateral flow (immunochromatographic and immunofluorescence) technology and 1\xa0test (QuikRead Go Strep\xa0A test) is a turbidimetric immunoassay (see table\xa01). Depending on the technology, the results of the lateral flow tests are read by visual inspection or by using a test reader device.\n\nSeveral manufacturers recommend that negative rapid antigen detection test results are confirmed by microbiological culture of a throat swab.\n\n## Table\xa01 Summary of rapid antigen detection tests\n\nProduct (manufacturer)\n\nTest format\n\nLimit of detection\n\nTime to result\n \n a\n\n(minutes)\n\nResults\n\nConfirmation of negative result?\n\nClearview exact Strep A cassette (Abbott)b\n\nCassette\n\n×104 organisms/test\n\n\n\nQualitative\n\nYes\n\nClearview exact Strep A dipstick (Abbott)c\n\nTest strip\n\n×104 organisms/test\n\n\n\nQualitative\n\nYes\n\nBD Veritor plus system group A Strep (Becton Dickinson)\n\nCassette\n\n×105 to 5×104 CFU/ml\n\n\n\nQualitative\n\nYes\n\nStrep A rapid test (Biopanda reagents)\n\nCassette\n\nE+05 organisms/swab\n\n\n\nQualitative\n\nYes\n\nStrep A rapid test (Biopanda reagents)\n\nTest strip\n\nE+05 organisms/swab\n\n\n\nQualitative\n\nYes\n\nNADAL Strep A (nal von minden GmbH)\n\nTest strip\n\n×105 organisms/swab\n\n\n\nQualitative\n\nNo\n\nNADAL Strep A (nal von minden GmbH)\n\nCassette\n\n×105 organisms/swab\n\n\n\nQualitative\n\nNo\n\nNADAL Strep A plus (nal von minden GmbH)\n\nCassette\n\n×105 organisms/swab\n\n\n\nQualitative\n\nNo\n\nNADAL Strep A plus (nal von minden GmbH)\n\nTest strip\n\n×105 organisms/swab\n\n\n\nQualitative\n\nNo\n\nNADAL Strep A scan test (nal von minden GmbH)d\n\nCassette\n\n×105 organisms/swab\n\n\n\nQualitative\n\nNo\n\nOSOM Strep A test (Sekisui diagnostics)\n\nTest strip\n\nNot known\n\n\n\nQualitative\n\nYes\n\nQuikRead Go Strep A test kit (Orion Diagnostica)e\n\nN/A\n\n×104 CFU/swab\n\nLess than 7\n\nQualitative\n\nNot known\n\nAlere TestPack Plus Strep A (Abbott)\n\nCassette\n\nNot known\n\n\n\nQualitative\n\nYes (if symptoms persist)\n\nBionexia Strep A plus (Biomerieux)\n\nCassette\n\n×104 organisms/swab\n\n\n\nQualitative\n\nNot known\n\nBionexia Strep A dipstick (Biomerieux)\n\nTest strip\n\nNot known\n\n\n\nQualitative\n\nNot known\n\nBiosynex Strep A (Biosynex)\n\nCassette\n\n×105 bacteria/swab\n\n\n\nQualitative\n\nNot known\n\nSofia Strep A FIA (Quidel)f\n\nCassette\n\n×104 to 9.24×103 CFU/test\n\nto 6\n\nQualitative\n\nYes\n\nAbbreviations: CFU, colony forming units; N/A, not applicable.\n\na Read time (does not include sample preparation time).\n\nb Replaced by Clearview Strep A cassette 2.\n\nc Replaced by Clearview Strep A dipstick 2.\n\nd Needs BD Veritor Plus analyser.\n\ne Needs QuikRead go instrument.\n\nf Needs Sofia analyser.\n\n## Molecular tests\n\nOf the molecular tests, 2\xa0use isothermal nucleic acid amplification (Alere\xa0i Strep\xa0A and Alere\xa0i Strep\xa0A 2\xa0tests) and 2\xa0use PCR (Cobas Strep\xa0A assay and Xpert Xpress Strep\xa0A); see table\xa02.\n\n## Table\xa02 Summary of molecular tests for rapid strep\xa0A detection\n\nProduct\n\nAnalyser\n\nLimit of detection\n\nTime to result (minutes)\n \n 1\n\nResult\n\nConfirmation of negative result?\n\nAlere i Strep A (Abbott)2\n\nAlere i instrument\n\nto 42 CFU/ml\n\nLess than 8\n\nQualitative\n\nYes\n\nAlere i Strep A 2 (Abbott)3\n\nAlere i instrument\n\nNot known\n\nLess than 6\n\nQualitative\n\nNo\n\nCobas Strep A assay (Roche Diagnostics)\n\nCobas Liat analyser\n\nto 10 CFU/ml\n\nLess than 15\n\nQualitative\n\nNo\n\nXpert Xpress Strep A (Cepheid)\n\nGeneXpert system\n\nNot known\n\nor more\n\nNot known\n\nNot known\n\nAbbreviation: CFU, colony forming units.\n\nRead time (does not include sample preparation time).\n\nReplaced by ID NOW Strep A 2 test.\n\nRebranded to ID NOW Strep A 2.\n\n# The comparator\n\nAntibiotic prescribing decisions using clinical judgement and a clinical scoring tool such as FeverPAIN or Centor, outlined in section\xa02.9.\n\n# Reference standard\n\nThe reference standard for assessing the accuracy of the rapid strep\xa0A tests is microbiological culture of throat swabs.\n\nThe reference standard is unlikely to be 100% accurate. Its accuracy may depend on the culture media and swabbing technique used to collect the sample.", 'Evidence': "The diagnostics advisory committee (section\xa07) considered evidence on rapid tests for group\xa0A streptococcal infections (strep\xa0A) in people with a sore throat from several sources. Full details of the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) did a systematic review to identify evidence on the clinical effectiveness of rapid tests for detecting strep\xa0A infection in people with a sore throat. Evidence on the following outcomes was of interest:\n\ndiagnostic performance\n\neffect on prescribing behaviours and clinical outcomes\n\ncontribution to antimicrobial stewardship and onward transmission of infection.\n\nThe EAG found 38\xa0studies that met the inclusion criteria:\n\nstudies reported test accuracy data, 12\xa0reported antibiotic prescribing behaviours (9\xa0studies reported both outcomes), and none reported clinical outcomes such as morbidity, mortality or onward transmission rate.\n\nstudies were reported in peer-reviewed journals (full-text articles), 3\xa0in conference abstracts, 4\xa0in Food and Drug Administration (FDA) documents and 5\xa0in unpublished manufacturers' data.\n\nAcross studies, the prevalence of strep\xa0A ranged from 15% to 49%. There were no clear demographic or clinical patterns accounting for this variation, and no identified differences between primary and secondary care settings.\n\nPopulations in most studies did not fit the scope for this assessment. Only 2\xa0studies included people with a Centor score of 3\xa0or more, or FeverPAIN score of 4\xa0or more; the people who would have a rapid test in current practice. Both studies reported antibiotic prescribing behaviours only. There were 2\xa0test accuracy studies that reported outcomes separately by Centor score. All other studies enrolled people with lower clinical scores than those in the scope, or did not use clinical scores as an inclusion criterion.\n\nThe relevant subgroups in the review included children (aged 5\xa0to\xa014), adults (aged 15\xa0to\xa075) and older people (aged over\xa075). However, age group definitions varied between studies. Only 2\xa0studies met the age criterion for children and 2\xa0studies met the age criterion for adults defined in the topic scope. There were no studies reporting data for the older population (aged over\xa075).\n\nThe quality of all 26\xa0published accuracy studies was assessed using QUADAS‑2 criteria. All studies were considered at high risk of bias in at least 1\xa0domain, and 13\xa0studies were considered at high risk of bias in 2\xa0or more domains. Studies reported in FDA documents or unpublished manufacturer data could not be quality assessed because of the lack of information. The main applicability issue was related to not using clinical scoring tools, described in section\xa03.4.\n\nOf studies reporting antibiotic prescribing behaviours, the methodological quality of the 3\xa0randomised controlled trials was fair, as assessed by the Cochrane risk of bias tool. No domains were considered at high risk of bias but 1\xa0to 3\xa0domains per study had unclear risk of bias. Of 9\xa0cohort studies, 3\xa0assessed hypothetical prescribing behaviours according to the prescribing guidelines and were not quality assessed. The remaining 6\xa0cohort studies were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for analytical cross-sectional studies. There was 1\xa0study with unclear risk of bias in 1\xa0domain, and 5\xa0studies were at high risk of bias in 1\xa0or more domains.\n\n## Evidence on diagnostic performance of rapid tests for strep\xa0A infections\n\nOnly 2\xa0studies reported the diagnostic accuracy of the rapid tests in people who are more (FeverPAIN score of 2\xa0or\xa03), or most (Centor score of 3\xa0or\xa04, or a FeverPAIN score of 3\xa0or\xa04) likely to benefit from antibiotics. Accuracy data from these 2\xa0studies is in table\xa03.\n\n## Table\xa03 Diagnostic accuracy of rapid tests in people who are more or most likely to benefit from antibiotics\n\nCitation\n\nTest\n\nPopulation\n\nSetting\n\nCentor threshold\n\nSensitivity (95% confidence interval) %\n\nSpecificity (95% confidence interval) %\n\nHumair et al. (2006)\n\nAlere TestPack Plus Strep A\n\nAdults with a Centor score of 2 or more\n\nPrimary care in Switzerland\n\nCentor 3 or more\n\n% (89% to 98%)\n\n% (88% to 98%)\n\nCentor 2\n\n% (63% to 92%)\n\n% (91% to 99%)\n\nLlor et al. (2011)\n\nOSOM Strep A\n\nAdults with a Centor score of 1 or more\n\nPrimary care in Spain\n\nCentor 3 or more\n\n% (76% to 98%)\n\n% (89% to 99%)\n\nCentor 1 or 2\n\n% (55% to 98%)\n\n% (87% to 96%)\n\nMost studies included either all patients with acute sore throat, without using the clinical scoring tools, or used these tools at a lower threshold than in UK practice. Across these studies (any population or healthcare setting), accuracy data were available for 18\xa0of 21\xa0tests:\n\nThere were no accuracy data for 3\xa0tests: Strep\xa0A Rapid Test Strip (Biopanda), Biosynex Strep\xa0A Cassette test, and Bionexia Strep\xa0A Plus Cassette test.\n\nAccuracy estimates for 8\xa0tests (Strep\xa0A rapid test cassette [Biopanda], 5\xa0NADAL Strep\xa0A tests, Alere\xa0i Strep\xa0A 2\xa0tests and Xpert Xpress Strep\xa0A test) were only available from unpublished manufacturer data or FDA reports.\n\nOnly 5\xa0tests had data from 2\xa0or more published studies (BD\xa0Veritor Plus System, GuickRead Go Strep\xa0A Kit, Alere\xa0i Strep\xa0A, OSOM Strep\xa0A Strip, Alere TestPack Plus Cassette). Meta-analysis was possible for these tests.\n\nAcross studies, there was a wide variation in sensitivity (67.9% to 100%), and specificity (73.3% to 100%) of the rapid tests. There was a wide variation in accuracy estimates even for the same test. For example, the sensitivity of the Alere TestPack Plus cassette ranged from 73% (95% confidence interval [CI] 45% to 92%) to 96% (95%\xa0CI 91% to 99%). Its specificity ranged from 86% (95%\xa0CI 81% to 91%) to 100% (95%\xa0CI 96% to 100%) across 10\xa0studies. Data from the manufacturer and FDA submissions consistently provided higher estimates of sensitivity and specificity than peer-reviewed studies.\n\nHead-to-head comparison of the diagnostic accuracy of different tests was only reported in 4\xa0studies. These studies suggested there is some variation in accuracy between tests. Because of the large degree of inter-study variability, it was not possible to compare the relative accuracy of different tests across different studies.\n\nThere were 3\xa0studies that enrolled both adults and children, with separate accuracy data for each age group, allowing for a within-study comparison. These studies showed no clear trends in the diagnostic accuracy of the rapid tests between different age groups. In addition, there were 7\xa0studies that enrolled adults only and 10\xa0studies that enrolled children only. All other studies enrolled a mixed population of adults and children or did not report the age group.\n\nNo studies compared the diagnostic accuracy of the rapid tests in different healthcare settings. A total of 10\xa0studies were done in primary care and 14\xa0in secondary care; healthcare setting was not reported in the remaining studies. There were no studies done in a pharmacy setting.\n\nConflicting results between the rapid tests and microbiological culture of throat swabs were resolved using polymerase chain reaction (PCR) in 4\xa0studies. A large proportion of conflicting results (both false positive and false negative) tested positive with PCR. This suggests that the reference standard used in this assessment is not 100% accurate, and may be under or overestimating the accuracy of rapid tests.\n\nRapid test failure rates were generally low, as reported in 5\xa0studies:\n\nAlere\xa0i Strep\xa0A: 0% and 2.8% (2\xa0studies).\n\nAlere TestPack Plus Strep\xa0A: 0.3% and 1.3% (2\xa0studies).\n\nSofia Strep A FIA: 4.7% (1\xa0study).The EAG noted that these differences could be because of environmental factors such as staff training rather than issues with the tests.\n\n## Evidence on antibiotic prescribing behaviour\n\nThe 3\xa0randomised controlled trials reporting on antibiotic prescribing showed a decrease in antibiotic prescribing with the rapid tests:\n\nIn a UK study of adults and children aged 3\xa0years or more with acute sore throat in primary care (Little et al. 2013), the rate of immediate prescribing was 10% (21\xa0of 207\xa0patients) in the control (delayed antibiotic) group, 16% (33\xa0of 211\xa0patients) in the clinical scoring tool (FeverPAIN) group, and 18% (38\xa0of 213 patients) in the FeverPAIN plus rapid strep\xa0A (Alere TestPack Plus Strep\xa0A) test group. The rate of delayed prescribing was 79%, 41% and 23%, respectively. The rate of immediate or delayed prescriptions was lower with the rapid strep\xa0A test compared with the clinical scoring group, but the reported use of antibiotics was comparable between the groups (35% and 37% respectively, compared with 46% in the control group). Data on reported antibiotic use were only available for 80% of enrolled patients so should be interpreted with caution.\n\nIn a Spanish study of adults in primary care (Llor et al. 2011), 44% of people who had the OSOM Strep\xa0A test as well as the Centor tool had an antibiotic prescription, compared with 64% of people in the Centor only group.\n\nIn a Canadian study of adults in primary care (Worrall et al. 2007), antibiotics were prescribed for 58% of patients in the control group (usual care), 55% of people in the sore throat decision rules group (STDR; modified Centor), 27% of people in the rapid test group (Clearview Exact Strep\xa0A), and 38% of patients in the STDR plus rapid test group.\n\nThe before-and-after study by Bird et al. (2018) assessed antibiotic prescribing rates before and after introducing the McIsaac clinical scoring tool and a rapid strep\xa0A test (Bionexia Strep\xa0A) in a UK paediatric emergency department. After introducing this strategy, antibiotic prescribing rates decreased from 79% at baseline (October to November 2014) to 24% in the first year (August to November 2015) and 28% in the second year (September to November 2016). However, random annual fluctuations and seasonality could have confounded the results.\n\n# Cost effectiveness\n\n## Systematic review of cost-effectiveness evidence\n\nThe EAG found 3\xa0cost-effectiveness studies for the rapid strep\xa0A tests. However, 2\xa0of these studies only reported cost per person and did not report enough information for full data extraction and their quality appraisal. The economic evaluation by Little et al. (2014) was considered high quality according to the consolidated health-economic evaluation reporting standards checklist.\n\nLittle et al. (2014) did an economic analysis alongside a randomised controlled trial (reported in Little et al. 2013). The trial was based in UK primary care clinics, and included both adults and children aged 3\xa0years or more with acute sore throat. Patients were randomised to targeted antibiotic use according to:\n\ndelayed prescribing\n\nFeverPAIN clinical scoring tool\n\nrapid strep\xa0A test (Alere TestPack Plus Strep\xa0A; used with FeverPAIN tool).\n\nThe economic analysis was from the NHS perspective and the time horizon was short (14\xa0and 28\xa0days), so long-term effects were not captured. The analysis included a cost-effectiveness analysis (cost per change in symptom severity) and a cost–utility analysis (cost per quality-adjusted life year [QALY]). QALYs were calculated using the mean EQ-5D scores from the 14‑day diary records, and were adjusted for differences in baseline characteristics.\n\nIn the cost–utility analysis, the delayed prescribing group was dominated by the FeverPAIN group for both time frames. The incremental cost-effectiveness ratio (ICER) for the rapid test compared with FeverPAIN was £74,286 per QALY gained for the 14‑day time frame and £24,528 per QALY gained for the 28‑day time frame. At £30,000 per QALY gained, the probabilities of each strategy being cost effective were 28%, 38% and 35% for delayed prescribing, FeverPAIN clinical score and the rapid test, respectively, for the 28‑day time frame.\n\n## Economic analysis\n\nThe study by Little et al. (2014) included only 1\xa0of the 21\xa0rapid tests relevant to this assessment. Also, it only considered a primary care setting, and did not assess adults and children separately. Therefore, the EAG constructed 4\xa0de novo economic models to assess the cost effectiveness of all relevant rapid tests in people with acute sore throat:\n\nadults in primary care\n\nadults in secondary care\n\nchildren in primary care\n\nchildren in secondary care.\n\nEconomic assessment for older people or for the pharmacy setting was not possible because of the lack of evidence.\n\nA decision tree was created to simulate the potential care pathways associated with using rapid tests and clinical scoring tools, compared with using clinical scoring tools only (current practice), in people with acute sore throat.\n\nThe economic analysis was from the UK NHS and personal social services perspective. A 1‑year time horizon was used to see the effect of rare but serious complications of strep\xa0A infection on costs and outcomes (a shorter time frame of 14\xa0days was used in sensitivity analyses). No discounting was applied to costs and benefits because of the short time horizon. Because of the lack of published data, the models did not consider wider public health benefits such as the potential effect on antimicrobial stewardship or onward transmission rates.\n\nA prevalence of 22.6% was used for adults, based on the study by Little et al. (2014). The study enrolled patients aged 3\xa0years or older in UK primary care. For children, an estimate of 30.2% was assumed, based on the median of 3\xa0non-UK studies of children in primary care.\n\nThe accuracy estimates for the Centor clinical scoring tool were taken from the meta-analysis by Aalbers et al. (2011). It focused on Centor to predict strep\xa0A pharyngitis in adults (15\xa0years or older) in primary care. At the Centor threshold of 3\xa0or more, the sensitivity was estimated as 49% (95% CI 38% to 60%), and specificity as 82% (95% CI 72% to 88%). There were no studies reporting the accuracy of the FeverPAIN clinical scoring tool so it could not be modelled.\n\nThe accuracy estimates for the rapid strep\xa0A tests were from the systematic literature review done by the EAG. The sensitivity of the rapid tests ranged from 68% to 100%, and the specificity from 79% to 100% (see table\xa04 and table\xa05). The estimates of accuracy based on unpublished manufacturers' data or FDA reports were consistently higher than the estimates from the published peer-reviewed studies. Therefore, the economic models based solely on manufacturers' test accuracy data should be interpreted with caution.\n\n## Table\xa04 Test accuracy data used in the economic model for adults in primary care\n\nTest name (manufacturer)\n\nSensitivity (95% confidence interval) %\n\nSpecificity (95% confidence interval) %\n\nData source\n\nClearview Exact Strep A cassette (Abbott)\n\n(54 to 80)\n\n(92 to 97)\n\nabstract\n\nClearview Exact Strep A dipstick (Abbott)\n\n(54 to 80)\n\n(92 to 97)\n\nabstract\n\nBD Veritor Plus system group A Strep Assay cassette (Becton Dickinson)\n\n(67 to 87)\n\n(86 to 93)\n\npublished studies\n\nStrep A rapid test cassette (Biopanda Reagents)\n\n(90 to 98)\n\n(96 to 99)\n\nunpublished study1\n\nStrep A rapid test dipstick (Biopanda Reagents)\n\n(90 to 98)\n\n(96 to 99)\n\nNo data2\n\nNADAL Strep A test strip (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nNADAL Strep A cassette (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nNADAL Strep A plus cassette (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nNADAL Strep A plus test strip (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nNADAL Strep A scan test cassette (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nOSOM Strep A test strip (Sekisui Diagnostics)\n\n(76 to 98)\n\n(89 to 99)\n\npublished studies\n\nQuikRead Go Strep A test kit (Orion Diagnostica)\n\n(85 to 100)\n\n(60 to 92)\n\npublished study\n\nAlere TestPack Plus Strep A cassette (Abbott)\n\n(89 to 98)\n\n(88 to 98)\n\npublished study\n\nBionexia Strep A plus cassette (Biomerieux)\n\n−\n\n−\n\nNo data\n\nBionexia Strep A dipstick test strip (Biomerieux)\n\n(74 to 92)\n\n(84 to 95)\n\nabstract\n\nBiosynex Strep A cassette (Biosynex)\n\n−\n\n−\n\nNo data\n\nSofia Strep A FIA (Quidel)\n\n(81 to 89)\n\n(93 to 97)\n\npublished study\n\nAlere i Strep A (Abbott)3\n\n(74 to 100)\n\n(92 to 99)\n\npublished study\n\nAlere i Strep A 2 (Abbott)4\n\n(96 to 100)\n\n(91 to 95)\n\nFDA Report\n\nCobas Strep A assay on Liat system (Roche Diagnostics)\n\n(93 to 100)\n\n(90 to 96)\n\npublished study\n\nXpert Xpress Strep A (Cepheid)\n\n(99 to 100)\n\n(92 to 96)\n\nunpublished study1 and 1 FDA report\n\nUnpublished manufacturer data.\n\nAssumed the same accuracy as the cassette version of the test.\n\nReplaced by ID NOW Strep\xa0A.\n\nRebranded to ID NOW Strep\xa0A 2.\n\n## Table\xa05 Test accuracy data used in the economic model for children in primary care\n\nTest name (manufacturer)\n\nSensitivity (95% confidence interval) %\n\nSpecificity (95% confidence interval) %\n\nData source\n\nClearview Exact Strep A cassette (Abbott)\n\n(54 to 80)\n\n(92 to 97)\n\nabstract\n\nClearview Exact Strep A dipstick (Abbott)\n\n(54 to 80)\n\n(92 to 97)\n\nabstract\n\nBD Veritor Plus system group A Strep Assay cassette (Becton Dickinson)\n\n(61 to 88)\n\n(89 to 97)\n\npublished study\n\nStrep A rapid test cassette (Biopanda Reagents)\n\n(90 to 98)\n\n(96 to 99)\n\nunpublished study1\n\nStrep A rapid test dipstick (Biopanda Reagents)\n\n(90 to 98)\n\n(96 to 99)\n\nNo data2\n\nNADAL Strep A test strip (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nNADAL Strep A cassette (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nNADAL Strep A plus cassette (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nNADAL Strep A plus test strip (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nNADAL Strep A scan test cassette (nal von minden GmbH)\n\n(92 to 100)\n\n(94 to 99)\n\nunpublished study1\n\nOSOM Strep A test strip (Sekisui Diagnostics)\n\n(89 to 98)\n\n(91 to 98)\n\npublished study\n\nQuikRead Go Strep A test kit (Orion Diagnostica)\n\n(56 to 94)\n\n(72 to 99)\n\npublished study\n\nAlere TestPack Plus Strep A cassette (Abbott)\n\n(79 to 91)\n\n(97 to 100)\n\npublished study\n\nBionexia Strep A plus cassette (Biomerieux)\n\n−\n\n−\n\nNo data\n\nBionexia Strep A dipstick test strip (Biomerieux)\n\n(74 to 92)\n\n(84 to 95)\n\nabstract\n\nBiosynex Strep A cassette (Biosynex)\n\n−\n\n−\n\nNo data\n\nSofia Strep A FIA (Quidel)\n\n(81 to 89)\n\n(93 to 97)\n\npublished study\n\nAlere i Strep A (Abbott)3\n\n(95 to 100)\n\n(89 to 100)\n\npublished studies\n\nAlere i Strep A 2 (Abbott)4\n\n(96 to 100)\n\n(91 to 95)\n\nFDA Report\n\nCobas Strep A assay on Liat system (Roche Diagnostics)\n\n(93 to 100)\n\n(90 to 96)\n\npublished study\n\nXpert Xpress Strep A (Cepheid)\n\n(99 to 100)\n\n(92 to 96)\n\nunpublished study1 and 1 FDA report\n\nUnpublished manufacturer data.\n\nAssumed the same accuracy as the cassette version of the test.\n\nReplaced by ID NOW Strep\xa0A.\n\nRebranded to ID NOW Strep\xa0A 2.\n\nTreatment-related probabilities and complication rates used in the models are in table\xa06.\n\n## Table\xa06 Treatment-related probabilities and complication rates\n\nDescription of parameter\n\nMean\n\nStandard error\n \n 1\n\nGP practice\n\nProportion attending repeat GP consultation following group\xa0A streptococcal infection\n\n\n\n\n\nAntibiotic prescribing probabilities\n\nProbability of immediate prescription if Centor score is 3 or higher, or positive test\n\n\n\n−\n\nProbability of delayed prescription if Centor score is below 3 (current practice arm)\n\n\n\n\n\nProbability of delayed prescription if negative test (intervention arm)\n\n\n\n\n\nProbability of antibiotics used given delayed prescription\n\n\n\n\n\nProbability of antibiotics used given immediate prescription\n\n\n\n−\n\nComplication rates following group\xa0A streptococcal infection\n\nProbability of complication if antibiotics given (treated infection)\n\n\n\n\n\nProbability of complications if no antibiotics given (untreated infection)\n\n\n\n\n\nProportion of complications that are non-suppurative (that is, rheumatic fever)\n\n\n\n−\n\nAdverse effects of penicillin\n\nPenicillin-induced rash\n\n\n\n−\n\nPenicillin-induced anaphylaxis\n\n\n\n−\n\nStandard error derived assuming upper and lower bound equal to 10% of the mean estimate.\n\nThe health impact of each pathway was expressed in QALYs. These were calculated by subtracting the disutilities associated with treated and untreated strep\xa0A infection, complications of strep\xa0A infection and adverse effects of penicillin (see table\xa07) over 1\xa0year from the mean baseline utilities. The mean baseline utilities in the models were based on a general UK population: 0.863 for adults and 0.94 for people under 25\xa0years (Kind et al. 1998). The latter is the closest age group to children and therefore was used as a baseline utility in the children's models. Mean disutilities were based on published literature (Neuner et al. 2003; reported as quality-adjusted life days), by converting quality-adjusted life days to utility decrements.\n\n## Table\xa07 Utility decrements associated with strep\xa0A infection and complications\n\n\n\nMean quality-adjusted life days lost\n\nMean utility decrement used in the models\n \n 1\n\nStandard error\n \n 2\n\nUtility decrement associated with strep\xa0A infections\n\nUntreated infection\n\n\n\n\n\n\n\nTreated infection\n\n\n\n\n\n\n\nUtility decrement associated with strep\xa0A infection complications\n\nPeritonsillar abscess\n\n\n\n\n\n\n\nRheumatic fever\n\n\n\n\n\n\n\nUtility decrement associated with adverse effects of penicillin\n\nPenicillin-induced anaphylaxis\n\n\n\n\n\n\n\nPenicillin-induced rash\n\n\n\n\n\n\n\nCalculated by converting quality-adjusted life days to utilities.\n\nStandard error derived assuming upper and lower bound equal to 10% of the mean estimate.\n\nCosts were calculated using 2017/18 prices. The total costs for each strategy (current practice and rapid tests) include GP consultations, antimicrobial therapy, and managing strep\xa0A infection-related complications and adverse effects of penicillin (see table\xa08).\n\n## Table\xa08 Treatment costs (2017/18 price year)\n\nTreatment costs\n\nMean\n\nStandard error\n\nSource\n\nAntibiotics (phenoxymethylpenicillin 250\xa0mg, 28‑tablet pack)\n\n£0.91\n\n£0.046\n\nBNF 72 (2017)\n\nPain relief (paracetamol 500\xa0mg, 32-tablet pack)\n\n£0.74\n\n£0.037\n\nBNF 72 (2017)\n\nGP consultation (9.22\xa0minutes)\n\n£37.4\n\n£1.91\n\nPersonal social services research unit costs 2017\n\nTreatment costs, penicillin-induced rash (switch to erythromycin 500\xa0mg)\n\n£10.00\n\n£0.51\n\nBNF 72 (2017)\n\nTreatment costs, penicillin-induced anaphylaxis1\n\n£1,744.64\n\n£89.01\n\nDerived from Hex et al. 2017\n\nTreatment costs, abscess (tonsillectomy)\n\n£1,571.28\n\n£80\n\nNHS reference costs\n\nTreatment costs, acute rheumatic fever\n\n£1,772.44\n\n£90.43\n\nNHS reference costs\n\nBased on expert opinion, costs of penicillin-induced anaphylaxis were assumed to be equivalent to the initial cost of treating sepsis, as derived from Hex et al. 2017.\n\nCost data were available for 14\xa0of the 21\xa0rapid tests in this assessment (see table\xa09). The cost of testing also accounted for:\n\nAdditional GP time needed to process the test, ranging from 5\xa0to 12\xa0minutes depending on the test.\n\nApportioned cost of analyser or test cassette reader (that is, cost of analyser or reader adjusted for its average life span and the average number of samples analysed).\n\nCost of the microbiological culture of throat swabs (£8 per sample) to confirm negative test results, when needed.\n\n## Table\xa09 Test costs\n\nTest ID\n\nTest name\n\nCost\n \n 1\n\nTest process time\n\nThroat culture\n \n 2\n\n\n\nClearview Exact Strep A cassette (Abbott)\n\n£2.72\n\n\n\nYes\n\n\n\nClearview Exact Strep A dipstick (Abbott)\n\n£1.92\n\n\n\nYes\n\n\n\nBD Veritor Plus system group A Strep Assay cassette (Becton Dickinson)\n\nNot known\n\n\n\nStrep A rapid test cassette (Biopanda Reagents)\n\n£0.82\n\n\n\nYes\n\n\n\nStrep A rapid test dipstick (Biopanda Reagents)\n\n£0.64\n\n\n\nYes\n\n\n\nNADAL Strep A test strip (nal von minden GmbH)\n\n£1.20\n\n\n\nNo\n\n\n\nNADAL Strep A cassette (nal von minden GmbH)\n\n£1.40\n\n\n\nNo\n\n\n\nNADAL Strep A plus cassette (nal von minden GmbH)\n\n£1.50\n\n\n\nNo\n\n\n\nNADAL Strep A plus test strip (nal von minden GmbH)\n\n£1.30\n\n\n\nNo\n\n\n\nNADAL Strep A scan test cassette (nal von minden GmbH)\n\n£1.96\n\n\n\nNo\n\n\n\nOSOM Strep A test strip (Sekisui Diagnostics)\n\nNot known\n\n\n\nQuikRead Go Strep A test kit (Orion Diagnostica)\n\n£4.34\n\n\n\nAssumed yes3\n\n\n\nAlere TestPack Plus Strep A cassette (Abbott)\n\n£2.70\n\n\n\nAssumed no4\n\n\n\nBionexia Strep A plus cassette (Biomerieux)\n\nNot known\n\n\n\nBionexia Strep A dipstick (Biomerieux)\n\nNot known\n\n\n\nBiosynex Strep A cassette (Biosynex)\n\nNot known\n\n\n\nSofia Strep A FIA (Quidel)\n\nNot known\n\n\n\nAlere i Strep A (Abbott)5\n\nNot known\n\n\n\nAlere i Strep A 2 (Abbott)6\n\n£22.94\n\n\n\nNo\n\n\n\nCobas Strep A assay on Liat system (Roche Diagnostics)\n\n£357\n\n\n\nNo\n\n\n\nXpert Xpress Strep A (Cepheid)\n\n£4.258\n\n\n\nAssumed yes2\n\nIncludes apportioned cost of analyser or test cassette reader (that is, cost of analyser or reader adjusted for its average life span and the average number of samples analysed), when relevant.\n\nConfirmatory microbiological culture of throat swabs for negative results of rapid tests is needed, as specified in the information for use documents.\n\nNot known whether confirmatory test is needed, assumed that it is.\n\nConfirmatory testing warranted only if symptoms persist.\n\nThis test has been replaced by ID NOW Strep A 2 test.\n\nRebranded to ID NOW Strep A 2.\n\nAverage test selling price based on volume-based discounts (submitted by company during consultation; does not include apportioned analyser cost).\n\nBased on the list price provided by the company and EAG's assumptions.\n\nThe model was created for adults in primary care and then adapted for children and secondary care:\n\nIn current practice, antibiotic prescribing (immediate, delayed or no prescribing) is based on the Centor score.\n\nIn the rapid test cohort, people with a Centor score of 3\xa0or more are offered the rapid test. Antibiotic prescribing decisions (immediate, delayed or no prescribing) are based on the test results.\n\nOf people offered delayed prescription, 46% use their prescription.\n\nThere are 1.3% to 1.5% of people with strep\xa0A infection who develop complications, depending on whether or not they had antibiotics.\n\nPeople who take antibiotics are at risk of penicillin-related adverse effects (2% have penicillin-induced rash and 0.01% have penicillin-induced anaphylaxis).\n\nWhen recommended by manufacturers, negative results for rapid strep\xa0A tests were followed up with a microbiological culture or throat swabs to confirm the results.\n\nThe model for adults in secondary care was adapted from the adult primary care model by excluding the cost of the initial GP consultation. Also, it was assumed that all rapid tests could be done in the standard time allocated for secondary care appointments. The accuracy of rapid tests was assumed to be the same as in primary care (because of the lack of specific data in secondary care) except for 3\xa0tests for which the sensitivity estimates from secondary care were available: OSOM Strep\xa0A test (94%), QuikRead Go Strep\xa0A test kit (87%) and the Alere TestPack Plus Strep\xa0A (90%). All other assumptions and inputs are the same as in the primary care model.\n\nThe model for children in primary care was adapted from the corresponding adult model by adjusting the prevalence of strep\xa0A infections from 22.6% to 30.2%, and using the accuracy estimates from studies in children whenever these were available (see table 5). The costs of treating peritonsillar abscess and related complications in children were assumed to be lower than in adults (£1,420.50 compared with £1,571.28), based on the NHS reference costs for both age groups.\n\nThe test accuracy data for children in secondary care were assumed to be the same as in primary care (because of the lack of specific data in secondary care), except for 3\xa0tests for which the accuracy estimates from secondary care were available: OSOM Strep\xa0A test (test strip; sensitivity: 94%, specificity: 97%), QuikRead Go Strep\xa0A test kit (sensitivity: 87%, specificity: 78%), and Alere TestPack Plus Strep\xa0A (sensitivity: 77%, specificity: 97%).\n\n## Economic analysis results\n\nIn the base-case adult primary care model, current practice dominated (that is, current practice was more effective and cheaper than the testing strategy) 2\xa0tests: the Clearview Exact Strep\xa0A cassette and dipstick. The ICERs for the remaining 12\xa0tests ranged from £1,353,677 to £6,059,081 per QALY gained, compared with current practice (see table\xa010). Costs and QALYs were multiplied by 1,000 because of the very small incremental QALYs.\n\nThe results of the base-case adult secondary care model were in line with the results of the adult primary care model, but the ICERs were much lower (see table 11).\n\nIn both models for children, current practice dominated 4\xa0tests: the Clearview Exact Strep\xa0A cassette and dipstick, QuikRead Go Strep\xa0A test kit and Alere TestPack Plus Strep A cassette (see table\xa011). In the children's primary care model, the ICERs for the remaining 10\xa0tests ranged from £1,762,306 to £7,893,857 per QALY gained, compared with current practice. In the children's secondary care model, the ICERs for the remaining 10\xa0tests ranged from £65,122 to £5,723,279 per QALY gained, compared with current practice.\n\n## Table\xa010 Base-case cost-effectiveness results: adult primary care model\n\nTest\n\nMean costs\n \n 1\n\nMean quality-adjusted life years\n \n 1\n\n\n\nIncremental costs\n \n 1\n\nIncremental quality-adjusted life years\n \n 1\n\nIncremental cost-effectiveness ratio versus current practice\n\nCurrent practice2\n\n£49,147\n\n\n\n£0\n\n\n\n−\n\nClearview Exact Strep A cassette (Abbott)3\n\n£56,180\n\n\n\n£7,033\n\n−0.0039595\n\nDominated\n\nClearview Exact Strep A dipstick (Abbott)3\n\n£55,980\n\n\n\n£6,833\n\n−0.0039595\n\nDominated\n\nStrep A rapid test cassette (Biopanda Reagents)4\n\n£55,442\n\n\n\n£6,295\n\n\n\n£2,026,496\n\nStrep A rapid test dipstick (Biopanda Reagents)4,5\n\n£55,397\n\n\n\n£6,250\n\n\n\n£2,012,006\n\nNADAL Strep A test strip (nal von minden GmbH)4\n\n£54,394\n\n\n\n£5,248\n\n\n\n£1,353,677\n\nNADAL Strep A cassette (nal von minden GmbH)4\n\n£54,444\n\n\n\n£5,298\n\n\n\n£1,366,577\n\nNADAL Strep A plus cassette (nal von minden GmbH)4\n\n£54,469\n\n\n\n£5,323\n\n\n\n£1,373,029\n\nNADAL Strep A plus test strip (nal von minden GmbH)4\n\n£54,419\n\n\n\n£5,273\n\n\n\n£1,360,126\n\nNADAL Strep A scan test cassette (nal von minden GmbH)4\n\n£54,584\n\n\n\n£5,438\n\n\n\n£1,402,700\n\nQuikRead Go Strep A test kit (Orion Diagnostica)\n\n£56,083\n\n\n\n£6,936\n\n\n\n£1,974,319\n\nAlere TestPack Plus Strep A cassette (Abbott)\n\n£54,781\n\n\n\n£5,634\n\n\n\n£1,924,717\n\nAlere i Strep A 2 (Abbott)4,6\n\n£59,837\n\n\n\n£10,691\n\n\n\n£2,926,915\n\nCobas Strep A assay on Liat system (Roche Diagnostics)7\n\n£63,868\n\n\n\n£14,722\n\n\n\n£4,030,533\n\nXpert Xpress Strep A (Cepheid)4\n\n£63,323\n\n\n\n£14,177\n\n\n\n£3,585,436\n\nNotes: Cost-effectiveness analyses were not done for 7 tests that had no cost data (Bionexia Strep A plus cassette and Biosynex Strep A cassette had neither costs nor accuracy data available).\n\nPer 1,000 individuals.\n\nClinical scoring based on Centor 3 or higher plus clinical assessment.\n\nBased on the accuracy data presented in a conference abstract only.\n\nBased on the accuracy data from the FDA or manufacturer's data.\n\nAssumed equal accuracy to the cassette version of this test.\n\nRebranded to ID NOW Strep A 2.\n\nBased on average selling price submitted by the company during consultation (based on volume-based discounts; without including apportioned analyser costs).\n\n## Table\xa011 Base-case cost-effectiveness results: other models\n\nTest\n\nIncremental cost-effectiveness ratio versus current practice\n\nAdults secondary care\n\nChildren primary care\n\nChildren secondary care\n\nCurrent practice2\n\n–\n\n–\n\n–\n\nClearview Exact Strep A cassette (Abbott)3\n\nDominated\n\nDominated\n\nDominated\n\nClearview Exact Strep A dipstick (Abbott)3\n\nDominated\n\nDominated\n\nDominated\n\nStrep A rapid test cassette (Biopanda Reagents)4\n\n£392,342\n\n£2,992,743\n\n£517,066\n\nStrep A rapid test dipstick (Biopanda Reagents)4,5\n\n£377,852\n\n£2,970,792\n\n£495,115\n\nNADAL Strep A test strip (nal von minden GmbH)4\n\n£44,184\n\n£1,762,306\n\n£65,122\n\nNADAL Strep A cassette (nal von minden GmbH)4\n\n£57,085\n\n£1,779,026\n\n£81,845\n\nNADAL Strep A plus cassette (nal von minden GmbH)4\n\n£63,537\n\n£1,787,386\n\n£90,205\n\nNADAL Strep A plus test strip (nal von minden GmbH)4\n\n£50,636\n\n£1,770,666\n\n£73,482\n\nNADAL Strep A scan test cassette (nal von minden GmbH)4\n\n£93,211\n\n£1,825,846\n\n£128,662\n\nQuikRead Go Strep A test kit (Orion Diagnostica)\n\n£12,700,432\n\nDominated\n\nDominated\n\nAlere TestPack Plus Strep A cassette (Abbott)\n\n£335,358\n\nDominated\n\nDominated\n\nAlere i Strep A 2 (Abbott)4,6\n\n£1,537,126\n\n£3,817,336\n\n£2,008,522\n\nCobas Strep A assay on Liat system (Roche Diagnostics)7\n\n£2,362,784\n\n£5,253,699\n\n£4,396,205\n\nXpert Xpress Strep A (Cepheid)4\n\n£504,287\n\n£4,396,205\n\n£574,900\n\nNotes: Cost-effectiveness analyses were not done for 7 tests that had no cost data (Bionexia Strep A plus cassette and Biosynex Strep A cassette had neither costs nor accuracy data available).\n\nPer 1,000 individuals.\n\nClinical scoring based on Centor 3 or higher plus clinical assessment.\n\nBased on the accuracy data presented in a conference abstract only.\n\nBased on the accuracy data from the FDA or manufacturer's data.\n\nAssumed equal accuracy to the cassette version of this test.\n\nRebranded to ID NOW Strep A 2.\n\nBased on average selling price submitted by the company during consultation (based on volume-based discounts; without including apportioned analyser costs).\n\nThe results of the probabilistic sensitivity analysis mirrored the results of the deterministic base-case analysis in all models.\n\nThe probability of a rapid test being cost effective was\xa00 in all 4\xa0models, regardless of the rapid test used.\n\nA range of scenario analyses was done. For the adult primary care model, none produced ICERs that were around or below £30,000 per QALY gained, compared with current practice.\n\nFor the adult secondary care model, changing the rate of penicillin-induced anaphylaxis from 0.01% (Neuner et al. 2003) to 0.64% (Van Howe and Kusnier 2006), resulted in 6\xa0rapid tests dominating current practice (that is, testing was cheaper and more effective than current practice). These were the 5\xa0NADAL tests and Alere TestPack Plus Strep\xa0A. The ICERs for 4\xa0tests (2\xa0Clearview Exact Strep\xa0A tests and 2\xa0Strep\xa0A rapid tests from Biopanda) decreased to around or below £30,000 per QALY gained, compared with current practice.\n\nIn addition, for the adult secondary care model, the ICERs for the 5\xa0NADAL tests decreased to around or below £30,000 per QALY gained, compared with current practice, for the following assumptions:\n\nchanging the Centor threshold for starting antibiotics and testing to 2\xa0or more (ICERs: £30,230 to £69,690 per QALY gained)\n\nchanging the Centor threshold for starting antibiotics and testing to 1\xa0or more (ICERs: £22,220 to £56,190 per QALY gained)\n\nlowering the prevalence of strep\xa0A infection to 10% (ICERs: £20,628 to £53,506 per QALY gained)\n\ndoubling the rate of penicillin-related rash to 4% (ICERs: £8,913 to £32,557 per QALY gained)\n\ndoubling the utility decrement of penicillin-induced rash (ICERs: £21,309 to £44,953 per QALY gained).\n\nFor the children's primary care model, no scenario analyses produced ICERs that were around or below £30,000 per QALY gained.\n\nThe scenario analyses for the children's secondary care model largely mirrored scenario analyses for the adult secondary care model, except that changing Centor threshold for starting antibiotics and testing to a score of 2\xa0or more had no major effect on the ICERs.\n\nIn addition, several analyses favoured testing strategies, and all or some of the tests dominated by current practice in base-case analyses were no longer dominated. However, the ICERs were around or above £100,000 per QALY gained:\n\ndoubling the complication rate of treated strep\xa0A infection to 2.6%\n\nhalving the complication rate of untreated strep\xa0A infection to 0.75% (children's primary care model only)\n\nhalving the utility decrement of untreated strep\xa0A infection\n\ndoubling the utility decrement of treated strep\xa0A infection\n\nchanging the accuracy estimates to the lower confidence limits for both the rapid test and Centor clinical scoring tool (children's primary care model only).\n\nSeveral scenario analyses favoured current practice. In all 4\xa0models, doubling the utility decrement associated with untreated strep\xa0A infection resulted in an additional 2\xa0to 4\xa0tests being dominated by current practice, compared with base-case results. These tests were the Strep\xa0A rapid test cassette and the test strip from Biopanda (all models), the Alere TestPack Plus Strep\xa0A cassette (adult primary and secondary care models) and the QuikRead Go Strep\xa0A test kit (adult secondary care model). In the adult secondary care model, the following assumptions also resulted in additional tests being dominated by current practice:\n\nincreasing the prevalence rate to 35.9%\n\nhalving the complication rate of treated strep\xa0A infection to 0.65%\n\ndoubling the complication rate of untreated strep\xa0A infection to 3%\n\nhalving the rate of penicillin-related rash to 1%\n\nhalving the utility decrement of treated strep\xa0A infection\n\nhalving the utility decrement of penicillin-induced rash\n\ndoubling the utility decrement of an abscess.", 'Committee discussion': "# Clinical need and practice\n\n## Antimicrobial resistance is a growing public health concern\n\nA clinical expert explained concerns about the global increase in bacteria developing resistance to antibiotics (antimicrobial resistance). Data from the UK's 5-year action plan for antimicrobial resistance 2019 to 2024 estimate that 700,000\xa0people die every year globally because of infections caused by resistant strains of bacteria and this number will increase if no action is taken. The report notes that no new classes of antibiotics have been developed since the 1980s. Tackling antimicrobial resistance has been one of the key UK public health priorities for several years, and the use of antibiotics is gradually reducing. From 2014 to 2017, antibiotic use decreased by 7.3%, from 23.4\xa0to\xa021.7 defined daily doses per 1,000\xa0inhabitants per day. A key aim of the UK's 5‑year action plan for antimicrobial resistance is to implement diagnostic tests that can guide antimicrobial prescribing decisions. The committee noted that rapid tests for group\xa0A streptococcal infections (strep\xa0A) have been promoted for this purpose.\n\n## Sore throat is usually a self-limiting condition and clinical need for the rapid tests is unclear\n\nA clinical expert explained that sore throat is a common condition that is usually self-limiting, that is, it usually resolves without any antibiotic treatment. Usually a sore throat is caused by a virus and so treatment with antibiotics is not needed. The committee was aware of NICE's guideline on antimicrobial prescribing for acute sore throat. This highlights that treatment with antibiotics only reduces symptom duration by around 16\xa0hours. However, the committee noted that this guideline covers all bacterial infections of the throat, and it was not clear what the treatment effect of antibiotics would be in people with a confirmed strep\xa0A infection. Antibiotics could reduce the risk of some complications of strep\xa0A, but these are usually either very rare or not serious. The committee heard that antibiotics are often prescribed because of perceived clinical need or patient and carers' expectations to have treatment. Clinical experts explained that NICE's guideline on antimicrobial prescribing for acute sore throat focuses on measures of self-care and advises that antibiotics should only be considered for people who are most likely to benefit from them. Delayed prescribing is an option for most people who need antibiotics; that is, when antibiotics are only dispensed if symptoms do not improve within a few days of the person visiting their GP. Full implementation of this guideline is anticipated to reduce the use of antibiotics in people with a sore throat. Patients may be reassured by a discussion that highlights the likelihood of a sore throat becoming more severe balanced with the risk associated with taking antibiotics. The committee concluded that, in people who are otherwise healthy, antibiotics are usually not needed for a sore throat. Therefore, the clinical need for rapid testing for strep\xa0A infections is unclear.\n\n## People with a sore throat may have different testing needs and preferences\n\nA patient expert explained about the needs of patients and carers when they are seeking medical advice for a sore throat, and making a decision about whether to have antibiotics or whether to self-care. Patients would value information on what the results of the rapid strep\xa0A tests mean, how reliable they are, what the test involves and whether this information influences a treatment decision. The patient expert noted that it could be more difficult to explain the test procedure or take a throat swab in younger children and in people with cognitive impairment or learning difficulties. Therefore, this could be challenging to do routinely in a standard appointment. They noted that some people with sore throat may appreciate point-of-care testing and almost immediate results, whereas others may prefer the samples being sent for laboratory processing because this may be seen as more reliable. The committee concluded that patients and carers seeking advice for sore throat may have different testing needs and preferences, and treatment expectations.\n\n# Clinical effectiveness\n\n## Most accuracy studies are not applicable to NHS practice\n\nThe committee discussed the available data on the diagnostic accuracy of the rapid tests for strep\xa0A in people with a sore throat. It noted that although 26\xa0accuracy studies were identified by the external assessment group (EAG), most included a broad population and only 2\xa0reported data separately for people with a high clinical score (Centor score of 3\xa0or more). The rapid tests for strep\xa0A are most likely to be useful for people with a high clinical score. The committee noted that the prevalence of strep\xa0A is higher in people with high clinical scores than in people with low clinical scores or in an unselected population of people with a sore throat. Therefore, it concluded that studies in unselected populations or populations with lower clinical scores may not be applicable to NHS practice.\n\n## The accuracy of the rapid tests in routine clinical practice is uncertain and likely to be very variable\n\nThe committee discussed the accuracy data available for each of the tests. It noted that no data were available for 3\xa0of the tests (Strep\xa0A Rapid Test Strip from Biopanda, Biosynex Strep\xa0A Cassette test, and Bionexia Strep\xa0A Plus Cassette test). The EAG highlighted the high level of uncertainty in the estimates of rapid test accuracy because of the limited evidence available and the high variability between the studies. The committee noted that some tests only had accuracy data from studies done under ideal conditions (such as in unpublished manufacturer studies), which are unlikely to be repeatable in routine clinical practice. This is because the rapid tests' performance is linked to the quality of sampling and processing the sample. A clinical expert commented that positive test results are usually correct, but negative results could be related to absence of strep\xa0A infection, poor test sensitivity, or poor sampling technique. The committee also noted the imperfect accuracy of the reference standard (microbiological culture of throat swabs), which is subject to similar limitations. Laboratory polymerase chain reaction (PCR) tests have higher sensitivity than microbiological culture of throat swabs, but the clinical significance of this is unclear. For example, laboratory PCR tests could detect strep\xa0A carriers rather than infection, resulting in false positive results. The committee noted that the imperfect reference standard could under- or overestimate the accuracy of the rapid tests but that the size of either bias was not known. Overall, the committee concluded that the performance of the rapid tests in routine clinical practice is uncertain and difficult to predict, and is likely to vary from practice to practice.\n\n## Rapid tests (used with clinical scoring tools) are unlikely to improve clinical outcomes compared with the use of clinical scoring tools alone\n\nThe committee reviewed the available evidence on the clinical effectiveness of using the rapid tests for people with suspected strep\xa0A throat infections. There was no evidence available on clinical outcomes such as morbidity, mortality, or onward transmission rate. The committee noted that severe complications of strep\xa0A are rare and there is no evidence to suggest that the rapid tests would reduce the risk of them happening. There were only 3\xa0randomised controlled trials that reported antibiotic prescribing behaviours with or without rapid testing. The committee discussed the study by Little et al. (2013), done in UK primary care. The rate of delayed prescribing was lower in the rapid test group (23%) compared with the clinical score only group (43%). However, the reported use of antibiotics appeared similar in both groups (35% and 37%, respectively) and the level of immediate prescribing was also similar in both groups (18% and 16%, respectively). The EAG explained that data on reported antibiotic use were only available for 80% of enrolled patients so should be interpreted with caution. Also, a clinical expert commented that symptom severity and time to symptom resolution were comparable between these 2\xa0groups (although the 2\xa0groups were not formally tested for a difference). The committee concluded that the clinical benefit of the rapid tests was uncertain. The only study (Little et al. 2013) providing some evidence on this suggested there may be no benefit of rapid testing (used with the clinical scoring tool), compared with the use of clinical scoring tools alone.\n\n# Cost effectiveness\n\n## There is no evidence to assess the cost effectiveness of the rapid tests in pharmacies\n\nThe committee was aware that the rapid tests may be available in some community pharmacies. The EAG found no evidence on the diagnostic or clinical utility of rapid test accuracy when used in pharmacies, and therefore could not model this. Also, the committee noted that FeverPAIN had not been validated for use in pharmacies and that staff might need training to use clinical scoring tools. The committee concluded that it was not possible to assess the cost effectiveness of rapid tests for use in pharmacies.\n\n## The accuracy inputs for the rapid tests are highly uncertain\n\nThe committee noted that test accuracy inputs for 9\xa0of 14\xa0rapid tests for which cost-effectiveness analysis was possible were from unpublished manufacturer data. This is likely to overestimate the accuracy of tests in routine clinical practice. Most accuracy estimates were from studies that were not applicable to NHS practice (see sections\xa04.4 and\xa04.5) because they did not use the tests with clinical scoring tools, or included unselected populations who did not necessarily have high scores from clinical scoring tools. The committee therefore concluded that the incremental cost-effectiveness ratios (ICERs) produced by the models were highly uncertain because of bias in the data used to model the accuracy of the rapid tests.\n\n## The costs of using the tests in routine practice are likely to be underestimated in the models\n\nThe committee discussed the estimated costs of the tests and of the staff time for running the tests in the models. It raised concerns about the Xpert Xpress Strep\xa0A test cost, which was much lower than the costs of the other 3\xa0molecular tests. The EAG explained that the test costs also included analyser or test cassette reader costs (when this equipment is needed). For all tests except Xpert Xpress Strep\xa0A, it was assumed that 2\xa0tests per day would be done in a medium-sized GP practice, based on expert opinion. For the Xpert Xpress Strep\xa0A test, it was assumed that 28\xa0tests per day would be run, resulting in a lower cost per test and therefore more favourable ICERs. The committee noted that an updated price for the Cobas Strep\xa0A assay was submitted by the company during consultation. It understood this to be an average selling price, based on volume-based discounts; the range associated with the average selling price was not provided to NICE. The updated test cost did not change the conclusions of the analyses. Also, the committee noted that the updated cost did not include analyser costs. Therefore, the incremental costs associated with this test are likely to have been underestimated. Clinical experts commented that the time to process the rapid tests in routine clinical practice was likely underestimated in the models. They explained that the time included appeared to account only for the time for the test read-out, and not for the time needed to prepare the test and take the throat swab. The total time necessary to run the test would depend on the experience of the healthcare professional doing the test. This could vary considerably between practices depending on their set-up for point-of-care testing. The time needed to take the throat swab might also be longer for certain populations, for example younger children. The committee concluded that including a more realistic estimate of test processing time would further increase the costs and ICERs for the rapid tests.\n\n## Penicillin-induced anaphylaxis is very rare\n\nThe committee considered the adverse events in the models and noted that the rate of penicillin-induced anaphylaxis had a big effect on the ICERs in scenario analyses. Clinical experts advised that the rate of penicillin-related anaphylaxis, when penicillin is taken orally, is very low (about 1\xa0in a million). Therefore, the rate assumed in the base-case scenario (0.01%) is more appropriate than the rate assumed in the scenario analyses (0.64%), but could even overestimate the rate of penicillin-related anaphylaxis in the UK. Clinical experts also noted that the costs of sepsis are not generalisable to the treatment costs of penicillin-induced anaphylaxis, as had been assumed by the EAG. The committee concluded that penicillin-induced anaphylaxis is rare, and that the results of the scenario analyses which included a higher rate were unrealistic.\n\n## The models predict a decrease in antibiotic use, but this might not be replicated in NHS practice\n\nThe committee recalled that one of the suggested benefits of the tests was providing a more targeted approach to antibiotic prescribing (see section\xa04.1). It discussed the antibiotic use predicted by the models for both current practice and for the rapid tests (used with clinical scoring tools). The models predicted a 10% to 15% decrease in the absolute rate of antibiotic use with rapid tests, compared with current practice. This was based on predicted treatment decisions related to the Centor score or the rapid test results (see table 6). The committee questioned the external validity of this prediction because the study by Little et al. (2013) suggested similar antibiotic use between people who had the rapid test (with the clinical scoring tool), or the clinical scoring tool only (see section\xa04.6). It also recalled that the recent publication of NICE's guideline on antimicrobial prescribing for acute sore throat is expected to reduce antibiotic prescribing in sore throat further (see section\xa04.2). This could result in the tests having the potential to increase antibiotic prescribing. Clinical experts also advised that the FeverPAIN clinical scoring tool is more discriminative for strep\xa0A than the Centor tool. Therefore, the potential clinical benefits of the rapid tests compared with FeverPAIN could be even lower. The committee concluded that the predicted decrease in antibiotic use associated with the rapid tests might not be replicated in NHS practice.\n\n## The models do not account for all complications of strep\xa0A, but this is appropriate because they are very rare\n\nThe committee noted that the models do not capture all complications of strep\xa0A and discussed the effect of excluding those that are more serious. Clinical experts advised that the risk of serious complications, such as invasive strep\xa0A or sepsis, is very low and therefore unlikely to have a major effect on the modelling results. The rates of invasive strep\xa0A appear to have been increasing in the UK in recent years, but are still very low considering the high number of people presenting with a sore throat. The rate of serious complications is higher in people over 75\xa0years, and the risk of associated mortality is higher for these people. Therefore, modelling serious complications could be important. However, modelling the use of rapid tests for people over\xa075 was not possible because of the lack of data for the models. The committee also discussed that the models did not capture the risk of scarlet fever, although they acknowledged that this was a possible complication in children presenting early with a sore throat. Scarlet fever is more likely in children than adults. The rates of scarlet fever appear to have been increasing in the UK in recent years but are still low considering the total number of children presenting with a sore throat. For the children and adult models, the committee concluded that excluding the more severe complications was unlikely to have had a big effect on the results.\n\n## Wider public health benefits are not captured in the models\n\nThe committee noted that the wider public health benefits of the rapid tests, such as contribution to antimicrobial stewardship or effect on onward transmission rate, were not captured in the models. The committee discussed the risk of onward transmission of untreated strep\xa0A infection to other household members, particularly the risk of onward transmission leading to invasive strep\xa0A infection. It noted that although this risk exists, it is very small. The risk of onward transmission could be higher during an outbreak, for example, in a care home. However, using the tests during an outbreak was outside the scope of this assessment. The committee also noted that currently the effect on public health (health effects and costs) of reduced antibiotic use has not been quantified. The modelling predicted a 10% to 15% reduction in the absolute rate of antibiotic use with the rapid tests (with clinical scoring tools), compared with using clinical scoring tools only. However, this had minimal effect on the total cost of the pathway because penicillin costs are very low. The only differences in costs and quality-adjusted life years (QALYs) related to antibiotic prescribing were those of managing less severe strep\xa0A complications and side effects of penicillin. The committee discussed that although bacterial resistance to penicillin is not thought to be as great a problem as resistance to other classes of antibiotics such as macrolides (for example, erythromycin) or cephalosporins, there is very limited evidence to quantify this. Therefore, further research on the contribution of different classes of antibiotics to antimicrobial resistance, and to quantify the wider effect of antimicrobial stewardship, is needed (see section\xa05.1). The committee concluded that this evidence will be important for developing tests to improve prescribing decisions, which have the greatest effect on reducing antimicrobial resistance.\n\n## The rapid tests for strep\xa0A are unlikely to be a cost-effective use of NHS resources\n\nThe modelling predicted very small incremental costs and even smaller incremental QALYs. This resulted in ICERs between £1\xa0million and £6\xa0million per QALY gained, compared with current clinical practice, for most rapid tests (adult primary care model). These ICERs are far higher than those normally considered to be a cost-effective use of NHS resources and are based on the modelling predicting a decrease in antibiotic use that may not be replicated in NHS practice (see section\xa04.11). The committee noted that there is uncertainty about the model inputs and the most plausible ICERs. However, all sensitivity analyses suggested that the rapid tests are unlikely to be a cost-effective use of NHS resources. Also, the magnitude of any uncaptured benefit is not likely to be sufficient to change the interpretation of the results. The committee recalled the uncertain clinical role of the rapid tests in the context of NICE's recent guidance on antimicrobial prescribing for acute sore throat. The guidance advises that sore throat is self-limiting, and so in people who are otherwise healthy, antibiotics are usually not needed. The committee noted that the diagnostic accuracy of the tests in routine clinical practice is uncertain and likely to be highly variable. Also, there was no evidence to suggest that the rapid tests could reduce the rate of antibiotic prescribing or improve clinical outcomes in people with a sore throat. Therefore, the committee concluded that the most plausible ICERs for the rapid tests were too high, and their effect on wider public health benefits too uncertain (see section\xa04.13), to recommend routine adoption.", 'Recommendations for further research': 'The committee recommended that further research is needed to measure the wider effects on public health and the costs of antimicrobial stewardship associated with different classes of antibiotics used in different healthcare settings. This will help to inform the development of technologies to guide more targeted use of antibiotics and wider UK antimicrobial resistance policy.'}
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https://www.nice.org.uk/guidance/dg38
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Evidence-based recommendations on rapid tests for group A streptococcal infections in people aged 5 and over with a sore throat.
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2d35e19e83c48888e3bb1cb31bed6835f53c9a0c
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nice
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Rucaparib for maintenance treatment of relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer
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Rucaparib for maintenance treatment of relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer
Evidence-based recommendations on rucaparib (Rubraca) for treating relapsed platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer that has responded to platinum-based chemotherapy in adults.
# Recommendations
Rucaparib is recommended for use within the Cancer Drugs Fund as an option for maintenance treatment of relapsed platinum-sensitive high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to platinum-based chemotherapy in adults, only if the conditions in the managed access agreement for rucaparib are followed.
This recommendation is not intended to affect treatment with rucaparib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
The clinical evidence shows that rucaparib extends the time until cancer progresses compared with routine care. How much longer people live after taking rucaparib is uncertain because the data from the trial are not available yet. Because of the uncertainty in the clinical evidence, the estimates of cost effectiveness are very uncertain. Therefore, rucaparib cannot be recommended for routine use in the NHS.
Rucaparib has the potential to be cost effective if further data confirm the estimated overall-survival benefit. Rucaparib is therefore recommended for use within the Cancer Drugs Fund as an option for the maintenance treatment of relapsed platinum-sensitive high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to platinum-based chemotherapy in adults, while further data are collected.# Information about rucaparib
Marketing authorisation indication
Rucaparib (Rubraca, Clovis Oncology) is indicated as 'monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.'
Dosage in the marketing authorisation
Rucaparib is taken orally as tablets. The recommended dosage is 600 mg (2 × 300-mg tablets) twice daily, with or without food (1,200 mg total daily dose).
Interruption of treatment or dose reduction can be considered for adverse event management (600 mg to 500 mg to 400 mg to 300 mg ).
Patients should start maintenance treatment no later than 8 weeks after completion of their final dose of the platinum-containing regimen.
Price
The list price for rucaparib taken from the company submission is £3,562.00 per 60‑tablet pack of 300-mg, 250-mg or 200-mg tablets.
The company estimates that the average cost of a course of treatment until discontinuation is £110,897 (estimated from the deterministic base-case economic analysis using the list price).
The company has a commercial arrangement. This makes rucaparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 6) considered evidence submitted by Clovis Oncology, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 1 issue was resolved during the technical engagement stage, and agreed that:
For the long-term extrapolation of progression-free survival for the subgroup of people without a BRCA mutation it is most plausible to use the lognormal distribution, because this is more aligned with time to treatment discontinuation.
For the subgroup of people with a BRCA mutation who have had 2 lines of platinum-based chemotherapy it is most plausible to use the lognormal distribution, because this is more aligned with what was seen in Study 19 at 6‑year follow up.
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 34), and took these into account in its decision making. It discussed the following issues (issues 1, 2, 3, 4, 5, 7 and 8), which were outstanding after the technical engagement stage.
# Clinical need and treatment pathway
## Relapsed ovarian, fallopian tube and peritoneal cancer has a high disease burden
The patient experts explained in their written submissions that ovarian cancer negatively affects many aspects of life including physical and mental wellbeing, self-esteem and body image. The disease is often diagnosed after the cancer has spread beyond the ovary, making curative treatment difficult, and the diagnosis is often associated with devastation, shock, disbelief and fear. People with advanced disease are likely to face a future of recurrent disease, needing multiple rounds of treatment to manage it. Living under the shadow of the disease and not knowing when it will recur can significantly affect their quality of life. The committee understood these factors and concluded that there is a high disease burden for people with recurrent, platinum-sensitive disease.
## Limited treatment options are available
The patient experts explained that the risk of developing resistance to platinum is high, and treatments for platinum-resistant disease are extremely limited. Recurrence and the development of resistance to platinum need to be delayed for as long as possible. Maintenance treatment with a poly‑ADP-ribose polymerase (PARP) inhibitor such as rucaparib may extend time between recurrences, allowing people more freedom to lead a normal life. For some people, PARP inhibitors can have a long-lasting effect. There are currently no PARP inhibitors routinely commissioned for maintenance treatment after response to second-line platinum-based chemotherapy, although niraparib is currently available through the Cancer Drugs Fund. Olaparib capsules are recommended for routine commissioning after third-line chemotherapy for people with a BRCA mutation. There is also an ongoing NICE appraisal of olaparib tablets for maintenance treatment in people with relapsed disease that has responded to platinum. The committee concluded that the availability of a PARP inhibitor after response to second-line platinum would be greatly valued by patients and their families.
# Most relevant population
## The intention-to-treat population is the most relevant population for decision making
ARIEL3 is a double-blind randomised controlled trial of rucaparib compared with placebo in people with platinum-sensitive, high-grade serous or endometroid ovarian, fallopian tube or primary peritoneal carcinoma who have had 2 or more platinum-based chemotherapy regimens with a complete or partial response to the last regimen. The company submitted results for the overall intention-to-treat (ITT) population and also a subgroup of people who have a BRCA mutation and have had 3 or more courses of platinum-based chemotherapy (the BRCA 3L+ population) for the comparison of rucaparib with olaparib. At clarification stage, the ERG requested additional subgroup analyses of people without a BRCA mutation, and people with a BRCA mutation who have had 2 courses of platinum-based chemotherapy (the BRCA 2L population). However, the company commented that these analyses are not robust because they are post hoc and based on small sample sizes. The clinical experts explained that PARP inhibitors have been shown to have greater benefit in the subgroup of people with a BRCA mutation, but there are some people without a BRCA mutation whose disease responds in a similar way. Some people without a BRCA mutation may gain long-term benefit from PARP inhibitors, as seen in a trial of olaparib (Study 19). The clinical experts therefore considered that the ITT population is the most relevant population for the decision problem. The committee concluded that the results for the subgroups were not robust, and that the ITT population is the most relevant for decision making.
# Clinical trial results from ARIEL3
## ARIEL3 is generalisable to UK clinical practice
The clinical experts explained that ARIEL3 is representative of patients treated in the UK. Importantly, inclusion in ARIEL3 was not restricted based on the extent of residual disease, unlike some previous studies of PARP inhibitors. The clinical experts also explained that the proportions of people whose disease had a partial or complete response to platinum were similar to what would be seen in clinical practice. The committee noted that the proportion of people with a BRCA mutation is higher in ARIEL3 than in clinical practice (35% compared with 20%). The clinical experts explained that although this is higher than would be expected in the UK population, it is closer to the UK percentage than some other studies of PARP inhibitors. For example, 50% of people in Study 19 had a BRCA mutation. The committee concluded that ARIEL3 is broadly generalisable to clinical practice in England.
## Rucaparib improves progression-free survival
The primary endpoint of ARIEL3 was progression-free survival (PFS). A statistically significant improvement in PFS was seen at data cut-off for the overall ITT population. Median PFS was 10.8 months in the rucaparib arm and 5.4 months in the placebo arm (hazard ratio 0.36, 95% confidence interval 0.30 to 0.45). The committee concluded that rucaparib improves PFS compared with placebo.
## Overall-survival data are immature but rucaparib is expected to be similar to other PARP inhibitors
Overall survival (OS) was a secondary endpoint in ARIEL3. At data cut-off, 88% of patients were still alive. Median OS was not reached and no statistically significant difference between the treatment arms had been seen. The clinical experts explained that there is a high possibility of a class effect for PARP inhibitors, and they expect rucaparib to show a broadly similar improvement in OS to that shown by olaparib in Study 19. The committee concluded that rucaparib is expected to provide a similar survival benefit to other PARP inhibitors.
## Study 19 provides the most mature OS data for PARP inhibitors
Because of its immaturity, the company did not use ARIEL3 OS data in the cost-effectiveness analysis. It used OS data from Study 19 to model the long-term outcomes of rucaparib compared with routine surveillance. The committee noted that there were several differences between ARIEL3 and Study 19 in terms of trial design and patient characteristics, which may have influenced the results. For example, BRCA mutation status, a known prognostic factor, was a stratification factor at randomisation in ARIEL3 but it was confirmed retrospectively in Study 19. Also, a lower proportion of people had a BRCA mutation in ARIEL3 (35% compared with 50% in Study 19). The clinical experts highlighted that a higher proportion of people in ARIEL3 had rucaparib after 2 lines of platinum-based chemotherapy rather than after 3 or more lines (63% compared with 43% in Study 19), and that earlier use of PARP inhibitors is associated with better outcomes. Conversely, the use of a PARP inhibitor in subsequent treatment lines in the placebo arm was substantially higher in ARIEL3 than in Study 19, which probably reduced the magnitude of the difference in OS between rucaparib and placebo in ARIEL3. The committee appreciated that the populations in the trials were not strictly comparable. However, it noted that Study 19 provides the most mature data available for a PARP inhibitor, with over 6 years of follow up. The committee concluded that Study 19 provides the best OS data currently available for a PARP inhibitor, and that it is reasonable to use this data for modelling in the absence of mature OS data from ARIEL3.
# Cost effectiveness
## The company's economic model is suitable for decision making
The company submitted a partitioned survival model with 3 states (progression-free, progressed disease and death) to estimate the cost effectiveness of rucaparib compared with routine surveillance. The committee considered that the model is suitable for decision making.
## Post-progression survival is uncertain, but the ERG's modelling of post-progression survival is the most plausible
The way post-progression survival (PPS) is modelled is one of the key drivers of the model results. Time spent in the progression-free health state is informed by ARIEL3 data. However, to model PPS for rucaparib, the company used the difference between Study 19 PFS and OS outcomes, assuming that PPS outcomes for rucaparib are equivalent to those for olaparib in Study 19. The ERG considered that this method is unconventional because the calculation of PPS is disconnected from the PFS used elsewhere in the model, and results in OS benefits that are implausible. The ERG's preferred approach is to calculate PPS as the difference between OS in Study 19 and PFS in ARIEL3. However, the company considered the ERG's approach to be inappropriate because it leads to a higher rate of death after progression for rucaparib than for olaparib. This results in shorter PPS outcomes for rucaparib, because PFS in ARIEL3 is longer than in Study 19. The committee considered that the company's approach is optimistic because it combines a greater PFS benefit for rucaparib from ARIEL3 and all the PPS benefit of olaparib from Study 19, resulting in a higher OS with rucaparib than for olaparib. The committee questioned the plausibility of this and recalled its earlier conclusion that rucaparib is expected to provide a similar survival benefit to other PARP inhibitors (see section 3.6). Therefore, the committee concluded that the ERG's approach is preferable, although it acknowledged that there is uncertainty associated with the modelling that will not be fully resolved until more mature OS data from ARIEL3 are available.
## Rucaparib has not been shown to be cost effective compared with routine surveillance
At the appraisal committee meeting, the company's base-case incremental cost-effectiveness ratio (ICER) for rucaparib compared with routine surveillance in the ITT population was above the range that is normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per quality-adjusted life year gained). None of the company's scenario analyses substantially changed the results. The committee concluded that it could not recommend rucaparib as a cost-effective use of NHS resources for people with relapsed platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer. After consultation, the company agreed to provide rucaparib to the NHS with a higher discount. The company and the ERG presented revised base-case ICERs including the agreed discount for rucaparib. The estimated ICERs for the ITT population incorporating the updated patient access scheme range from £29,138 (company) to £32,455 (ERG) per QALY. Most of the difference is because of the alternative approaches used for modelling PPS (see section 3.9). The committee considered that the results are uncertain because of the immaturity of the OS data and concluded that this uncertainty could only be resolved with the availability of more mature data from ARIEL3. Therefore, the committee was not confident that rucaparib represents a cost-effective use of NHS resources and could not recommend it for routine use in the NHS. However, if the company projections for PFS and OS prove to be correct when further evidence becomes available, then rucaparib would have the potential to be cost effective.
## Rucaparib has not been shown to be cost effective compared with olaparib in people with a BRCA mutation who have had 3 lines of platinum-based chemotherapy
Olaparib capsules are a treatment option for people with a BRCA mutation who have had 3 lines of platinum-based chemotherapy. The company presented a cost-effectiveness analysis for this subgroup in which it was assumed that rucaparib and olaparib have equivalent efficacy. The results of the analysis showed that rucaparib was dominated by olaparib (that is, rucaparib costs more and worked equally as well). The committee noted that there is currently no robust efficacy data to inform this comparison. Therefore, the cost effectiveness of rucaparib compared with olaparib in this subgroup of patients is uncertain. The committee concluded that rucaparib cannot be recommended for routine use in people with a BRCA mutation who have had 3 lines of platinum-based chemotherapy.
# Cancer Drugs Fund
## Rucaparib meets the criteria for inclusion in the Cancer Drugs Fund for the maintenance treatment of relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer
Having concluded that rucaparib cannot be recommended for routine use, the committee considered if it could be recommended for use within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee recognised that PARP inhibitors are innovative treatments for recurrent disease. The key uncertainty associated with rucaparib is the immature OS data, and this could be addressed through the collection of additional data from ARIEL3. The committee took the view that if mature OS data from ARIEL3 supports the survival estimate in the company's model, the ICERs for rucaparib could be within the range normally considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee therefore concluded that the criteria for inclusion in the Cancer Drugs Fund are met because:
rucaparib cannot be recommended for routine commissioning based on current clinical data but there is plausible potential for cost effectiveness
there is outstanding clinical uncertainty about the overall survival with rucaparib
the uncertainty is likely to be resolved by further data from ARIEL3.
# Conclusion
## Rucaparib is recommended for use within the Cancer Drugs Fund as an option for the maintenance treatment of relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer
Rucaparib increases PFS compared with routine surveillance but the benefit in OS is uncertain because mature data are not available yet from the trial. Because of the uncertainty about the OS benefit, the estimates of cost effectiveness are very uncertain and rucaparib cannot be recommended for routine use in the NHS. If mature OS data from ARIEL3 support the survival estimates in the company's model, rucaparib has the potential to be cost effective. Therefore, rucaparib is recommended for use within the Cancer Drugs Fund as an option for the maintenance treatment of relapsed platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer after response to platinum-based chemotherapy.# Recommendations for data collection
As a condition to the positive recommendation, the company is required to collect overall-survival data from the ARIEL3 trial.
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{'Recommendations': 'Rucaparib is recommended for use within the Cancer Drugs Fund as an option for maintenance treatment of relapsed platinum-sensitive high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to platinum-based chemotherapy in adults, only if the conditions in the managed access agreement for rucaparib are followed.\n\nThis recommendation is not intended to affect treatment with rucaparib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThe clinical evidence shows that rucaparib extends the time until cancer progresses compared with routine care. How much longer people live after taking rucaparib is uncertain because the data from the trial are not available yet. Because of the uncertainty in the clinical evidence, the estimates of cost effectiveness are very uncertain. Therefore, rucaparib cannot be recommended for routine use in the NHS.\n\nRucaparib has the potential to be cost effective if further data confirm the estimated overall-survival benefit. Rucaparib is therefore recommended for use within the Cancer Drugs Fund as an option for the maintenance treatment of relapsed platinum-sensitive high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to platinum-based chemotherapy in adults, while further data are collected.', 'Information about rucaparib': "Marketing authorisation indication\n\nRucaparib (Rubraca, Clovis Oncology) is indicated as 'monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.'\n\nDosage in the marketing authorisation\n\nRucaparib is taken orally as tablets. The recommended dosage is 600\xa0mg (2 × 300-mg tablets) twice daily, with or without food (1,200\xa0mg total daily dose).\n\nInterruption of treatment or dose reduction can be considered for adverse event management (600\xa0mg to 500\xa0mg [2 × 250-mg tablets] to 400\xa0mg [2 × 200-mg tablets] to 300\xa0mg [1 × 300-mg tablet]).\n\nPatients should start maintenance treatment no later than 8\xa0weeks after completion of their final dose of the platinum-containing regimen.\n\nPrice\n\nThe list price for rucaparib taken from the company submission is £3,562.00 per 60‑tablet pack of 300-mg, 250-mg or 200-mg tablets.\n\nThe company estimates that the average cost of a course of treatment until discontinuation is £110,897 (estimated from the deterministic base-case economic analysis using the list price).\n\nThe company has a commercial arrangement. This makes rucaparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa06) considered evidence submitted by Clovis Oncology, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 1\xa0issue was resolved during the technical engagement stage, and agreed that:\n\nFor the long-term extrapolation of progression-free survival for the subgroup of people without a BRCA mutation it is most plausible to use the lognormal distribution, because this is more aligned with time to treatment discontinuation.\n\nFor the subgroup of people with a BRCA mutation who have had 2\xa0lines of platinum-based chemotherapy it is most plausible to use the lognormal distribution, because this is more aligned with what was seen in Study\xa019 at 6‑year follow up.\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa034), and took these into account in its decision making. It discussed the following issues (issues 1, 2, 3, 4, 5, 7 and 8), which were outstanding after the technical engagement stage.\n\n# Clinical need and treatment pathway\n\n## Relapsed ovarian, fallopian tube and peritoneal cancer has a high disease burden\n\nThe patient experts explained in their written submissions that ovarian cancer negatively affects many aspects of life including physical and mental wellbeing, self-esteem and body image. The disease is often diagnosed after the cancer has spread beyond the ovary, making curative treatment difficult, and the diagnosis is often associated with devastation, shock, disbelief and fear. People with advanced disease are likely to face a future of recurrent disease, needing multiple rounds of treatment to manage it. Living under the shadow of the disease and not knowing when it will recur can significantly affect their quality of life. The committee understood these factors and concluded that there is a high disease burden for people with recurrent, platinum-sensitive disease.\n\n## Limited treatment options are available\n\nThe patient experts explained that the risk of developing resistance to platinum is high, and treatments for platinum-resistant disease are extremely limited. Recurrence and the development of resistance to platinum need to be delayed for as long as possible. Maintenance treatment with a poly‑ADP-ribose polymerase (PARP) inhibitor such as rucaparib may extend time between recurrences, allowing people more freedom to lead a normal life. For some people, PARP inhibitors can have a long-lasting effect. There are currently no PARP inhibitors routinely commissioned for maintenance treatment after response to second-line platinum-based chemotherapy, although niraparib is currently available through the Cancer Drugs Fund. Olaparib capsules are recommended for routine commissioning after third-line chemotherapy for people with a BRCA mutation. There is also an ongoing NICE appraisal of olaparib tablets for maintenance treatment in people with relapsed disease that has responded to platinum. The committee concluded that the availability of a PARP inhibitor after response to second-line platinum would be greatly valued by patients and their families.\n\n# Most relevant population\n\n## The intention-to-treat population is the most relevant population for decision making\n\nARIEL3 is a double-blind randomised controlled trial of rucaparib compared with placebo in people with platinum-sensitive, high-grade serous or endometroid ovarian, fallopian tube or primary peritoneal carcinoma who have had 2\xa0or more platinum-based chemotherapy regimens with a complete or partial response to the last regimen. The company submitted results for the overall intention-to-treat (ITT) population and also a subgroup of people who have a BRCA mutation and have had 3\xa0or more courses of platinum-based chemotherapy (the BRCA\xa03L+ population) for the comparison of rucaparib with olaparib. At clarification stage, the ERG requested additional subgroup analyses of people without a BRCA mutation, and people with a BRCA mutation who have had 2\xa0courses of platinum-based chemotherapy (the BRCA\xa02L population). However, the company commented that these analyses are not robust because they are post hoc and based on small sample sizes. The clinical experts explained that PARP inhibitors have been shown to have greater benefit in the subgroup of people with a BRCA mutation, but there are some people without a BRCA mutation whose disease responds in a similar way. Some people without a BRCA mutation may gain long-term benefit from PARP inhibitors, as seen in a trial of olaparib (Study\xa019). The clinical experts therefore considered that the ITT population is the most relevant population for the decision problem. The committee concluded that the results for the subgroups were not robust, and that the ITT population is the most relevant for decision making.\n\n# Clinical trial results from ARIEL3\n\n## ARIEL3 is generalisable to UK clinical practice\n\nThe clinical experts explained that ARIEL3 is representative of patients treated in the UK. Importantly, inclusion in ARIEL3 was not restricted based on the extent of residual disease, unlike some previous studies of PARP inhibitors. The clinical experts also explained that the proportions of people whose disease had a partial or complete response to platinum were similar to what would be seen in clinical practice. The committee noted that the proportion of people with a BRCA mutation is higher in ARIEL3 than in clinical practice (35% compared with 20%). The clinical experts explained that although this is higher than would be expected in the UK population, it is closer to the UK percentage than some other studies of PARP inhibitors. For example, 50% of people in Study\xa019 had a BRCA mutation. The committee concluded that ARIEL3 is broadly generalisable to clinical practice in England.\n\n## Rucaparib improves progression-free survival\n\nThe primary endpoint of ARIEL3 was progression-free survival (PFS). A statistically significant improvement in PFS was seen at data cut-off for the overall ITT population. Median PFS was 10.8\xa0months in the rucaparib arm and 5.4\xa0months in the placebo arm (hazard ratio\xa00.36, 95% confidence interval 0.30\xa0to\xa00.45). The committee concluded that rucaparib improves PFS compared with placebo.\n\n## Overall-survival data are immature but rucaparib is expected to be similar to other PARP inhibitors\n\nOverall survival (OS) was a secondary endpoint in ARIEL3. At data cut-off, 88% of patients were still alive. Median OS was not reached and no statistically significant difference between the treatment arms had been seen. The clinical experts explained that there is a high possibility of a class effect for PARP inhibitors, and they expect rucaparib to show a broadly similar improvement in OS to that shown by olaparib in Study\xa019. The committee concluded that rucaparib is expected to provide a similar survival benefit to other PARP inhibitors.\n\n## Study\xa019 provides the most mature OS data for PARP inhibitors\n\nBecause of its immaturity, the company did not use ARIEL3 OS data in the cost-effectiveness analysis. It used OS data from Study\xa019 to model the long-term outcomes of rucaparib compared with routine surveillance. The committee noted that there were several differences between ARIEL3 and Study\xa019 in terms of trial design and patient characteristics, which may have influenced the results. For example, BRCA mutation status, a known prognostic factor, was a stratification factor at randomisation in ARIEL3 but it was confirmed retrospectively in Study\xa019. Also, a lower proportion of people had a BRCA mutation in ARIEL3 (35% compared with 50% in Study\xa019). The clinical experts highlighted that a higher proportion of people in ARIEL3 had rucaparib after 2\xa0lines of platinum-based chemotherapy rather than after 3\xa0or more lines (63% compared with 43% in Study\xa019), and that earlier use of PARP inhibitors is associated with better outcomes. Conversely, the use of a PARP inhibitor in subsequent treatment lines in the placebo arm was substantially higher in ARIEL3 than in Study\xa019, which probably reduced the magnitude of the difference in OS between rucaparib and placebo in ARIEL3. The committee appreciated that the populations in the trials were not strictly comparable. However, it noted that Study\xa019 provides the most mature data available for a PARP inhibitor, with over 6\xa0years of follow up. The committee concluded that Study\xa019 provides the best OS data currently available for a PARP inhibitor, and that it is reasonable to use this data for modelling in the absence of mature OS data from ARIEL3.\n\n# Cost effectiveness\n\n## The company's economic model is suitable for decision making\n\nThe company submitted a partitioned survival model with 3\xa0states (progression-free, progressed disease and death) to estimate the cost effectiveness of rucaparib compared with routine surveillance. The committee considered that the model is suitable for decision making.\n\n## Post-progression survival is uncertain, but the ERG's modelling of post-progression survival is the most plausible\n\nThe way post-progression survival (PPS) is modelled is one of the key drivers of the model results. Time spent in the progression-free health state is informed by ARIEL3 data. However, to model PPS for rucaparib, the company used the difference between Study\xa019 PFS and OS outcomes, assuming that PPS outcomes for rucaparib are equivalent to those for olaparib in Study\xa019. The ERG considered that this method is unconventional because the calculation of PPS is disconnected from the PFS used elsewhere in the model, and results in OS benefits that are implausible. The ERG's preferred approach is to calculate PPS as the difference between OS in Study\xa019 and PFS in ARIEL3. However, the company considered the ERG's approach to be inappropriate because it leads to a higher rate of death after progression for rucaparib than for olaparib. This results in shorter PPS outcomes for rucaparib, because PFS in ARIEL3 is longer than in Study\xa019. The committee considered that the company's approach is optimistic because it combines a greater PFS benefit for rucaparib from ARIEL3 and all the PPS benefit of olaparib from Study\xa019, resulting in a higher OS with rucaparib than for olaparib. The committee questioned the plausibility of this and recalled its earlier conclusion that rucaparib is expected to provide a similar survival benefit to other PARP inhibitors (see section\xa03.6). Therefore, the committee concluded that the ERG's approach is preferable, although it acknowledged that there is uncertainty associated with the modelling that will not be fully resolved until more mature OS data from ARIEL3 are available.\n\n## Rucaparib has not been shown to be cost effective compared with routine surveillance\n\nAt the appraisal committee meeting, the company's base-case incremental cost-effectiveness ratio (ICER) for rucaparib compared with routine surveillance in the ITT population was above the range that is normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per quality-adjusted life year [QALY] gained). None of the company's scenario analyses substantially changed the results. The committee concluded that it could not recommend rucaparib as a cost-effective use of NHS resources for people with relapsed platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer. After consultation, the company agreed to provide rucaparib to the NHS with a higher discount. The company and the ERG presented revised base-case ICERs including the agreed discount for rucaparib. The estimated ICERs for the ITT population incorporating the updated patient access scheme range from £29,138 (company) to £32,455 (ERG) per QALY. Most of the difference is because of the alternative approaches used for modelling PPS (see section\xa03.9). The committee considered that the results are uncertain because of the immaturity of the OS data and concluded that this uncertainty could only be resolved with the availability of more mature data from ARIEL3. Therefore, the committee was not confident that rucaparib represents a cost-effective use of NHS resources and could not recommend it for routine use in the NHS. However, if the company projections for PFS and OS prove to be correct when further evidence becomes available, then rucaparib would have the potential to be cost effective.\n\n## Rucaparib has not been shown to be cost effective compared with olaparib in people with a BRCA mutation who have had 3\xa0lines of platinum-based chemotherapy\n\nOlaparib capsules are a treatment option for people with a BRCA mutation who have had 3\xa0lines of platinum-based chemotherapy. The company presented a cost-effectiveness analysis for this subgroup in which it was assumed that rucaparib and olaparib have equivalent efficacy. The results of the analysis showed that rucaparib was dominated by olaparib (that is, rucaparib costs more and worked equally as well). The committee noted that there is currently no robust efficacy data to inform this comparison. Therefore, the cost effectiveness of rucaparib compared with olaparib in this subgroup of patients is uncertain. The committee concluded that rucaparib cannot be recommended for routine use in people with a BRCA mutation who have had 3\xa0lines of platinum-based chemotherapy.\n\n# Cancer Drugs Fund\n\n## Rucaparib meets the criteria for inclusion in the Cancer Drugs Fund for the maintenance treatment of relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer\n\nHaving concluded that rucaparib cannot be recommended for routine use, the committee considered if it could be recommended for use within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee recognised that PARP inhibitors are innovative treatments for recurrent disease. The key uncertainty associated with rucaparib is the immature OS data, and this could be addressed through the collection of additional data from ARIEL3. The committee took the view that if mature OS data from ARIEL3 supports the survival estimate in the company's model, the ICERs for rucaparib could be within the range normally considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee therefore concluded that the criteria for inclusion in the Cancer Drugs Fund are met because:\n\nrucaparib cannot be recommended for routine commissioning based on current clinical data but there is plausible potential for cost effectiveness\n\nthere is outstanding clinical uncertainty about the overall survival with rucaparib\n\nthe uncertainty is likely to be resolved by further data from ARIEL3.\n\n# Conclusion\n\n## Rucaparib is recommended for use within the Cancer Drugs Fund as an option for the maintenance treatment of relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer\n\nRucaparib increases PFS compared with routine surveillance but the benefit in OS is uncertain because mature data are not available yet from the trial. Because of the uncertainty about the OS benefit, the estimates of cost effectiveness are very uncertain and rucaparib cannot be recommended for routine use in the NHS. If mature OS data from ARIEL3 support the survival estimates in the company's model, rucaparib has the potential to be cost effective. Therefore, rucaparib is recommended for use within the Cancer Drugs Fund as an option for the maintenance treatment of relapsed platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer after response to platinum-based chemotherapy.", 'Recommendations for data collection': 'As a condition to the positive recommendation, the company is required to collect overall-survival data from the ARIEL3 trial.'}
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https://www.nice.org.uk/guidance/ta611
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Evidence-based recommendations on rucaparib (Rubraca) for treating relapsed platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer that has responded to platinum-based chemotherapy in adults.
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e955f05fa373ca2f9a2277f0118956e10835355f
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nice
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Pentosan polysulfate sodium for treating bladder pain syndrome
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Pentosan polysulfate sodium for treating bladder pain syndrome
Evidence-based recommendations on pentosan polysulfate sodium (Elmiron) for bladder pain syndrome in adults.
# Recommendations
Pentosan polysulfate sodium is recommended as an option for treating bladder pain syndrome with glomerulations or Hunner's lesions in adults with urinary urgency and frequency, and moderate to severe pain, only if:
their condition has not responded to an adequate trial of standard oral treatments
it is not offered in combination with bladder instillations
any previous treatment with bladder instillations was not stopped because of lack of response
it is used in secondary care and
the company provides pentosan polysulfate sodium according to the commercial arrangement.
This recommendation is not intended to affect treatment with pentosan polysulfate sodium that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Bladder pain syndrome causes extreme pain and severely affects quality of life. It is challenging to treat and there is an unmet need for other treatments. It is currently managed with oral treatments, then bladder instillations if symptoms don't improve. Pentosan polysulfate sodium is an oral treatment.
Clinical trials suggest that pentosan polysulfate sodium may be more effective at relieving pain than placebo. A comparison of clinical trials that includes best supportive care and bladder instillations suggests that pentosan polysulfate sodium may have a modest benefit over these alternatives. But how much benefit it provides is unclear because these treatments haven't been compared directly. Also, the available evidence is not of high quality.
Pentosan polysulfate sodium is not cost effective compared with best supportive care. But the most plausible cost-effectiveness estimates for pentosan polysulfate sodium compared with bladder instillations are likely to be a cost-effective use of NHS resources. So, it is recommended for a defined population.# Information about pentosan polysulfate sodium
Marketing authorisation indication
Pentosan polysulfate sodium (Elmiron, Consilient Health) has a marketing authorisation for treating 'bladder pain syndrome characterised by either glomerulations or Hunner's lesions in adults with moderate to severe pain, urgency and frequency of micturition'.
Dosage in the marketing authorisation
mg/day taken as 1 × 100-mg capsule orally 3 times daily.
Treatment is stopped if no improvement is reached 6 months after starting treatment. In people whose condition responds, treatment should be continued as long as the response is maintained. Response to treatment should be reassessed every 6 months.
Price
A pack of 90 capsules (100 mg each) costs £450.
The company has a commercial arrangement. This makes pentosan polysulfate sodium available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Consilient Health, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that these were acceptable:
using a lifetime time horizon in the economic model (issue 2, see technical report page 21)
assuming response rates to best supportive care did not recede over time in the model (issue 3, see technical report pages 7 to 10)
using the ERG's updated survival analysis that censored those who died and used a log-normal extrapolation (issue 4, see technical report page 21)
assuming utility scores and costs returned to baseline in the model for people whose condition did not respond to treatment who moved on to best supportive care (issue 6, see technical report pages 21 to 22).It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, pages 19 to 20), and took these into account in its decision making.
# The condition
## Bladder pain syndrome is challenging to manage and affects quality of life
The clinical experts explained that bladder pain syndrome is a chronic bladder condition characterised by pain, urinary urgency, frequency and getting up at night to pass urine. The patient expert explained that people with bladder pain syndrome need the toilet up to 60 times a day and that some people had considered suicide because of the pain. Treatments generally aim to control the symptoms because there is no cure for the condition. The committee concluded that bladder pain syndrome is incurable, very challenging to manage and causes extreme pain, which severely affects quality of life.
# Clinical management
## The relevant population is people with bladder pain syndrome and either glomerulations or Hunner's lesions
The clinical experts explained that bladder pain syndrome may affect approximately 400,000 people in the UK but only around 10% of these will present for treatment. The committee acknowledged that within the broader bladder pain syndrome population are people who also have glomerulations or Hunner's lesions. The marketing authorisation for pentosan polysulfate sodium is for treating 'bladder pain syndrome characterised by either glomerulations or Hunner's lesions in adults with moderate to severe pain, urgency and frequency of micturition'. The committee considered that this was the relevant population for the appraisal.
## There is an unmet need for effective treatment options
Treatment options for people with bladder pain syndrome and either glomerulations or Hunner's lesions include:
-ral treatments (such as amitriptyline, gabapentin, pregabalin, paracetamol, non-steroidal anti-inflammatory drugs, hydroxyzine, cimetidine and ranitidine) and
bladder instillations (a plastic tube inserted into the bladder to administer liquid medication).The patient expert stated that there were few treatment options and people often need multiple treatments to manage the symptoms. The clinical experts explained that bladder instillations were invasive and can cause adverse effects. The patient and clinical experts explained that pentosan polysulfate sodium may also affect quality of life because it has to be taken 3 times a day on an empty stomach, which affects mealtimes. The committee concluded that there was an unmet need for effective treatment options that can be used instead of invasive bladder instillations.
## There is substantial variability in the treatment pathway
The clinical experts explained that the treatment pathway for bladder pain syndrome can vary substantially between services across the country. They added that the condition is difficult to diagnose and the presence of glomerulations is not specific to bladder pain syndrome. Services use international guidelines to guide clinical management and the recommendations for treating the condition vary. The company noted that bladder pain syndrome is initially treated with oral medication (see section 3.3). If glomerulations or Hunner's lesions are found, then people can continue to have oral treatments as best supportive care or be offered bladder instillations. The patient experts explained that not all treatments are available in all areas of the country. Treatments typically depend on where a person lives and what is offered at their local hospital rather than what is best for their condition. The company and clinical experts stated that pentosan polysulfate sodium would only be used in secondary care. The committee recognised that there is substantial variability in the clinical management of bladder pain syndrome and the treatment pathway is poorly defined. However, the committee agreed that pentosan polysulfate sodium would only be available as a treatment option in secondary care.
## The comparison with bladder instillations is relevant for decision making
The company submitted analyses comparing pentosan polysulfate sodium with bladder instillations. At the second committee meeting, the company said that it was positioning pentosan polysulfate sodium as an alternative to bladder instillations. Bladder instillations are offered to people who can tolerate them. The clinical experts explained that other treatment options for the condition are available. They noted that laser surgery for Hunner's lesions can be considered at any point in the treatment pathway. Also, botulinum toxin type A and sacral neuromodulation are generally used in research and not routine clinical practice. The clinical experts explained that, if available, pentosan polysulfate sodium would be tried before bladder instillations. The committee recognised that pentosan polysulfate sodium could be offered at different points in the treatment pathway but would tend to be used before bladder instillations. Considering the information from the clinical experts, the committee agreed that bladder instillations were a standard clinical management option for this condition and were a relevant comparator.
## The comparison with best supportive care is also relevant for decision making
The company's submission included analyses comparing pentosan polysulfate sodium with best supportive care (which is the continuation of oral medication). However, after consultation the company stated that it did not consider pentosan polysulfate sodium to be an alternative to best supportive care. At the first committee meeting, the clinical experts advised that best supportive care is offered to people who can't tolerate bladder instillations, or if bladder instillations are unsuitable for them. They highlighted that some people would choose best supportive care because bladder instillations are invasive. The clinical experts estimated that bladder instillations would not be suitable for less than 5% of patients. The committee recognised that the proportion of people who would have best supportive care instead of bladder instillations was low. However, it considered that pentosan polysulfate sodium would be an alternative treatment option for this group of people. Because of this, the committee concluded that best supportive care was still a relevant comparator for this limited population.
# Clinical effectiveness
## There is substantial uncertainty in the pentosan polysulfate sodium evidence
The company's clinical effectiveness evidence came from 4 randomised controlled trials comparing pentosan polysulfate sodium with placebo in people with bladder pain syndrome and either glomerulations or Hunner's lesions. The trials were published between 1987 and 2003. The ERG noted that:
-f the trials were of good methodological quality but the other trial should be interpreted with caution because of uncertainty about allocation concealment and numbers of patients withdrawing from treatment
sample sizes were not calculated for 3 of the trials and the target sample size for the other trial was not met
the author was common to all 4 trials and there were no independent studies validating the results
the definition of the primary outcome used in the company's model varied and
follow-up times varied between all trials.The committee concluded that the company's evidence for pentosan polysulfate sodium was based on the most relevant trials available but acknowledged the limitations of the trials. It considered that there was substantial uncertainty in the clinical effectiveness evidence.
## There are substantial uncertainties in determining the relative treatment effect using an indirect treatment comparison
To compare pentosan polysulfate sodium with bladder instillations, the company used an indirect treatment comparison. Both the company and the ERG acknowledged that this was necessary, but agreed it was challenging because of:
Differences in trial populations: Uracyst was the only bladder instillation suitable for indirect comparison with pentosan polysulfate sodium via placebo. The pentosan polysulfate sodium trials were in people with interstitial cystitis or bladder pain syndrome who had Hunner's lesions or glomerulations or both. But the Uracyst trials were in people with the broader bladder pain syndrome.
Differences in placebos: Pentosan polysulfate sodium was compared with an oral placebo, whereas Uracyst was compared with a placebo instillation.
Differences in the timings of outcome measurement.
Differences in the definition of the main outcome (global response assessment).The company compared meta-analysed data from 2 Uracyst trials with meta-analysed data from 4 pentosan polysulfate sodium trials using the Bucher method of indirect treatment comparison (an adjusted method that retains patients' original randomisation). Response rates to treatment were 33% for pentosan polysulfate sodium compared with 22% for bladder instillations. The ERG considered that the Bucher method did not adequately acknowledge the heterogeneity in treatment effect between the studies. Instead, it proposed using a Bayesian network meta-analysis, which provides a more flexible framework for incorporating and exploring the uncertainties in the evidence. The committee acknowledged that both the Bucher method and Bayesian approach were valid methods of analysis in this setting, but the company's application of the Bucher method did not account for heterogeneity. The committee agreed that there was significant heterogeneity in the treatment effect and therefore concluded that it would prefer a Bayesian network meta-analysis.
## The ERG's Bayesian network meta-analysis is an acceptable method for an indirect treatment comparison
The ERG did a Bayesian network meta-analysis, which showed response rates of 33% for pentosan polysulfate sodium compared with 24% for bladder instillations. After the technical engagement stage, the company also did a Bayesian network meta-analysis comparing pentosan polysulfate sodium with bladder instillations as a scenario analysis. This showed response rates of 38% for pentosan polysulfate sodium compared with 28% for bladder instillations. The ERG advised that the company's network meta-analysis had methodological limitations because it did not use separate baseline and treatment effects models to estimate absolute response rates. The committee understood that although both the company's and the ERG's approaches had their limitations, the best possible methods should be used for an indirect treatment comparison. At the first meeting, the committee concluded that the ERG's Bayesian network meta-analysis was acceptable because it better characterised the uncertainty in comparing active treatments. After consultation, the company argued that neither method was ideal and so kept the Bucher method in its base-case analysis. The committee agreed that all the indirect treatment comparisons it had seen had limitations. But it considered that it had not heard anything to change its original decision that the ERG's Bayesian network meta-analysis was more acceptable than the company's Bucher method.
## It is acceptable to use the 16% response rate to placebo from the pentosan polysulfate sodium trials in the cost-effectiveness analysis
The company noted that the high response rates (16%) in the placebo arms of the pentosan polysulfate sodium trials did not reflect clinical practice. It considered these high response rates would underestimate the effectiveness of pentosan polysulfate sodium. The ERG noted that the high response rates could be explained by regression to the mean, which would also be present in the intervention arms. The ERG also noted that in the company's model, the absolute difference in treatment effect becomes greater with increasing best supportive care response. This would result in the high response rate in the placebo arm favouring pentosan polysulfate sodium because the company's analysis used relative risks. The company's base-case analysis modelled a 15.8% placebo response rate. The company's Bayesian scenario analysis included the placebo arms of the bladder instillation trials, which gave an 18.9% estimated response rate. The clinical experts explained that real-world evidence may suggest even higher placebo response rates. This is expected because patients with the condition initially have benefit, but this is not sustained beyond 3 months. The committee acknowledged that the clinical experts' views and the ERG's analysis results (15.5%) were broadly in line with the placebo response rates from the pentosan polysulfate sodium trials (16%). The committee concluded that a 16% response rate to placebo was acceptable to use in the cost-effectiveness analysis, and that the company's base-case analysis was in line with this.
# Utilities
## Missing data on utility values are not adequately accounted for in the company's model
In its base-case model, the company applied a utility decrement associated with bladder instillations. The company mapped patient survey data collected in the Sant et al. (2003) trial to EQ‑5D data. The company used responses to a question in the survey on the use of bladder instillations in the previous 6 months. The ERG noted that the wording of this survey question was vague. This could have meant that patients who had never had bladder instillations did not answer the question and this was recorded incorrectly as missing data. The ERG's preferred method to account for the missing data was to use multiple imputation (a statistical method used to reduce bias arising from missing data). After consultation, the company outlined that multiple imputation was not appropriate because the missing data were not missing at random. The company also highlighted methodological challenges because the data predicted by the imputation would depend on the data that informed the imputation. The committee understood that there were very few responses from the patient survey about quality of life associated with pentosan polysulfate sodium treatment. The committee concluded that missing data from the patient survey was not adequately accounted for in the company's model.
## There is insufficient evidence of a direct link between bladder instillations and urinary tract infections
After the technical engagement stage, the company provided clinical expert evidence and a systematic review to support its assumption that bladder instillations are associated with an increase in urinary tract infections (UTIs). The company explained that the evidence showed that people with UTIs have substantially lower quality of life than those without UTIs. It also proposed that UTIs in people with bladder pain syndrome have a bigger impact on quality of life than UTIs in the general population. The ERG noted that the company's model assumed that everyone having bladder instillations would have a UTI and that the associated decrement was modelled for a lifetime. The clinical experts explained that not all people having bladder instillations would get a UTI and although the symptoms may last longer than for the general population these would not continue indefinitely. They also noted that people would have the choice of continuing bladder instillation treatment if they did get a UTI. The company noted that UTIs are only 1 aspect of the decrement associated with bladder instillations. After consultation, the company emphasised the evidence relating to the impact of UTIs on quality of life including the quality of life data reported by Cervigni et al. (2017). The committee considered that the Cervigni study was not generalisable to the population covered by the pentosan polysulfate sodium marketing authorisation. This was because the study included a trial population who were not covered by the marketing authorisation (pentosan polysulfate sodium was used as initial treatment for some patients and for others, pentosan polysulfate sodium treatment had already failed before), which introduced some uncertainty into the analyses. The study was based on Italian EQ‑5D valuation and the values in the study didn't correspond with response to treatment. The committee considered that it had not seen any new information about the duration of UTIs or the proportion of patients who had UTIs. The committee concluded that there was insufficient evidence to assume a direct link between bladder instillations and UTIs and that any associated decrement was likely to be short-lived.
## It is not appropriate to include a utility decrement for bladder instillations
The company justified modelling a utility decrement for bladder instillations because it considered them to be invasive and associated with adverse effects. The committee noted that the utility decrement was applied for all patients who had bladder instillations for the lifetime of the company's model. It also noted that the utility score for patients having subsequent bladder instillations was counterintuitive when compared with the utility score for people whose condition did not respond to treatment and who moved onto best supportive care (these results are academic in confidence and cannot be reported here). The ERG noted that the difference in utility score in the survey between people who had and people who had not recently had bladder instillations may have reflected baseline patient characteristics rather than treatment. The clinical experts also added that any decrement associated with bladder instillations was likely to be short-lived because the treatment would be stopped if there were any adverse events. The committee concluded that applying a utility decrement for bladder instillations was not appropriate.
# Resource use
## It is acceptable to assume 6‑weekly administration of subsequent bladder instillations and first-time bladder instillations after the first year
The company modelled weekly administration of first-time bladder instillations for the first 4 weeks, and 4‑weekly administration after this point. This frequency also applied to all subsequent bladder instillations. The clinical experts explained that initial treatment with bladder instillations would be weekly for 4 weeks followed by maintenance treatment once every 4 weeks for 4 to 6 months. Continuation would be based on response to treatment. They also noted that it was reasonable to administer maintenance treatment at 6‑weekly intervals for subsequent bladder instillations if this achieved the same response in patients as 4‑weekly administration. The patient expert explained that maintenance treatment intervals vary according to the person and can be either monthly or when symptoms return. If maintenance treatment is led by the patient based on their symptoms, this would lengthen the interval between instillations beyond 4 weeks. The ERG's model accounted for this variation. It included 6‑weekly maintenance intervals for subsequent bladder instillations and for first-time bladder instillations after a year of treatment. The committee acknowledged the variation in clinical practice and recognised that administration would be different for first-time and subsequent bladder instillations. The committee considered the company's response to consultation. This outlined that 4‑weekly administration is in line with the manufacturer's recommendations, treatment is tailored to individual patient needs, and variability in dosing frequency results in some intervals being shorter than 4‑weekly whereas others are longer. However, based on the evidence from the ERG and clinical experts, the committee concluded that it was acceptable to assume 6‑weekly administration for subsequent bladder instillations and for first-time bladder instillations after the first year (in line with the ERG's model).
## Most people having bladder instillations would not stay on treatment indefinitely
Both the company's and the ERG's models assumed that bladder instillations were administered indefinitely. The clinical experts explained that bladder instillations would not continue for a lifetime and estimated that only 5% of patients would continue with them after 5 years. The committee acknowledged that in clinical practice bladder instillations would not continue indefinitely and most patients would stop within 5 years. It also recognised that best supportive care becomes a more relevant comparator if more patients stop treatment with bladder instillations.
## Inpatient resource use is overestimated in the company's model
The company's model included a proportion of patients who would have inpatient care for bladder instillations. The ERG noted that the disease-related costs in the company's model had been overestimated because not all of the resource use was a result of bladder pain syndrome with glomerulations or Hunner's lesions. The clinical experts explained that most people having bladder instillations are seen in outpatient care; the number having inpatient care is negligible. The committee considered that the company had overestimated the disease-related costs by modelling a proportion of patients to have inpatient care. The committee concluded that inpatient resource use would be minimal in a population having bladder instillations. However, it was aware that the incremental cost-effectiveness ratio (ICER) was not sensitive to this parameter in the model.
# Cost-effectiveness estimates
## There are uncertainties in the cost-effectiveness estimates that are unlikely to be resolved
The committee noted the substantial uncertainty in the model inputs, specifically:
the considerable variability in the treatment pathway (see section 3.4)
the significant uncertainty in the pentosan polysulfate sodium evidence (see section 3.7)
the methodological limitations with all approaches to indirect treatment comparisons (see section 3.8)
the challenges with the missing data on utility values (see section 3.11).The committee concluded that these substantial uncertainties were unlikely to be resolved in the cost-effectiveness modelling.
## Pentosan polysulfate sodium is likely to be cost effective for bladder pain syndrome compared with bladder instillations
The company's base case included the following assumptions:
a lifetime time horizon in the model (issue 2 of the technical report)
time to discontinuation based on the ERG's time-to-discontinuation data set and a log-normal extrapolation (issue 4 of the technical report)
a utility decrement associated with having bladder instillations in the previous 6 months (issue 5 of the technical report)
excluded missing data on previous bladder instillations (issue 5 of the technical report)
a 4‑weekly administration of bladder instillations for first-time and subsequent treatment (issue 7 of the technical report)
treatment with bladder instillations continued indefinitely (issue 7 of the technical report).When the confidential commercial arrangement was applied, the company's base-case analysis showed that pentosan polysulfate sodium cost less and had higher quality-adjusted life year (QALY) gain than bladder instillations.The ERG's analyses included the following committee-preferred assumptions:
a Bayesian network meta-analysis using the ERG's preferred approach (see section 3.9)
a lifetime time horizon in the model (issue 2 of the technical report)
time to discontinuation based on the ERG's time-to-discontinuation data set and a log-normal extrapolation (issue 4 of the technical report)
treatment with bladder instillations continued indefinitely (see section 3.15)
no utility decrement associated with having bladder instillations in the previous 6 months (see sections 3.11 to 3.13)
‑weekly administration of bladder instillations (see section 3.14).The ERG's revised ICER using the committee's preferred assumptions and applying the confidential commercial arrangement was £14,418 per QALY gained when compared with bladder instillations. Based on the ERG's analysis, the committee concluded that the most plausible cost-effectiveness estimate for pentosan polysulfate sodium compared with bladder instillations was likely to be a cost-effective use of NHS resources (see NICE's guide to the methods of technology appraisal).
## Pentosan polysulfate sodium is unlikely to be cost effective for bladder pain syndrome compared with best supportive care
The company's base case included the following assumptions:
a lifetime time horizon in the model (issue 2 of the technical report)
best supportive care response rates did not recede over time (issue 3 of the technical report)
% placebo response rate estimated from the pentosan polysulfate sodium trials (issue 3 of the technical report)
time to discontinuation based on the ERG's time-to-discontinuation data set and a log-normal extrapolation (issue 4 of the technical report)
utility scores and costs returned to baseline for people whose condition did not respond to treatment who moved on to best supportive care (issue 6 of the technical report).The company's base-case ICER compared with best supportive care (including the confidential commercial arrangement) was £52,264 per QALY gained.The ERG's analyses included the following committee-preferred assumptions:
a Bayesian network meta-analysis using the ERG's preferred approach (see section 3.9)
a lifetime time horizon in the model (issue 2 of the technical report)
best supportive care response rates did not recede over time (issue 3 of the technical report)
time to discontinuation based on the ERG's time-to-discontinuation data set and a log-normal extrapolation (issue 4 of the technical report)
utility scores and costs returned to baseline for people whose condition did not respond to treatment who moved on to best supportive care (issue 6 of the technical report)
% placebo response rate from the pentosan polysulfate sodium trials (see section 3.10).The ERG's revised ICER using the committee's preferred assumptions and applying the confidential commercial arrangement was £50,740 per QALY gained when compared with best supportive care. The committee concluded that the most plausible cost-effectiveness estimate for pentosan polysulfate sodium compared with best supportive care was higher than usually considered a cost-effective use of NHS resources (see NICE's guide to the methods of technology appraisal).
# Positioning of treatment
## The complex treatment pathway makes it hard to separate the comparison with bladder instillations from the comparison with best supportive care
The committee acknowledged that the treatment pathway for bladder pain syndrome was complex and varied between services. The clinical experts advised that pentosan polysulfate sodium would generally be used before bladder instillations or for people who could not have bladder instillations. However, the experts and responses to consultation indicated that pentosan polysulfate sodium may be used after bladder instillations have been tried. The committee accepted that the complex pathway made it difficult to separate populations based on comparators.
## Neither the company nor the ERG's models capture the use of pentosan polysulfate sodium in combination with or after bladder instillations
In the company's and the ERG's models, patients having bladder instillations were assumed to stay on them indefinitely. The models did not capture the cost effectiveness of pentosan polysulfate sodium when it was taken after a lack of response to treatment with bladder instillations. The models also did not capture the cost effectiveness of pentosan polysulfate sodium when it was taken in combination with bladder instillations. The committee concluded that it could not assess the cost effectiveness of pentosan polysulfate sodium for these populations.
## Pentosan polysulfate sodium is only for people whose condition has not responded well to other less expensive oral treatments
The clinical experts stated that there are many different types of oral treatments for bladder pain syndrome and that these have to be tried repeatedly. The committee was aware that best supportive care consisted of less expensive oral treatments than pentosan polysulfate sodium. It was also aware that some people get good disease control from standard oral treatments. The company and clinical experts agreed that pentosan polysulfate sodium would be used after inadequate response to standard oral treatments. The committee concluded that standard oral treatments should be tried first (see section 3.3) and that pentosan polysulfate sodium should only be used for people who have stopped these treatments because of a lack of response.
## The proportion of people who have best supportive care because bladder instillations are unsuitable for them is low
The clinical experts explained that bladder instillations would be unsuitable for less than 5% of people. The committee acknowledged that because this is likely to be a small population, the estimated impact on NHS resources is also likely to be small (see section 6.2.14 in NICE's guide to the methods of technology appraisal).
# Conclusion
## Pentosan polysulfate sodium is recommended for some people
The ICER for the comparison with best supportive care was higher than what is considered to be cost effective. But the ICER for the comparison with bladder instillations was considered to be a cost-effective use of NHS resources, taking into account:
the small proportion of people who would not tolerate bladder instillations or for whom they would not be suitable
the unmet need for effective treatment options for this population and
the committee's most plausible assumptions.Therefore, the committee concluded that pentosan polysulfate sodium is recommended as an option for treating bladder pain syndrome with glomerulations or Hunner's lesions in adults with urinary urgency and frequency and moderate to severe pain, only if:
their condition has not responded to an adequate trial of standard oral treatments
it is not offered in combination with bladder instillations
any previous treatment with bladder instillations was not stopped because of lack of response
it is used in secondary care and
the company provides pentosan polysulfate sodium according to the commercial arrangement.
# Other factors
## There are no equalities issues that can be addressed in the guidance
The company and a clinical expert highlighted that bladder pain syndrome affects more women than men. However, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal.
|
{'Recommendations': "Pentosan polysulfate sodium is recommended as an option for treating bladder pain syndrome with glomerulations or Hunner's lesions in adults with urinary urgency and frequency, and moderate to severe pain, only if:\n\ntheir condition has not responded to an adequate trial of standard oral treatments\n\nit is not offered in combination with bladder instillations\n\nany previous treatment with bladder instillations was not stopped because of lack of response\n\nit is used in secondary care and\n\nthe company provides pentosan polysulfate sodium according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with pentosan polysulfate sodium that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nBladder pain syndrome causes extreme pain and severely affects quality of life. It is challenging to treat and there is an unmet need for other treatments. It is currently managed with oral treatments, then bladder instillations if symptoms don't improve. Pentosan polysulfate sodium is an oral treatment.\n\nClinical trials suggest that pentosan polysulfate sodium may be more effective at relieving pain than placebo. A comparison of clinical trials that includes best supportive care and bladder instillations suggests that pentosan polysulfate sodium may have a modest benefit over these alternatives. But how much benefit it provides is unclear because these treatments haven't been compared directly. Also, the available evidence is not of high quality.\n\nPentosan polysulfate sodium is not cost effective compared with best supportive care. But the most plausible cost-effectiveness estimates for pentosan polysulfate sodium compared with bladder instillations are likely to be a cost-effective use of NHS resources. So, it is recommended for a defined population.", 'Information about pentosan polysulfate sodium': "Marketing authorisation indication\n\nPentosan polysulfate sodium (Elmiron, Consilient Health) has a marketing authorisation for treating 'bladder pain syndrome characterised by either glomerulations or Hunner's lesions in adults with moderate to severe pain, urgency and frequency of micturition'.\n\nDosage in the marketing authorisation\n\nmg/day taken as 1 × 100-mg capsule orally 3\xa0times daily.\n\nTreatment is stopped if no improvement is reached 6\xa0months after starting treatment. In people whose condition responds, treatment should be continued as long as the response is maintained. Response to treatment should be reassessed every 6\xa0months.\n\nPrice\n\nA pack of 90\xa0capsules (100\xa0mg each) costs £450.\n\nThe company has a commercial arrangement. This makes pentosan polysulfate sodium available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Consilient Health, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that these were acceptable:\n\nusing a lifetime time horizon in the economic model (issue\xa02, see technical report page\xa021)\n\nassuming response rates to best supportive care did not recede over time in the model (issue\xa03, see technical report pages 7\xa0to\xa010)\n\nusing the ERG's updated survival analysis that censored those who died and used a log-normal extrapolation (issue\xa04, see technical report page\xa021)\n\nassuming utility scores and costs returned to baseline in the model for people whose condition did not respond to treatment who moved on to best supportive care (issue\xa06, see technical report pages 21\xa0to\xa022).It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, pages 19\xa0to\xa020), and took these into account in its decision making.\n\n# The condition\n\n## Bladder pain syndrome is challenging to manage and affects quality of life\n\nThe clinical experts explained that bladder pain syndrome is a chronic bladder condition characterised by pain, urinary urgency, frequency and getting up at night to pass urine. The patient expert explained that people with bladder pain syndrome need the toilet up to 60\xa0times a day and that some people had considered suicide because of the pain. Treatments generally aim to control the symptoms because there is no cure for the condition. The committee concluded that bladder pain syndrome is incurable, very challenging to manage and causes extreme pain, which severely affects quality of life.\n\n# Clinical management\n\n## The relevant population is people with bladder pain syndrome and either glomerulations or Hunner's lesions\n\nThe clinical experts explained that bladder pain syndrome may affect approximately 400,000\xa0people in the UK but only around 10% of these will present for treatment. The committee acknowledged that within the broader bladder pain syndrome population are people who also have glomerulations or Hunner's lesions. The marketing authorisation for pentosan polysulfate sodium is for treating 'bladder pain syndrome characterised by either glomerulations or Hunner's lesions in adults with moderate to severe pain, urgency and frequency of micturition'. The committee considered that this was the relevant population for the appraisal.\n\n## There is an unmet need for effective treatment options\n\nTreatment options for people with bladder pain syndrome and either glomerulations or Hunner's lesions include:\n\noral treatments (such as amitriptyline, gabapentin, pregabalin, paracetamol, non-steroidal anti-inflammatory drugs, hydroxyzine, cimetidine and ranitidine) and\n\nbladder instillations (a plastic tube inserted into the bladder to administer liquid medication).The patient expert stated that there were few treatment options and people often need multiple treatments to manage the symptoms. The clinical experts explained that bladder instillations were invasive and can cause adverse effects. The patient and clinical experts explained that pentosan polysulfate sodium may also affect quality of life because it has to be taken 3\xa0times a day on an empty stomach, which affects mealtimes. The committee concluded that there was an unmet need for effective treatment options that can be used instead of invasive bladder instillations.\n\n## There is substantial variability in the treatment pathway\n\nThe clinical experts explained that the treatment pathway for bladder pain syndrome can vary substantially between services across the country. They added that the condition is difficult to diagnose and the presence of glomerulations is not specific to bladder pain syndrome. Services use international guidelines to guide clinical management and the recommendations for treating the condition vary. The company noted that bladder pain syndrome is initially treated with oral medication (see section\xa03.3). If glomerulations or Hunner's lesions are found, then people can continue to have oral treatments as best supportive care or be offered bladder instillations. The patient experts explained that not all treatments are available in all areas of the country. Treatments typically depend on where a person lives and what is offered at their local hospital rather than what is best for their condition. The company and clinical experts stated that pentosan polysulfate sodium would only be used in secondary care. The committee recognised that there is substantial variability in the clinical management of bladder pain syndrome and the treatment pathway is poorly defined. However, the committee agreed that pentosan polysulfate sodium would only be available as a treatment option in secondary care.\n\n## The comparison with bladder instillations is relevant for decision making\n\nThe company submitted analyses comparing pentosan polysulfate sodium with bladder instillations. At the second committee meeting, the company said that it was positioning pentosan polysulfate sodium as an alternative to bladder instillations. Bladder instillations are offered to people who can tolerate them. The clinical experts explained that other treatment options for the condition are available. They noted that laser surgery for Hunner's lesions can be considered at any point in the treatment pathway. Also, botulinum toxin type\xa0A and sacral neuromodulation are generally used in research and not routine clinical practice. The clinical experts explained that, if available, pentosan polysulfate sodium would be tried before bladder instillations. The committee recognised that pentosan polysulfate sodium could be offered at different points in the treatment pathway but would tend to be used before bladder instillations. Considering the information from the clinical experts, the committee agreed that bladder instillations were a standard clinical management option for this condition and were a relevant comparator.\n\n## The comparison with best supportive care is also relevant for decision making\n\nThe company's submission included analyses comparing pentosan polysulfate sodium with best supportive care (which is the continuation of oral medication). However, after consultation the company stated that it did not consider pentosan polysulfate sodium to be an alternative to best supportive care. At the first committee meeting, the clinical experts advised that best supportive care is offered to people who can't tolerate bladder instillations, or if bladder instillations are unsuitable for them. They highlighted that some people would choose best supportive care because bladder instillations are invasive. The clinical experts estimated that bladder instillations would not be suitable for less than 5% of patients. The committee recognised that the proportion of people who would have best supportive care instead of bladder instillations was low. However, it considered that pentosan polysulfate sodium would be an alternative treatment option for this group of people. Because of this, the committee concluded that best supportive care was still a relevant comparator for this limited population.\n\n# Clinical effectiveness\n\n## There is substantial uncertainty in the pentosan polysulfate sodium evidence\n\nThe company's clinical effectiveness evidence came from 4\xa0randomised controlled trials comparing pentosan polysulfate sodium with placebo in people with bladder pain syndrome and either glomerulations or Hunner's lesions. The trials were published between 1987 and 2003. The ERG noted that:\n\nof the trials were of good methodological quality but the other trial should be interpreted with caution because of uncertainty about allocation concealment and numbers of patients withdrawing from treatment\n\nsample sizes were not calculated for 3\xa0of the trials and the target sample size for the other trial was not met\n\nthe author was common to all 4\xa0trials and there were no independent studies validating the results\n\nthe definition of the primary outcome used in the company's model varied and\n\nfollow-up times varied between all trials.The committee concluded that the company's evidence for pentosan polysulfate sodium was based on the most relevant trials available but acknowledged the limitations of the trials. It considered that there was substantial uncertainty in the clinical effectiveness evidence.\n\n## There are substantial uncertainties in determining the relative treatment effect using an indirect treatment comparison\n\nTo compare pentosan polysulfate sodium with bladder instillations, the company used an indirect treatment comparison. Both the company and the ERG acknowledged that this was necessary, but agreed it was challenging because of:\n\nDifferences in trial populations: Uracyst was the only bladder instillation suitable for indirect comparison with pentosan polysulfate sodium via placebo. The pentosan polysulfate sodium trials were in people with interstitial cystitis or bladder pain syndrome who had Hunner's lesions or glomerulations or both. But the Uracyst trials were in people with the broader bladder pain syndrome.\n\nDifferences in placebos: Pentosan polysulfate sodium was compared with an oral placebo, whereas Uracyst was compared with a placebo instillation.\n\nDifferences in the timings of outcome measurement.\n\nDifferences in the definition of the main outcome (global response assessment).The company compared meta-analysed data from 2\xa0Uracyst trials with meta-analysed data from 4\xa0pentosan polysulfate sodium trials using the Bucher method of indirect treatment comparison (an adjusted method that retains patients' original randomisation). Response rates to treatment were 33% for pentosan polysulfate sodium compared with 22% for bladder instillations. The ERG considered that the Bucher method did not adequately acknowledge the heterogeneity in treatment effect between the studies. Instead, it proposed using a Bayesian network meta-analysis, which provides a more flexible framework for incorporating and exploring the uncertainties in the evidence. The committee acknowledged that both the Bucher method and Bayesian approach were valid methods of analysis in this setting, but the company's application of the Bucher method did not account for heterogeneity. The committee agreed that there was significant heterogeneity in the treatment effect and therefore concluded that it would prefer a Bayesian network meta-analysis.\n\n## The ERG's Bayesian network meta-analysis is an acceptable method for an indirect treatment comparison\n\nThe ERG did a Bayesian network meta-analysis, which showed response rates of 33% for pentosan polysulfate sodium compared with 24% for bladder instillations. After the technical engagement stage, the company also did a Bayesian network meta-analysis comparing pentosan polysulfate sodium with bladder instillations as a scenario analysis. This showed response rates of 38% for pentosan polysulfate sodium compared with 28% for bladder instillations. The ERG advised that the company's network meta-analysis had methodological limitations because it did not use separate baseline and treatment effects models to estimate absolute response rates. The committee understood that although both the company's and the ERG's approaches had their limitations, the best possible methods should be used for an indirect treatment comparison. At the first meeting, the committee concluded that the ERG's Bayesian network meta-analysis was acceptable because it better characterised the uncertainty in comparing active treatments. After consultation, the company argued that neither method was ideal and so kept the Bucher method in its base-case analysis. The committee agreed that all the indirect treatment comparisons it had seen had limitations. But it considered that it had not heard anything to change its original decision that the ERG's Bayesian network meta-analysis was more acceptable than the company's Bucher method.\n\n## It is acceptable to use the 16% response rate to placebo from the pentosan polysulfate sodium trials in the cost-effectiveness analysis\n\nThe company noted that the high response rates (16%) in the placebo arms of the pentosan polysulfate sodium trials did not reflect clinical practice. It considered these high response rates would underestimate the effectiveness of pentosan polysulfate sodium. The ERG noted that the high response rates could be explained by regression to the mean, which would also be present in the intervention arms. The ERG also noted that in the company's model, the absolute difference in treatment effect becomes greater with increasing best supportive care response. This would result in the high response rate in the placebo arm favouring pentosan polysulfate sodium because the company's analysis used relative risks. The company's base-case analysis modelled a 15.8% placebo response rate. The company's Bayesian scenario analysis included the placebo arms of the bladder instillation trials, which gave an 18.9% estimated response rate. The clinical experts explained that real-world evidence may suggest even higher placebo response rates. This is expected because patients with the condition initially have benefit, but this is not sustained beyond 3\xa0months. The committee acknowledged that the clinical experts' views and the ERG's analysis results (15.5%) were broadly in line with the placebo response rates from the pentosan polysulfate sodium trials (16%). The committee concluded that a 16% response rate to placebo was acceptable to use in the cost-effectiveness analysis, and that the company's base-case analysis was in line with this.\n\n# Utilities\n\n## Missing data on utility values are not adequately accounted for in the company's model\n\nIn its base-case model, the company applied a utility decrement associated with bladder instillations. The company mapped patient survey data collected in the Sant et al. (2003) trial to EQ‑5D data. The company used responses to a question in the survey on the use of bladder instillations in the previous 6\xa0months. The ERG noted that the wording of this survey question was vague. This could have meant that patients who had never had bladder instillations did not answer the question and this was recorded incorrectly as missing data. The ERG's preferred method to account for the missing data was to use multiple imputation (a statistical method used to reduce bias arising from missing data). After consultation, the company outlined that multiple imputation was not appropriate because the missing data were not missing at random. The company also highlighted methodological challenges because the data predicted by the imputation would depend on the data that informed the imputation. The committee understood that there were very few responses from the patient survey about quality of life associated with pentosan polysulfate sodium treatment. The committee concluded that missing data from the patient survey was not adequately accounted for in the company's model.\n\n## There is insufficient evidence of a direct link between bladder instillations and urinary tract infections\n\nAfter the technical engagement stage, the company provided clinical expert evidence and a systematic review to support its assumption that bladder instillations are associated with an increase in urinary tract infections (UTIs). The company explained that the evidence showed that people with UTIs have substantially lower quality of life than those without UTIs. It also proposed that UTIs in people with bladder pain syndrome have a bigger impact on quality of life than UTIs in the general population. The ERG noted that the company's model assumed that everyone having bladder instillations would have a UTI and that the associated decrement was modelled for a lifetime. The clinical experts explained that not all people having bladder instillations would get a UTI and although the symptoms may last longer than for the general population these would not continue indefinitely. They also noted that people would have the choice of continuing bladder instillation treatment if they did get a UTI. The company noted that UTIs are only 1\xa0aspect of the decrement associated with bladder instillations. After consultation, the company emphasised the evidence relating to the impact of UTIs on quality of life including the quality of life data reported by Cervigni et al. (2017). The committee considered that the Cervigni study was not generalisable to the population covered by the pentosan polysulfate sodium marketing authorisation. This was because the study included a trial population who were not covered by the marketing authorisation (pentosan polysulfate sodium was used as initial treatment for some patients and for others, pentosan polysulfate sodium treatment had already failed before), which introduced some uncertainty into the analyses. The study was based on Italian EQ‑5D valuation and the values in the study didn't correspond with response to treatment. The committee considered that it had not seen any new information about the duration of UTIs or the proportion of patients who had UTIs. The committee concluded that there was insufficient evidence to assume a direct link between bladder instillations and UTIs and that any associated decrement was likely to be short-lived.\n\n## It is not appropriate to include a utility decrement for bladder instillations\n\nThe company justified modelling a utility decrement for bladder instillations because it considered them to be invasive and associated with adverse effects. The committee noted that the utility decrement was applied for all patients who had bladder instillations for the lifetime of the company's model. It also noted that the utility score for patients having subsequent bladder instillations was counterintuitive when compared with the utility score for people whose condition did not respond to treatment and who moved onto best supportive care (these results are academic in confidence and cannot be reported here). The ERG noted that the difference in utility score in the survey between people who had and people who had not recently had bladder instillations may have reflected baseline patient characteristics rather than treatment. The clinical experts also added that any decrement associated with bladder instillations was likely to be short-lived because the treatment would be stopped if there were any adverse events. The committee concluded that applying a utility decrement for bladder instillations was not appropriate.\n\n# Resource use\n\n## It is acceptable to assume 6‑weekly administration of subsequent bladder instillations and first-time bladder instillations after the first year\n\nThe company modelled weekly administration of first-time bladder instillations for the first 4\xa0weeks, and 4‑weekly administration after this point. This frequency also applied to all subsequent bladder instillations. The clinical experts explained that initial treatment with bladder instillations would be weekly for 4\xa0weeks followed by maintenance treatment once every 4\xa0weeks for 4\xa0to\xa06 months. Continuation would be based on response to treatment. They also noted that it was reasonable to administer maintenance treatment at 6‑weekly intervals for subsequent bladder instillations if this achieved the same response in patients as 4‑weekly administration. The patient expert explained that maintenance treatment intervals vary according to the person and can be either monthly or when symptoms return. If maintenance treatment is led by the patient based on their symptoms, this would lengthen the interval between instillations beyond 4\xa0weeks. The ERG's model accounted for this variation. It included 6‑weekly maintenance intervals for subsequent bladder instillations and for first-time bladder instillations after a year of treatment. The committee acknowledged the variation in clinical practice and recognised that administration would be different for first-time and subsequent bladder instillations. The committee considered the company's response to consultation. This outlined that 4‑weekly administration is in line with the manufacturer's recommendations, treatment is tailored to individual patient needs, and variability in dosing frequency results in some intervals being shorter than 4‑weekly whereas others are longer. However, based on the evidence from the ERG and clinical experts, the committee concluded that it was acceptable to assume 6‑weekly administration for subsequent bladder instillations and for first-time bladder instillations after the first year (in line with the ERG's model).\n\n## Most people having bladder instillations would not stay on treatment indefinitely\n\nBoth the company's and the ERG's models assumed that bladder instillations were administered indefinitely. The clinical experts explained that bladder instillations would not continue for a lifetime and estimated that only 5% of patients would continue with them after 5\xa0years. The committee acknowledged that in clinical practice bladder instillations would not continue indefinitely and most patients would stop within 5\xa0years. It also recognised that best supportive care becomes a more relevant comparator if more patients stop treatment with bladder instillations.\n\n## Inpatient resource use is overestimated in the company's model\n\nThe company's model included a proportion of patients who would have inpatient care for bladder instillations. The ERG noted that the disease-related costs in the company's model had been overestimated because not all of the resource use was a result of bladder pain syndrome with glomerulations or Hunner's lesions. The clinical experts explained that most people having bladder instillations are seen in outpatient care; the number having inpatient care is negligible. The committee considered that the company had overestimated the disease-related costs by modelling a proportion of patients to have inpatient care. The committee concluded that inpatient resource use would be minimal in a population having bladder instillations. However, it was aware that the incremental cost-effectiveness ratio (ICER) was not sensitive to this parameter in the model.\n\n# Cost-effectiveness estimates\n\n## There are uncertainties in the cost-effectiveness estimates that are unlikely to be resolved\n\nThe committee noted the substantial uncertainty in the model inputs, specifically:\n\nthe considerable variability in the treatment pathway (see section\xa03.4)\n\nthe significant uncertainty in the pentosan polysulfate sodium evidence (see section\xa03.7)\n\nthe methodological limitations with all approaches to indirect treatment comparisons (see section\xa03.8)\n\nthe challenges with the missing data on utility values (see section\xa03.11).The committee concluded that these substantial uncertainties were unlikely to be resolved in the cost-effectiveness modelling.\n\n## Pentosan polysulfate sodium is likely to be cost effective for bladder pain syndrome compared with bladder instillations\n\nThe company's base case included the following assumptions:\n\na lifetime time horizon in the model (issue\xa02 of the technical report)\n\ntime to discontinuation based on the ERG's time-to-discontinuation data set and a log-normal extrapolation (issue\xa04 of the technical report)\n\na utility decrement associated with having bladder instillations in the previous 6\xa0months (issue\xa05 of the technical report)\n\nexcluded missing data on previous bladder instillations (issue\xa05 of the technical report)\n\na 4‑weekly administration of bladder instillations for first-time and subsequent treatment (issue\xa07 of the technical report)\n\ntreatment with bladder instillations continued indefinitely (issue\xa07 of the technical report).When the confidential commercial arrangement was applied, the company's base-case analysis showed that pentosan polysulfate sodium cost less and had higher quality-adjusted life year (QALY) gain than bladder instillations.The ERG's analyses included the following committee-preferred assumptions:\n\na Bayesian network meta-analysis using the ERG's preferred approach (see section\xa03.9)\n\na lifetime time horizon in the model (issue\xa02 of the technical report)\n\ntime to discontinuation based on the ERG's time-to-discontinuation data set and a log-normal extrapolation (issue\xa04 of the technical report)\n\ntreatment with bladder instillations continued indefinitely (see section\xa03.15)\n\nno utility decrement associated with having bladder instillations in the previous 6\xa0months (see sections\xa03.11 to\xa03.13)\n\n‑weekly administration of bladder instillations (see section\xa03.14).The ERG's revised ICER using the committee's preferred assumptions and applying the confidential commercial arrangement was £14,418 per QALY gained when compared with bladder instillations. Based on the ERG's analysis, the committee concluded that the most plausible cost-effectiveness estimate for pentosan polysulfate sodium compared with bladder instillations was likely to be a cost-effective use of NHS resources (see NICE's guide to the methods of technology appraisal).\n\n## Pentosan polysulfate sodium is unlikely to be cost effective for bladder pain syndrome compared with best supportive care\n\nThe company's base case included the following assumptions:\n\na lifetime time horizon in the model (issue\xa02 of the technical report)\n\nbest supportive care response rates did not recede over time (issue\xa03 of the technical report)\n\n% placebo response rate estimated from the pentosan polysulfate sodium trials (issue\xa03 of the technical report)\n\ntime to discontinuation based on the ERG's time-to-discontinuation data set and a log-normal extrapolation (issue\xa04 of the technical report)\n\nutility scores and costs returned to baseline for people whose condition did not respond to treatment who moved on to best supportive care (issue\xa06 of the technical report).The company's base-case ICER compared with best supportive care (including the confidential commercial arrangement) was £52,264 per QALY gained.The ERG's analyses included the following committee-preferred assumptions:\n\na Bayesian network meta-analysis using the ERG's preferred approach (see section\xa03.9)\n\na lifetime time horizon in the model (issue\xa02 of the technical report)\n\nbest supportive care response rates did not recede over time (issue\xa03 of the technical report)\n\ntime to discontinuation based on the ERG's time-to-discontinuation data set and a log-normal extrapolation (issue\xa04 of the technical report)\n\nutility scores and costs returned to baseline for people whose condition did not respond to treatment who moved on to best supportive care (issue\xa06 of the technical report)\n\n% placebo response rate from the pentosan polysulfate sodium trials (see section\xa03.10).The ERG's revised ICER using the committee's preferred assumptions and applying the confidential commercial arrangement was £50,740 per QALY gained when compared with best supportive care. The committee concluded that the most plausible cost-effectiveness estimate for pentosan polysulfate sodium compared with best supportive care was higher than usually considered a cost-effective use of NHS resources (see NICE's guide to the methods of technology appraisal).\n\n# Positioning of treatment\n\n## The complex treatment pathway makes it hard to separate the comparison with bladder instillations from the comparison with best supportive care\n\nThe committee acknowledged that the treatment pathway for bladder pain syndrome was complex and varied between services. The clinical experts advised that pentosan polysulfate sodium would generally be used before bladder instillations or for people who could not have bladder instillations. However, the experts and responses to consultation indicated that pentosan polysulfate sodium may be used after bladder instillations have been tried. The committee accepted that the complex pathway made it difficult to separate populations based on comparators.\n\n## Neither the company nor the ERG's models capture the use of pentosan polysulfate sodium in combination with or after bladder instillations\n\nIn the company's and the ERG's models, patients having bladder instillations were assumed to stay on them indefinitely. The models did not capture the cost effectiveness of pentosan polysulfate sodium when it was taken after a lack of response to treatment with bladder instillations. The models also did not capture the cost effectiveness of pentosan polysulfate sodium when it was taken in combination with bladder instillations. The committee concluded that it could not assess the cost effectiveness of pentosan polysulfate sodium for these populations.\n\n## Pentosan polysulfate sodium is only for people whose condition has not responded well to other less expensive oral treatments\n\nThe clinical experts stated that there are many different types of oral treatments for bladder pain syndrome and that these have to be tried repeatedly. The committee was aware that best supportive care consisted of less expensive oral treatments than pentosan polysulfate sodium. It was also aware that some people get good disease control from standard oral treatments. The company and clinical experts agreed that pentosan polysulfate sodium would be used after inadequate response to standard oral treatments. The committee concluded that standard oral treatments should be tried first (see section\xa03.3) and that pentosan polysulfate sodium should only be used for people who have stopped these treatments because of a lack of response.\n\n## The proportion of people who have best supportive care because bladder instillations are unsuitable for them is low\n\nThe clinical experts explained that bladder instillations would be unsuitable for less than 5% of people. The committee acknowledged that because this is likely to be a small population, the estimated impact on NHS resources is also likely to be small (see section\xa06.2.14 in NICE's guide to the methods of technology appraisal).\n\n# Conclusion\n\n## Pentosan polysulfate sodium is recommended for some people\n\nThe ICER for the comparison with best supportive care was higher than what is considered to be cost effective. But the ICER for the comparison with bladder instillations was considered to be a cost-effective use of NHS resources, taking into account:\n\nthe small proportion of people who would not tolerate bladder instillations or for whom they would not be suitable\n\nthe unmet need for effective treatment options for this population and\n\nthe committee's most plausible assumptions.Therefore, the committee concluded that pentosan polysulfate sodium is recommended as an option for treating bladder pain syndrome with glomerulations or Hunner's lesions in adults with urinary urgency and frequency and moderate to severe pain, only if:\n\ntheir condition has not responded to an adequate trial of standard oral treatments\n\nit is not offered in combination with bladder instillations\n\nany previous treatment with bladder instillations was not stopped because of lack of response\n\nit is used in secondary care and\n\nthe company provides pentosan polysulfate sodium according to the commercial arrangement.\n\n# Other factors\n\n## There are no equalities issues that can be addressed in the guidance\n\nThe company and a clinical expert highlighted that bladder pain syndrome affects more women than men. However, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal."}
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https://www.nice.org.uk/guidance/ta610
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Evidence-based recommendations on pentosan polysulfate sodium (Elmiron) for bladder pain syndrome in adults.
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51102849578f33e594ceb02f693fe42657916dce
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nice
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Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management
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Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management
This guideline covers investigating and managing gastro-oesophageal reflux disease (GORD) and dyspepsia in people aged 18 and over. It aims to improve the treatment of GORD and dyspepsia by making detailed recommendations on Helicobacter pylori eradication, and specifying when to consider laparoscopic fundoplication and referral to specialist services.
# Introduction
Dyspepsia describes a range of symptoms arising from the upper gastrointestinal (GI) tract, but it has no universally accepted definition. The British Society of Gastroenterology (BSG) defines dyspepsia as a group of symptoms that alert doctors to consider disease of the upper GI tract, and states that dyspepsia itself is not a diagnosis. These symptoms, which typically are present for 4 weeks or more, include upper abdominal pain or discomfort, heartburn, gastric reflux, nausea or vomiting. In this guideline, gastro-oesophageal reflux disease (GORD) refers to endoscopically determined oesophagitis or endoscopy-negative reflux disease.
Some of the costs associated with treating dyspepsia are decreasing, but the overall use of treatments is increasing. As a result, the management of dyspepsia continues to have potentially significant costs to the NHS.
The use of endoscopy has increased considerably over the past decade, as awareness of its value in investigating dyspepsia and GORD has grown.
The review of 'Dyspepsia: management of dyspepsia in adults in primary care' (NICE guideline CG17) highlighted some concerns about the drug regimens that were recommended in the guideline for Helicobacter pylori (hereafter referred to as H pylori) eradication, because some bacterial resistance has developed. Overall, the review process concluded that some guidance in this area should be updated and expanded to cover aspects of specialist hospital care.
NICE guideline CG17 covered the management of several underlying causes of dyspepsia in primary care, but there is a lack of comprehensive national guidance about managing GORD (in particular, surgical management) when pharmacological treatments fail. Because of this, and the possible role of GORD (with the subsequent development of Barrett's oesophagus) as a risk factor for cancer, the scope of the guideline update was extended to cover managing GORD in secondary care.
This guideline update covers adults (18 years and older) with symptoms of dyspepsia, symptoms suggestive of GORD, or both. It also covers endoscopic surveillance for adults with a diagnosis of Barrett's oesophagus, but it does not cover the management of Barrett's oesophagus. It is important to note that children and young people (younger than 18 years) and people with a diagnosis of oesophagogastric cancer are not covered in this guideline update.
In this guideline, specialist care is defined as treatment decisions made by a consultant-led service in secondary or tertiary care.
# Drug recommendations
The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.
This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.
Specific dosage information on proton pump inhibitors (PPIs) is detailed in appendix A.# Recommendations
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
These recommendations apply to adults (aged 18 and over) with symptoms of dyspepsia, symptoms suggestive of gastro-oesophageal reflux disease (GORD), or both.
People have the right to be involved in discussions and make informed decisions about their care, as described in your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Terms used in this guideline
In this guideline, GORD refers to endoscopically determined oesophagitis or endoscopy-negative reflux disease.
# The community pharmacist
Community pharmacists should offer initial and ongoing help for people with symptoms of dyspepsia. This includes advice about lifestyle changes, using over-the-counter medication, help with prescribed drugs and advice about when to consult a GP.
Community pharmacists should record adverse reactions to treatment and may participate in primary care medication review clinics.
# Common elements of care
Offer simple lifestyle advice, including advice on healthy eating, weight reduction and smoking cessation.
Advise people to avoid known precipitants they associate with their dyspepsia where possible. These include smoking, alcohol, coffee, chocolate, fatty foods and being overweight. Raising the head of the bed and having a main meal well before going to bed may help some people.
Provide people with access to educational materials to support the care they receive.
Recognise that psychological therapies, such as cognitive behavioural therapy and psychotherapy, may reduce dyspeptic symptoms in the short term in individual people.
Encourage people who need long-term management of dyspepsia symptoms to reduce their use of prescribed medication stepwise: by using the effective lowest dose, by trying 'as-needed' use when appropriate, and by returning to self-treatment with antacid and/or alginate therapy (unless there is an underlying condition or comedication that needs continuing treatment).
# Referral guidance for endoscopy
For people presenting with dyspepsia together with significant acute gastrointestinal bleeding, refer them immediately (on the same day) to a specialist. (Also see the NICE guideline on acute upper gastrointestinal bleeding.)
Review medications for possible causes of dyspepsia (for example, calcium antagonists, nitrates, theophyllines, bisphosphonates, corticosteroids and non-steroidal anti-inflammatory drugs ). In people needing referral, suspend NSAID use.
Think about the possibility of cardiac or biliary disease as part of the differential diagnosis.
If people have had a previous endoscopy and do not have any new alarm signs, consider continuing management according to previous endoscopic findings.
For more information about when to refer people to specialists when they present with symptoms that could be caused by cancer, see the NICE guideline on suspected cancer: recognition and referral.
# Interventions for uninvestigated dyspepsia
Be aware that dyspepsia in unselected people in primary care is defined broadly to include people with recurrent epigastric pain, heartburn or acid regurgitation, with or without bloating, nausea or vomiting. Also see common elements of care.
Leave a 2‑week washout period after proton pump inhibitor (PPI) use before testing for Helicobacter pylori (hereafter referred to as H pylori) with a breath test or a stool antigen test.
Offer empirical full-dose PPI therapy (see table 1 in appendix A) for 4 weeks to people with dyspepsia.
Offer H pylori 'test and treat' to people with dyspepsia.
If symptoms return after initial care strategies, step down PPI therapy to the lowest dose needed to control symptoms. Discuss using the treatment on an 'as-needed' basis with people to manage their own symptoms.
Offer H2 receptor antagonist (H2RA) therapy if there is an inadequate response to a PPI.
# Reviewing patient care
Offer people who need long-term management of dyspepsia symptoms an annual review of their condition, and encourage them to try stepping down or stopping treatment (unless there is an underlying condition or comedication that needs continuing treatment).
Advise people that it may be appropriate for them to return to self‑treatment with antacid and/or alginate therapy (either prescribed or purchased over-the-counter and taken as needed).
# Interventions for GORD
Manage uninvestigated 'reflux-like' symptoms as uninvestigated dyspepsia.
Offer people with GORD a full-dose PPI (see table 1 in appendix A) for 4 or 8 weeks.
If symptoms recur after initial treatment, offer a PPI at the lowest dose possible to control symptoms.
Discuss with people how they can manage their own symptoms by using the treatment when they need it.
Offer H2RA therapy if there is an inadequate response to a PPI.
People who have had dilatation of an oesophageal stricture should remain on long-term full-dose PPI therapy (see table 1 in appendix A).
Offer people a full-dose PPI (see table 2 in appendix A) for 8 weeks to heal severe oesophagitis, taking into account the person's preference and clinical circumstances (for example, underlying health conditions and possible interactions with other drugs).
If initial treatment for healing severe oesophagitis fails, consider a high dose of the initial PPI, switching to another full-dose PPI (see table 2) or switching to another high-dose PPI (see table 2 in appendix A), taking into account the person's preference and clinical circumstances (for example, tolerability of the initial PPI, underlying health conditions and possible interactions with other drugs).
Offer a full-dose PPI (see table 2 in appendix A) long-term as maintenance treatment for people with severe oesophagitis, taking into account the person's preference and clinical circumstances (for example, tolerability of the PPI, underlying health conditions and possible interactions with other drugs), and the acquisition cost of the PPI.
If the person's severe oesophagitis fails to respond to maintenance treatment, carry out a clinical review. Consider switching to another PPI at full dose or high dose (see table 2 in appendix A), taking into account the person's preference and clinical circumstances, and/or seeking specialist advice.
Do not routinely offer endoscopy to diagnose Barrett's oesophagus, but consider it if the person has GORD. Discuss the person's preferences and their individual risk factors (for example, long duration of symptoms, increased frequency of symptoms, previous oesophagitis, previous hiatus hernia, oesophageal stricture or oesophageal ulcers, or male gender).
# Interventions for peptic ulcer disease
Offer H pylori eradication therapy to people who have tested positive for H pylori and who have peptic ulcer disease. Also see H pylori testing and eradication.
For people using NSAIDs with diagnosed peptic ulcer, stop the use of NSAIDs where possible. Offer full-dose PPI (see table 1 in appendix A) or H2RA therapy for 8 weeks and, if H pylori is present, subsequently offer eradication therapy.
Offer people with gastric ulcer and H pylori repeat endoscopy 6 to 8 weeks after beginning treatment, depending on the size of the lesion.
Offer people with peptic ulcer (gastric or duodenal) and H pylori retesting for H pylori 6 to 8 weeks after beginning treatment, depending on the size of the lesion.
Offer full-dose PPI (see table 1 in appendix A) or H2RA therapy for 4 to 8 weeks to people who have tested negative for H pylori who are not taking NSAIDs.
For people continuing to take NSAIDs after a peptic ulcer has healed, discuss the potential harm from NSAID treatment. Review the need for NSAID use regularly (at least every 6 months) and offer a trial of use on a limited, 'as-needed' basis. Consider reducing the dose, substituting an NSAID with paracetamol, or using an alternative analgesic or low-dose ibuprofen (1.2 g daily).
In people at high risk (previous ulceration) and for whom NSAID continuation is necessary, consider a COX-2 selective NSAID instead of a standard NSAID. In either case, prescribe with a PPI.
In people with an unhealed ulcer, exclude non-adherence, malignancy, failure to detect H pylori, inadvertent NSAID use, other ulcer‑inducing medication and rare causes such as Zollinger–Ellison syndrome or Crohn's disease.
If symptoms recur after initial treatment, offer a PPI to be taken at the lowest dose possible to control symptoms. Discuss using the treatment on an 'as-needed' basis with people to manage their own symptoms.
Offer H2RA therapy if there is an inadequate response to a PPI.
# Interventions for functional dyspepsia
Manage endoscopically determined functional dyspepsia using initial treatment for H pylori if present, followed by symptomatic management and periodic monitoring.
Offer eradication therapy to people testing positive for H pylori.
Do not routinely offer re-testing after eradication, although the information it provides may be valued by individual people.
If H pylori has been excluded and symptoms persist, offer either a low-dose PPI (see table 1 in appendix A) or an H2RA for 4 weeks.
If symptoms continue or recur after initial treatment, offer a PPI or H2RA to be taken at the lowest dose possible to control symptoms.
Discuss using PPI treatment on an 'as-needed' basis with people to manage their own symptoms.
Avoid long-term, frequent dose, continuous antacid therapy (it only relieves symptoms in the short term rather than preventing them).
# Helicobacter pylori testing and eradication
## Testing
Test for H pylori using a carbon‑13 urea breath test or a stool antigen test, or laboratory-based serology where its performance has been locally validated.
Perform re-testing for H pylori using a carbon‑13 urea breath test. (There is currently insufficient evidence to recommend the stool antigen test as a test of eradication.)
Do not use office-based serological tests for H pylori because of their inadequate performance.
## Eradication
Offer people who test positive for H pylori a 7‑day, twice-daily course of treatment with:
a PPI (see table 3 in appendix A) and
amoxicillin and
either clarithromycin or metronidazole.Choose the treatment regimen with the lowest acquisition cost, and take into account previous exposure to clarithromycin or metronidazole.
Offer people who are allergic to penicillin a 7‑day, twice-daily course of treatment with:
a PPI (see table 3 in appendix A) and
clarithromycin and
metronidazole.
Offer people who are allergic to penicillin and who have had previous exposure to clarithromycin a 7-day course of treatment with:
a PPI (see table 3 in appendix A) and
bismuth and
metronidazole and
tetracycline.
Discuss treatment adherence with the person and emphasise its importance. For more information about supporting adherence, see the NICE guideline on medicines adherence.
Offer people who still have symptoms after first-line eradication treatment a 7‑day, twice-daily course of treatment with:
a PPI (see table 3 in appendix A) and
amoxicillin and
either clarithromycin or metronidazole (whichever was not used first-line).
Offer people who have had previous exposure to clarithromycin and metronidazole a 7‑day course of treatment with:
a PPI (see table 3 in appendix A) and
amoxicillin and
tetracycline (or, if a tetracycline cannot be used, levofloxacin).
Offer people who are allergic to penicillin (and who have not had previous exposure to a fluoroquinolone antibiotic) a 7‑day, twice-daily course of treatment with:
a PPI (see table 3 in appendix A) and
metronidazole and
levofloxacin.
Offer people who are allergic to penicillin and who have had previous exposure to a fluoroquinolone antibiotic a 7-day course of:
a PPI (see table 3 in appendix A) and
bismuth and
metronidazole and
tetracycline.
Seek advice from a gastroenterologist if eradication of H pylori is not successful with second-line treatment.
# Laparoscopic fundoplication
Consider laparoscopic fundoplication for people who have:
a confirmed diagnosis of acid reflux and adequate symptom control with acid suppression therapy, but who do not wish to continue with this therapy long term
a confirmed diagnosis of acid reflux and symptoms that are responding to a PPI, but who cannot tolerate acid suppression therapy.
# Referral to a specialist service
Consider referral to a specialist service for people:
-f any age with gastro-oesophageal symptoms that are non‑responsive to treatment or unexplained
with suspected GORD who are thinking about surgery
with H pylori that has not responded to second-line eradication therapy.
# Surveillance for people with Barrett's oesophagus
Consider surveillance to check progression to cancer for people who have a diagnosis of Barrett's oesophagus (confirmed by endoscopy and histopathology), taking into account:
the presence of dysplasia (also see the NICE guideline on Barrett's oesophagus: ablative therapy)
the person's individual preference
the person's risk factors (for example, male gender, older age and the length of the Barrett's oesophagus segment).Emphasise that the harms of endoscopic surveillance may outweigh the benefits in people who are at low risk of progression to cancer (for example, people with stable non-dysplastic Barrett's oesophagus).
For more information about alarm signs please see the NICE guideline on suspected cancer: recognition and referral.
This refers to evidence reviewed in 2004.
For the assessment of allergy to beta-lactam antibiotics and referral to specialist care, see the NICE guideline on drug allergy.
See MHRA advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).
In the NICE guideline on suspected cancer: recognition and referral, 'unexplained' is defined as 'a symptom(s) and/or sign(s) that has not led to a diagnosis being made by the primary care professional after initial assessment of the history, examination and primary care investigations (if any)'.# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Patient characteristics, risk factors and predictors that indicate endoscopy for excluding Barrett's oesophagus
In people who experience symptoms of gastro-oesophageal reflux disease (GORD) or symptoms suggestive of GORD, what patient characteristics, risk factors and predictors indicate when endoscopy is needed to exclude Barrett's oesophagus?
## Why this is important
The aim is to identify adults with symptoms of GORD or symptoms suggestive of GORD who may benefit from having an endoscopy for the purpose of early identification of Barrett's oesophagus (or to exclude Barrett's oesophagus).
# Laparoscopic fundoplication compared with medical management
What is the effectiveness of laparoscopic fundoplication compared with medical management in people with GORD that does not respond to optimal proton pump inhibitor (PPI) treatment?
## Why this is important
Current evidence on the clinical and cost effectiveness of laparoscopic fundoplication compared with medical management involves people who had relatively good treatment control with PPIs at baseline. The driver was the desire to be free from medication rather than their GORD being non-responsive to PPIs.
# Effective proton pump inhibitor dosage for severe erosive reflux disease
What is the clinical effectiveness of double-dose PPIs in people with severe erosive reflux disease (Los Angeles classification grade C/D or Savary–Miller grade 3/4):
to reduce severe oesophagitis
to control symptoms
as maintenance therapy?
## Why this is important
People with severe erosive reflux disease or severe oesophagitis (Los Angeles classification grade C/D or Savary–Miller grade 3/4) experience severe heartburn, and prolonged acid and pepsin exposure in the lower oesophagus, which can affect their day-to-day wellbeing. It would substantially improve people's quality of life if an optimal treatment regimen could be identified. Currently, there is a lack of evidence on the efficacy of 'double-dose' PPIs in treating severe erosive reflux disease.
# Other specialist management
What specialist management is effective for people whose symptoms do not respond to PPIs despite optimum primary care, or for people whose symptoms return after surgery?
## Why this is important
There is a small group of people whose symptoms do not resolve, despite medical management and/or surgery for reflux. The group should be divided into people with proven (by pH monitoring) GORD and people with symptoms but no diagnosed reflux. The first group should have a trial of a twice-daily, high-dose PPI versus a standard or full-dose PPI. The second group should have a trial of tricyclic antidepressants versus standard or full-dose PPI. The purpose of any treatment should focus on improving quality of life.
# Specialist investigation
What specialist investigations should be conducted to exclude a diagnosis of functional dyspepsia in people with uninvestigated dyspepsia that does not respond to PPIs or H2 receptor antagonists (H2RAs) despite optimum primary care?
## Why this is important
People with uninvestigated dyspepsia that fails to respond to PPIs or H2RAs, despite optimum primary care, can have a poor quality of life. It is important to ensure that appropriate investigations are carried out to make the correct diagnosis or to correct misdiagnosis, so that the most appropriate treatment can be offered.# Finding more information and resources
You can see everything NICE says on gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management in our interactive flowchart on dyspepsia and gastro-oesophageal reflux disease.
To find out what NICE has said on topics related to this guideline, see our web page on gastro-oesophageal reflux, including Barrett's oesophagus.
For full details of the evidence and the guideline committee's discussions, see the full version of the guideline. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.# Appendix A: Dosage information on proton pump inhibitors
In 2004, when the original guideline was developed (CG17), doses of proton pump inhibitors (PPIs) were based on the British National Formulary (BNF) at the time, as in table 1 below.
During the update of this guideline (2014), the Guideline Development Group (GDG) has further defined the PPI doses specifically for severe oesophagitis and H pylori eradication therapy, as in tables 2 and 3 below.
Table 1 PPI doses relating to evidence synthesis and recommendations in the original guideline (CG17; 2004)
Proton pump inhibitor
Full/standard dose
Low dose (on-demand dose)
Double dose
Esomeprazole
mg1 once a day
Not available
mg3 once a day
Lansoprazole
mg once a day
mg once a day
mg2 twice a day
Omeprazole
mg once a day
mg2 once a day
mg once a day
Pantoprazole
mg once a day
mg once a day
mg2 twice a day
Rabeprazole
mg once a day
mg once a day
mg2 twice a day
Lower than the licensed starting dose for esomeprazole in gastro-oesophageal reflux disease (GORD), which is 40 mg, but considered to be dose-equivalent to other PPI. When undertaking meta-analysis of dose-related effects, NICE classed esomeprazole 20 mg as a full-dose equivalent to omeprazole 20 mg.
Off-label dose for GORD.
40 mg is recommended as a double dose of esomeprazole because the 20‑mg dose is considered equivalent to omeprazole 20 mg.
Table 2 PPI doses for severe oesophagitis in this guideline update (2014)
Proton pump inhibitor
Full/standard dose
Low dose (on‑demand dose)
High/double dose
Esomeprazole
mg1 once a day
mg1 once a day
mg1 twice a day
Lansoprazole
mg once a day
mg once a day
mg2 twice a day
Omeprazole
mg1 once a day)
mg1 once a day)
mg1 twice a day
Pantoprazole
mg once a day
mg once a day
mg2 twice a day
Rabeprazole
mg once a day
mg once a day
mg2 twice a day
Change from the 2004 dose, specifically for severe oesophagitis, agreed by the GDG during the update of CG17.
Off-label dose for gastro-oesophageal reflux disease.
Table 3 PPI doses for
H pylori
eradication therapy in this guideline update (2014)
Proton pump inhibitor
Dose
Esomeprazole
mg
Lansoprazole
mg
Omeprazole
–40 mg
Pantoprazole
mg
Rabeprazole
mg
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{'Introduction': "Dyspepsia describes a range of symptoms arising from the upper gastrointestinal (GI) tract, but it has no universally accepted definition. The British Society of Gastroenterology (BSG) defines dyspepsia as a group of symptoms that alert doctors to consider disease of the upper GI tract, and states that dyspepsia itself is not a diagnosis. These symptoms, which typically are present for 4\xa0weeks or more, include upper abdominal pain or discomfort, heartburn, gastric reflux, nausea or vomiting. In this guideline, gastro-oesophageal reflux disease (GORD) refers to endoscopically determined oesophagitis or endoscopy-negative reflux disease.\n\nSome of the costs associated with treating dyspepsia are decreasing, but the overall use of treatments is increasing. As a result, the management of dyspepsia continues to have potentially significant costs to the NHS.\n\nThe use of endoscopy has increased considerably over the past decade, as awareness of its value in investigating dyspepsia and GORD has grown.\n\nThe review of 'Dyspepsia: management of dyspepsia in adults in primary care' (NICE guideline CG17) highlighted some concerns about the drug regimens that were recommended in the guideline for Helicobacter pylori (hereafter referred to as H\xa0pylori) eradication, because some bacterial resistance has developed. Overall, the review process concluded that some guidance in this area should be updated and expanded to cover aspects of specialist hospital care.\n\nNICE guideline CG17 covered the management of several underlying causes of dyspepsia in primary care, but there is a lack of comprehensive national guidance about managing GORD (in particular, surgical management) when pharmacological treatments fail. Because of this, and the possible role of GORD (with the subsequent development of Barrett's oesophagus) as a risk factor for cancer, the scope of the guideline update was extended to cover managing GORD in secondary care.\n\nThis guideline update covers adults (18\xa0years and older) with symptoms of dyspepsia, symptoms suggestive of GORD, or both. It also covers endoscopic surveillance for adults with a diagnosis of Barrett's oesophagus, but it does not cover the management of Barrett's oesophagus. It is important to note that children and young people (younger than 18\xa0years) and people with a diagnosis of oesophagogastric cancer are not covered in this guideline update.\n\nIn this guideline, specialist care is defined as treatment decisions made by a consultant-led service in secondary or tertiary care.\n\n# Drug recommendations\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.\n\nSpecific dosage information on proton pump inhibitors (PPIs) is detailed in appendix\xa0A.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nThese recommendations apply to adults (aged 18 and over) with symptoms of dyspepsia, symptoms suggestive of gastro-oesophageal reflux disease (GORD), or both.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Terms used in this guideline\n\nIn this guideline, GORD refers to endoscopically determined oesophagitis or endoscopy-negative reflux disease.\n\n# The community pharmacist\n\nCommunity pharmacists should offer initial and ongoing help for people with symptoms of dyspepsia. This includes advice about lifestyle changes, using over-the-counter medication, help with prescribed drugs and advice about when to consult a GP. \n\nCommunity pharmacists should record adverse reactions to treatment and may participate in primary care medication review clinics. \n\n# Common elements of care\n\nOffer simple lifestyle advice, including advice on healthy eating, weight reduction and smoking cessation. \n\nAdvise people to avoid known precipitants they associate with their dyspepsia where possible. These include smoking, alcohol, coffee, chocolate, fatty foods and being overweight. Raising the head of the bed and having a main meal well before going to bed may help some people. \n\nProvide people with access to educational materials to support the care they receive. \n\nRecognise that psychological therapies, such as cognitive behavioural therapy and psychotherapy, may reduce dyspeptic symptoms in the short term in individual people. [2004, amended 2014]\n\nEncourage people who need long-term management of dyspepsia symptoms to reduce their use of prescribed medication stepwise: by using the effective lowest dose, by trying 'as-needed' use when appropriate, and by returning to self-treatment with antacid and/or alginate therapy (unless there is an underlying condition or comedication that needs continuing treatment). [2004, amended 2014]\n\n# Referral guidance for endoscopy\n\nFor people presenting with dyspepsia together with significant acute gastrointestinal bleeding, refer them immediately (on the same day) to a specialist. (Also see the NICE guideline on acute upper gastrointestinal bleeding.)\n\nReview medications for possible causes of dyspepsia (for example, calcium antagonists, nitrates, theophyllines, bisphosphonates, corticosteroids and non-steroidal anti-inflammatory drugs [NSAIDs]). In people needing referral, suspend NSAID use. \n\nThink about the possibility of cardiac or biliary disease as part of the differential diagnosis. [2004, amended 2014]\n\nIf people have had a previous endoscopy and do not have any new alarm signs, consider continuing management according to previous endoscopic findings. \n\nFor more information about when to refer people to specialists when they present with symptoms that could be caused by cancer, see the NICE guideline on suspected cancer: recognition and referral.\n\n# Interventions for uninvestigated dyspepsia\n\nBe aware that dyspepsia in unselected people in primary care is defined broadly to include people with recurrent epigastric pain, heartburn or acid regurgitation, with or without bloating, nausea or vomiting. Also see common elements of care. [2004, amended 2014]\n\nLeave a 2‑week washout period after proton pump inhibitor (PPI) use before testing for Helicobacter pylori (hereafter referred to as H\xa0pylori) with a breath test or a stool antigen test. [2004, amended 2014]\n\nOffer empirical full-dose PPI therapy (see table\xa01 in appendix\xa0A) for 4\xa0weeks to people with dyspepsia. \n\nOffer H\xa0pylori 'test and treat' to people with dyspepsia. \n\nIf symptoms return after initial care strategies, step down PPI therapy to the lowest dose needed to control symptoms. Discuss using the treatment on an 'as-needed' basis with people to manage their own symptoms. \n\nOffer H2 receptor antagonist (H2RA) therapy if there is an inadequate response to a PPI. [2004, amended 2014]\n\n# Reviewing patient care\n\nOffer people who need long-term management of dyspepsia symptoms an annual review of their condition, and encourage them to try stepping down or stopping treatment (unless there is an underlying condition or comedication that needs continuing treatment). [2004, amended 2014]\n\nAdvise people that it may be appropriate for them to return to self‑treatment with antacid and/or alginate therapy (either prescribed or purchased over-the-counter and taken as needed). [2004, amended 2014]\n\n# Interventions for GORD\n\nManage uninvestigated 'reflux-like' symptoms as uninvestigated dyspepsia. [2004, amended 2014]\n\nOffer people with GORD a full-dose PPI (see table\xa01 in appendix\xa0A) for 4 or 8\xa0weeks. \n\nIf symptoms recur after initial treatment, offer a PPI at the lowest dose possible to control symptoms. [2004, amended 2014]\n\nDiscuss with people how they can manage their own symptoms by using the treatment when they need it. \n\nOffer H2RA therapy if there is an inadequate response to a PPI. [2004, amended 2014]\n\nPeople who have had dilatation of an oesophageal stricture should remain on long-term full-dose PPI therapy (see table\xa01 in appendix\xa0A). \n\nOffer people a full-dose PPI (see table\xa02 in appendix\xa0A) for 8\xa0weeks to heal severe oesophagitis, taking into account the person's preference and clinical circumstances (for example, underlying health conditions and possible interactions with other drugs). [new 2014]\n\nIf initial treatment for healing severe oesophagitis fails, consider a high dose of the initial PPI, switching to another full-dose PPI (see table\xa02) or switching to another high-dose PPI (see table\xa02 in appendix\xa0A), taking into account the person's preference and clinical circumstances (for example, tolerability of the initial PPI, underlying health conditions and possible interactions with other drugs). [new 2014]\n\nOffer a full-dose PPI (see table\xa02 in appendix\xa0A) long-term as maintenance treatment for people with severe oesophagitis, taking into account the person's preference and clinical circumstances (for example, tolerability of the PPI, underlying health conditions and possible interactions with other drugs), and the acquisition cost of the PPI. [new 2014]\n\nIf the person's severe oesophagitis fails to respond to maintenance treatment, carry out a clinical review. Consider switching to another PPI at full dose or high dose (see table\xa02 in appendix\xa0A), taking into account the person's preference and clinical circumstances, and/or seeking specialist advice. [new 2014]\n\nDo not routinely offer endoscopy to diagnose Barrett's oesophagus, but consider it if the person has GORD. Discuss the person's preferences and their individual risk factors (for example, long duration of symptoms, increased frequency of symptoms, previous oesophagitis, previous hiatus hernia, oesophageal stricture or oesophageal ulcers, or male gender). [new 2014]\n\n# Interventions for peptic ulcer disease\n\nOffer H\xa0pylori eradication therapy to people who have tested positive for H\xa0pylori and who have peptic ulcer disease. Also see H\xa0pylori testing and eradication. \n\nFor people using NSAIDs with diagnosed peptic ulcer, stop the use of NSAIDs where possible. Offer full-dose PPI (see table\xa01 in appendix\xa0A) or H2RA therapy for 8\xa0weeks and, if H\xa0pylori is present, subsequently offer eradication therapy. \n\nOffer people with gastric ulcer and H\xa0pylori repeat endoscopy 6 to 8\xa0weeks after beginning treatment, depending on the size of the lesion. [2004, amended 2014]\n\nOffer people with peptic ulcer (gastric or duodenal) and H\xa0pylori retesting for H\xa0pylori 6 to 8\xa0weeks after beginning treatment, depending on the size of the lesion. [2004, amended 2014]\n\nOffer full-dose PPI (see table\xa01 in appendix\xa0A) or H2RA therapy for 4 to 8\xa0weeks to people who have tested negative for H\xa0pylori who are not taking NSAIDs. \n\nFor people continuing to take NSAIDs after a peptic ulcer has healed, discuss the potential harm from NSAID treatment. Review the need for NSAID use regularly (at least every 6\xa0months) and offer a trial of use on a limited, 'as-needed' basis. Consider reducing the dose, substituting an NSAID with paracetamol, or using an alternative analgesic or low-dose ibuprofen (1.2\xa0g daily). \n\nIn people at high risk (previous ulceration) and for whom NSAID continuation is necessary, consider a COX-2 selective NSAID instead of a standard NSAID. In either case, prescribe with a PPI. [2004, amended 2014]\n\nIn people with an unhealed ulcer, exclude non-adherence, malignancy, failure to detect H\xa0pylori, inadvertent NSAID use, other ulcer‑inducing medication and rare causes such as Zollinger–Ellison syndrome or Crohn's disease. \n\nIf symptoms recur after initial treatment, offer a PPI to be taken at the lowest dose possible to control symptoms. Discuss using the treatment on an 'as-needed' basis with people to manage their own symptoms. [2004, amended 2014]\n\nOffer H2RA therapy if there is an inadequate response to a PPI. \n\n# Interventions for functional dyspepsia\n\nManage endoscopically determined functional dyspepsia using initial treatment for H\xa0pylori if present, followed by symptomatic management and periodic monitoring. \n\nOffer eradication therapy to people testing positive for H\xa0pylori. \n\nDo not routinely offer re-testing after eradication, although the information it provides may be valued by individual people. \n\nIf H\xa0pylori has been excluded and symptoms persist, offer either a low-dose PPI (see table\xa01 in appendix\xa0A) or an H2RA for 4\xa0weeks. [2004, amended 2014]\n\nIf symptoms continue or recur after initial treatment, offer a PPI or H2RA to be taken at the lowest dose possible to control symptoms. [2004, amended 2014]\n\nDiscuss using PPI treatment on an 'as-needed' basis with people to manage their own symptoms. \n\nAvoid long-term, frequent dose, continuous antacid therapy (it only relieves symptoms in the short term rather than preventing them). [2004, amended 2014]\n\n# Helicobacter pylori testing and eradication\n\n## Testing\n\nTest for H\xa0pylori using a carbon‑13 urea breath test or a stool antigen test, or laboratory-based serology where its performance has been locally validated. [2004, amended 2014]\n\nPerform re-testing for H\xa0pylori using a carbon‑13 urea breath test. (There is currently insufficient evidence to recommend the stool antigen test as a test of eradication.) \n\nDo not use office-based serological tests for H\xa0pylori because of their inadequate performance. [2004, amended 2014]\n\n## Eradication\n\nOffer people who test positive for H\xa0pylori a 7‑day, twice-daily course of treatment with:\n\na PPI (see table\xa03 in appendix\xa0A) and\n\namoxicillin and\n\neither clarithromycin or metronidazole.Choose the treatment regimen with the lowest acquisition cost, and take into account previous exposure to clarithromycin or metronidazole. [new 2014]\n\nOffer people who are allergic to penicillin a 7‑day, twice-daily course of treatment with:\n\na PPI (see table\xa03 in appendix\xa0A) and\n\nclarithromycin and\n\nmetronidazole. [new 2014]\n\nOffer people who are allergic to penicillin and who have had previous exposure to clarithromycin a 7-day course of treatment with:\n\na PPI (see table\xa03 in appendix\xa0A) and\n\nbismuth and\n\nmetronidazole and\n\ntetracycline. [new 2014, amended 2019]\n\nDiscuss treatment adherence with the person and emphasise its importance. For more information about supporting adherence, see the NICE guideline on medicines adherence. [new 2014]\n\nOffer people who still have symptoms after first-line eradication treatment a 7‑day, twice-daily course of treatment with:\n\na PPI (see table\xa03 in appendix\xa0A) and\n\namoxicillin and\n\neither clarithromycin or metronidazole (whichever was not used first-line). [new 2014]\n\nOffer people who have had previous exposure to clarithromycin and metronidazole a 7‑day course of treatment with:\n\na PPI (see table\xa03 in appendix\xa0A) and\n\namoxicillin and\n\ntetracycline (or, if a tetracycline cannot be used, levofloxacin). [new 2014, amended 2019]\n\nOffer people who are allergic to penicillin (and who have not had previous exposure to a fluoroquinolone antibiotic) a 7‑day, twice-daily course of treatment with:\n\na PPI (see table\xa03 in appendix\xa0A) and\n\nmetronidazole and\n\nlevofloxacin. [new 2014, amended 2019]\n\nOffer people who are allergic to penicillin and who have had previous exposure to a fluoroquinolone antibiotic a 7-day course of:\n\na PPI (see table\xa03 in appendix\xa0A) and\n\nbismuth and\n\nmetronidazole and\n\ntetracycline. [new 2014, amended 2019]\n\nSeek advice from a gastroenterologist if eradication of H\xa0pylori is not successful with second-line treatment. [new 2014]\n\n# Laparoscopic fundoplication\n\nConsider laparoscopic fundoplication for people who have:\n\na confirmed diagnosis of acid reflux and adequate symptom control with acid suppression therapy, but who do not wish to continue with this therapy long term\n\na confirmed diagnosis of acid reflux and symptoms that are responding to a PPI, but who cannot tolerate acid suppression therapy. [new 2014]\n\n# Referral to a specialist service\n\nConsider referral to a specialist service for people:\n\nof any age with gastro-oesophageal symptoms that are non‑responsive to treatment or unexplained\n\nwith suspected GORD who are thinking about surgery\n\nwith H\xa0pylori that has not responded to second-line eradication therapy. [new 2014]\n\n# Surveillance for people with Barrett's oesophagus\n\nConsider surveillance to check progression to cancer for people who have a diagnosis of Barrett's oesophagus (confirmed by endoscopy and histopathology), taking into account:\n\nthe presence of dysplasia (also see the NICE guideline on Barrett's oesophagus: ablative therapy)\n\nthe person's individual preference\n\nthe person's risk factors (for example, male gender, older age and the length of the Barrett's oesophagus segment).Emphasise that the harms of endoscopic surveillance may outweigh the benefits in people who are at low risk of progression to cancer (for example, people with stable non-dysplastic Barrett's oesophagus). [new 2014]\n\n For more information about alarm signs please see the NICE guideline on suspected cancer: recognition and referral.\n\n This refers to evidence reviewed in 2004.\n\n For the assessment of allergy to beta-lactam antibiotics and referral to specialist care, see the NICE guideline on drug allergy.\n\n See MHRA advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).\n\n In the NICE guideline on suspected cancer: recognition and referral, 'unexplained' is defined as 'a symptom(s) and/or sign(s) that has not led to a diagnosis being made by the primary care professional after initial assessment of the history, examination and primary care investigations (if any)'.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Patient characteristics, risk factors and predictors that indicate endoscopy for excluding Barrett's oesophagus\n\nIn people who experience symptoms of gastro-oesophageal reflux disease (GORD) or symptoms suggestive of GORD, what patient characteristics, risk factors and predictors indicate when endoscopy is needed to exclude Barrett's oesophagus?\n\n## Why this is important\n\nThe aim is to identify adults with symptoms of GORD or symptoms suggestive of GORD who may benefit from having an endoscopy for the purpose of early identification of Barrett's oesophagus (or to exclude Barrett's oesophagus).\n\n# Laparoscopic fundoplication compared with medical management\n\nWhat is the effectiveness of laparoscopic fundoplication compared with medical management in people with GORD that does not respond to optimal proton pump inhibitor (PPI) treatment?\n\n## Why this is important\n\nCurrent evidence on the clinical and cost effectiveness of laparoscopic fundoplication compared with medical management involves people who had relatively good treatment control with PPIs at baseline. The driver was the desire to be free from medication rather than their GORD being non-responsive to PPIs.\n\n# Effective proton pump inhibitor dosage for severe erosive reflux disease\n\nWhat is the clinical effectiveness of double-dose PPIs in people with severe erosive reflux disease (Los Angeles classification grade C/D or Savary–Miller grade 3/4):\n\nto reduce severe oesophagitis\n\nto control symptoms\n\nas maintenance therapy?\n\n## Why this is important\n\nPeople with severe erosive reflux disease or severe oesophagitis (Los Angeles classification grade C/D or Savary–Miller grade 3/4) experience severe heartburn, and prolonged acid and pepsin exposure in the lower oesophagus, which can affect their day-to-day wellbeing. It would substantially improve people's quality of life if an optimal treatment regimen could be identified. Currently, there is a lack of evidence on the efficacy of 'double-dose' PPIs in treating severe erosive reflux disease.\n\n# Other specialist management\n\nWhat specialist management is effective for people whose symptoms do not respond to PPIs despite optimum primary care, or for people whose symptoms return after surgery?\n\n## Why this is important\n\nThere is a small group of people whose symptoms do not resolve, despite medical management and/or surgery for reflux. The group should be divided into people with proven (by pH monitoring) GORD and people with symptoms but no diagnosed reflux. The first group should have a trial of a twice-daily, high-dose PPI versus a standard or full-dose PPI. The second group should have a trial of tricyclic antidepressants versus standard or full-dose PPI. The purpose of any treatment should focus on improving quality of life.\n\n# Specialist investigation\n\nWhat specialist investigations should be conducted to exclude a diagnosis of functional dyspepsia in people with uninvestigated dyspepsia that does not respond to PPIs or H2 receptor antagonists (H2RAs) despite optimum primary care?\n\n## Why this is important\n\nPeople with uninvestigated dyspepsia that fails to respond to PPIs or H2RAs, despite optimum primary care, can have a poor quality of life. It is important to ensure that appropriate investigations are carried out to make the correct diagnosis or to correct misdiagnosis, so that the most appropriate treatment can be offered.", 'Finding more information and resources': "You can see everything NICE says on gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management in our interactive flowchart on dyspepsia and gastro-oesophageal reflux disease.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on gastro-oesophageal reflux, including Barrett's oesophagus.\n\nFor full details of the evidence and the guideline committee's discussions, see the full version of the guideline. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.", 'Appendix A: Dosage information on proton pump inhibitors': 'In 2004, when the original guideline was developed (CG17), doses of proton pump inhibitors (PPIs) were based on the British National Formulary (BNF) at the time, as in table\xa01 below.\n\nDuring the update of this guideline (2014), the Guideline Development Group (GDG) has further defined the PPI doses specifically for severe oesophagitis and H\xa0pylori eradication therapy, as in tables\xa02 and 3 below.\n\nTable 1 PPI doses relating to evidence synthesis and recommendations in the original guideline (CG17; 2004)\n\nProton pump inhibitor\n\nFull/standard dose\n\nLow dose (on-demand dose)\n\nDouble dose\n\nEsomeprazole\n\nmg1 once a day\n\nNot available\n\nmg3 once a day\n\nLansoprazole\n\nmg once a day\n\nmg once a day\n\nmg2 twice a day\n\nOmeprazole\n\nmg once a day\n\nmg2 once a day\n\nmg once a day\n\nPantoprazole\n\nmg once a day\n\nmg once a day\n\nmg2 twice a day\n\nRabeprazole\n\nmg once a day\n\nmg once a day\n\nmg2 twice a day\n\nLower than the licensed starting dose for esomeprazole in gastro-oesophageal reflux disease (GORD), which is 40\xa0mg, but considered to be dose-equivalent to other PPI. When undertaking meta-analysis of dose-related effects, NICE classed esomeprazole 20\xa0mg as a full-dose equivalent to omeprazole 20\xa0mg.\n\nOff-label dose for GORD.\n\n40\xa0mg is recommended as a double dose of esomeprazole because the 20‑mg dose is considered equivalent to omeprazole 20\xa0mg.\n\nTable 2 PPI doses for severe oesophagitis in this guideline update (2014)\n\nProton pump inhibitor\n\nFull/standard dose\n\nLow dose (on‑demand dose)\n\nHigh/double dose\n\nEsomeprazole\n\nmg1 once a day\n\nmg1 once a day\n\nmg1 twice a day\n\nLansoprazole\n\nmg once a day\n\nmg once a day\n\nmg2 twice a day\n\nOmeprazole\n\nmg1 once a day)\n\nmg1 once a day)\n\nmg1 twice a day\n\nPantoprazole\n\nmg once a day\n\nmg once a day\n\nmg2 twice a day\n\nRabeprazole\n\nmg once a day\n\nmg once a day\n\nmg2 twice a day\n\nChange from the 2004 dose, specifically for severe oesophagitis, agreed by the GDG during the update of CG17.\n\nOff-label dose for gastro-oesophageal reflux disease.\n\nTable 3 PPI doses for \n \n H\xa0pylori\n \n eradication therapy in this guideline update (2014)\n\nProton pump inhibitor\n\nDose\n\nEsomeprazole\n\nmg\n\nLansoprazole\n\nmg\n\nOmeprazole\n\n–40\xa0mg\n\nPantoprazole\n\nmg\n\nRabeprazole\n\nmg'}
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https://www.nice.org.uk/guidance/cg184
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This guideline covers investigating and managing gastro-oesophageal reflux disease (GORD) and dyspepsia in people aged 18 and over. It aims to improve the treatment of GORD and dyspepsia by making detailed recommendations on Helicobacter pylori eradication, and specifying when to consider laparoscopic fundoplication and referral to specialist services.
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67b68e8f12d6757f7f5904492286d77b99ce5e2b
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nice
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Rivaroxaban for preventing atherothrombotic events in people with coronary or peripheral artery disease
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Rivaroxaban for preventing atherothrombotic events in people with coronary or peripheral artery disease
Evidence-based recommendations on rivaroxaban (Xarelto) for preventing atherothrombotic events in adults with coronary or peripheral artery disease.
# Recommendations
Rivaroxaban plus aspirin is recommended within its marketing authorisation, as an option for preventing atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease who are at high risk of ischaemic events.
For people with coronary artery disease, high risk of ischaemic events is defined as:
aged 65 or over, or
atherosclerosis in at least 2 vascular territories (such as coronary, cerebrovascular, or peripheral arteries), or
-r more of the following risk factors:
current smoking
diabetes
kidney dysfunction with an estimated glomerular filtration rate (eGFR) of less than 60 ml/min (note that rivaroxaban is contraindicated if the eGFR is less than 15 ml/min)
heart failure
previous non-lacunar ischaemic stroke.
Assess the person's risk of bleeding before considering rivaroxaban. Treatment should only be started after an informed discussion with them about the risks and benefits of rivaroxaban, weighing up the risk of atherothrombotic events against the risk of bleeding. The risks and benefits of continuing treatment with rivaroxaban should be regularly reviewed.
Why the committee made these recommendations
People with chronic coronary artery disease or symptomatic peripheral artery disease can have atherothrombotic events such as myocardial infarction and stroke.
A clinical trial of people at high risk of ischaemic events shows that, compared with aspirin alone, rivaroxaban plus aspirin reduces the risk of having an ischaemic stroke, myocardial infarction or dying from cardiovascular disease. However, it increases the risk of bleeding.
The benefits and risks of rivaroxaban plus aspirin are only known for the specific population in the trial; that is, people at high risk of ischaemic events as defined by the inclusion criteria of the trial. A person's risk of bleeding should be assessed before rivaroxaban is considered. The decision to start treatment should be taken after an informed discussion about the risks and benefits, weighing up the risk of ischaemic events against the bleeding risk.
The cost effectiveness of rivaroxaban is within the range that is considered an acceptable use of NHS resources. Aspirin plus rivaroxaban is therefore recommended as a treatment option for people at high risk of having atherothrombotic events, who are not identified as having an increased risk of bleeding.# Information about rivaroxaban
Marketing authorisation indication
Rivaroxaban (Xarelto, Bayer), co-administered with aspirin, is indicated for 'the prevention of atherothrombotic events in adult patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events'.
Dosage in the marketing authorisation
The recommended dosage for rivaroxaban is 2.5 mg taken orally twice daily in combination with a daily dose of 75 to 100 mg aspirin taken orally.
Price
The list price for 56 tablets of rivaroxaban 2.5 mg is £50.40 (company submission). The treatment period is indefinite.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Bayer, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
It is more clinically plausible to substitute transition probability values used in the economic model that were numerically zero with non-zero values taken from the REACH registry.
The company's economic model underestimates the effect of varying the stratified mortality outcome 'cardiovascular death' in its sensitivity analyses. The company used the hazard ratio (HR) value for 'all cardiovascular death' from the COMPASS trial and assumed the same HR for all stratified death events in its model. Each mortality HR was then varied separately in the deterministic and probabilistic sensitivity analyses. Because each death rate only included a small proportion of all cardiovascular deaths, the effect of varying the HRs individually in the sensitivity analyses was underestimated. This issue had no effect on the results of the base-case analysis and only related to the uncertainty in the sensitivity analyses.
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 7), and took these into account in its decision making. It discussed the following issues (issues 1, 2 and 3), which were outstanding after the technical engagement stage.
# Clinical need and current management
## Patients rely on clinicians to discuss with them the benefits and risks of treatment options
The patient expert explained that people with coronary or peripheral artery disease have serious concerns about the risk of having events such as heart attack and stroke. They noted that coronary or peripheral artery disease is a challenging condition requiring significant lifestyle adjustments, including diet and exercise, which can affect the whole family. It is important that people understand why they are being offered a dual therapy and how the drugs work, because this can help with adherence to treatment. The patient expert explained that patients rely on clinicians to discuss with them the best treatment options. All options should be discussed, weighing up the potential benefits and risks of potentially long-term medication. The committee concluded that patients rely on clinicians to present the best treatment options to them, and all potential benefits and risks should be fully discussed.
## Patients would welcome an additional treatment option with an acceptable benefit-risk ratio for the prevention of atherothrombotic events
NICE's guideline on myocardial infarction: cardiac rehabilitation and prevention of further cardiovascular disease recommends dual antiplatelet therapy for people who have had an acute myocardial infarction. NICE's guideline on management of stable angina recommends considering aspirin 75 mg daily for secondary prevention of cardiovascular disease. NICE's technology appraisal guidance recommends ticagrelor in combination with aspirin for preventing atherothrombotic events in people who have had a myocardial infarction and are at high risk of a further event. The clinical experts noted that despite widespread use of aspirin in both acute and secondary care, the risk of stroke, myocardial infarction and dying from cardiovascular disease remains high for these patients. An additional treatment option that could reduce this risk would be welcomed by patients. The potential clinical benefit from treatment would need to be assessed, taking into consideration the potential risk of major bleeding events. The committee concluded that people with coronary artery disease or peripheral artery disease would welcome an additional treatment option with an acceptable benefit-risk ratio for the prevention of atherothrombotic events.
# Clinical evidence
## It is appropriate to consider the overall COMPASS population for decision making
COMPASS is a double-blind randomised clinical trial comparing rivaroxaban plus aspirin against aspirin alone in people with stable coronary artery disease or peripheral artery disease who are at high risk of ischaemic events. The company presented data for the overall trial population and also for 3 subpopulations that it identified as being at especially high baseline risk of ischaemic events: people with coronary artery disease and peripheral artery disease, people with coronary artery disease and heart failure, and people with coronary artery disease and poor kidney function. The risk of ischaemic events is related to the person's medical history and the extent of atheroma. People with heart failure, diabetes, poor kidney function or diffuse atherosclerosis affecting several areas (such as the coronary and peripheral arteries) are at higher risk of events. However other factors also increase risk including diabetes, high body mass index and smoking. At technical engagement, it was queried whether the company's subgroups are clinically relevant and represent people at highest risk of atherothrombotic events who are likely to benefit most from treatment with rivaroxaban plus aspirin. The clinical experts agreed that although these subgroups are clinically identifiable and relevant, there are other groups of people who are also at high risk. These include people who have had myocardial infarction or stroke, and those with multi-vessel coronary disease and diabetes. These people could derive similar benefit from rivaroxaban plus aspirin as seen in the 3 subgroups, because there was no between-group heterogeneity in relative treatment effects reported in COMPASS. The committee acknowledged the company's attempt to predict people with higher baseline risk using the 3 subgroups but noted that although the subgroups are illustrative of people at high risk, they do not identify all people at highest absolute risk of ischaemic events. The clinical experts also highlighted the difficulty in identifying people who are at greatest risk in clinical practice and agreed that, because there is no inter-group difference in treatment effects in COMPASS, the results from the overall population should be considered for decision making. However, the committee was aware that, within the overall eligible population, clinicians are likely to identify people at highest absolute risk of ischaemic events and offer rivaroxaban to those who are likely to have the highest potential absolute benefit. People at high risk of ischaemic events and no known increased bleeding risk will have the most favourable benefit−risk profile. The committee concluded that the efficacy results from the whole COMPASS population should be considered rather than the 3 subpopulations identified by the company, and it did not consider the subgroups further.
## Rivaroxaban plus aspirin reduces the risk of cardiovascular events
The primary efficacy outcome in COMPASS was a composite of 3 major cardiovascular events: myocardial infarction, ischaemic stroke and 'cardiovascular death'. The committee noted that rivaroxaban plus aspirin showed a statistically significant relative risk reduction of 24% in major cardiovascular events compared with aspirin (HR 0.76, 95% confidence interval 0.66 to 0.86; p<0.001). Two of the individual components of the primary composite outcome also showed statistically significant relative risk reductions in the treatment arm: 42% for ischaemic stroke (HR 0.58, 95% CI 0.44 to 0.76; p<0.001) and 22% for cardiovascular death (HR 0.78, 95% CI 0.64 to 0.96; p=0.02). The committee concluded that rivaroxaban plus aspirin reduces the risk of cardiovascular events compared with aspirin alone, and that the greatest effect is for ischaemic stroke.
## Rivaroxaban plus aspirin increases the risk of major bleeding
The primary safety outcome in COMPASS was major bleeding based on a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria. Major bleeding was defined as a composite of fatal bleeding, and/or symptomatic bleeding in a critical area or organ (such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, intramuscular with compartment syndrome, or bleeding into the surgical site requiring re-operation), and/or bleeding leading to hospitalisation (with or without an overnight stay). The risk of major bleeding, as defined by the modified ISTH criteria, increased by 70% in the rivaroxaban plus aspirin group compared with aspirin alone (HR 1.70, 95% CI 1.40 to 2.05; p<0.001). The bleeds in the rivaroxaban plus aspirin group were mostly gastrointestinal, with non-significant differences for the other components of the primary safety outcome. The committee concluded that rivaroxaban plus aspirin increases the risk of major bleeding compared with aspirin alone.
## Rivaroxaban should only be used in people at high risk of ischaemic events defined by the inclusion criteria of COMPASS
The clinical experts highlighted that COMPASS is a highly selected population that includes people at high risk of ischaemic events but excludes people with a known increased bleeding risk. The committee noted that the benefits and risks of rivaroxaban plus aspirin are only known for the specific population of people in COMPASS; that is, people with a high risk of ischaemic events as defined by the inclusion criteria of the trial. The committee recalled that the clinical benefits and risks associated with rivaroxaban plus aspirin are finely balanced (see section 3.4 and section 3.5). The committee noted that rivaroxaban plus aspirin is contraindicated in cases of active clinically significant bleeding and in people with lesions or conditions considered to be a significant risk factor for major bleeding. It agreed that a person's risk of bleeding should be assessed before rivaroxaban is considered as a treatment option. The decision to start treatment should only be taken after an informed discussion about the risks and benefits of rivaroxaban, weighing up the risk of ischaemic events against the bleeding risk. The committee concluded that rivaroxaban should only be considered a treatment option for people at high risk of ischaemic events as defined by the inclusion criteria of COMPASS.
# Comparators
## Clopidogrel is not a relevant comparator for the overall COMPASS population
The company did not present evidence for rivaroxaban plus aspirin compared with clopidogrel. The clinical experts explained that clopidogrel is the preferred antiplatelet treatment for people with peripheral artery disease (based on NICE's technology appraisal guidance for the prevention of occlusive vascular events), but it is not a relevant comparator for the whole COMPASS population. This is because aspirin is the preferred treatment for secondary prevention of cardiovascular disease in people with stable coronary artery disease, and clopidogrel is only recommended when aspirin is unsuitable because of contraindication or hypersensitivity. The committee concluded that clopidogrel is not a relevant comparator for the overall COMPASS population and that it is appropriate to base its recommendation on a comparison of rivaroxaban plus aspirin with aspirin alone.
## The indirect comparison of rivaroxaban against ticagrelor does not provide reliable estimates of relative effectiveness or risk of bleeding
To estimate the relative efficacy of rivaroxaban plus aspirin compared with ticagrelor plus aspirin, the company did an indirect treatment comparison of COMPASS against data from another trial (PEGASUS). The ERG highlighted that the indirect comparison is methodologically sound, but there are important differences between the patients included in the 2 trials. The proportion of people who had had a myocardial infarction was 100% in PEGASUS, but 62% in COMPASS. Also, the time since a myocardial infarction was between 1 and 3 years in PEGASUS, but in COMPASS people could have had a myocardial infarction at any time within the past 20 years. A clinical expert also noted that people in PEGASUS and COMPASS did not necessarily have the same baseline bleeding risk, and the trials used different methods to define significant bleeding (modified ISTH in COMPASS and TIMI in PEGASUS), making it difficult to compare the rates of bleeding in the 2 trials. The committee noted that the company did not use the results of the indirect comparison in its economic model. It concluded that COMPASS and PEGASUS have too many differences to allow a reliable estimate of the relative efficacy or bleeding risk of rivaroxaban plus aspirin compared with ticagrelor plus aspirin.
# The company's economic model
## The model is appropriate for decision making
The company modelled cost effectiveness using a Markov model with 5 states (event-free, non-fatal myocardial infarction, ischaemic stroke, intracranial haemorrhage and death). These were subdivided into acute event (0 to 3 months after an acute event), post-event (3 or more months after an acute event) and second acute event. The efficacy and clinical parameters in the model were derived from COMPASS for the comparison of rivaroxaban plus aspirin against aspirin alone. For the comparison against ticagrelor plus aspirin, the results from the indirect comparison of COMPASS and PEGASUS were not directly used to inform the economic model. Instead, the model used HRs from the COMPASS and PEGASUS trials, which the committee considered appropriate. The committee concluded that the structure of the company's model is appropriate for decision making.
# Cost-effectiveness estimates
## Rivaroxaban plus aspirin is cost effective compared with aspirin alone
The company's base-case incremental cost-effectiveness ratio (ICER) for rivaroxaban plus aspirin compared with aspirin alone is £14,185 per quality-adjusted life year gained. The committee noted that the ICER is in the range normally considered cost effective and therefore concluded that rivaroxaban plus aspirin is a cost-effective use of NHS resources in people who are at high risk of ischaemic events as defined by the inclusion criteria of COMPASS (see section 3.6).
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{'Recommendations': "Rivaroxaban plus aspirin is recommended within its marketing authorisation, as an option for preventing atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease who are at high risk of ischaemic events.\n\nFor people with coronary artery disease, high risk of ischaemic events is defined as:\n\naged\xa065 or over, or\n\natherosclerosis in at least 2\xa0vascular territories (such as coronary, cerebrovascular, or peripheral arteries), or\n\nor more of the following risk factors:\n\n\n\ncurrent smoking\n\ndiabetes\n\nkidney dysfunction with an estimated glomerular filtration rate (eGFR) of less than 60\xa0ml/min (note that rivaroxaban is contraindicated if the eGFR is less than 15\xa0ml/min)\n\nheart failure\n\nprevious non-lacunar ischaemic stroke.\n\n\n\nAssess the person's risk of bleeding before considering rivaroxaban. Treatment should only be started after an informed discussion with them about the risks and benefits of rivaroxaban, weighing up the risk of atherothrombotic events against the risk of bleeding. The risks and benefits of continuing treatment with rivaroxaban should be regularly reviewed.\n\nWhy the committee made these recommendations\n\nPeople with chronic coronary artery disease or symptomatic peripheral artery disease can have atherothrombotic events such as myocardial infarction and stroke.\n\nA clinical trial of people at high risk of ischaemic events shows that, compared with aspirin alone, rivaroxaban plus aspirin reduces the risk of having an ischaemic stroke, myocardial infarction or dying from cardiovascular disease. However, it increases the risk of bleeding.\n\nThe benefits and risks of rivaroxaban plus aspirin are only known for the specific population in the trial; that is, people at high risk of ischaemic events as defined by the inclusion criteria of the trial. A person's risk of bleeding should be assessed before rivaroxaban is considered. The decision to start treatment should be taken after an informed discussion about the risks and benefits, weighing up the risk of ischaemic events against the bleeding risk.\n\nThe cost effectiveness of rivaroxaban is within the range that is considered an acceptable use of NHS resources. Aspirin plus rivaroxaban is therefore recommended as a treatment option for people at high risk of having atherothrombotic events, who are not identified as having an increased risk of bleeding.", 'Information about rivaroxaban': "Marketing authorisation indication\n\nRivaroxaban (Xarelto, Bayer), co-administered with aspirin, is indicated for 'the prevention of atherothrombotic events in adult patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events'.\n\nDosage in the marketing authorisation\n\nThe recommended dosage for rivaroxaban is 2.5\xa0mg taken orally twice daily in combination with a daily dose of 75\xa0to\xa0100\xa0mg aspirin taken orally.\n\nPrice\n\nThe list price for 56\xa0tablets of rivaroxaban 2.5\xa0mg is £50.40 (company submission). The treatment period is indefinite.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Bayer, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nIt is more clinically plausible to substitute transition probability values used in the economic model that were numerically zero with non-zero values taken from the REACH registry.\n\nThe company's economic model underestimates the effect of varying the stratified mortality outcome 'cardiovascular death' in its sensitivity analyses. The company used the hazard ratio (HR) value for 'all cardiovascular death' from the COMPASS trial and assumed the same HR for all stratified death events in its model. Each mortality HR was then varied separately in the deterministic and probabilistic sensitivity analyses. Because each death rate only included a small proportion of all cardiovascular deaths, the effect of varying the HRs individually in the sensitivity analyses was underestimated. This issue had no effect on the results of the base-case analysis and only related to the uncertainty in the sensitivity analyses.\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa07), and took these into account in its decision making. It discussed the following issues (issues\xa01,\xa02 and\xa03), which were outstanding after the technical engagement stage.\n\n# Clinical need and current management\n\n## Patients rely on clinicians to discuss with them the benefits and risks of treatment options\n\nThe patient expert explained that people with coronary or peripheral artery disease have serious concerns about the risk of having events such as heart attack and stroke. They noted that coronary or peripheral artery disease is a challenging condition requiring significant lifestyle adjustments, including diet and exercise, which can affect the whole family. It is important that people understand why they are being offered a dual therapy and how the drugs work, because this can help with adherence to treatment. The patient expert explained that patients rely on clinicians to discuss with them the best treatment options. All options should be discussed, weighing up the potential benefits and risks of potentially long-term medication. The committee concluded that patients rely on clinicians to present the best treatment options to them, and all potential benefits and risks should be fully discussed.\n\n## Patients would welcome an additional treatment option with an acceptable benefit-risk ratio for the prevention of atherothrombotic events\n\nNICE's guideline on myocardial infarction: cardiac rehabilitation and prevention of further cardiovascular disease recommends dual antiplatelet therapy for people who have had an acute myocardial infarction. NICE's guideline on management of stable angina recommends considering aspirin 75\xa0mg daily for secondary prevention of cardiovascular disease. NICE's technology appraisal guidance recommends ticagrelor in combination with aspirin for preventing atherothrombotic events in people who have had a myocardial infarction and are at high risk of a further event. The clinical experts noted that despite widespread use of aspirin in both acute and secondary care, the risk of stroke, myocardial infarction and dying from cardiovascular disease remains high for these patients. An additional treatment option that could reduce this risk would be welcomed by patients. The potential clinical benefit from treatment would need to be assessed, taking into consideration the potential risk of major bleeding events. The committee concluded that people with coronary artery disease or peripheral artery disease would welcome an additional treatment option with an acceptable benefit-risk ratio for the prevention of atherothrombotic events.\n\n# Clinical evidence\n\n## It is appropriate to consider the overall COMPASS population for decision making\n\nCOMPASS is a double-blind randomised clinical trial comparing rivaroxaban plus aspirin against aspirin alone in people with stable coronary artery disease or peripheral artery disease who are at high risk of ischaemic events. The company presented data for the overall trial population and also for 3\xa0subpopulations that it identified as being at especially high baseline risk of ischaemic events: people with coronary artery disease and peripheral artery disease, people with coronary artery disease and heart failure, and people with coronary artery disease and poor kidney function. The risk of ischaemic events is related to the person's medical history and the extent of atheroma. People with heart failure, diabetes, poor kidney function or diffuse atherosclerosis affecting several areas (such as the coronary and peripheral arteries) are at higher risk of events. However other factors also increase risk including diabetes, high body mass index and smoking. At technical engagement, it was queried whether the company's subgroups are clinically relevant and represent people at highest risk of atherothrombotic events who are likely to benefit most from treatment with rivaroxaban plus aspirin. The clinical experts agreed that although these subgroups are clinically identifiable and relevant, there are other groups of people who are also at high risk. These include people who have had myocardial infarction or stroke, and those with multi-vessel coronary disease and diabetes. These people could derive similar benefit from rivaroxaban plus aspirin as seen in the 3\xa0subgroups, because there was no between-group heterogeneity in relative treatment effects reported in COMPASS. The committee acknowledged the company's attempt to predict people with higher baseline risk using the 3\xa0subgroups but noted that although the subgroups are illustrative of people at high risk, they do not identify all people at highest absolute risk of ischaemic events. The clinical experts also highlighted the difficulty in identifying people who are at greatest risk in clinical practice and agreed that, because there is no inter-group difference in treatment effects in COMPASS, the results from the overall population should be considered for decision making. However, the committee was aware that, within the overall eligible population, clinicians are likely to identify people at highest absolute risk of ischaemic events and offer rivaroxaban to those who are likely to have the highest potential absolute benefit. People at high risk of ischaemic events and no known increased bleeding risk will have the most favourable benefit−risk profile. The committee concluded that the efficacy results from the whole COMPASS population should be considered rather than the 3\xa0subpopulations identified by the company, and it did not consider the subgroups further.\n\n## Rivaroxaban plus aspirin reduces the risk of cardiovascular events\n\nThe primary efficacy outcome in COMPASS was a composite of 3\xa0major cardiovascular events: myocardial infarction, ischaemic stroke and 'cardiovascular death'. The committee noted that rivaroxaban plus aspirin showed a statistically significant relative risk reduction of 24% in major cardiovascular events compared with aspirin (HR 0.76, 95% confidence interval [CI] 0.66 to 0.86; p<0.001). Two of the individual components of the primary composite outcome also showed statistically significant relative risk reductions in the treatment arm: 42% for ischaemic stroke (HR 0.58, 95% CI 0.44 to 0.76; p<0.001) and 22% for cardiovascular death (HR 0.78, 95% CI 0.64 to 0.96; p=0.02). The committee concluded that rivaroxaban plus aspirin reduces the risk of cardiovascular events compared with aspirin alone, and that the greatest effect is for ischaemic stroke.\n\n## Rivaroxaban plus aspirin increases the risk of major bleeding\n\nThe primary safety outcome in COMPASS was major bleeding based on a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria. Major bleeding was defined as a composite of fatal bleeding, and/or symptomatic bleeding in a critical area or organ (such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, intramuscular with compartment syndrome, or bleeding into the surgical site requiring re-operation), and/or bleeding leading to hospitalisation (with or without an overnight stay). The risk of major bleeding, as defined by the modified ISTH criteria, increased by 70% in the rivaroxaban plus aspirin group compared with aspirin alone (HR 1.70, 95% CI 1.40 to 2.05; p<0.001). The bleeds in the rivaroxaban plus aspirin group were mostly gastrointestinal, with non-significant differences for the other components of the primary safety outcome. The committee concluded that rivaroxaban plus aspirin increases the risk of major bleeding compared with aspirin alone.\n\n## Rivaroxaban should only be used in people at high risk of ischaemic events defined by the inclusion criteria of COMPASS\n\nThe clinical experts highlighted that COMPASS is a highly selected population that includes people at high risk of ischaemic events but excludes people with a known increased bleeding risk. The committee noted that the benefits and risks of rivaroxaban plus aspirin are only known for the specific population of people in COMPASS; that is, people with a high risk of ischaemic events as defined by the inclusion criteria of the trial. The committee recalled that the clinical benefits and risks associated with rivaroxaban plus aspirin are finely balanced (see section\xa03.4 and section\xa03.5). The committee noted that rivaroxaban plus aspirin is contraindicated in cases of active clinically significant bleeding and in people with lesions or conditions considered to be a significant risk factor for major bleeding. It agreed that a person's risk of bleeding should be assessed before rivaroxaban is considered as a treatment option. The decision to start treatment should only be taken after an informed discussion about the risks and benefits of rivaroxaban, weighing up the risk of ischaemic events against the bleeding risk. The committee concluded that rivaroxaban should only be considered a treatment option for people at high risk of ischaemic events as defined by the inclusion criteria of COMPASS.\n\n# Comparators\n\n## Clopidogrel is not a relevant comparator for the overall COMPASS population\n\nThe company did not present evidence for rivaroxaban plus aspirin compared with clopidogrel. The clinical experts explained that clopidogrel is the preferred antiplatelet treatment for people with peripheral artery disease (based on NICE's technology appraisal guidance for the prevention of occlusive vascular events), but it is not a relevant comparator for the whole COMPASS population. This is because aspirin is the preferred treatment for secondary prevention of cardiovascular disease in people with stable coronary artery disease, and clopidogrel is only recommended when aspirin is unsuitable because of contraindication or hypersensitivity. The committee concluded that clopidogrel is not a relevant comparator for the overall COMPASS population and that it is appropriate to base its recommendation on a comparison of rivaroxaban plus aspirin with aspirin alone.\n\n## The indirect comparison of rivaroxaban against ticagrelor does not provide reliable estimates of relative effectiveness or risk of bleeding\n\nTo estimate the relative efficacy of rivaroxaban plus aspirin compared with ticagrelor plus aspirin, the company did an indirect treatment comparison of COMPASS against data from another trial (PEGASUS). The ERG highlighted that the indirect comparison is methodologically sound, but there are important differences between the patients included in the 2\xa0trials. The proportion of people who had had a myocardial infarction was 100% in PEGASUS, but 62% in COMPASS. Also, the time since a myocardial infarction was between 1\xa0and 3\xa0years in PEGASUS, but in COMPASS people could have had a myocardial infarction at any time within the past 20\xa0years. A clinical expert also noted that people in PEGASUS and COMPASS did not necessarily have the same baseline bleeding risk, and the trials used different methods to define significant bleeding (modified ISTH in COMPASS and TIMI in PEGASUS), making it difficult to compare the rates of bleeding in the 2\xa0trials. The committee noted that the company did not use the results of the indirect comparison in its economic model. It concluded that COMPASS and PEGASUS have too many differences to allow a reliable estimate of the relative efficacy or bleeding risk of rivaroxaban plus aspirin compared with ticagrelor plus aspirin.\n\n# The company's economic model\n\n## The model is appropriate for decision making\n\nThe company modelled cost effectiveness using a Markov model with 5\xa0states (event-free, non-fatal myocardial infarction, ischaemic stroke, intracranial haemorrhage and death). These were subdivided into acute event (0\xa0to\xa03 months after an acute event), post-event (3\xa0or more months after an acute event) and second acute event. The efficacy and clinical parameters in the model were derived from COMPASS for the comparison of rivaroxaban plus aspirin against aspirin alone. For the comparison against ticagrelor plus aspirin, the results from the indirect comparison of COMPASS and PEGASUS were not directly used to inform the economic model. Instead, the model used HRs from the COMPASS and PEGASUS trials, which the committee considered appropriate. The committee concluded that the structure of the company's model is appropriate for decision making.\n\n# Cost-effectiveness estimates\n\n## Rivaroxaban plus aspirin is cost effective compared with aspirin alone\n\nThe company's base-case incremental cost-effectiveness ratio (ICER) for rivaroxaban plus aspirin compared with aspirin alone is £14,185 per quality-adjusted life year gained. The committee noted that the ICER is in the range normally considered cost effective and therefore concluded that rivaroxaban plus aspirin is a cost-effective use of NHS resources in people who are at high risk of ischaemic events as defined by the inclusion criteria of COMPASS (see section\xa03.6)."}
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https://www.nice.org.uk/guidance/ta607
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Evidence-based recommendations on rivaroxaban (Xarelto) for preventing atherothrombotic events in adults with coronary or peripheral artery disease.
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cddd98a7a6544b69935c62e0d0ab45e254b12b7b
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nice
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Midcarpal hemiarthroplasty for wrist arthritis
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Midcarpal hemiarthroplasty for wrist arthritis
Evidence-based recommendations on midcarpal hemiarthroplasty for wrist arthritis in adults. This involves using a metal implant to create an artificial wrist joint, to relieve pain and maintain movement.
# Recommendations
Evidence on the safety and efficacy of midcarpal hemiarthroplasty for wrist arthritis is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research could be in the form of case series. It should report patient selection, type and severity of arthritis, patient-reported outcome measures and the need for revision in the longer term (at least 5 years).# The condition, current treatments and procedure
# The condition
Wrist arthritis can be caused by rheumatoid arthritis, osteoarthritis, trauma or sepsis. It can cause pain, stiffness and swelling.
# Current treatments
Treatments include analgesics, non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs and corticosteroid injections. If these do not work well enough, surgical treatments can be used. These include proximal row carpectomy, limited or partial carpal fusion, total wrist arthrodesis or total wrist arthroplasty.
# The procedure
The procedure is done using general or regional anaesthesia, with a tourniquet applied to the upper arm. A radiographic template is created preoperatively to determine the implant size. An incision is made over the wrist, in line with the third metacarpal. The joint is exposed, and the first row of carpal bones and the radial articular cartilage are removed. A trial implant is put into position, the carpus is reduced onto the bearing surface and the implant size, range of motion and stability are assessed. The final implant is then put in place and fully seated on the contoured subchondral plate.
Strengthening exercises are started 4 to 6 weeks after surgery and full activity can start several weeks after that. The aim is to relieve pain while keeping the midcarpal articulation and the anatomic centre of wrist rotation.
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{'Recommendations': 'Evidence on the safety and efficacy of midcarpal hemiarthroplasty for wrist arthritis is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research could be in the form of case series. It should report patient selection, type and severity of arthritis, patient-reported outcome measures and the need for revision in the longer term (at least 5\xa0years).', 'The condition, current treatments and procedure': '# The condition\n\nWrist arthritis can be caused by rheumatoid arthritis, osteoarthritis, trauma or sepsis. It can cause pain, stiffness and swelling.\n\n# Current treatments\n\nTreatments include analgesics, non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs and corticosteroid injections. If these do not work well enough, surgical treatments can be used. These include proximal row carpectomy, limited or partial carpal fusion, total wrist arthrodesis or total wrist arthroplasty.\n\n# The procedure\n\nThe procedure is done using general or regional anaesthesia, with a tourniquet applied to the upper arm. A radiographic template is created preoperatively to determine the implant size. An incision is made over the wrist, in line with the third metacarpal. The joint is exposed, and the first row of carpal bones and the radial articular cartilage are removed. A trial implant is put into position, the carpus is reduced onto the bearing surface and the implant size, range of motion and stability are assessed. The final implant is then put in place and fully seated on the contoured subchondral plate.\n\nStrengthening exercises are started 4\xa0to 6\xa0weeks after surgery and full activity can start several weeks after that. The aim is to relieve pain while keeping the midcarpal articulation and the anatomic centre of wrist rotation.'}
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https://www.nice.org.uk/guidance/ipg663
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Evidence-based recommendations on midcarpal hemiarthroplasty for wrist arthritis in adults. This involves using a metal implant to create an artificial wrist joint, to relieve pain and maintain movement.
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f1f80876232366be0f6aad57c668376c86d00c2d
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nice
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End of life care for adults: service delivery
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End of life care for adults: service delivery
This guideline covers organising and delivering end of life care services, which provide care and support in the final weeks and months of life (or for some conditions, years), and the planning and preparation for this. It aims to ensure that people have access to the care that they want and need in all care settings. It also includes advice on services for carers.
# Context
End of life care is defined by NHS England as care that is provided in the 'last year of life'; although for some conditions, end of life care may be provided for months or years. After the Liverpool Care Pathway was withdrawn in 2014, a number of national reports, guidelines and policy documents began to describe the changes needed for a new approach to end of life care services. They identified that high-quality, timely, compassionate personalised care and support planning, including advance care planning, should be accessible to all those who need it. To progress this intention, the models of care and the service delivery arrangements that need to be put in place for people as they approach the end of their life need to be defined.
End of life care may be delivered by disease-specific specialists and their associated teams; by generalists such as primary care teams or hospital-based generalists (for example, elderly care); or by palliative care specialists in hospices, hospitals and community settings. Giving this type of care can ensure that people live well until they die. Care that is given alongside, and to enhance, disease-modifying and potentially life-prolonging therapies, often for years, can be called 'supportive care'. Care that is primarily conservative and aimed at giving comfort and maintaining quality of life in the last months of life is commonly referred to as palliative care. Palliative care particularly aims to provide relief from pain and other distressing symptoms, integrate the psychological, social and spiritual aspects of the person's care, and continue to offer a support system to help people to live as actively as possible until their death. In this guideline, end of life care includes both supportive and palliative care. However, the terms used for this can vary, for example, end of life care is referred to as 'conservative care' in the NICE guideline on renal replacement therapy and conservative management.
This guideline describes the provision of end of life care services for adults approaching the end of their life with any conditions and diseases. The guideline advises on service models for care in acute settings by disease-specific specialists and their supportive services, and in community settings by primary care or specialists in palliative care (for example, in hospices). It is intended to be used alongside the NICE guideline on care of dying adults in the last days of life, which covers care planning and clinical interventions for people who are considered to be in the last days of life.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
End of life care includes the care and support given in the final weeks and months of life, and the planning and preparation for this. For some conditions, this could be months or years.
This includes people with:
advanced, progressive, incurable conditions
general frailty and coexisting conditions that mean they are at increased risk of dying within the next 12 months
existing conditions if they are at risk of dying from a sudden acute crisis in their condition
life-threatening acute conditions caused by sudden catastrophic events.
This guideline does not cover the clinical care of adults who are expected to die within a few hours or days. For advice on this, see the NICE guideline on care of dying adults in the last days of life.
# Identifying adults who may be approaching the end of their life, their carers and other people important to them
People managing and delivering services should develop systems to identify adults who are likely to be approaching the end of their life (for example, using tools such as the Gold Standards Framework, the Amber Care Bundle or the Supportive and Palliative Care Indicators Tool ). This will enable health and social care practitioners to start discussions about advance care planning, provide the care needed, and to support people's preferences for where they would like to be cared for and die.
Health and social care practitioners should identify carers and other people important to adults who are likely to be approaching the end of their life.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on identifying adults who may be approaching the end of their life, their carers and other people important to them .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review A: identifying people who may be entering the last year of life
Evidence review C: barriers to accessing end of life care services
Evidence review H: carer support services
Evidence review I: information sharing.
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# Assessing holistic needs
If it is thought that an adult is approaching the end of their life, carry out an initial holistic needs assessment with the person and document this. This will enable the right support to be provided when it is needed.
People managing services should ensure that health and social care practitioners caring for adults approaching the end of their life have the training and skills to sensitively carry out holistic needs assessments.
Healthcare practitioners should be aware of the requirement to offer a carer's needs assessment in line with the Care Act 2014 and a young carer's needs assessment in line with the Children and Families Act 2014.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on assessing holistic needs .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review B: timing of referral to palliative care services
Evidence review C: barriers to accessing end of life care services
Evidence review H: carer support services.
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# Supporting carers
People managing and delivering services should think about what practical and emotional support can be provided to carers of adults approaching the end of their life and review this when needed. For more information, see the NICE guideline on supporting adult carers.
When carers' needs are identified, take into account that the support needs of a young carer are likely to be different to those of an older carer.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on supporting carers .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review C: barriers to accessing end of life care services
Evidence review H: carer support services
Evidence review G: involving carers.
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# Providing information
For advice on communication, information and shared decision making, see the NICE guidelines on patient experience in adult NHS services, people's experience in adult social care services and shared decision making. Apply the same principles for communication and information giving to carers of all ages.
For people with learning disabilities, use this guideline alongside the recommendations on end of life care in the NICE guideline on care and support of people growing older with learning disabilities.
Support and enable adults approaching the end of their life to actively participate in decision making by having in place:
processes to establish the amount and type of information they would prefer
systems to provide information in a way that meets their communication needs and preferences, for example, how it is given (verbally, on paper, by text, email, or other assistive technologies) and provision of professional interpreters
arrangements to review and anticipate their information needs and preferences as circumstances change.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on providing information .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review C: barriers to accessing end of life care services
Evidence review G: involving carers.
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# Reviewing current treatment
For advice on reducing treatment burden and reviewing medicines and other treatments, see the NICE guidelines on multimorbidity and medicines optimisation.
Develop policies for reviewing treatment within all specialties to meet the changing needs of adults approaching the end of their life and to reduce the burden of unhelpful treatments. Different services should work together and share information about treatment reviews (see section 1.10 on providing end of life care coordination).
The lead healthcare professional should ensure that the person approaching the end of their life is offered opportunities to discuss their existing treatment plans with a healthcare professional. The person's carers and other people important to them should be included in the discussions, if the person agrees. This should include discussing:
any changes that could optimise care and improve their quality of life (for example, reducing the number of unnecessary routine appointments, organising appointments close to the person's home, starting new treatments or stopping unhelpful treatments)
community support available to help with their treatment.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on reviewing current treatment .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review D: care coordinator and lead healthcare professional
Evidence review J: service provision.
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# Advance care planning
Service providers should develop policies to ensure that advance care planning is offered to adults who are approaching the end of their life. Policies should take into account under-served and vulnerable groups.
Service providers should develop processes to support carers and other people important to the person to be involved in advance care planning, if the person approaching the end of their life agrees.
Service providers should have systems in place to ensure that adults approaching the end of their life each have a copy of their advance care plan available in their place of residence or with them if admitted to a hospital, care home or hospice.
Service providers should develop processes to take into account the views of carers and other people important to the person if the person approaching the end of their life lacks capacity to make decisions in line with the Mental Capacity Act 2005.
For advice on supporting decision making, assessing mental capacity and advance care planning, see the NICE guideline on decision-making and mental capacity.
For advice on starting advance care planning in adults who:
are at risk of a medical emergency, see the NICE guideline on emergency and acute medical care in over 16s
have motor neurone disease, see the NICE guideline on motor neurone disease
have multimorbidity, see the NICE guideline on multimorbidity
have dementia, see the NICE guideline on dementia
have learning disabilities, see the NICE guideline on care and support of people growing older with learning disabilities.A NICE guideline on social work interventions for adults with complex needs is being developed, with publication expected in January 2022.
For advice on organ donation, see the NICE guideline on organ donation for transplantation.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on advance care planning .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review C: barriers to accessing end of life care services
Evidence review F: advance care planning
Evidence review G: involving carers
Evidence review I: information sharing.
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# Reviewing needs
Develop systems enabling adults approaching the end of their life to have:
regular discussions with a member of their care team about changes in their health and social care needs and preferences
repeat assessments of their holistic needs and reviews of their advance care plan when needed, for example at key transition points, such as at discharge from hospital or when the goals of treatment have changed.
For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on reviewing needs .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review C: barriers to accessing end of life care services
Evidence review G: involving carers
Evidence review J: service provision.
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# Communicating and sharing information between services
Adults approaching the end of their life should have care that is coordinated between health and social care practitioners within and across different services and organisations, to ensure good communication and a shared understanding of the person's needs and care.
Use electronic information-sharing systems that are accessible between different services and organisations to enable information to be reviewed, updated and shared efficiently within and between multipractitioner teams, across different services and organisations.
For specific advice on coordinating end of life support in residential settings, see the NICE guideline on people's experience in adult social care services.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on communicating and sharing information between services .
Full details of the evidence and the committee's discussion are in evidence review I: information sharing.
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# Providing multipractitioner care
Provide access to the expertise of highly skilled health and social care practitioners, when needed, for adults approaching the end of their life, their carers and other people important to them. They should have the skills to:
meet complex care and support needs
anticipate and prevent or minimise crises
support people's preferences for where they would like to be cared for and die, if possible.
Health and social care practitioners should have the skills to provide care for adults approaching the end of their life who need support in the following areas:
disease-specific, including symptom management, hydration and nutrition, and access to medication
physical
psychological
social, including support and advice (for example, signposting advice on benefits, finance and third-sector, local or national support services)
support with activities of daily living, including access to equipment and rehabilitation services
pastoral, religious and spiritual
cultural.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on providing multipractitioner care .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review E: multiprofessional team
Evidence review L: additional services and inappropriate admissions.
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# Providing end of life care coordination
Provide end of life care coordination for adults who are approaching the end of their life through:
community and primary care services for adults, provided by the person's GP or another health or social care practitioner in the primary or community care team
hospital services for adults whose treatment is based in secondary or tertiary care, provided by health and social care practitioners based in hospices or disease-specific specialists in hospitals.
For people in under-served and vulnerable groups who are approaching the end of their life, provide additional support that takes into account the challenges of coordinating care for people in these groups.
Ensure that there is good communication between health and social care practitioners coordinating community-based care and health and social care practitioners coordinating hospital care.
Health and social care practitioners providing end of life care coordination should:
-ffer information to the person approaching the end of their life, their carers and others important to them, about who the multipractitioner team members are (including the lead healthcare professionals in each setting responsible for their care), the roles of the team members and how services are accessed
ensure that holistic needs assessments are offered, and the person's wishes and needs are discussed and acted on whenever possible
ensure that care is coordinated across and between the multipractitioner teams and between care settings
ensure that regular discussions and reviews of care, holistic needs and advance care plans are offered
share information about the person's care between members of the multipractitioner teams.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on providing end of life care coordination .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review C: barriers to accessing end of life care services
Evidence review D: care coordinator and lead healthcare professional
Evidence review G: involving carers.
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# Transferring people between care settings
For advice on transitions between care settings for adults with social care needs, see the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.
Develop systems to support smooth and rapid transfer between care settings for adults approaching the end of their life. For example, organise services so that:
ambulances or other transport services can move people between care settings without delay and in an efficient and compassionate way
care packages and equipment are available to enable adults approaching the end of their life to move to the place where they would like to be cared for and die.
Develop an agreed transfer policy between ambulance service providers and acute care providers to enable the rapid transfer of adults approaching the end of their life to the place where they would like to be cared for and die whenever rapid transfer is a priority.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on transferring people between care settings .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review C: barriers to accessing end of life care services
Evidence review M: optimal transition and facilitating discharge.
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# Providing out-of-hours care
Adults approaching the end of their life, their carers and other people important to them should have access to:
a healthcare professional available 24 hours a day, 7 days a week, who can access the person's records and advance care plan, and make informed decisions about changes to care
an out-of-hours end of life care advice line
an out-of-hours pharmacy service that has access to medicines for symptom management in adults approaching the end of their life.
For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on providing out-of-hours care .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review C: barriers to accessing end of life care services
Evidence review G: involving carers
Evidence review K: out-of-hours services.
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# Terms used in this guideline
## Advance care planning
Advance care planning is a voluntary process of discussion about future care between an individual and their care providers, irrespective of discipline.
An advance care planning discussion might include:
the individual's concerns and wishes
their important values or personal goals for care
their understanding about their illness and prognosis
their preferences and wishes for types of care or treatment that may be beneficial in the future and the availability of these.
Advance care planning is one part of the process of personalised care and support planning.
## Approaching the end of life
People in the final weeks and months of life, although for people with some conditions, this could be months or years.
It includes people with:
advanced, progressive, incurable conditions
general frailty and coexisting conditions that mean they are at increased risk of dying within the next 12 months
existing conditions if they are at risk of dying from a sudden acute crisis in their condition
life-threatening acute conditions caused by sudden catastrophic events.
## Carers
A carer is someone who helps another person, usually a relative, partner or friend, in their day-to-day life. This term does not refer to someone who provides care professionally or through a voluntary organisation. A young carer is aged under 18.
## People managing services
Commissioners, planners and service providers responsible for overseeing local health and social care provision and accountable for public service outcomes.
## Holistic needs assessment
An assessment that considers all aspects of a person's wellbeing, their spiritual and health and social care needs. Undertaking a holistic needs assessment ensures that the person's concerns and problems are identified so that support can be provided to address them. There are validated tools that can be used to support the assessment process.
## Lead healthcare professional
A lead healthcare professional is a member of the multipractitioner team who assumes overall clinical responsibility for the delivery of care to a patient. They are usually a senior doctor or senior nurse.
## Multipractitioner team
A multipractitioner team is a group of practitioners from different clinical professions, disciplines, organisations and agencies who together make decisions on the recommended treatment for individual patients.
## People important to adults approaching the end of their life
These may include family members and anyone else who the person regards as significant, such as a partner or close friend. It may be someone who the person wants involved in discussions about their care. It is important that health and social care practitioners understand that assumptions should not be made when asking about the people important to the person, for example, assuming everyone is in a heterosexual relationship.
## Personalised care and support planning
Personalised care and support planning is a series of facilitated conversations in which the person, or those who know them well, actively participates to explore the management of their health and wellbeing within the context of their whole life and family situation.
Personalised care and support planning is key for people receiving health and social care services. It is an essential tool to integrate the person's experience of all the services they access so they have one joined-up plan that covers their health and wellbeing needs.
Personalised care and support planning is not to be confused with personalised medicine. The latter is the approach to tailor treatments to people's individual health needs based on their biological risk factors and predictors of response to treatments.
## Service providers
All organisations (including primary, secondary, tertiary, ambulance and hospice services) that provide NHS services for people approaching the end of their life.
## Shared decision making
Shared decision making is when health and social care professionals and patients work together. This puts people at the centre of decisions about their own treatment and care. During shared decision making, it's important that:
care or treatment options are fully explored, along with their risks and benefits
different choices available to the patient are discussed
a decision is reached together with a health and social care professional.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Early review of service provision and referral to additional specialist palliative care services
Does early review of service provision and referral to additional specialist palliative care services improve outcomes for adults with progressive non-cancer disease thought to be approaching the end of their life?
## Why this is important
There is a body of research into the optimal timing of referral to specialist palliative care in cancer patients, which generally points to earlier referral leading to better patient-reported outcomes. The committee noted that similar evidence is very limited for patients with a non-cancer diagnosis, for example in patients with progressive organ failure, such as advanced heart failure, or patients with life-limiting neurological disease, such as motor neurone disease or dementia. Such patients are typically referred very late to specialist palliative care, if at all. Further research would compare outcomes for people having a combination of early identification and specialist palliative care input with those for people having usual care.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on reviewing current treatment .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review D: care coordinator and lead healthcare professional
Evidence review J: service provision.
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## Electronic registers and information-sharing databases
Which of the electronic information-sharing systems perform best for the care of people approaching the end of their life?
## Why this is important
The guideline committee made recommendations on sharing information about people who are approaching the end of their life with other members of the multipractitioner teams involved in their care. The committee was aware that in the past, most information recording and sharing was done using paper-based systems, with information shared between teams and care settings using telephone, fax and emails. However, fully electronic databases and information-sharing systems using internet protocols are becoming more established in the NHS and also in hospice services. NHS Digital has a stated aim to develop joined-up digital systems in the health service. The committee looked for research about which systems performed best and were reliable for sharing confidential information but was unable to find it. The committee were aware of deficiencies in the current systems. Studies conducted in other countries using electronic systems were not applicable to the NHS.
It is therefore recommended that research should be done on the systems that are currently available in the UK. The purpose of this research would be to inform healthcare planners and service providers on the most efficient, reliable, secure, confidential and cost-effective systems to be used for sharing information about people approaching the end of their life across a range of care settings.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on communicating and sharing information between services .
Full details of the evidence and the committee's discussion are in evidence review I: information sharing.
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## Frequency of community-based reviews
What are the benefits of planned, regular community-based reviews compared with as-required review of non-cancer patients approaching the end of their life?
## Why this is important
There is little relevant research evidence for the optimum frequency of review of people with progressive non-cancer conditions who may be approaching the end of their life. Many of the studies attempted in this area have been conducted in other countries where the healthcare systems are very different from the UK. 'Usual care' for non-cancer conditions tends to provide demand-led review by specialists and primary care staff. This may be appropriate if people are well supported at home or in care settings. However, it could lead to unrecognised deterioration in symptoms or functioning, and place people at risk of crises and unplanned hospital admissions if they are living alone or have little professional support. A policy of regular, planned reviews of patients in their place of residence could improve symptom management, maintain a better level of functioning, prevent crises and may pre-empt emergency hospital visits and admission. However, there is a risk that they could impose unnecessary burdens on the patient, family and the healthcare system.
This research would study non-cancer patients receiving usual care (with or without any concurrent specialist level care), and assess their outcomes against different levels of frequency of planned specialist reviews in the community.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on reviewing current treatment .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review D: care coordinator and lead healthcare professional
Evidence review J: service provision.
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## Discharge and transfer from hospital
What is the optimal way of discharging people approaching the end of their life from hospitals back to their place of residence?
## Why this is important
The committee found there was very little evidence on discharging adults approaching the end of their life and transferring them between settings. One of the most important transfers is from hospital to home or the person's place of residence, such as a nursing home, especially when death is imminent. Such discharges are often delayed because of medical or nursing problems, or by unmet social care needs. However, some of these problems could be managed well in the community with key equipment or medication and improved social care. The consequences of delayed discharge can be distressing to the person approaching the end of life and their carers and important people. It could mean people staying and dying in inappropriate care settings, such as an acute hospital ward, when it is not their preferred place to be cared for and die. Delayed discharge would also be unnecessary from a medical or nursing perspective.
Key factors in ensuring prompt discharge with care and compassion include clear communication and processes between services providing care in the 2 settings and also those providing transport.
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on transferring people between care settings .
Full details of the evidence and the committee's discussion are in the following evidence reviews:
Evidence review C: barriers to accessing end of life care services
Evidence review M: optimal transition and facilitating discharge.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect services. They link to details of the evidence and a full description of the committee's discussion.
# Identifying adults who may be approaching the end of their life, their carers and people important to them
Recommendations 1.1.1 and 1.1.2
## Why the committee made the recommendations
Talking to people about dying can be difficult and there is often a reluctance to start conversations about preparing for the end of life. Although the evidence was limited, the committee agreed that identifying adults who may be approaching the end of their life supports health and social care practitioners to start discussions about advance care planning. This should ensure that the person near the end of life is provided with the support that they may need now or later to help them stay where they would like to be cared for and die. It also gives them time to consider and re‑evaluate their needs with their health and social care practitioners.
The committee wanted to emphasise the importance of identifying people systematically. There are already some systems in use for identifying people approaching the end of their life, which are given as examples in the recommendations. However, there were no studies comparing and evaluating their effectiveness in service delivery so the committee could not recommend a particular system.
The committee noted the importance of identifying people who are at particular risk of missing out on access to end of life care, including people living alone without support, people with learning difficulties and people who are homeless.
The committee agreed that using a shared coordination of care system would improve coordination of care between all health and social care practitioners involved in a person's care, and in turn improve service delivery.
## How the recommendations might affect services
The recommendations reflect current good practice available in some services, but there is variation in how and when people are identified across different patient groups and settings. The recommendations are expected to increase the number of people identified. The net impact on services is uncertain. Some investment will be required to establish systems to systematically identify patients in some areas. However, this will ensure that people approaching the end of their life will receive the appropriate care, and their carers will receive support, which will help to avoid unnecessary hospital admissions.
Return to recommendations
# Assessing holistic needs
Recommendations 1.2.1 to 1.2.3
## Why the committee made the recommendations
The evidence reviewed showed that early assessment was beneficial. However, the studies used different definitions for early and late assessment in various settings and so the evidence wasn't clear enough to recommend an optimal timing for an initial assessment. The committee agreed that an assessment with the person should be carried out to enable the right support to be provided when it is needed.
The evidence showed that carers' quality of life was improved and the burden of care reduced when carers are supported. The committee agreed that assessment of carers' needs is important to ensure they are supported to help care for the person approaching the end of their life. However, these assessments are often overlooked so the recommendation reminds healthcare practitioners that carers should be offered an assessment in line with legislation, and they should refer to social care practitioners accordingly.
## How the recommendations might affect services
The recommendations reflect current good practice available in some services, but there is some variation, for example, in ensuring access to carers' needs assessments.
The assessment of a person's needs will result in appropriate care being delivered. This may reduce some resource use when unnecessary interventions are stopped, but may increase the use of other resources if interventions for end of life care, such as symptom management or aids for daily living, are needed.
The number of carers being assessed may increase, but this should result in better support to help the person stay where they would like to be cared for and die, and may reduce the number of attendances and admissions to hospitals.
Return to recommendations
# Supporting carers
Recommendations 1.3.1 and 1.3.2
## Why the committee made the recommendations
The information and support needs of carers will vary and the evidence did not identify one particular way of supporting carers. However, it did show that carers have better outcomes, such as maintaining quality of life and reduced carer burden, when supported. The committee agreed that health and social care providers should go beyond the strict statutory requirement for carers' assessments to ensure that the needs of carers are considered (including respite and psychological support), and that the varied needs of different carer groups are taken into account.
## How the recommendations might affect services
Increased investment may be needed for increased numbers of assessments and increased support accessed. This approach should result in better support for adults approaching the end of their life to stay where they would like to be cared for and die. The impact on hospital admission is uncertain. Increased support may reduce the number of hospital admissions or it may result in increased (and perhaps more appropriate) admissions.
Taking into account the individual support needs of young and older carers should reduce the physical and emotional strains that are often experienced by carers. This may help reduce the need for, and therefore costs of, interventions for physical and mental health problems common in these groups of carers.
Return to recommendations
# Providing information
Recommendations 1.4.1 to 1.4.3
## Why the committee made the recommendations
The evidence showed that a lack of knowledge about end of life care and the support and services available, and poor communication between adults approaching the end of their life and health and social care practitioners, are barriers to understanding treatment options and confidently making decisions about care.
Based on this evidence and the committee's experience, the recommendations reflect the importance of systematically seeking and acting on the information needs and preferences of people approaching the end of their life, their carers and other people important to them. The committee also acknowledged that people's information needs will vary and change over time, so regular reviews are needed and referral to specialist communication support could be needed.
The committee also noted that service providers across the NHS and adult social care system should follow the NHS England Accessible Information Standard to ensure that the information and communication support needs of disabled people are met.
## How the recommendations might affect services
The recommendations reflect good current practice available in some services, but there is variation nationally.
Improving understanding and communication will benefit services, ensuring that people make informed decisions and receive the appropriate care.
Return to recommendations
# Reviewing current treatment
Recommendations 1.5.1 to 1.5.3
## Why the committee made the recommendations
There was no evidence identified on how and when to carry out an initial review of service provision for people approaching the end of their life. However, the committee agreed that it was important for all lead healthcare professionals responsible for the person's care to review and discuss the person's current care needs with them. In particular, they discussed identifying services that may be needed or could be stopped, and acknowledged that the involvement of too many services can be as problematic as too few.
The committee also agreed that adapting care for treating conditions in adults needing end of life care would help to ensure that the right care is provided at the right time. Policies within different specialties would support this, and the committee were aware that these have been developed for some specialist areas, such as diabetes (see Diabetes UK End of life diabetes care: clinical care recommendations) and for neurological conditions. To encourage more research in this area, the committee developed research recommendations on early review of service provision and referral to additional specialist palliative care services and frequency of community-based reviews.
## How the recommendations might affect services
The recommendations reflect current good practice available in some services, but there is variation nationally. Reviewing current treatment of people approaching the end of their life means appropriate care will be given and may reduce the burden of unnecessary appointments and treatments.
Return to recommendations
# Advance care planning
Recommendations 1.6.1 to 1.6.7
## Why the committee made the recommendations
The evidence for advance care planning was unclear, although it did show some benefit in supporting people to stay where they would like to be cared for and die. The committee acknowledged that the implementation of advance care planning is complex and agreed that there was not enough evidence to recommend a specific service model for advance care planning. However, the committee agreed that advance care planning helps people to achieve the care and support they want, and that policies should be in place to provide it to adults approaching the end of their life. They noted that some under-served and vulnerable groups (for example, people who are homeless and people in prison) may not have opportunities to engage in advance care planning, and that provision for these groups should be highlighted. The committee also felt that advance care planning should not be restricted to planning for possible future loss of mental capacity.
The evidence on barriers to care described how carers felt a lack of control and a lack of trust in health and social care practitioners, resulting in scepticism about the benefits of advance care planning. The committee agreed that better communication and processes to involve carers in advance care planning would help to address this.
Evidence suggested that individual patient-held records did not improve patient satisfaction with communication. However, the committee agreed that a copy of the advance care plan available in the person's home may be useful for health and social care practitioners to refer to in emergency situations when access to other information is unavailable.
## How the recommendations might affect services
The recommendations reflect good current practice available in some services, but there is variation in the timing and availability of advance care planning in different areas and for different patient groups.
Advance care planning supports adults approaching the end of their life to be cared for and die in their preferred place, which is often in the community. This may reduce the need for hospital services but increase demand for services in the community. The advance care plan documents the person's current, future and emergency needs, improving coordination of care across the multipractitioner team and should help avoid unnecessary hospital attendances and admissions.
Return to recommendations
# Reviewing needs
Recommendation 1.7.1
## Why the committee made the recommendation
There was no evidence to indicate the best time to undertake reviews of service provision for people approaching the end of their life. Every person's journey is individual, reflecting how their health can fluctuate unpredictably, with periods of deterioration, stabilisation and sometimes improvement. In addition, their psychological, social, financial and other support needs will vary, not always in step with the physical illness. The committee therefore agreed that regular reviews of care are important when people are approaching the end of their life to identify when changes in care or other forms of support are needed, for example, when the goals of disease-modifying treatment change.
The committee recognised that regular discussions with the care team would help to identify changes in the person's needs and preferences. They also agreed that repeating holistic needs assessments and reviews of advance care plans would ensure that people continue to receive the right care and support.
## How the recommendation might affect services
The recommendation reflects current good practice available in some services, but there is variation nationally. Reviewing the ongoing care of people approaching the end of their life means that appropriate care will be given and may reduce some resource use when unnecessary interventions are stopped.
Return to recommendations
# Communicating and sharing information between services
Recommendations 1.8.1 to 1.8.3
## Why the committee made the recommendations
The committee agreed that electronic information systems should be used because they would be the most effective and efficient method to share information. However, the evidence was too limited for the committee to recommend a particular system. The committee developed a research recommendation on electronic registers and information-sharing databases to encourage further research in this area.
The committee did not have the evidence to recommend what information should be shared, but agreed that everyone involved in a person's care should have access to relevant health and social care information, including the person's care plan.
The recommendations are underpinned by the Health and Social Care (Safety and Quality) Act 2015, which introduced a legal duty requiring health and social care bodies to share information when this will facilitate care.
## How the recommendations might affect services
The recommendations reflect current good practice available in some services. The use of electronic-based systems to coordinate the care of people approaching the end of their life has been increasing across England and Wales. The committee agreed that there is variation in the implementation of these systems across the NHS and investment would be needed in areas without systems in place. The committee considered that electronic systems would result in more efficient, well-coordinated care through better access to information, reducing duplication and improving communication.
Return to recommendations
# Providing multipractitioner care
Recommendations 1.9.1 and 1.9.2
## Why the committee made the recommendations
The evidence showed that a multipractitioner approach to care was favourable and had a positive impact on supporting adults to stay where they would like to be cared for and die. The committee agreed that the skills and expertise of many specialties and disciplines is needed to meet people's varied and changing needs. However, there is no clear evidence on the ideal composition of a multipractitioner team and so instead of identifying specific roles, the committee set out the type of support people may need access to as they approach the end of their life.
## How the recommendations might affect services
The recommendations reflect current good practice available in some services, but there is variation nationally. Care that meets the person's identified needs and is delivered by health and social care practitioners with the relevant skills may reduce costs by minimising crises and helping to avoid emergency unplanned care and unnecessary hospital attendances and admissions. However, this will require some investment upstream.
Return to recommendations
# Providing end of life care coordination
Recommendations 1.10.1 to 1.10.4
## Why the committee made the recommendations
The evidence on identifying barriers to accessing services showed that continuity and coordination of care are often identified as being unsatisfactory for adults approaching the end of their life and their carers. The evidence also highlighted a lack of information and poor communication with carers, which could be improved with better coordination of care.
The committee agreed that good coordination of care and effective communication systems are especially important when people have contact with multiple services and organisations and for under-served and vulnerable groups.
The committee also agreed that good coordination of care should include systems to review appointments and home visits, both to support efficiency of care and also to avoid overwhelming the person with multiple visits from different services.
The evidence showed that having someone to organise care was of some benefit, particularly in reducing unscheduled and emergency hospital visits and admissions. However, it was not clear if this should be a specific role or who should do this. Therefore, the committee listed the key principles within end of life care coordination that community, hospital and hospice services could provide in collaboration rather than specifying who should take on this role and where it should be located.
## How the recommendations might affect services
The recommendation reflects current good practice available in some services, but there is variation nationally. In areas where good coordination of care is lacking, it should result in more efficient service provision and help to minimise crises, and support people to stay where they would like to be cared for and die. Good care coordination should also reduce the use of unnecessary services and avoid duplication of care.
Care coordination by health and social care professionals is taking place currently in the NHS but the committee was uncertain how extensively it is practised. Additional resources may be needed to coordinate care across services and deliver the key roles of end of life care coordination, but it should help to reduce the use of unnecessary services and avoid duplication of care.
Return to recommendations
# Transferring people between care settings
Recommendations 1.11.1 to 1.11.3
## Why the committee made the recommendations
There was very little evidence on transferring adults between settings when they are approaching the end of their life. However, the committee agreed that the availability of efficient and timely transfer is important to ensure that people can be moved quickly, when needed, to where they would like to be cared for and die.
The committee also discussed the consequences of delayed transfer, which can result in people staying in inappropriate care settings or being cared for and dying in settings other than where they would like to be cared for and die. They also discussed how clear communication and processes between services providing care and those providing transport can help to avoid delays and enable efficient transfer.
The committee developed recommendations to reinforce good practice and support the advice in NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs. The committee also noted that more research is needed to determine the optimal service configuration for transfer of people with different conditions and at different stages as people approach the end of their life (see the research recommendation on discharge and transfer from hospital).
The committee also agreed that poor and slow access to care packages and equipment can delay transfer between settings and prevent people from being cared for and dying in their preferred place, so highlighted the need to organise this support to enable timely transfer.
## How the recommendations might affect services
Effective and timely transfer is likely to reduce the number of people dying in hospital, because most people wish to die in a community setting (for example, their own home or care home, or in a hospice). This may reduce the need for hospital services but increase demand for services in the community.
Return to recommendations
# Providing out-of-hours care
Recommendation 1.12.1
## Why the committee made the recommendation
The evidence for providing an out-of-hours service showed some benefit in supporting people to stay where they would like to be cared for and die. The committee agreed that the services described in the studies reflected existing out-of-hours services in areas of good practice. However, there was evidence that elements of service provision important for people approaching the end of their life may be variable or lacking, so these were the focus for the recommendation.
The evidence supported the committee's experience that access to healthcare advice is critical in providing reassurance and ensuring people have access to the services they need. The committee agreed that a healthcare practitioner should be available at all times to provide this, and that they would need access to the person's records and advance care plan, preferably through a shared electronic information system, to enable them to make informed decisions about care.
Evidence exploring the views of people approaching the end of their life and their carers highlighted the importance of having access to advice from someone who has expertise and understands their needs. The committee agreed that an out-of-hours end of life care advice line could help to provide this support.
Another common concern for people at the end of life and their carers is the limited provision of pharmacy services outside traditional working hours. The committee discussed how a lack of access to medicines that may be needed quickly can result in people being transferred and admitted to hospital.
An analysis of the evidence for providing a dedicated out-of-hours end of life care advice line and an out-of-hours pharmacy service showed that the costs of providing these services could be balanced by the savings incurred by a relatively small reduction in emergency admissions and length of stay of admissions, and an increase in the number of people remaining in the community. The committee noted that the net resource impact of caring for people in the community is uncertain. On balance, they felt that providing out-of-hours care was a good use of resources and key to meeting the needs of patients.
## How the recommendation might affect services
Current provision of out-of-hours services is variable nationally, but the recommendation reflects current good practice in some areas. The committee are uncertain how extensively it is practised. Where services such as an out-of-hours pharmacy service or dedicated end of life care advice line are lacking, increased resources may be needed to set up these services. However, this is likely to reduce the number of people being transferred to hospital for care that could be given at home. This may reduce the need for hospital services but increase demand for services in the community.
Return to recommendations# Finding more information and resources
You can see everything NICE says on end of life care for adults in NICE's interactive flowchart on end of life care for people with life-limiting conditions.
To find out what NICE has said on topics related to this guideline, see our web page on end of life care.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
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{'Context': "End of life care is defined by NHS England as care that is provided in the 'last year of life'; although for some conditions, end of life care may be provided for months or years. After the Liverpool Care Pathway was withdrawn in 2014, a number of national reports, guidelines and policy documents began to describe the changes needed for a new approach to end of life care services. They identified that high-quality, timely, compassionate personalised care and support planning, including advance care planning, should be accessible to all those who need it. To progress this intention, the models of care and the service delivery arrangements that need to be put in place for people as they approach the end of their life need to be defined.\n\nEnd of life care may be delivered by disease-specific specialists and their associated teams; by generalists such as primary care teams or hospital-based generalists (for example, elderly care); or by palliative care specialists in hospices, hospitals and community settings. Giving this type of care can ensure that people live well until they die. Care that is given alongside, and to enhance, disease-modifying and potentially life-prolonging therapies, often for years, can be called 'supportive care'. Care that is primarily conservative and aimed at giving comfort and maintaining quality of life in the last months of life is commonly referred to as palliative care. Palliative care particularly aims to provide relief from pain and other distressing symptoms, integrate the psychological, social and spiritual aspects of the person's care, and continue to offer a support system to help people to live as actively as possible until their death. In this guideline, end of life care includes both supportive and palliative care. However, the terms used for this can vary, for example, end of life care is referred to as 'conservative care' in the NICE guideline on renal replacement therapy and conservative management.\n\nThis guideline describes the provision of end of life care services for adults approaching the end of their life with any conditions and diseases. The guideline advises on service models for care in acute settings by disease-specific specialists and their supportive services, and in community settings by primary care or specialists in palliative care (for example, in hospices). It is intended to be used alongside the NICE guideline on care of dying adults in the last days of life, which covers care planning and clinical interventions for people who are considered to be in the last days of life.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nEnd of life care includes the care and support given in the final weeks and months of life, and the planning and preparation for this. For some conditions, this could be months or years.\n\nThis includes people with:\n\nadvanced, progressive, incurable conditions\n\ngeneral frailty and coexisting conditions that mean they are at increased risk of dying within the next 12\xa0months\n\nexisting conditions if they are at risk of dying from a sudden acute crisis in their condition\n\nlife-threatening acute conditions caused by sudden catastrophic events.\n\nThis guideline does not cover the clinical care of adults who are expected to die within a few hours or days. For advice on this, see the NICE guideline on care of dying adults in the last days of life.\n\n# Identifying adults who may be approaching the end of their life, their carers and other people important to them\n\nPeople managing and delivering services should develop systems to identify adults who are likely to be approaching the end of their life (for example, using tools such as the Gold Standards Framework, the Amber Care Bundle or the Supportive and Palliative Care Indicators Tool [SPICT]). This will enable health and social care practitioners to start discussions about advance care planning, provide the care needed, and to support people's preferences for where they would like to be cared for and die.\n\nHealth and social care practitioners should identify carers and other people important to adults who are likely to be approaching the end of their life.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on identifying adults who may be approaching the end of their life, their carers and other people important to them\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review A: identifying people who may be entering the last year of life\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review H: carer support services\n\nEvidence review I: information sharing.\n\nLoading. Please wait.\n\n# Assessing holistic needs\n\nIf it is thought that an adult is approaching the end of their life, carry out an initial holistic needs assessment with the person and document this. This will enable the right support to be provided when it is needed.\n\nPeople managing services should ensure that health and social care practitioners caring for adults approaching the end of their life have the training and skills to sensitively carry out holistic needs assessments.\n\nHealthcare practitioners should be aware of the requirement to offer a carer's needs assessment in line with the Care Act 2014 and a young carer's needs assessment in line with the Children and Families Act 2014.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on assessing holistic needs\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review B: timing of referral to palliative care services\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review H: carer support services.\n\nLoading. Please wait.\n\n# Supporting carers\n\nPeople managing and delivering services should think about what practical and emotional support can be provided to carers of adults approaching the end of their life and review this when needed. For more information, see the NICE guideline on supporting adult carers.\n\nWhen carers' needs are identified, take into account that the support needs of a young carer are likely to be different to those of an older carer.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on supporting carers\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review H: carer support services\n\nEvidence review G: involving carers.\n\nLoading. Please wait.\n\n# Providing information\n\nFor advice on communication, information and shared decision making, see the NICE guidelines on patient experience in adult NHS services, people's experience in adult social care services and shared decision making. Apply the same principles for communication and information giving to carers of all ages.\n\nFor people with learning disabilities, use this guideline alongside the recommendations on end of life care in the NICE guideline on care and support of people growing older with learning disabilities.\n\nSupport and enable adults approaching the end of their life to actively participate in decision making by having in place:\n\nprocesses to establish the amount and type of information they would prefer\n\nsystems to provide information in a way that meets their communication needs and preferences, for example, how it is given (verbally, on paper, by text, email, or other assistive technologies) and provision of professional interpreters\n\narrangements to review and anticipate their information needs and preferences as circumstances change.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on providing information\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review G: involving carers.\n\nLoading. Please wait.\n\n# Reviewing current treatment\n\nFor advice on reducing treatment burden and reviewing medicines and other treatments, see the NICE guidelines on multimorbidity and medicines optimisation.\n\nDevelop policies for reviewing treatment within all specialties to meet the changing needs of adults approaching the end of their life and to reduce the burden of unhelpful treatments. Different services should work together and share information about treatment reviews (see section\xa01.10 on providing end of life care coordination).\n\nThe lead healthcare professional should ensure that the person approaching the end of their life is offered opportunities to discuss their existing treatment plans with a healthcare professional. The person's carers and other people important to them should be included in the discussions, if the person agrees. This should include discussing:\n\nany changes that could optimise care and improve their quality of life (for example, reducing the number of unnecessary routine appointments, organising appointments close to the person's home, starting new treatments or stopping unhelpful treatments)\n\ncommunity support available to help with their treatment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on reviewing current treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review D: care coordinator and lead healthcare professional\n\nEvidence review J: service provision.\n\nLoading. Please wait.\n\n# Advance care planning\n\nService providers should develop policies to ensure that advance care planning is offered to adults who are approaching the end of their life. Policies should take into account under-served and vulnerable groups.\n\nService providers should develop processes to support carers and other people important to the person to be involved in advance care planning, if the person approaching the end of their life agrees.\n\nService providers should have systems in place to ensure that adults approaching the end of their life each have a copy of their advance care plan available in their place of residence or with them if admitted to a hospital, care home or hospice.\n\nService providers should develop processes to take into account the views of carers and other people important to the person if the person approaching the end of their life lacks capacity to make decisions in line with the Mental Capacity Act 2005.\n\nFor advice on supporting decision making, assessing mental capacity and advance care planning, see the NICE guideline on decision-making and mental capacity.\n\nFor advice on starting advance care planning in adults who:\n\nare at risk of a medical emergency, see the NICE guideline on emergency and acute medical care in over\xa016s\n\nhave motor neurone disease, see the NICE guideline on motor neurone disease\n\nhave multimorbidity, see the NICE guideline on multimorbidity\n\nhave dementia, see the NICE guideline on dementia\n\nhave learning disabilities, see the NICE guideline on care and support of people growing older with learning disabilities.A NICE guideline on social work interventions for adults with complex needs is being developed, with publication expected in January 2022.\n\nFor advice on organ donation, see the NICE guideline on organ donation for transplantation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on advance care planning\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review F: advance care planning\n\nEvidence review G: involving carers\n\nEvidence review I: information sharing.\n\nLoading. Please wait.\n\n# Reviewing needs\n\nDevelop systems enabling adults approaching the end of their life to have:\n\nregular discussions with a member of their care team about changes in their health and social care needs and preferences\n\nrepeat assessments of their holistic needs and reviews of their advance care plan when needed, for example at key transition points, such as at discharge from hospital or when the goals of treatment have changed.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on reviewing needs\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review G: involving carers\n\nEvidence review J: service provision.\n\nLoading. Please wait.\n\n# Communicating and sharing information between services\n\nAdults approaching the end of their life should have care that is coordinated between health and social care practitioners within and across different services and organisations, to ensure good communication and a shared understanding of the person's needs and care.\n\nUse electronic information-sharing systems that are accessible between different services and organisations to enable information to be reviewed, updated and shared efficiently within and between multipractitioner teams, across different services and organisations.\n\nFor specific advice on coordinating end of life support in residential settings, see the NICE guideline on people's experience in adult social care services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on communicating and sharing information between services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: information sharing.\n\nLoading. Please wait.\n\n# Providing multipractitioner care\n\nProvide access to the expertise of highly skilled health and social care practitioners, when needed, for adults approaching the end of their life, their carers and other people important to them. They should have the skills to:\n\nmeet complex care and support needs\n\nanticipate and prevent or minimise crises\n\nsupport people's preferences for where they would like to be cared for and die, if possible.\n\nHealth and social care practitioners should have the skills to provide care for adults approaching the end of their life who need support in the following areas:\n\ndisease-specific, including symptom management, hydration and nutrition, and access to medication\n\nphysical\n\npsychological\n\nsocial, including support and advice (for example, signposting advice on benefits, finance and third-sector, local or national support services)\n\nsupport with activities of daily living, including access to equipment and rehabilitation services\n\npastoral, religious and spiritual\n\ncultural.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on providing multipractitioner care\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review E: multiprofessional team\n\nEvidence review L: additional services and inappropriate admissions.\n\nLoading. Please wait.\n\n# Providing end of life care coordination\n\nProvide end of life care coordination for adults who are approaching the end of their life through:\n\ncommunity and primary care services for adults, provided by the person's GP or another health or social care practitioner in the primary or community care team\n\nhospital services for adults whose treatment is based in secondary or tertiary care, provided by health and social care practitioners based in hospices or disease-specific specialists in hospitals.\n\nFor people in under-served and vulnerable groups who are approaching the end of their life, provide additional support that takes into account the challenges of coordinating care for people in these groups.\n\nEnsure that there is good communication between health and social care practitioners coordinating community-based care and health and social care practitioners coordinating hospital care.\n\nHealth and social care practitioners providing end of life care coordination should:\n\noffer information to the person approaching the end of their life, their carers and others important to them, about who the multipractitioner team members are (including the lead healthcare professionals in each setting responsible for their care), the roles of the team members and how services are accessed\n\nensure that holistic needs assessments are offered, and the person's wishes and needs are discussed and acted on whenever possible\n\nensure that care is coordinated across and between the multipractitioner teams and between care settings\n\nensure that regular discussions and reviews of care, holistic needs and advance care plans are offered\n\nshare information about the person's care between members of the multipractitioner teams.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on providing end of life care coordination\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review D: care coordinator and lead healthcare professional\n\nEvidence review G: involving carers.\n\nLoading. Please wait.\n\n# Transferring people between care settings\n\nFor advice on transitions between care settings for adults with social care needs, see the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.\n\nDevelop systems to support smooth and rapid transfer between care settings for adults approaching the end of their life. For example, organise services so that:\n\nambulances or other transport services can move people between care settings without delay and in an efficient and compassionate way\n\ncare packages and equipment are available to enable adults approaching the end of their life to move to the place where they would like to be cared for and die.\n\nDevelop an agreed transfer policy between ambulance service providers and acute care providers to enable the rapid transfer of adults approaching the end of their life to the place where they would like to be cared for and die whenever rapid transfer is a priority.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on transferring people between care settings\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review M: optimal transition and facilitating discharge.\n\nLoading. Please wait.\n\n# Providing out-of-hours care\n\nAdults approaching the end of their life, their carers and other people important to them should have access to:\n\na healthcare professional available 24\xa0hours a day, 7\xa0days a week, who can access the person's records and advance care plan, and make informed decisions about changes to care\n\nan out-of-hours end of life care advice line\n\nan out-of-hours pharmacy service that has access to medicines for symptom management in adults approaching the end of their life.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on providing out-of-hours care\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review G: involving carers\n\nEvidence review K: out-of-hours services.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Advance care planning\n\nAdvance care planning is a voluntary process of discussion about future care between an individual and their care providers, irrespective of discipline.\n\nAn advance care planning discussion might include:\n\nthe individual's concerns and wishes\n\ntheir important values or personal goals for care\n\ntheir understanding about their illness and prognosis\n\ntheir preferences and wishes for types of care or treatment that may be beneficial in the future and the availability of these.\n\nAdvance care planning is one part of the process of personalised care and support planning.\n\n## Approaching the end of life\n\nPeople in the final weeks and months of life, although for people with some conditions, this could be months or years.\n\nIt includes people with:\n\nadvanced, progressive, incurable conditions\n\ngeneral frailty and coexisting conditions that mean they are at increased risk of dying within the next 12\xa0months\n\nexisting conditions if they are at risk of dying from a sudden acute crisis in their condition\n\nlife-threatening acute conditions caused by sudden catastrophic events.\n\n## Carers\n\nA carer is someone who helps another person, usually a relative, partner or friend, in their day-to-day life. This term does not refer to someone who provides care professionally or through a voluntary organisation. A young carer is aged under\xa018.\n\n## People managing services\n\nCommissioners, planners and service providers responsible for overseeing local health and social care provision and accountable for public service outcomes.\n\n## Holistic needs assessment\n\nAn assessment that considers all aspects of a person's wellbeing, their spiritual and health and social care needs. Undertaking a holistic needs assessment ensures that the person's concerns and problems are identified so that support can be provided to address them. There are validated tools that can be used to support the assessment process.\n\n## Lead healthcare professional\n\nA lead healthcare professional is a member of the multipractitioner team who assumes overall clinical responsibility for the delivery of care to a patient. They are usually a senior doctor or senior nurse.\n\n## Multipractitioner team\n\nA multipractitioner team is a group of practitioners from different clinical professions, disciplines, organisations and agencies who together make decisions on the recommended treatment for individual patients.\n\n## People important to adults approaching the end of their life\n\nThese may include family members and anyone else who the person regards as significant, such as a partner or close friend. It may be someone who the person wants involved in discussions about their care. It is important that health and social care practitioners understand that assumptions should not be made when asking about the people important to the person, for example, assuming everyone is in a heterosexual relationship.\n\n## Personalised care and support planning\n\nPersonalised care and support planning is a series of facilitated conversations in which the person, or those who know them well, actively participates to explore the management of their health and wellbeing within the context of their whole life and family situation.\n\nPersonalised care and support planning is key for people receiving health and social care services. It is an essential tool to integrate the person's experience of all the services they access so they have one joined-up plan that covers their health and wellbeing needs.\n\nPersonalised care and support planning is not to be confused with personalised medicine. The latter is the approach to tailor treatments to people's individual health needs based on their biological risk factors and predictors of response to treatments.\n\n## Service providers\n\nAll organisations (including primary, secondary, tertiary, ambulance and hospice services) that provide NHS services for people approaching the end of their life.\n\n## Shared decision making\n\nShared decision making is when health and social care professionals and patients work together. This puts people at the centre of decisions about their own treatment and care.\xa0During shared decision making, it's important that:\n\ncare or treatment options are fully explored, along with their risks and benefits\n\ndifferent choices available to the patient are discussed\n\na decision is reached together with a health and social care professional.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Early review of service provision and referral to additional specialist palliative care services\n\nDoes early review of service provision and referral to additional specialist palliative care services improve outcomes for adults with progressive non-cancer disease thought to be approaching the end of their life?\n\n## Why this is important\n\nThere is a body of research into the optimal timing of referral to specialist palliative care in cancer patients, which generally points to earlier referral leading to better patient-reported outcomes. The committee noted that similar evidence is very limited for patients with a non-cancer diagnosis, for example in patients with progressive organ failure, such as advanced heart failure, or patients with life-limiting neurological disease, such as motor neurone disease or dementia. Such patients are typically referred very late to specialist palliative care, if at all. Further research would compare outcomes for people having a combination of early identification and specialist palliative care input with those for people having usual care.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on reviewing current treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review D: care coordinator and lead healthcare professional\n\nEvidence review J: service provision.\n\nLoading. Please wait.\n\n## Electronic registers and information-sharing databases\n\nWhich of the electronic information-sharing systems perform best for the care of people approaching the end of their life?\n\n## Why this is important\n\nThe guideline committee made recommendations on sharing information about people who are approaching the end of their life with other members of the multipractitioner teams involved in their care. The committee was aware that in the past, most information recording and sharing was done using paper-based systems, with information shared between teams and care settings using telephone, fax and emails. However, fully electronic databases and information-sharing systems using internet protocols are becoming more established in the NHS and also in hospice services. NHS Digital has a stated aim to develop joined-up digital systems in the health service. The committee looked for research about which systems performed best and were reliable for sharing confidential information but was unable to find it. The committee were aware of deficiencies in the current systems. Studies conducted in other countries using electronic systems were not applicable to the NHS.\n\nIt is therefore recommended that research should be done on the systems that are currently available in the UK. The purpose of this research would be to inform healthcare planners and service providers on the most efficient, reliable, secure, confidential and cost-effective systems to be used for sharing information about people approaching the end of their life across a range of care settings.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on communicating and sharing information between services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: information sharing.\n\nLoading. Please wait.\n\n## Frequency of community-based reviews\n\nWhat are the benefits of planned, regular community-based reviews compared with as-required review of non-cancer patients approaching the end of their life?\n\n## Why this is important\n\nThere is little relevant research evidence for the optimum frequency of review of people with progressive non-cancer conditions who may be approaching the end of their life. Many of the studies attempted in this area have been conducted in other countries where the healthcare systems are very different from the UK. 'Usual care' for non-cancer conditions tends to provide demand-led review by specialists and primary care staff. This may be appropriate if people are well supported at home or in care settings. However, it could lead to unrecognised deterioration in symptoms or functioning, and place people at risk of crises and unplanned hospital admissions if they are living alone or have little professional support. A policy of regular, planned reviews of patients in their place of residence could improve symptom management, maintain a better level of functioning, prevent crises and may pre-empt emergency hospital visits and admission. However, there is a risk that they could impose unnecessary burdens on the patient, family and the healthcare system.\n\nThis research would study non-cancer patients receiving usual care (with or without any concurrent specialist level care), and assess their outcomes against different levels of frequency of planned specialist reviews in the community.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on reviewing current treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review D: care coordinator and lead healthcare professional\n\nEvidence review J: service provision.\n\nLoading. Please wait.\n\n## Discharge and transfer from hospital\n\nWhat is the optimal way of discharging people approaching the end of their life from hospitals back to their place of residence?\n\n## Why this is important\n\nThe committee found there was very little evidence on discharging adults approaching the end of their life and transferring them between settings. One of the most important transfers is from hospital to home or the person's place of residence, such as a nursing home, especially when death is imminent. Such discharges are often delayed because of medical or nursing problems, or by unmet social care needs. However, some of these problems could be managed well in the community with key equipment or medication and improved social care. The consequences of delayed discharge can be distressing to the person approaching the end of life and their carers and important people. It could mean people staying and dying in inappropriate care settings, such as an acute hospital ward, when it is not their preferred place to be cared for and die. Delayed discharge would also be unnecessary from a medical or nursing perspective.\n\nKey factors in ensuring prompt discharge with care and compassion include clear communication and processes between services providing care in the 2\xa0settings and also those providing transport.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on transferring people between care settings\xa0.\n\nFull details of the evidence and the committee's discussion are in the following evidence reviews:\n\nEvidence review C: barriers to accessing end of life care services\n\nEvidence review M: optimal transition and facilitating discharge.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect services. They link to details of the evidence and a full description of the committee's discussion.\n\n# Identifying adults who may be approaching the end of their life, their carers and people important to them\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendations\n\nTalking to people about dying can be difficult and there is often a reluctance to start conversations about preparing for the end of life. Although the evidence was limited, the committee agreed that identifying adults who may be approaching the end of their life supports health and social care practitioners to start discussions about advance care planning. This should ensure that the person near the end of life is provided with the support that they may need now or later to help them stay where they would like to be cared for and die. It also gives them time to consider and re‑evaluate their needs with their health and social care practitioners.\n\nThe committee wanted to emphasise the importance of identifying people systematically. There are already some systems in use for identifying people approaching the end of their life, which are given as examples in the recommendations. However, there were no studies comparing and evaluating their effectiveness in service delivery so the committee could not recommend a particular system.\n\nThe committee noted the importance of identifying people who are at particular risk of missing out on access to end of life care, including people living alone without support, people with learning difficulties and people who are homeless.\n\nThe committee agreed that using a shared coordination of care system would improve coordination of care between all health and social care practitioners involved in a person's care, and in turn improve service delivery.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current good practice available in some services, but there is variation in how and when people are identified across different patient groups and settings. The recommendations are expected to increase the number of people identified. The net impact on services is uncertain. Some investment will be required to establish systems to systematically identify patients in some areas. However, this will ensure that people approaching the end of their life will receive the appropriate care, and their carers will receive support, which will help to avoid unnecessary hospital admissions.\n\nReturn to recommendations\n\n# Assessing holistic needs\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nThe evidence reviewed showed that early assessment was beneficial. However, the studies used different definitions for early and late assessment in various settings and so the evidence wasn't clear enough to recommend an optimal timing for an initial assessment. The committee agreed that an assessment with the person should be carried out to enable the right support to be provided when it is needed.\n\nThe evidence showed that carers' quality of life was improved and the burden of care reduced when carers are supported. The committee agreed that assessment of carers' needs is important to ensure they are supported to help care for the person approaching the end of their life. However, these assessments are often overlooked so the recommendation reminds healthcare practitioners that carers should be offered an assessment in line with legislation, and they should refer to social care practitioners accordingly.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current good practice available in some services, but there is some variation, for example, in ensuring access to carers' needs assessments.\n\nThe assessment of a person's needs will result in appropriate care being delivered. This may reduce some resource use when unnecessary interventions are stopped, but may increase the use of other resources if interventions for end of life care, such as symptom management or aids for daily living, are needed.\n\nThe number of carers being assessed may increase, but this should result in better support to help the person stay where they would like to be cared for and die, and may reduce the number of attendances and admissions to hospitals.\n\nReturn to recommendations\n\n# Supporting carers\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nThe information and support needs of carers will vary and the evidence did not identify one particular way of supporting carers. However, it did show that carers have better outcomes, such as maintaining quality of life and reduced carer burden, when supported. The committee agreed that health and social care providers should go beyond the strict statutory requirement for carers' assessments to ensure that the needs of carers are considered (including respite and psychological support), and that the varied needs of different carer groups are taken into account.\n\n## How the recommendations might affect services\n\nIncreased investment may be needed for increased numbers of assessments and increased support accessed. This approach should result in better support for adults approaching the end of their life to stay where they would like to be cared for and die. The impact on hospital admission is uncertain. Increased support may reduce the number of hospital admissions or it may result in increased (and perhaps more appropriate) admissions.\n\nTaking into account the individual support needs of young and older carers should reduce the physical and emotional strains that are often experienced by carers. This may help reduce the need for, and therefore costs of, interventions for physical and mental health problems common in these groups of carers.\n\nReturn to recommendations\n\n# Providing information\n\nRecommendations 1.4.1 to 1.4.3\n\n## Why the committee made the recommendations\n\nThe evidence showed that a lack of knowledge about end of life care and the support and services available, and poor communication between adults approaching the end of their life and health and social care practitioners, are barriers to understanding treatment options and confidently making decisions about care.\n\nBased on this evidence and the committee's experience, the recommendations reflect the importance of systematically seeking and acting on the information needs and preferences of people approaching the end of their life, their carers and other people important to them. The committee also acknowledged that people's information needs will vary and change over time, so regular reviews are needed and referral to specialist communication support could be needed.\n\nThe committee also noted that service providers across the NHS and adult social care system should follow the NHS England Accessible Information Standard to ensure that the information and communication support needs of disabled people are met.\n\n## How the recommendations might affect services\n\nThe recommendations reflect good current practice available in some services, but there is variation nationally.\n\nImproving understanding and communication will benefit services, ensuring that people make informed decisions and receive the appropriate care.\n\nReturn to recommendations\n\n# Reviewing current treatment\n\nRecommendations 1.5.1 to 1.5.3\n\n## Why the committee made the recommendations\n\nThere was no evidence identified on how and when to carry out an initial review of service provision for people approaching the end of their life. However, the committee agreed that it was important for all lead healthcare professionals responsible for the person's care to review and discuss the person's current care needs with them. In particular, they discussed identifying services that may be needed or could be stopped, and acknowledged that the involvement of too many services can be as problematic as too few.\n\nThe committee also agreed that adapting care for treating conditions in adults needing end of life care would help to ensure that the right care is provided at the right time. Policies within different specialties would support this, and the committee were aware that these have been developed for some specialist areas, such as diabetes (see Diabetes UK End of life diabetes care: clinical care recommendations) and for neurological conditions. To encourage more research in this area, the committee developed research recommendations on early review of service provision and referral to additional specialist palliative care services and frequency of community-based reviews.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current good practice available in some services, but there is variation nationally. Reviewing current treatment of people approaching the end of their life means appropriate care will be given and may reduce the burden of unnecessary appointments and treatments.\n\nReturn to recommendations\n\n# Advance care planning\n\nRecommendations 1.6.1 to 1.6.7\n\n## Why the committee made the recommendations\n\nThe evidence for advance care planning was unclear, although it did show some benefit in supporting people to stay where they would like to be cared for and die. The committee acknowledged that the implementation of advance care planning is complex and agreed that there was not enough evidence to recommend a specific service model for advance care planning. However, the committee agreed that advance care planning helps people to achieve the care and support they want, and that policies should be in place to provide it to adults approaching the end of their life. They noted that some under-served and vulnerable groups (for example, people who are homeless and people in prison) may not have opportunities to engage in advance care planning, and that provision for these groups should be highlighted. The committee also felt that advance care planning should not be restricted to planning for possible future loss of mental capacity.\n\nThe evidence on barriers to care described how carers felt a lack of control and a lack of trust in health and social care practitioners, resulting in scepticism about the benefits of advance care planning. The committee agreed that better communication and processes to involve carers in advance care planning would help to address this.\n\nEvidence suggested that individual patient-held records did not improve patient satisfaction with communication. However, the committee agreed that a copy of the advance care plan available in the person's home may be useful for health and social care practitioners to refer to in emergency situations when access to other information is unavailable.\n\n## How the recommendations might affect services\n\nThe recommendations reflect good current practice available in some services, but there is variation in the timing and availability of advance care planning in different areas and for different patient groups.\n\nAdvance care planning supports adults approaching the end of their life to be cared for and die in their preferred place, which is often in the community. This may reduce the need for hospital services but increase demand for services in the community. The advance care plan documents the person's current, future and emergency needs, improving coordination of care across the multipractitioner team and should help avoid unnecessary hospital attendances and admissions.\n\nReturn to recommendations\n\n# Reviewing needs\n\nRecommendation 1.7.1\n\n## Why the committee made the recommendation\n\nThere was no evidence to indicate the best time to undertake reviews of service provision for people approaching the end of their life. Every person's journey is individual, reflecting how their health can fluctuate unpredictably, with periods of deterioration, stabilisation and sometimes improvement. In addition, their psychological, social, financial and other support needs will vary, not always in step with the physical illness. The committee therefore agreed that regular reviews of care are important when people are approaching the end of their life to identify when changes in care or other forms of support are needed, for example, when the goals of disease-modifying treatment change.\n\nThe committee recognised that regular discussions with the care team would help to identify changes in the person's needs and preferences. They also agreed that repeating holistic needs assessments and reviews of advance care plans would ensure that people continue to receive the right care and support.\n\n## How the recommendation might affect services\n\nThe recommendation reflects current good practice available in some services, but there is variation nationally. Reviewing the ongoing care of people approaching the end of their life means that appropriate care will be given and may reduce some resource use when unnecessary interventions are stopped.\n\nReturn to recommendations\n\n# Communicating and sharing information between services\n\nRecommendations 1.8.1 to 1.8.3\n\n## Why the committee made the recommendations\n\nThe committee agreed that electronic information systems should be used because they would be the most effective and efficient method to share information. However, the evidence was too limited for the committee to recommend a particular system. The committee developed a research recommendation on electronic registers and information-sharing databases to encourage further research in this area.\n\nThe committee did not have the evidence to recommend what information should be shared, but agreed that everyone involved in a person's care should have access to relevant health and social care information, including the person's care plan.\n\nThe recommendations are underpinned by the Health and Social Care (Safety and Quality) Act 2015, which introduced a legal duty requiring health and social care bodies to share information when this will facilitate care.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current good practice available in some services. The use of electronic-based systems to coordinate the care of people approaching the end of their life has been increasing across England and Wales. The committee agreed that there is variation in the implementation of these systems across the NHS and investment would be needed in areas without systems in place. The committee considered that electronic systems would result in more efficient, well-coordinated care through better access to information, reducing duplication and improving communication.\n\nReturn to recommendations\n\n# Providing multipractitioner care\n\nRecommendations 1.9.1 and 1.9.2\n\n## Why the committee made the recommendations\n\nThe evidence showed that a multipractitioner approach to care was favourable and had a positive impact on supporting adults to stay where they would like to be cared for and die. The committee agreed that the skills and expertise of many specialties and disciplines is needed to meet people's varied and changing needs. However, there is no clear evidence on the ideal composition of a multipractitioner team and so instead of identifying specific roles, the committee set out the type of support people may need access to as they approach the end of their life.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current good practice available in some services, but there is variation nationally. Care that meets the person's identified needs and is delivered by health and social care practitioners with the relevant skills may reduce costs by minimising crises and helping to avoid emergency unplanned care and unnecessary hospital attendances and admissions. However, this will require some investment upstream.\n\nReturn to recommendations\n\n# Providing end of life care coordination\n\nRecommendations 1.10.1 to 1.10.4\n\n## Why the committee made the recommendations\n\nThe evidence on identifying barriers to accessing services showed that continuity and coordination of care are often identified as being unsatisfactory for adults approaching the end of their life and their carers. The evidence also highlighted a lack of information and poor communication with carers, which could be improved with better coordination of care.\n\nThe committee agreed that good coordination of care and effective communication systems are especially important when people have contact with multiple services and organisations and for under-served and vulnerable groups.\n\nThe committee also agreed that good coordination of care should include systems to review appointments and home visits, both to support efficiency of care and also to avoid overwhelming the person with multiple visits from different services.\n\nThe evidence showed that having someone to organise care was of some benefit, particularly in reducing unscheduled and emergency hospital visits and admissions. However, it was not clear if this should be a specific role or who should do this. Therefore, the committee listed the key principles within end of life care coordination that community, hospital and hospice services could provide in collaboration rather than specifying who should take on this role and where it should be located.\n\n## How the recommendations might affect services\n\nThe recommendation reflects current good practice available in some services, but there is variation nationally. In areas where good coordination of care is lacking, it should result in more efficient service provision and help to minimise crises, and support people to stay where they would like to be cared for and die. Good care coordination should also reduce the use of unnecessary services and avoid duplication of care.\n\nCare coordination by health and social care professionals is taking place currently in the NHS but the committee was uncertain how extensively it is practised. Additional resources may be needed to coordinate care across services and deliver the key roles of end of life care coordination, but it should help to reduce the use of unnecessary services and avoid duplication of care.\n\nReturn to recommendations\n\n# Transferring people between care settings\n\nRecommendations 1.11.1 to 1.11.3\n\n## Why the committee made the recommendations\n\nThere was very little evidence on transferring adults between settings when they are approaching the end of their life. However, the committee agreed that the availability of efficient and timely transfer is important to ensure that people can be moved quickly, when needed, to where they would like to be cared for and die.\n\nThe committee also discussed the consequences of delayed transfer, which can result in people staying in inappropriate care settings or being cared for and dying in settings other than where they would like to be cared for and die. They also discussed how clear communication and processes between services providing care and those providing transport can help to avoid delays and enable efficient transfer.\n\nThe committee developed recommendations to reinforce good practice and support the advice in NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs. The committee also noted that more research is needed to determine the optimal service configuration for transfer of people with different conditions and at different stages as people approach the end of their life (see the research recommendation on discharge and transfer from hospital).\n\nThe committee also agreed that poor and slow access to care packages and equipment can delay transfer between settings and prevent people from being cared for and dying in their preferred place, so highlighted the need to organise this support to enable timely transfer.\n\n## How the recommendations might affect services\n\nEffective and timely transfer is likely to reduce the number of people dying in hospital, because most people wish to die in a community setting (for example, their own home or care home, or in a hospice). This may reduce the need for hospital services but increase demand for services in the community.\n\nReturn to recommendations\n\n# Providing out-of-hours care\n\nRecommendation 1.12.1\n\n## Why the committee made the recommendation\n\nThe evidence for providing an out-of-hours service showed some benefit in supporting people to stay where they would like to be cared for and die. The committee agreed that the services described in the studies reflected existing out-of-hours services in areas of good practice. However, there was evidence that elements of service provision important for people approaching the end of their life may be variable or lacking, so these were the focus for the recommendation.\n\nThe evidence supported the committee's experience that access to healthcare advice is critical in providing reassurance and ensuring people have access to the services they need. The committee agreed that a healthcare practitioner should be available at all times to provide this, and that they would need access to the person's records and advance care plan, preferably through a shared electronic information system, to enable them to make informed decisions about care.\n\nEvidence exploring the views of people approaching the end of their life and their carers highlighted the importance of having access to advice from someone who has expertise and understands their needs. The committee agreed that an out-of-hours end of life care advice line could help to provide this support.\n\nAnother common concern for people at the end of life and their carers is the limited provision of pharmacy services outside traditional working hours. The committee discussed how a lack of access to medicines that may be needed quickly can result in people being transferred and admitted to hospital.\n\nAn analysis of the evidence for providing a dedicated out-of-hours end of life care advice line and an out-of-hours pharmacy service showed that the costs of providing these services could be balanced by the savings incurred by a relatively small reduction in emergency admissions and length of stay of admissions, and an increase in the number of people remaining in the community. The committee noted that the net resource impact of caring for people in the community is uncertain. On balance, they felt that providing out-of-hours care was a good use of resources and key to meeting the needs of patients.\n\n## How the recommendation might affect services\n\nCurrent provision of out-of-hours services is variable nationally, but the recommendation reflects current good practice in some areas. The committee are uncertain how extensively it is practised. Where services such as an out-of-hours pharmacy service or dedicated end of life care advice line are lacking, increased resources may be needed to set up these services. However, this is likely to reduce the number of people being transferred to hospital for care that could be given at home. This may reduce the need for hospital services but increase demand for services in the community.\n\nReturn to recommendations", 'Finding more information and resources': "You can see everything NICE says on end of life care for adults in NICE's interactive flowchart on end of life care for people with life-limiting conditions.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on end of life care.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}
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https://www.nice.org.uk/guidance/ng142
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This guideline covers organising and delivering end of life care services, which provide care and support in the final weeks and months of life (or for some conditions, years), and the planning and preparation for this. It aims to ensure that people have access to the care that they want and need in all care settings. It also includes advice on services for carers.
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a84c5ec7eb5c8a5aeb6513f7246647aec795bd33
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nice
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Lanadelumab for preventing recurrent attacks of hereditary angioedema
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Lanadelumab for preventing recurrent attacks of hereditary angioedema
Evidence-based recommendations on lanadelumab (Takhzyro) for preventing recurrent attacks of hereditary angioedema in people aged 12 and over.
# Recommendations
Lanadelumab is recommended as an option for preventing recurrent attacks of hereditary angioedema in people aged 12 and older, only if:
they are eligible for preventive C1-esterase inhibitor (C1-INH) treatment in line with NHS England's commissioning policy, that is, they are having 2 or more clinically significant attacks (as defined in the policy) per week over 8 weeks despite oral preventive therapy, or oral therapy is contraindicated or not tolerated
the lowest dosing frequency of lanadelumab is used in line with the summary of product characteristics, that is, when the condition is in a stable, attack-free phase (see section 2) and
the company provides lanadelumab according to the commercial arrangement.
This recommendation is not intended to affect treatment with lanadelumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by the clinician and the young person or the young person's parents or carers.
Why the committee made these recommendations
People with hereditary angioedema have attacks that cause severe swelling of various parts of the body. Despite long-term oral preventive therapy (such as attenuated androgens) and C1-INH treatments, some people still have frequent severe attacks.
Lanadelumab's marketing authorisation is broad and covers prevention of recurrent attacks of hereditary angioedema. But there is no trial evidence comparing lanadelumab with long-term oral preventive therapy so it cannot be used instead of this therapy. Therefore the company wants lanadelumab to be used only for people who are eligible for long-term preventive C1-INH treatments in line with NHS England's commissioning policy. So C1-INH treatments are the most appropriate comparator for the company's proposed positioning.
Evidence from a randomised controlled trial suggests that people having lanadelumab have fewer hereditary angioedema attacks than with placebo. There are data indirectly comparing lanadelumab with C1-INHs.
Lanadelumab does not meet NICE's criteria to be considered a life-extending treatment at the end of life. In line with its summary of product characteristics, a lower dosing frequency of lanadelumab (once every 4 weeks) can be used if the condition is in a stable attack-free phase. But there is no clinical trial evidence on switching to this lower dosing frequency and the proportion of patients assumed to switch has a large impact on the cost-effectiveness estimates. Although all cost-effectiveness estimates for lanadelumab compared with C1-INHs are uncertain, most are within the range NICE normally considers an acceptable use of NHS resources. Therefore, lanadelumab is recommended only for people who are eligible for long-term preventive C1-INH treatments in line with NHS England's commissioning policy. The lowest dosing frequency of lanadelumab should be used in line with the summary of product characteristics, when the condition is in a stable attack-free phase.# Information about lanadelumab
Marketing authorisation indication
Lanadelumab (Takhzyro, Shire) is indicated for 'routine prevention of recurrent attacks of hereditary angioedema in patients aged 12 years and older'.
Dosage in the marketing authorisation
The recommended starting dose is 300 mg lanadelumab every 2 weeks. The summary of product of characteristics states that in patients who are stably attack-free on treatment, a dose reduction of 300 mg lanadelumab every 4 weeks may be considered, especially in patients with low weight. It is administered as a subcutaneous injection.
Price
The list price for lanadelumab is £12,420 per 300-mg vial.
The company has a commercial arrangement. This makes lanadelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Shire (now part of Takeda), a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that none of the key issues identified in the technical report were resolved during the technical engagement stage. It recognised that there were areas of uncertainty associated with the analyses presented (see technical report, issues 1 to 4), and took these into account in its decision making.
# New treatment option
## There is an unmet need for more effective treatment options
Hereditary angioedema is a rare genetic disorder. It usually develops in childhood or early adulthood and is associated with the build-up of excessive fluid (oedema) causing localised swelling. The swelling may happen in the mouth, gut or airway and can cause severe pain. Swelling of the airways can be life threatening. The patient experts described how swelling can enlarge quickly (30 to 40 minutes) and can take over 2 days to resolve. The patient experts explained that this can have a substantial impact on quality of life, particularly because attacks are often difficult to predict. The clinical experts explained that attacks can be triggered by anxiety and stress, for example caused by exams, surgery or dental treatment as well as positive life events such as weddings and holidays. The clinical experts advised that in clinical practice, people who have regular attacks and those who are at risk of severe swelling would benefit from long-term preventive treatment. Long-term preventive treatment with an intravenous C1 esterase inhibitor (C1-INH) is currently only available for a small subgroup of people meeting the criteria set out in NHS England's commissioning policy (see section 3.2). They also emphasised that long-term preventive oral treatment, such as attenuated androgens, is used earlier in the treatment pathway but is associated with side effects and has limited effectiveness (see section 3.3). The patient and clinical experts suggested that being able to control symptoms in the long term may reduce anxiety and therefore reduce attacks. The committee concluded that there is an unmet need for more effective treatment options.
# Treatment pathway and comparators
## The company's proposed positioning of lanadelumab, for people currently eligible for long-term preventive C1-INH treatment, is appropriate
After clarification, the company positioned lanadelumab for the population currently eligible for long-term preventive C1-INH treatment, in line with NHS England's commissioning policy. The policy includes people with 2 or more clinically significant attacks (as defined in the policy) per week over 8 weeks, despite long-term oral preventive treatment, or if long-term oral preventive treatment is not appropriate. The committee understood that this is a narrower population than covered by the full marketing authorisation for lanadelumab (indicated for routine prevention of recurrent attacks of hereditary angioedema in people aged 12 years and older). The clinical experts explained that the criteria used in NHS England's commissioning policy to identify people eligible for long-term preventive C1-INH treatment were well defined and used in clinical practice. The committee was aware that similar criteria were used in the company's subgroup analysis from HELP-03. This included people with 8 or more attacks over the previous 4 weeks at baseline (see section 3.4). The committee accepted the company's positioning of lanadelumab and agreed to take this into account when making its recommendations.
## C1-INHs are the most appropriate comparator for the company's proposed positioning of lanadelumab
The company considered C1-INHs to be the only relevant comparator because it had positioned lanadelumab for people who are currently eligible for long-term preventive C1-INH treatment (see section 3.2). The company used a blended C1-INH comparator that included Berinert and Cinryze because, according to clinical advice, these were the most commonly used C1-INH treatments. The clinical experts explained that the use of individual C1-INHs varied between different treatment centres. But they agreed that Berinert and Cinryze were the most commonly used, with a third C1-INH treatment, Ruconest, being used very rarely in practice. The committee was aware that Berinert is only licensed to treat acute attacks, but the clinical experts advised that it is also used in clinical practice as a long-term preventive treatment. The clinical experts clarified that acute treatment with a C1-INH can be similar to long-term preventive C1-INH treatment (as described in NHS England's commissioning policy) if it is offered frequently (for example, several times per week). After clinical experts explained during the technical engagement stage that lanadelumab could be used earlier in the treatment pathway than a C1-INH, the committee considered analyses comparing lanadelumab with long-term preventive oral treatment, which is used earlier in the treatment pathway (the results are confidential and cannot be reported here). The committee also understood that there was no trial evidence for oral therapy, such as attenuated androgens, and therefore agreed it was not an appropriate comparator for the company's proposed positioning of lanadelumab. The clinical experts explained that most people who are eligible for a long-term preventive C1-INH would choose to have it. Those choosing not to have it would still have acute treatment during an attack. The committee concluded that C1-INHs are the only comparator for the company's proposed positioning of lanadelumab.
# Clinical evidence
## Results from the full HELP-03 population and the subgroup having 8 or more attacks are relevant for decision making, but the latter are less robust
The clinical evidence for lanadelumab came from HELP-03, a phase III randomised controlled trial. It compared 3 dose schedules of lanadelumab with placebo in 125 people aged 12 or older with type I or II hereditary angioedema who had had at least 1 attack in the last 4 weeks. The committee understood that the frequency of attacks in the trial inclusion criteria was lower than the company's proposed positioning, which specified at least 2 or more attacks per week (see section 3.2). The committee considered that the HELP-03 trial population had a lower frequency of attacks, on average, than the population currently eligible for C1-INH treatment in the NHS. The company reported a scenario analysis using a subgroup of the full HELP-03 population with a baseline risk of 8 or more attacks over 4 weeks, which is the same attack frequency (2 per week) as the criteria in NHS England's commissioning policy. The ERG explained that this analysis was based on very few patients (exact data are confidential and cannot be reported here) so may not be robust. In response to the technical engagement stage, the company also submitted subgroup analyses from HELP-03. These showed no difference in time to first attack after reaching an attack-free state with lanadelumab (that is, from day 70 onwards) in people with fewer than 3 attacks per month at baseline compared with people having 3 or more attacks per month). The ERG noted that this evidence was not consistent with the criteria set out by NHS England because it used a threshold of 3 attacks per month rather than 8. The clinical experts clarified that they would expect response rates with lanadelumab to be the same, irrespective of the number of attacks at baseline. The committee concluded that the trial results were generalisable to the population who would have lanadelumab in the NHS. It also concluded that both the results for the full HELP-03 population and for the subgroup with 8 or more attacks in the last 4 weeks at baseline were relevant, but that the latter were less robust because they were based on very few patients.
## There is no long-term evidence on using lanadelumab at its lower dosing frequency
HELP-03 used 2 different dosing schedules for the licensed dose of lanadelumab (300 mg): every 2 weeks (high frequency) and every 4 weeks (low frequency). The committee noted that the lanadelumab summary of product characteristics states that the low frequency dosing schedule could be used in 'patients who are stably attack-free, especially in patients with low weight'. HELP-03 did not allow switching between the dosing schedules and treatment continued at the same dose for 26 weeks. The committee was aware that longer-term evidence was being collected in the HELP-04 open-label extension study. This included people who continued from HELP-03 and other people who met the inclusion criteria but had not taken part in HELP-03. The committee understood that only the high frequency dosing schedule was used in HELP-04 and that data from HELP-04 were not used in the model. At the appraisal committee meeting, the company advised that 3 ongoing studies (1 in the USA, 1 in Europe and 1 in France) were collecting real-world data on the use of lanadelumab, including both licensed dosing schedules, but the earliest data would become available during mid-2020. The committee concluded that there was uncertainty around the long-term use of lanadelumab at the low dosing frequency because HELP-04 did not include this dose.
## The indirect treatment comparison should be used to estimate the treatment effect for lanadelumab and C1-INHs
HELP-03 compared lanadelumab with placebo and no evidence was identified that compared lanadelumab with C1-INHs directly. Therefore, the company did an indirect treatment comparison using HELP-03 and a crossover trial (CHANGE) of 22 patients, comparing a C1-INH with placebo. The company used a Bayesian indirect comparison with a fixed effects model, stating that a random effects model would not be robust because of the small sample size. The committee understood that the company's indirect comparison did not address uncertainty because it used a fixed effects model. The ERG explained that it was unable to validate the company's inputs (that is, estimates of treatment effect and associated standard errors) for the indirect treatment comparison, but broadly agreed with the company's approach. The committee understood that the company's revised base case used data from HELP-03 to inform the attack rate in the lanadelumab arm and results from the indirect comparison to inform the attack rate in the C1-INH arm. The ERG explained that the company's approach predicted a larger reduction in attacks for lanadelumab, compared with C1-INHs, than the indirect comparison predicted (exact data are confidential so not reported here). The committee considered both approaches and concluded that using the indirect treatment comparison to inform attack rates for both lanadelumab and C1-INHs was the more consistent and robust approach. The committee concluded that the indirect treatment comparison should be used to estimate the treatment effect for both lanadelumab and C1-INHs.
## Lanadelumab is clinically effective compared with C1-INHs
Results from HELP-03 showed that both the high and low lanadelumab dosing frequencies statistically significantly reduced mean monthly attack rates compared with placebo, by 87% and 73% respectively (p<0.001). The company's indirect treatment comparison produced very similar results for lanadelumab compared with placebo. It also showed that both dosing frequencies of lanadelumab had lower mean attack rates than a C1-INH (exact data are confidential so cannot be reported here). The committee concluded that lanadelumab is clinically effective compared with C1-INHs.
# Cost effectiveness
## The company's model is acceptable for decision making
The company submitted a cohort-level state-transition model with 2 health states; alive and dead. The alive health state was split into an attack-free and an attack period. The model used the average duration of an attack to estimate the time spent in the attack-free and the attack period in each cycle. The committee understood that in the company's base case, attack severity was not modelled explicitly, but that a single disutility and treatment cost was applied per attack to reflect the severity of a typical attack. The model used data from the full HELP-03 population. The committee recalled that it considered the trial population to be generalisable to people who would have treatment in the NHS (see section 3.4). It noted that the model did not include a survival benefit for lanadelumab compared with C1-INHs. The patient experts noted that data from the Office of National Statistics showed there were very few deaths from hereditary angioedema in 2017. The committee agreed that it was plausible that there may be a very small survival benefit associated with lanadelumab in practice, but it had not seen evidence to support this. The committee concluded that the company's model was acceptable for decision making, although the indirect treatment comparison should be used to model relative effectiveness (see section 3.6).
# Subsequent treatment
## Treatment discontinuation data from HELP-03 are acceptable for decision making
In its revised base case, the company assumed that 91% of people taking lanadelumab would continue to take it for a lifetime. This was based on 91% of patients completing treatment in HELP-03. The committee recalled that the treatment period in HELP-03 was 26 weeks and was concerned that more people would stop lanadelumab over a longer follow-up period. After the technical engagement stage, the company submitted new interim data from the ongoing HELP-04 study that showed only 6% of patients had stopped over 15 months. The committee concluded that it was reasonable to use discontinuation rates from HELP-03 because the results were similar to longer-term data from HELP-04.
## It is plausible to assume that people who stop lanadelumab will start a C1-INH and those having a C1-INH will continue to have it for a lifetime
The company's revised base case assumed that if treatment was stopped in the lanadelumab arm, people would go on to have treatment with a C1-INH. The company also assumed that people in the C1-INH arm would continue to have treatment over a lifetime. The clinical experts confirmed that in clinical practice, there are no other treatment options after a C1-INH. Therefore, people having a long-term preventive C1-INH were unlikely to stop treatment altogether. The clinical experts also advised that if lanadelumab was stopped, it was likely that C1-INH treatment would be started because it was the only available treatment. The committee concluded that it was clinically plausible to assume that people who stop lanadelumab will start a C1-INH and those having a C1-INH will continue to have it for a lifetime.
# Continued treatment effect of lanadelumab
## A continued treatment effect for lanadelumab is clinically plausible for most people, but assuming this for everyone is optimistic
The company's revised base case assumed that the effectiveness of lanadelumab would persist over time for everyone who continues to have treatment. The clinical experts advised that, similar to other biological therapies, it was clinically plausible to assume that for a small proportion (5% to 10%) of people, response to lanadelumab would be lost over time. The committee understood that the company's model did not account for this. The committee concluded that a continued treatment effect for lanadelumab was clinically plausible for most people, but for a small proportion, response may be lost. It also concluded that the cost-effectiveness estimates for lanadelumab would be optimistic because the model did not include this lack of response.
# C1-INH use and cost
## It is reasonable to assume 73% of people having a preventive C1-INH will have Berinert
In its revised base case, the company assumed that between 50% and 75% of people having a C1-INH would have Berinert instead of Cinryze. The company based this on hospital dispensing data from the Hospital Pharmacy Audit over a 3-month period. But it also reported 3-year data that showed the proportion of Berinert use was always higher than 50% (details of the revised base case and the dispensing data are confidential and cannot be reported here). The committee understood that the prescribing data did not differentiate between acute and preventive C1-INH use. The clinical experts stated that C1-INH use varied in clinical practice but Berinert and Cinryze were likely to be used in about equal proportions. The clinical and patient experts described current supply issues with both Berinert and Cinryze, and advised that people may prefer to use Berinert because it was the first C1-INH to become available and many people have experience using it. The committee recalled that the clinical experts advised that Ruconest (another C1-INH) was rarely used in practice (see section 3.3). The commissioning expert from NHS England explained that data collected as part of NHS England's commissioning policy showed that between 2017 and 2019, an average of 73% had preventive Berinert, but the proportion fluctuated year by year. It concluded that it was reasonable to assume that 73% of people having a preventive C1-INH would have Berinert.
## Cost-effectiveness results including the current discounted prices for C1-INH treatments are preferred
The company's economic model used the list prices of C1-INHs, including for the cost of treating acute attacks. The commissioning expert from NHS England advised that the NHS pays lower prices for preventive and acute C1-INH treatments than their current list prices. In its response to consultation, the company considered the long-term cost-effectiveness results that included the current discounted prices for C1-INHs to be unreliable because these discounts may change. The committee acknowledged that price discounts may change over time but considered that the cost-effectiveness analyses should include the current NHS prices. It concluded that the cost-effectiveness results should include the current discounted prices for C1-INH treatment.
# Dosing and dose reduction
## Berinert's dosing schedule is very uncertain but the company advisory board's dosing data are suitable for decision making
The company assumed that people having Berinert had a dose that varied by their body weight (the exact dose is confidential and cannot be reported here). But for Cinryze the licensed dose is 1,000 IU every 3 or 4 days for the routine prevention of angioedema attacks. The committee recalled that Berinert was not licensed as long-term preventive therapy but was used in clinical practice (see section 3.3). It noted that its summary of product characteristics recommended a dose of 20 IU per kilogram of body weight to treat an acute attack. The clinical experts explained that in clinical practice the dose of Berinert may be changed to avoid wastage, for example a weight-based dose of 1,100 IU may be underdosed to 1,000 IU so that 2 full vials are used instead of 3. The committee recognised that the company's preferred weight-based dose of Berinert was substantially higher than 1,000 IU per administration (the exact dose is confidential and cannot be reported here). The ERG noted that the trial used in the indirect treatment comparison (CHANGE) used a 1,000 IU dose of Cinryze only. The ERG also identified a publication using Berinert patient registry data from 47 patients in the US and Europe having long-term preventive treatment, which reported a median dose of 1,000 IU (range 500 IU to 3,000 IU). In its response to consultation, the company reported an average weekly dose of Berinert estimated from an advisory board meeting (with 22 clinical experts working in 16 specialist centres in England and Wales). Exact data are confidential and cannot be reported here. During consultation, the UK Primary Immunodeficiency Network (UKPIN) also submitted survey results from 28 immunology centres that included 33 patients having preventive treatment with Berinert. It reported an average weekly dose of 2,781 IU per week. The ERG explained that it was unclear whether the UKPIN results accounted for dose rounding or if there was any overlap between the centres taking part in the UKPIN survey and the company's advisory board. The company explained that its revised base case still used its preferred weight-based target dose of Berinert and applied this to the average baseline bodyweight from HELP‑03, rounding to the nearest 500 IU to reduce vial wastage. The committee was aware that the company's revised base case used a higher weekly dose of Berinert than the dose reported by the company's advisory board. It agreed that the average bodyweight in HELP-03, and therefore the company's base case dose, may be higher than it would be in the population who would have lanadelumab in England, given that most people with hereditary angioedema are women and the marketing authorisation includes young people (aged 12 and above). The committee noted that demographic data on the age and proportion of women patients included in the company's advisory board and the UKPIN survey were not available. But it reasoned that the company's preferred dose may not be generalisable to the NHS in England. The committee concluded that there was substantial uncertainty around the dosing schedule for Berinert, but the dosing data from the company's advisory board were suitable for decision making.
## The company's scenario analysis value of 61% for the proportion of people who would have lower frequency lanadelumab is suitable for decision making
The company assumed that 77% of people having lanadelumab would have the lower frequency dose (once every 4 weeks) after 1 year. The company reasoned that this was plausible because it was the proportion of patients in HELP-03 having the higher frequency dose of lanadelumab and who were attack-free between days 70 and 182 (a period of just under 4 months). It explained that in practice, it would be appropriate to reduce the lanadelumab dosing frequency for these people, as specified in its summary of product characteristics. The ERG clarified that changes to dosing frequency were not allowed in HELP-03. Therefore, the proportion used by the company was based on people who would have been eligible to reduce their dosing frequency in practice, but did not actually do so in the trial. The committee recalled that HELP-04 did not include the lower dosing frequency of lanadelumab, therefore there was a lack of long-term evidence around its use (see section 3.5). The clinical experts explained that it was clinically plausible that 77% of people would have their dosing frequency reduced, although they noted that this was difficult to predict. Other responses at the technical engagement stage also noted that given the nature of the disease, attack rates vary over a lifetime and even if dosing frequency increased, it was often lowered again. The patient experts described how people may wish to use the lowest effective dose to avoid repeated administration of an intravenous C1-INH. The committee noted that the ERG scenario analyses assuming 50% had the lower dosing frequency of lanadelumab substantially increased the cost-effectiveness estimates in both the full HELP-03 population and the subgroup with at least 8 attacks over 4 weeks. Given the lack of long-term data on the low dosing frequency of lanadelumab and its large impact on the cost-effectiveness results, the committee was not convinced that 77% was plausible. The committee reasoned that 77% was likely to be an upper limit. This was because a reduced dosing frequency would only be considered for people who are attack-free, some of whom might not choose to reduce their dosing schedule while the higher frequency dosing was controlling attacks. In its response to consultation, the company included a scenario analysis that assumed 61% of people had the lower dosing frequency of lanadelumab after 1 year. The committee understood that this was the midpoint of patients whose condition was stable and who were attack-free across both lanadelumab arms in HELP-03. It also noted that the company had not changed its assumption of 77% in its revised base case. The company explained that this assumption might be conservative because clinicians could potentially consider using the lower dosing frequency of lanadelumab in people having some minor peripheral attacks. However, the committee recalled that in the summary of product characteristics, the population eligible for the lower dosing frequency of lanadelumab were in a stable attack-free phase on treatment. The committee considered that there was substantial uncertainty around the proportion of people having the lower dosing frequency of lanadelumab. It concluded that 77% was the upper limit and preferred to use the company's scenario analysis of 61% for decision making, but noted that this remains uncertain.
# Health-related quality of life
## The company's preferred utility values are acceptable for decision making
The company used utility values from Nordenfelt (2014), a Swedish study that included EQ-5D-5L values for both the attack-free and the attack health states. The company also added a utility benefit for subcutaneous administration of lanadelumab, compared with an intravenous C1-INH. The committee understood that EQ-5D-5L values were collected in HELP‑03 but this was limited to 3 fixed time points (days 0, 98 and 182). For this reason, the company explained that the utility values collected in HELP‑03 were limited and could not be used in the model. The ERG acknowledged that an alternative data source to the trial would be needed to measure the quality-of-life decrement during an attack, because only 2 of the 807 recorded attacks in HELP-03 had completed EQ-5D data. The committee considered the company's approach to utility values and noted that the ERG had not changed this in its preferred analysis. It concluded that the company's preferred utility values that included a benefit for lanadelumab subcutaneous administration were acceptable for decision making.
# End of life
## Lanadelumab does not meet the criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It noted that lanadelumab is a long-term preventive treatment and that the company did not make a case for it to be considered a life-extending treatment. The committee was aware that the company's revised base case showed no difference between the modelled mean survival for lanadelumab and C1-INHs despite the very small survival benefit associated with lanadelumab (see section 3.8). However, based on the evidence presented, the committee concluded that lanadelumab did not meet the criteria to be considered a life-extending treatment at the end of life.
# Cost-effectiveness results
## The company's revised base case comparing lanadelumab with C1-INHs is not suitable for decision making
The company submitted a revised base case after consultation. This showed that lanadelumab was dominant (that is, less costly and more effective) compared with C1-INHs in the full HELP-03 population and in the subgroup of people with at least 8 attacks in the previous 4 weeks. However, the committee noted that this did not include all of its preferred assumptions, that is:
% of people having a C1-INH will have Berinert and the rest will have Cinryze (see section 3.12)
all cost-effectiveness results should include the current discounted costs paid by the NHS for acute and preventive C1-INH treatment (see section 3.13)
use dosing data from the company's advisory board for Berinert (see section 3.14)
% of people having lanadelumab would switch to a lower dosing frequency after 1 year (see section 3.15).Therefore, the committee concluded that the company's revised base case was not suitable for decision making.
## Lanadelumab compared with C1-INHs is mostly cost effective and is only recommended for people eligible for preventive C1-INHs
The committee firstly considered cost-effectiveness estimates for lanadelumab compared with C1-INHs for the full HELP-03 population. It noted that most estimates from the company's plausible scenario analyses were lower than £20,000 per quality-adjusted life year (QALY) gained after including the confidential price discounts for C1-INHs (exact incremental cost-effectiveness ratios are confidential and cannot be reported here). These scenarios used Berinert dosing data from the company's advisory board and assumed that 61% of people having lanadelumab switched to the lower dosing frequency. It noted that the most plausible cost-effectiveness estimate combining these preferred assumptions (see section 3.18) was also lower than £20,000 per QALY gained for the full HELP-03 population. Secondly, the committee considered all cost-effectiveness estimates for lanadelumab compared with C1-INHs for the subgroup from HELP-03 with at least 8 attacks in the last 4 weeks at baseline (that is, the population eligible for C1-INHs in NHS England's commissioning policy, see section 3.2). It noted that estimates from the company's plausible scenario analyses were lower than £20,000 per QALY gained after including the confidential price discounts for C1-INHs (exact ICERs are confidential and cannot be reported here). These scenarios used Berinert dosing data from the company's advisory board and assumed that 61% of people having lanadelumab switched to the lower dosing frequency. It noted that the most plausible cost-effectiveness estimate combining these preferred assumptions (see section 3.18) was also lower than £20,000 per QALY gained for the subgroup of people with at least 8 attacks in the last 4 weeks, and that this was lower than the estimate for the full HELP-03 population.The committee reiterated the uncertainty in all cost-effectiveness estimates, specifically that:
there was no evidence to support switching to a lower dosing frequency of lanadelumab (see section 3.5)
cost-effectiveness estimates would be even higher if fewer than 61% of people switched to the lower lanadelumab dosing frequency (see section 3.15)
the QALY gain for lanadelumab was small relative to its incremental cost, meaning the cost-effectiveness results could change dramatically between different clinically plausible scenarios.The committee recalled the company's proposed positioning of lanadelumab (see section 3.2) and the remaining uncertainty around the proportion of people switching to the lower dosing frequency of lanadelumab (see section 3.5 and section 3.15), which it understood could lead to higher cost-effectiveness estimates. It concluded that lanadelumab could only be recommended as a cost-effective use of NHS resources:
for the subgroup of people who are eligible for a long-term preventive C1-INH and
using the lowest dosing frequency of lanadelumab, in line with the summary of product characteristics.
# Innovation
## Lanadelumab is innovative but all benefits are captured in the model
The committee considered lanadelumab to be innovative because it provided an alternative subcutaneous treatment option for people with recurrent attacks of hereditary angioedema. It noted that the company added a utility benefit for subcutaneous administration of lanadelumab in its revised base case. It recalled there may be a very small survival benefit associated with reducing hereditary angioedema attacks (see section 3.8), but it had not seen any evidence for this. The committee concluded that lanadelumab is innovative, but all relevant benefits were captured in the cost-effectiveness estimates.
# Equalities considerations
## There are no equalities issues relevant to the recommendation
The company highlighted that C1-INH treatment is based on human or animal products and may not be acceptable for some people. The clinical experts confirmed that both Berinert and Cinryze were human plasma-derived blood products and some people prefer to use Ruconest (a non-plasma-derived C1-INH based on animal products). But they noted that Ruconest was not commonly used in clinical practice. The committee noted that some people may refuse human plasma-derived products but understood that the animal-based C1-INH may be used instead. The committee was also aware that oral treatment with attenuated androgens could affect a woman's fertility and is therefore not appropriate for women who could have children. However, the committee noted that C1-INH treatment was available if long-term prevention with oral therapy was contraindicated, for example in pregnant women. It also understood that oral prevention options are used earlier in the treatment pathway than the company's positioning of lanadelumab. Therefore, the committee concluded that this was not a relevant equalities issue.
|
{'Recommendations': "Lanadelumab is recommended as an option for preventing recurrent attacks of hereditary angioedema in people aged 12 and older, only if:\n\nthey are eligible for preventive C1-esterase inhibitor (C1-INH) treatment in line with NHS England's commissioning policy, that is, they are having 2 or more clinically significant attacks (as defined in the policy) per week over 8 weeks despite oral preventive therapy, or oral therapy is contraindicated or not tolerated\n\nthe lowest dosing frequency of lanadelumab is used in line with the summary of product characteristics, that is, when the condition is in a stable, attack-free phase (see section 2) and\n\nthe company provides lanadelumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with lanadelumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by the clinician and the young person or the young person's parents or carers.\n\nWhy the committee made these recommendations\n\nPeople with hereditary angioedema have attacks that cause severe swelling of various parts of the body. Despite long-term oral preventive therapy (such as attenuated androgens) and C1-INH treatments, some people still have frequent severe attacks.\n\nLanadelumab's marketing authorisation is broad and covers prevention of recurrent attacks of hereditary angioedema. But there is no trial evidence comparing lanadelumab with long-term oral preventive therapy so it cannot be used instead of this therapy. Therefore the company wants lanadelumab to be used only for people who are eligible for long-term preventive C1-INH treatments in line with NHS England's commissioning policy. So C1-INH treatments are the most appropriate comparator for the company's proposed positioning.\n\nEvidence from a randomised controlled trial suggests that people having lanadelumab have fewer hereditary angioedema attacks than with placebo. There are data indirectly comparing lanadelumab with C1-INHs.\n\nLanadelumab does not meet NICE's criteria to be considered a life-extending treatment at the end of life. In line with its summary of product characteristics, a lower dosing frequency of lanadelumab (once every 4\xa0weeks) can be used if the condition is in a stable attack-free phase. But there is no clinical trial evidence on switching to this lower dosing frequency and the proportion of patients assumed to switch has a large impact on the cost-effectiveness estimates. Although all cost-effectiveness estimates for lanadelumab compared with C1-INHs are uncertain, most are within the range NICE normally considers an acceptable use of NHS resources. Therefore, lanadelumab is recommended only for people who are eligible for long-term preventive C1-INH treatments in line with NHS England's commissioning policy. The lowest dosing frequency of lanadelumab should be used in line with the summary of product characteristics, when the condition is in a stable attack-free phase.", 'Information about lanadelumab': "Marketing authorisation indication\n\nLanadelumab (Takhzyro, Shire) is indicated for 'routine prevention of recurrent attacks of hereditary angioedema in patients aged 12\xa0years and older'.\n\nDosage in the marketing authorisation\n\nThe recommended starting dose is 300\xa0mg lanadelumab every 2\xa0weeks. The summary of product of characteristics states that in patients who are stably attack-free on treatment, a dose reduction of 300\xa0mg lanadelumab every 4\xa0weeks may be considered, especially in patients with low weight. It is administered as a subcutaneous injection.\n\nPrice\n\nThe list price for lanadelumab is £12,420 per 300-mg vial.\n\nThe company has a commercial arrangement. This makes lanadelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Shire (now part of Takeda), a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that none of the key issues identified in the technical report were resolved during the technical engagement stage. It recognised that there were areas of uncertainty associated with the analyses presented (see technical report, issues 1\xa0to\xa04), and took these into account in its decision making.\n\n# New treatment option\n\n## There is an unmet need for more effective treatment options\n\nHereditary angioedema is a rare genetic disorder. It usually develops in childhood or early adulthood and is associated with the build-up of excessive fluid (oedema) causing localised swelling. The swelling may happen in the mouth, gut or airway and can cause severe pain. Swelling of the airways can be life threatening. The patient experts described how swelling can enlarge quickly (30 to 40\xa0minutes) and can take over 2\xa0days to resolve. The patient experts explained that this can have a substantial impact on quality of life, particularly because attacks are often difficult to predict. The clinical experts explained that attacks can be triggered by anxiety and stress, for example caused by exams, surgery or dental treatment as well as positive life events such as weddings and holidays. The clinical experts advised that in clinical practice, people who have regular attacks and those who are at risk of severe swelling would benefit from long-term preventive treatment. Long-term preventive treatment with an intravenous C1 esterase inhibitor (C1-INH) is currently only available for a small subgroup of people meeting the criteria set out in NHS England's commissioning policy (see section\xa03.2). They also emphasised that long-term preventive oral treatment, such as attenuated androgens, is used earlier in the treatment pathway but is associated with side effects and has limited effectiveness (see section\xa03.3). The patient and clinical experts suggested that being able to control symptoms in the long term may reduce anxiety and therefore reduce attacks. The committee concluded that there is an unmet need for more effective treatment options.\n\n# Treatment pathway and comparators\n\n## The company's proposed positioning of lanadelumab, for people currently eligible for long-term preventive C1-INH treatment, is appropriate\n\nAfter clarification, the company positioned lanadelumab for the population currently eligible for long-term preventive C1-INH treatment, in line with NHS England's commissioning policy. The policy includes people with 2\xa0or more clinically significant attacks (as defined in the policy) per week over 8\xa0weeks, despite long-term oral preventive treatment, or if long-term oral preventive treatment is not appropriate. The committee understood that this is a narrower population than covered by the full marketing authorisation for lanadelumab (indicated for routine prevention of recurrent attacks of hereditary angioedema in people aged 12\xa0years and older). The clinical experts explained that the criteria used in NHS England's commissioning policy to identify people eligible for long-term preventive C1-INH treatment were well defined and used in clinical practice. The committee was aware that similar criteria were used in the company's subgroup analysis from HELP-03. This included people with 8\xa0or more attacks over the previous 4\xa0weeks at baseline (see section\xa03.4). The committee accepted the company's positioning of lanadelumab and agreed to take this into account when making its recommendations.\n\n## C1-INHs are the most appropriate comparator for the company's proposed positioning of lanadelumab\n\nThe company considered C1-INHs to be the only relevant comparator because it had positioned lanadelumab for people who are currently eligible for long-term preventive C1-INH treatment (see section\xa03.2). The company used a blended C1-INH comparator that included Berinert and Cinryze because, according to clinical advice, these were the most commonly used C1-INH treatments. The clinical experts explained that the use of individual C1-INHs varied between different treatment centres. But they agreed that Berinert and Cinryze were the most commonly used, with a third C1-INH treatment, Ruconest, being used very rarely in practice. The committee was aware that Berinert is only licensed to treat acute attacks, but the clinical experts advised that it is also used in clinical practice as a long-term preventive treatment. The clinical experts clarified that acute treatment with a C1-INH can be similar to long-term preventive C1-INH treatment (as described in NHS England's commissioning policy) if it is offered frequently (for example, several times per week). After clinical experts explained during the technical engagement stage that lanadelumab could be used earlier in the treatment pathway than a C1-INH, the committee considered analyses comparing lanadelumab with long-term preventive oral treatment, which is used earlier in the treatment pathway (the results are confidential and cannot be reported here). The committee also understood that there was no trial evidence for oral therapy, such as attenuated androgens, and therefore agreed it was not an appropriate comparator for the company's proposed positioning of lanadelumab. The clinical experts explained that most people who are eligible for a long-term preventive C1-INH would choose to have it. Those choosing not to have it would still have acute treatment during an attack. The committee concluded that C1-INHs are the only comparator for the company's proposed positioning of lanadelumab.\n\n# Clinical evidence\n\n## Results from the full HELP-03 population and the subgroup having 8\xa0or more attacks are relevant for decision making, but the latter are less robust\n\nThe clinical evidence for lanadelumab came from HELP-03, a phase\xa0III randomised controlled trial. It compared 3\xa0dose schedules of lanadelumab with placebo in 125\xa0people aged 12\xa0or older with type\xa0I or II hereditary angioedema who had had at least 1\xa0attack in the last 4\xa0weeks. The committee understood that the frequency of attacks in the trial inclusion criteria was lower than the company's proposed positioning, which specified at least 2\xa0or more attacks per week (see section\xa03.2). The committee considered that the HELP-03 trial population had a lower frequency of attacks, on average, than the population currently eligible for C1-INH treatment in the NHS. The company reported a scenario analysis using a subgroup of the full HELP-03 population with a baseline risk of 8\xa0or more attacks over 4\xa0weeks, which is the same attack frequency (2\xa0per week) as the criteria in NHS England's commissioning policy. The ERG explained that this analysis was based on very few patients (exact data are confidential and cannot be reported here) so may not be robust. In response to the technical engagement stage, the company also submitted subgroup analyses from HELP-03. These showed no difference in time to first attack after reaching an attack-free state with lanadelumab (that is, from day\xa070 onwards) in people with fewer than 3\xa0attacks per month at baseline compared with people having 3\xa0or more attacks per month). The ERG noted that this evidence was not consistent with the criteria set out by NHS England because it used a threshold of 3\xa0attacks per month rather than\xa08. The clinical experts clarified that they would expect response rates with lanadelumab to be the same, irrespective of the number of attacks at baseline. The committee concluded that the trial results were generalisable to the population who would have lanadelumab in the NHS. It also concluded that both the results for the full HELP-03 population and for the subgroup with 8\xa0or more attacks in the last 4\xa0weeks at baseline were relevant, but that the latter were less robust because they were based on very few patients.\n\n## There is no long-term evidence on using lanadelumab at its lower dosing frequency\n\nHELP-03 used 2\xa0different dosing schedules for the licensed dose of lanadelumab (300\xa0mg): every 2\xa0weeks (high frequency) and every 4\xa0weeks (low frequency). The committee noted that the lanadelumab summary of product characteristics states that the low frequency dosing schedule could be used in 'patients who are stably attack-free, especially in patients with low weight'. HELP-03 did not allow switching between the dosing schedules and treatment continued at the same dose for 26\xa0weeks. The committee was aware that longer-term evidence was being collected in the HELP-04 open-label extension study. This included people who continued from HELP-03 and other people who met the inclusion criteria but had not taken part in HELP-03. The committee understood that only the high frequency dosing schedule was used in HELP-04 and that data from HELP-04 were not used in the model. At the appraisal committee meeting, the company advised that 3\xa0ongoing studies (1\xa0in the USA, 1\xa0in Europe and 1\xa0in France) were collecting real-world data on the use of lanadelumab, including both licensed dosing schedules, but the earliest data would become available during mid-2020. The committee concluded that there was uncertainty around the long-term use of lanadelumab at the low dosing frequency because HELP-04 did not include this dose.\n\n## The indirect treatment comparison should be used to estimate the treatment effect for lanadelumab and C1-INHs\n\nHELP-03 compared lanadelumab with placebo and no evidence was identified that compared lanadelumab with C1-INHs directly. Therefore, the company did an indirect treatment comparison using HELP-03 and a crossover trial (CHANGE) of 22\xa0patients, comparing a C1-INH with placebo. The company used a Bayesian indirect comparison with a fixed effects model, stating that a random effects model would not be robust because of the small sample size. The committee understood that the company's indirect comparison did not address uncertainty because it used a fixed effects model. The ERG explained that it was unable to validate the company's inputs (that is, estimates of treatment effect and associated standard errors) for the indirect treatment comparison, but broadly agreed with the company's approach. The committee understood that the company's revised base case used data from HELP-03 to inform the attack rate in the lanadelumab arm and results from the indirect comparison to inform the attack rate in the C1-INH arm. The ERG explained that the company's approach predicted a larger reduction in attacks for lanadelumab, compared with C1-INHs, than the indirect comparison predicted (exact data are confidential so not reported here). The committee considered both approaches and concluded that using the indirect treatment comparison to inform attack rates for both lanadelumab and C1-INHs was the more consistent and robust approach. The committee concluded that the indirect treatment comparison should be used to estimate the treatment effect for both lanadelumab and C1-INHs.\n\n## Lanadelumab is clinically effective compared with C1-INHs\n\nResults from HELP-03 showed that both the high and low lanadelumab dosing frequencies statistically significantly reduced mean monthly attack rates compared with placebo, by 87% and 73% respectively (p<0.001). The company's indirect treatment comparison produced very similar results for lanadelumab compared with placebo. It also showed that both dosing frequencies of lanadelumab had lower mean attack rates than a C1-INH (exact data are confidential so cannot be reported here). The committee concluded that lanadelumab is clinically effective compared with C1-INHs.\n\n# Cost effectiveness\n\n## The company's model is acceptable for decision making\n\nThe company submitted a cohort-level state-transition model with 2\xa0health states; alive and dead. The alive health state was split into an attack-free and an attack period. The model used the average duration of an attack to estimate the time spent in the attack-free and the attack period in each cycle. The committee understood that in the company's base case, attack severity was not modelled explicitly, but that a single disutility and treatment cost was applied per attack to reflect the severity of a typical attack. The model used data from the full HELP-03 population. The committee recalled that it considered the trial population to be generalisable to people who would have treatment in the NHS (see section\xa03.4). It noted that the model did not include a survival benefit for lanadelumab compared with C1-INHs. The patient experts noted that data from the Office of National Statistics showed there were very few deaths from hereditary angioedema in 2017. The committee agreed that it was plausible that there may be a very small survival benefit associated with lanadelumab in practice, but it had not seen evidence to support this. The committee concluded that the company's model was acceptable for decision making, although the indirect treatment comparison should be used to model relative effectiveness (see section\xa03.6).\n\n# Subsequent treatment\n\n## Treatment discontinuation data from HELP-03 are acceptable for decision making\n\nIn its revised base case, the company assumed that 91% of people taking lanadelumab would continue to take it for a lifetime. This was based on 91% of patients completing treatment in HELP-03. The committee recalled that the treatment period in HELP-03 was 26\xa0weeks and was concerned that more people would stop lanadelumab over a longer follow-up period. After the technical engagement stage, the company submitted new interim data from the ongoing HELP-04 study that showed only 6% of patients had stopped over 15\xa0months. The committee concluded that it was reasonable to use discontinuation rates from HELP-03 because the results were similar to longer-term data from HELP-04.\n\n## It is plausible to assume that people who stop lanadelumab will start a C1-INH and those having a C1-INH will continue to have it for a lifetime\n\nThe company's revised base case assumed that if treatment was stopped in the lanadelumab arm, people would go on to have treatment with a C1-INH. The company also assumed that people in the C1-INH arm would continue to have treatment over a lifetime. The clinical experts confirmed that in clinical practice, there are no other treatment options after a C1-INH. Therefore, people having a long-term preventive C1-INH were unlikely to stop treatment altogether. The clinical experts also advised that if lanadelumab was stopped, it was likely that C1-INH treatment would be started because it was the only available treatment. The committee concluded that it was clinically plausible to assume that people who stop lanadelumab will start a C1-INH and those having a C1-INH will continue to have it for a lifetime.\n\n# Continued treatment effect of lanadelumab\n\n## A continued treatment effect for lanadelumab is clinically plausible for most people, but assuming this for everyone is optimistic\n\nThe company's revised base case assumed that the effectiveness of lanadelumab would persist over time for everyone who continues to have treatment. The clinical experts advised that, similar to other biological therapies, it was clinically plausible to assume that for a small proportion (5% to 10%) of people, response to lanadelumab would be lost over time. The committee understood that the company's model did not account for this. The committee concluded that a continued treatment effect for lanadelumab was clinically plausible for most people, but for a small proportion, response may be lost. It also concluded that the cost-effectiveness estimates for lanadelumab would be optimistic because the model did not include this lack of response.\n\n# C1-INH use and cost\n\n## It is reasonable to assume 73% of people having a preventive C1-INH will have Berinert\n\nIn its revised base case, the company assumed that between 50% and 75% of people having a C1-INH would have Berinert instead of Cinryze. The company based this on hospital dispensing data from the Hospital Pharmacy Audit over a 3-month period. But it also reported 3-year data that showed the proportion of Berinert use was always higher than 50% (details of the revised base case and the dispensing data are confidential and cannot be reported here). The committee understood that the prescribing data did not differentiate between acute and preventive C1-INH use. The clinical experts stated that C1-INH use varied in clinical practice but Berinert and Cinryze were likely to be used in about equal proportions. The clinical and patient experts described current supply issues with both Berinert and Cinryze, and advised that people may prefer to use Berinert because it was the first C1-INH to become available and many people have experience using it. The committee recalled that the clinical experts advised that Ruconest (another C1-INH) was rarely used in practice (see section\xa03.3). The commissioning expert from NHS England explained that data collected as part of NHS England's commissioning policy showed that between 2017 and 2019, an average of 73% had preventive Berinert, but the proportion fluctuated year by year. It concluded that it was reasonable to assume that 73% of people having a preventive C1-INH would have Berinert.\n\n## Cost-effectiveness results including the current discounted prices for C1-INH treatments are preferred\n\nThe company's economic model used the list prices of C1-INHs, including for the cost of treating acute attacks. The commissioning expert from NHS England advised that the NHS pays lower prices for preventive and acute C1-INH treatments than their current list prices. In its response to consultation, the company considered the long-term cost-effectiveness results that included the current discounted prices for C1-INHs to be unreliable because these discounts may change. The committee acknowledged that price discounts may change over time but considered that the cost-effectiveness analyses should include the current NHS prices. It concluded that the cost-effectiveness results should include the current discounted prices for C1-INH treatment.\n\n# Dosing and dose reduction\n\n## Berinert's dosing schedule is very uncertain but the company advisory board's dosing data are suitable for decision making\n\nThe company assumed that people having Berinert had a dose that varied by their body weight (the exact dose is confidential and cannot be reported here). But for Cinryze the licensed dose is 1,000\xa0IU every 3\xa0or 4\xa0days for the routine prevention of angioedema attacks. The committee recalled that Berinert was not licensed as long-term preventive therapy but was used in clinical practice (see section\xa03.3). It noted that its summary of product characteristics recommended a dose of 20\xa0IU per kilogram of body weight to treat an acute attack. The clinical experts explained that in clinical practice the dose of Berinert may be changed to avoid wastage, for example a weight-based dose of 1,100\xa0IU may be underdosed to 1,000\xa0IU so that 2\xa0full vials are used instead of 3. The committee recognised that the company's preferred weight-based dose of Berinert was substantially higher than 1,000\xa0IU per administration (the exact dose is confidential and cannot be reported here). The ERG noted that the trial used in the indirect treatment comparison (CHANGE) used a 1,000\xa0IU dose of Cinryze only. The ERG also identified a publication using Berinert patient registry data from 47\xa0patients in the US and Europe having long-term preventive treatment, which reported a median dose of 1,000\xa0IU (range 500\xa0IU to 3,000\xa0IU). In its response to consultation, the company reported an average weekly dose of Berinert estimated from an advisory board meeting (with 22\xa0clinical experts working in 16\xa0specialist centres in England and Wales). Exact data are confidential and cannot be reported here. During consultation, the UK Primary Immunodeficiency Network (UKPIN) also submitted survey results from 28\xa0immunology centres that included 33\xa0patients having preventive treatment with Berinert. It reported an average weekly dose of 2,781\xa0IU per week. The ERG explained that it was unclear whether the UKPIN results accounted for dose rounding or if there was any overlap between the centres taking part in the UKPIN survey and the company's advisory board. The company explained that its revised base case still used its preferred weight-based target dose of Berinert and applied this to the average baseline bodyweight from HELP‑03, rounding to the nearest 500\xa0IU to reduce vial wastage. The committee was aware that the company's revised base case used a higher weekly dose of Berinert than the dose reported by the company's advisory board. It agreed that the average bodyweight in HELP-03, and therefore the company's base case dose, may be higher than it would be in the population who would have lanadelumab in England, given that most people with hereditary angioedema are women and the marketing authorisation includes young people (aged\xa012 and above). The committee noted that demographic data on the age and proportion of women patients included in the company's advisory board and the UKPIN survey were not available. But it reasoned that the company's preferred dose may not be generalisable to the NHS in England. The committee concluded that there was substantial uncertainty around the dosing schedule for Berinert, but the dosing data from the company's advisory board were suitable for decision making.\n\n## The company's scenario analysis value of 61% for the proportion of people who would have lower frequency lanadelumab is suitable for decision making\n\nThe company assumed that 77% of people having lanadelumab would have the lower frequency dose (once every 4\xa0weeks) after 1\xa0year. The company reasoned that this was plausible because it was the proportion of patients in HELP-03 having the higher frequency dose of lanadelumab and who were attack-free between days\xa070 and 182 (a period of just under 4\xa0months). It explained that in practice, it would be appropriate to reduce the lanadelumab dosing frequency for these people, as specified in its summary of product characteristics. The ERG clarified that changes to dosing frequency were not allowed in HELP-03. Therefore, the proportion used by the company was based on people who would have been eligible to reduce their dosing frequency in practice, but did not actually do so in the trial. The committee recalled that HELP-04 did not include the lower dosing frequency of lanadelumab, therefore there was a lack of long-term evidence around its use (see section\xa03.5). The clinical experts explained that it was clinically plausible that 77% of people would have their dosing frequency reduced, although they noted that this was difficult to predict. Other responses at the technical engagement stage also noted that given the nature of the disease, attack rates vary over a lifetime and even if dosing frequency increased, it was often lowered again. The patient experts described how people may wish to use the lowest effective dose to avoid repeated administration of an intravenous C1-INH. The committee noted that the ERG scenario analyses assuming 50% had the lower dosing frequency of lanadelumab substantially increased the cost-effectiveness estimates in both the full HELP-03 population and the subgroup with at least 8\xa0attacks over 4\xa0weeks. Given the lack of long-term data on the low dosing frequency of lanadelumab and its large impact on the cost-effectiveness results, the committee was not convinced that 77% was plausible. The committee reasoned that 77% was likely to be an upper limit. This was because a reduced dosing frequency would only be considered for people who are attack-free, some of whom might not choose to reduce their dosing schedule while the higher frequency dosing was controlling attacks. In its response to consultation, the company included a scenario analysis that assumed 61% of people had the lower dosing frequency of lanadelumab after 1\xa0year. The committee understood that this was the midpoint of patients whose condition was stable and who were attack-free across both lanadelumab arms in HELP-03. It also noted that the company had not changed its assumption of 77% in its revised base case. The company explained that this assumption might be conservative because clinicians could potentially consider using the lower dosing frequency of lanadelumab in people having some minor peripheral attacks. However, the committee recalled that in the summary of product characteristics, the population eligible for the lower dosing frequency of lanadelumab were in a stable attack-free phase on treatment. The committee considered that there was substantial uncertainty around the proportion of people having the lower dosing frequency of lanadelumab. It concluded that 77% was the upper limit and preferred to use the company's scenario analysis of 61% for decision making, but noted that this remains uncertain.\n\n# Health-related quality of life\n\n## The company's preferred utility values are acceptable for decision making\n\nThe company used utility values from Nordenfelt (2014), a Swedish study that included EQ-5D-5L values for both the attack-free and the attack health states. The company also added a utility benefit for subcutaneous administration of lanadelumab, compared with an intravenous C1-INH. The committee understood that EQ-5D-5L values were collected in HELP‑03 but this was limited to 3\xa0fixed time points (days\xa00, 98 and 182). For this reason, the company explained that the utility values collected in HELP‑03 were limited and could not be used in the model. The ERG acknowledged that an alternative data source to the trial would be needed to measure the quality-of-life decrement during an attack, because only 2\xa0of the 807\xa0recorded attacks in HELP-03 had completed EQ-5D data. The committee considered the company's approach to utility values and noted that the ERG had not changed this in its preferred analysis. It concluded that the company's preferred utility values that included a benefit for lanadelumab subcutaneous administration were acceptable for decision making.\n\n# End of life\n\n## Lanadelumab does not meet the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It noted that lanadelumab is a long-term preventive treatment and that the company did not make a case for it to be considered a life-extending treatment. The committee was aware that the company's revised base case showed no difference between the modelled mean survival for lanadelumab and C1-INHs despite the very small survival benefit associated with lanadelumab (see section\xa03.8). However, based on the evidence presented, the committee concluded that lanadelumab did not meet the criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness results\n\n## The company's revised base case comparing lanadelumab with C1-INHs is not suitable for decision making\n\nThe company submitted a revised base case after consultation. This showed that lanadelumab was dominant (that is, less costly and more effective) compared with C1-INHs in the full HELP-03 population and in the subgroup of people with at least 8\xa0attacks in the previous 4\xa0weeks. However, the committee noted that this did not include all of its preferred assumptions, that is:\n\n% of people having a C1-INH will have Berinert and the rest will have Cinryze (see section\xa03.12)\n\nall cost-effectiveness results should include the current discounted costs paid by the NHS for acute and preventive C1-INH treatment (see section\xa03.13)\n\nuse dosing data from the company's advisory board for Berinert (see section\xa03.14)\n\n% of people having lanadelumab would switch to a lower dosing frequency after 1\xa0year (see section\xa03.15).Therefore, the committee concluded that the company's revised base case was not suitable for decision making.\n\n## Lanadelumab compared with C1-INHs is mostly cost effective and is only recommended for people eligible for preventive C1-INHs\n\nThe committee firstly considered cost-effectiveness estimates for lanadelumab compared with C1-INHs for the full HELP-03 population. It noted that most estimates from the company's plausible scenario analyses were lower than £20,000 per quality-adjusted life year (QALY) gained after including the confidential price discounts for C1-INHs (exact incremental cost-effectiveness ratios [ICERs] are confidential and cannot be reported here). These scenarios used Berinert dosing data from the company's advisory board and assumed that 61% of people having lanadelumab switched to the lower dosing frequency. It noted that the most plausible cost-effectiveness estimate combining these preferred assumptions (see section\xa03.18) was also lower than £20,000 per QALY gained for the full HELP-03 population. Secondly, the committee considered all cost-effectiveness estimates for lanadelumab compared with C1-INHs for the subgroup from HELP-03 with at least 8\xa0attacks in the last 4\xa0weeks at baseline (that is, the population eligible for C1-INHs in NHS England's commissioning policy, see section\xa03.2). It noted that estimates from the company's plausible scenario analyses were lower than £20,000 per QALY gained after including the confidential price discounts for C1-INHs (exact ICERs are confidential and cannot be reported here). These scenarios used Berinert dosing data from the company's advisory board and assumed that 61% of people having lanadelumab switched to the lower dosing frequency. It noted that the most plausible cost-effectiveness estimate combining these preferred assumptions (see section\xa03.18) was also lower than £20,000 per QALY gained for the subgroup of people with at least 8\xa0attacks in the last 4\xa0weeks, and that this was lower than the estimate for the full HELP-03 population.The committee reiterated the uncertainty in all cost-effectiveness estimates, specifically that:\n\nthere was no evidence to support switching to a lower dosing frequency of lanadelumab (see section\xa03.5)\n\ncost-effectiveness estimates would be even higher if fewer than 61% of people switched to the lower lanadelumab dosing frequency (see section\xa03.15)\n\nthe QALY gain for lanadelumab was small relative to its incremental cost, meaning the cost-effectiveness results could change dramatically between different clinically plausible scenarios.The committee recalled the company's proposed positioning of lanadelumab (see section\xa03.2) and the remaining uncertainty around the proportion of people switching to the lower dosing frequency of lanadelumab (see section\xa03.5 and section\xa03.15), which it understood could lead to higher cost-effectiveness estimates. It concluded that lanadelumab could only be recommended as a cost-effective use of NHS resources:\n\nfor the subgroup of people who are eligible for a long-term preventive C1-INH and\n\nusing the lowest dosing frequency of lanadelumab, in line with the summary of product characteristics.\n\n# Innovation\n\n## Lanadelumab is innovative but all benefits are captured in the model\n\nThe committee considered lanadelumab to be innovative because it provided an alternative subcutaneous treatment option for people with recurrent attacks of hereditary angioedema. It noted that the company added a utility benefit for subcutaneous administration of lanadelumab in its revised base case. It recalled there may be a very small survival benefit associated with reducing hereditary angioedema attacks (see section\xa03.8), but it had not seen any evidence for this. The committee concluded that lanadelumab is innovative, but all relevant benefits were captured in the cost-effectiveness estimates.\n\n# Equalities considerations\n\n## There are no equalities issues relevant to the recommendation\n\nThe company highlighted that C1-INH treatment is based on human or animal products and may not be acceptable for some people. The clinical experts confirmed that both Berinert and Cinryze were human plasma-derived blood products and some people prefer to use Ruconest (a non-plasma-derived C1-INH based on animal products). But they noted that Ruconest was not commonly used in clinical practice. The committee noted that some people may refuse human plasma-derived products but understood that the animal-based C1-INH may be used instead. The committee was also aware that oral treatment with attenuated androgens could affect a woman's fertility and is therefore not appropriate for women who could have children. However, the committee noted that C1-INH treatment was available if long-term prevention with oral therapy was contraindicated, for example in pregnant women. It also understood that oral prevention options are used earlier in the treatment pathway than the company's positioning of lanadelumab. Therefore, the committee concluded that this was not a relevant equalities issue."}
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https://www.nice.org.uk/guidance/ta606
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Evidence-based recommendations on lanadelumab (Takhzyro) for preventing recurrent attacks of hereditary angioedema in people aged 12 and over.
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c49c3daeaebb640ec7f0aafc36cf85f200d7bfb8
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nice
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Diabetic foot problems: prevention and management
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Diabetic foot problems: prevention and management
This guideline covers preventing and managing foot problems in children, young people and adults with diabetes. It aims to reduce variation in practice, including antibiotic prescribing for diabetic foot infections.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Care within 24 hours of a person with diabetic foot problems being admitted to hospital, or the detection of diabetic foot problems (if the person is already in hospital)
Each hospital should have a care pathway for people with diabetic foot problems who need inpatient care.
A named consultant should be accountable for the overall care of the person, and for ensuring that healthcare professionals provide timely care.
Refer the person to the multidisciplinary foot care service within 24 hours of the initial examination of the person's feet. Transfer the responsibility of care to a consultant member of the multidisciplinary foot care service if a diabetic foot problem is the dominant clinical factor for inpatient care.
The named consultant and the healthcare professionals from the existing team should remain accountable for the care of the person unless their care is transferred to the multidisciplinary foot care service.
# Care across all settings
Commissioners and service providers should ensure that the following are in place:
A foot protection service for preventing diabetic foot problems, and for treating and managing diabetic foot problems in the community.
A multidisciplinary foot care service for managing diabetic foot problems in hospital and in the community that cannot be managed by the foot protection service. This may also be known as an interdisciplinary foot care service.
Robust protocols and clear local pathways for the continued and integrated care of people across all settings including emergency care and general practice. The protocols should set out the relationship between the foot protection service and the multidisciplinary foot care service.
Regular reviews of treatment and patient outcomes, in line with the National Diabetes Foot Care Audit.
The foot protection service should be led by a podiatrist with specialist training in diabetic foot problems, and should have access to healthcare professionals with skills in the following areas:
Diabetology.
Biomechanics and orthoses.
Wound care.
The multidisciplinary foot care service should be led by a named healthcare professional, and consist of specialists with skills in the following areas:
Diabetology.
Podiatry.
Diabetes specialist nursing.
Vascular surgery.
Microbiology.
Orthopaedic surgery.
Biomechanics and orthoses.
Interventional radiology.
Casting.
Wound care.
The multidisciplinary foot care service should have access to rehabilitation services, plastic surgery, psychological services and nutritional services.
Healthcare professionals may need to discuss, agree and make special arrangements for disabled people and people who are housebound or living in care settings, to ensure equality of access to foot care assessments and treatments for people with diabetes.
Take into account any disabilities, including visual impairment, when planning and delivering care for people with diabetes.
# Assessing the risk of developing a diabetic foot problem
## Frequency of assessments
For children with diabetes who are under 12 years, give them, and their family members or carers (as appropriate), basic foot care advice.
For young people with diabetes who are 12 to 17 years, the paediatric care team or the transitional care team should assess the young person's feet as part of their annual assessment, and provide information about foot care. If a diabetic foot problem is found or suspected, the paediatric care team or the transitional care team should refer the young person to an appropriate specialist.
For adults with diabetes, assess their risk of developing a diabetic foot problem at the following times:
When diabetes is diagnosed, and at least annually thereafter (see the recommendation on carrying out reassessments at intervals, depending on the person's risk of developing a diabetic foot problem).
If any foot problems arise.
On any admission to hospital, and if there is any change in their status while they are in hospital.
## Assessing the risk of developing a diabetic foot problem
When examining the feet of a person with diabetes, remove their shoes, socks, bandages and dressings, and examine both feet for evidence of the following risk factors:
neuropathy (use a 10 g monofilament as part of a foot sensory examination)
limb ischaemia (see the NICE guideline on peripheral arterial disease)
ulceration
callus
infection and/or inflammation
deformity
gangrene
Charcot arthropathy.
Use ankle brachial pressure index in line with the NICE guideline on peripheral arterial disease. Interpret results carefully in people with diabetes because calcified arteries may falsely elevate results.
Assess the person's current risk of developing a diabetic foot problem or needing an amputation using the following risk stratification:
Low risk:
no risk factors present except callus alone.
Moderate risk:
deformity or
neuropathy or
peripheral arterial disease.
High risk:
previous ulceration or
previous amputation or
-n renal replacement therapy or
neuropathy and peripheral arterial disease together or
neuropathy in combination with callus and/or deformity or
peripheral arterial disease in combination with callus and/or deformity.
Active diabetic foot problem:
ulceration or
infection or
chronic limb-threatening ischaemia or
gangrene or
suspicion of an acute Charcot arthropathy, or an unexplained hot, swollen foot with a change in colour, with or without pain.
For a short explanation of why the committee did not change the recommendations that were reviewed in 2023, and how this might affect practice, see the rationale and impact section on assessing the risk of developing a diabetic foot problem .
Full details of the evidence and the committee's discussion are in evidence review B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.
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## Managing the risk of developing a diabetic foot problem
For people who are at low risk of developing a diabetic foot problem:
continue to carry out foot assessments at their annual diabetes review
emphasise the importance of foot care (see the section on patient information about the risk of developing a diabetic foot problem)
advise them that they could progress to moderate or high risk.
Refer people who are at moderate or high risk of developing a diabetic foot problem to the foot protection service.
The foot protection service should assess newly referred people as follows:
Within 2 to 4 weeks for people who are at high risk of developing a diabetic foot problem.
Within 6 to 8 weeks for people who are at moderate risk of developing a diabetic foot problem.
For people at moderate or high risk of developing a diabetic foot problem, the foot protection service should:
Assess the feet.
Give advice about, and provide, skin and nail care of the feet.
Assess the biomechanical status of the feet, including the need to provide specialist footwear and orthoses.
Assess the vascular status of the lower limbs.
Liaise with other healthcare professionals, for example, the person's GP, about the person's diabetes management and risk of cardiovascular disease.
Depending on the person's risk of developing a diabetic foot problem, carry out reassessments at the following intervals:
Annually for people who are at low risk, as part of their annual diabetes review.
Frequently (for example, every 3 to 6 months) for people who are at moderate risk.
More frequently (for example, every 1 to 2 months) for people who are at high risk, if there is no immediate concern.
Very frequently (for example, every 1 to 2 weeks) for people who are at high risk, if there is immediate concern.
Consider more frequent reassessments for people who are at moderate or high risk, and for people who are unable to check their own feet.
People in hospital who are at moderate or high risk of developing a diabetic foot problem should be given a pressure redistribution device to offload heel pressure. On discharge they should be referred or notified to the foot protection service.
For a short explanation of why the committee did not change the recommendations that were reviewed in 2023, and how this might affect practice, see the rationale and impact section on managing the risk of developing a diabetic foot problem .
Full details of the evidence and the committee's discussion are in evidence review B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.
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## Patient information about the risk of developing a diabetic foot problem
Provide information and clear explanations to people with diabetes and/or their family members or carers (as appropriate) when diabetes is diagnosed, during assessments, and if problems arise. Information should be oral and written, and include the following:
Basic foot care advice and the importance of foot care.
Foot emergencies and who to contact.
Footwear advice.
The person's current individual risk of developing a foot problem.
Information about diabetes and the importance of blood glucose control (also see recommendation 1.3.14).
For guidance on education programmes and information about diabetes, see the education and information section in the NICE guideline on type 1 diabetes in adults, the education section in the NICE guideline on type 2 diabetes in adults, and the sections on education and information for children and young people with type 1 diabetes and education and information for children and young people with type 2 diabetes in the NICE guideline on diabetes (type 1 and type 2) in children and young people.
# Diabetic foot problems
## Referral
If a person has a limb-threatening or life-threatening diabetic foot problem, refer them immediately to acute services and inform the multidisciplinary foot care service (according to local protocols and pathways; also see the recommendation on services and protocols commissioners and service providers should ensure are in place), so they can be assessed and an individualised treatment plan put in place. Examples of limb-threatening and life-threatening diabetic foot problems include the following:
Ulceration with fever or any signs of sepsis.
Ulceration with limb ischaemia (see the NICE guideline on peripheral arterial disease).
Clinical concern that there is a deep-seated soft tissue or bone infection (with or without ulceration).
Gangrene (with or without ulceration).
For all other active diabetic foot problems, refer the person within 1 working day to the multidisciplinary foot care service or foot protection service (according to local protocols and pathways; also see the recommendation on services and protocols commissioners and service providers should ensure are in place) for triage within 1 further working day.
## Patient information about diabetic foot problems
Provide information and clear explanations as part of the individualised treatment plan for people with a diabetic foot problem. Information should be oral and written, and include the following:
A clear explanation of the person's foot problem.
Pictures of diabetic foot problems.
Care of the other foot and leg.
Foot emergencies and who to contact.
Footwear advice.
Wound care.
Information about diabetes and the importance of blood glucose control (also see the recommendation on additional guidance on education programmes and information about diabetes).
If a person presents with a diabetic foot problem, take into account that they may have an undiagnosed, increased risk of cardiovascular disease that may need further investigation and treatment. For guidance on the primary prevention of cardiovascular disease, see the NICE guideline on cardiovascular disease: risk assessment and reduction, including lipid modification.
# Diabetic foot ulcer
## Investigation
If a person has a diabetic foot ulcer, assess and document the size, depth and position of the ulcer.
Use a standardised system to document the severity of the foot ulcer, such as the SINBAD (Site, Ischaemia, Neuropathy, Bacterial Infection, Area and Depth) or the University of Texas classification system.
Do not use the Wagner classification system to assess the severity of a diabetic foot ulcer.
## Treatment
Offer 1 or more of the following as standard care for treating diabetic foot ulcers:
Offloading.
Control of foot infection.
Control of ischaemia.
Wound debridement.
Wound dressings.
Offer non‑removable casting to offload plantar neuropathic, non-ischaemic, uninfected forefoot and midfoot diabetic ulcers. Offer an alternative offloading device until casting can be provided.
In line with the NICE guideline on pressure ulcers, use pressure-redistributing devices and strategies to minimise the risk of pressure ulcers developing.
When treating diabetic foot ulcers, debridement in hospital should only be done by healthcare professionals from the multidisciplinary foot care service, using the technique that best matches their specialist expertise and clinical experience, the site of the diabetic foot ulcer and the person's preference.
When treating diabetic foot ulcers, debridement in the community should only be done by healthcare professionals with the relevant training and skills, continuing the care described in the person's treatment plan.
Consider negative pressure wound therapy after surgical debridement for diabetic foot ulcers, on the advice of the multidisciplinary foot care service.
When deciding about wound dressings and offloading when treating diabetic foot ulcers, take into account the clinical assessment of the wound and the person's preference, and use devices and dressings with the lowest acquisition cost appropriate to the clinical circumstances.
Consider dermal or skin substitutes as an adjunct to standard care when treating diabetic foot ulcers, only when healing has not progressed and on the advice of the multidisciplinary foot care service.
Do not offer the following to treat diabetic foot ulcers, unless as part of a clinical trial:
Electrical stimulation therapy, autologous platelet-rich plasma gel, regenerative wound matrices and dalteparin.
Growth factors (granulocyte colony-stimulating factor , platelet-derived growth factor , epidermal growth factor and transforming growth factor beta ).
Hyperbaric oxygen therapy.
When deciding the frequency of follow‑up as part of the treatment plan, take into account the overall health of the person with diabetes, how healing has progressed, and any deterioration.
Ensure that the frequency of monitoring set out in the person's individualised treatment plan is maintained whether the person with diabetes is being treated in hospital or in the community.
# Diabetic foot infection
## Investigation
If a diabetic foot infection is suspected and a wound is present, send a soft tissue or bone sample from the base of the debrided wound for microbiological examination. If this cannot be obtained, take a deep swab because it may provide useful information on the choice of antibiotic treatment.
Consider an X‑ray of the person's affected foot (or feet) to determine the extent of the diabetic foot problem.
Think about osteomyelitis if the person with diabetes has a local infection, a deep foot wound or a chronic foot wound.
Be aware that osteomyelitis may be present in a person with diabetes despite normal inflammatory markers, X‑rays or probe-to-bone testing.
If osteomyelitis is suspected in a person with diabetes but is not confirmed by initial X‑ray, consider an MRI to confirm the diagnosis.
## Treatment
Start antibiotic treatment for people with suspected diabetic foot infection as soon as possible. Take samples for microbiological testing before, or as close as possible to, the start of antibiotic treatment.
When choosing an antibiotic for people with a suspected diabetic foot infection (see recommendations 1.6.8 and 1.6.9), take account of:
the severity of diabetic foot infection (mild, moderate or severe)
the risk of developing complications
previous microbiological results
previous antibiotic use
patient preferences.
For a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on treatment .
Full details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.
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## Choice of antibiotic
When prescribing antibiotics for a suspected diabetic foot infection in adults aged 18 years and over, follow table 1 for a mild infection or table 2 for a moderate or severe infection.
Seek specialist advice when prescribing antibiotics for a suspected diabetic foot infection in children and young people under 18 years.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
If intravenous antibiotics are given, review by 48 hours and consider switching to oral antibiotics if possible.
Base antibiotic course length on the severity of the infection and a clinical assessment of response to treatment. Review the need for continued antibiotics regularly.
Antibiotic
Dosage and course length
See BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding.
Oral doses are for immediate-release medicines.
Flucloxacillin
mg to 1 g four times a day for 7 days.
A longer course (up to a further 7 days) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 7 days is not expected.
In August 2015, the upper dose of 1 g four times a day was off label. See NICE's information on prescribing medicines.
Antibiotic
Dosage and course length
See BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding.
Oral doses are for immediate-release medicines.
Clarithromycin
mg twice a day for 7 days.
A longer course (up to a further 7 days) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 7 days is not expected.
Erythromycin (in pregnancy)
mg four times a day for 7 days.
A longer course (up to a further 7 days) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 7 days is not expected.
Doxycycline
mg on first day, then 100 mg once a day (can be increased to 200 mg daily) for 7 days.
A longer course (up to a further 7 days) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 7 days is not expected.
Antibiotic
Dosage
See BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding, and administering intravenous (IV; or, where appropriate, intramuscular) antibiotics.
Oral doses are for immediate-release medicines.
Flucloxacillin with or without
g four times a day orally or 1 to 2 g four times a day IV.
In August 2015, the dose of 1 g four times a day was off label. See NICE's information on prescribing medicines.
Gentamicin and/or
Initially 5 to 7 mg/kg once a day IV, subsequent doses adjusted according to serum gentamicin concentration.
See BNF for information on therapeutic drug monitoring and monitoring of patient parameters.
Metronidazole
mg three times a day orally or 500 mg three times a day IV.
Co-amoxiclav with or without
/125 mg three times a day orally or 1.2 g three times a day IV
Gentamicin
Initially 5 to 7 mg/kg once a day IV, subsequent doses adjusted according to serum gentamicin concentration.
See BNF for information on therapeutic drug monitoring and monitoring of patient parameters.
Co-trimoxazole (in penicillin allergy) with or without
mg twice a day orally or 960 mg twice a day IV (can be increased to 1.44 g twice a day).
See BNF for information on monitoring of patient parameters.
In August 2015, this was not licensed for diabetic foot infection, so was off‑label. See NICE's information on prescribing medicines.
Gentamicin and/or
Initially 5 to 7 mg/kg once a day IV, subsequent doses adjusted according to serum gentamicin concentration.
See BNF for information on therapeutic drug monitoring and monitoring of patient parameters.
Metronidazole
mg three times a day orally or 500 mg three times a day IV.
Ceftriaxone with
g once a day IV.
Metronidazole
mg three times a day orally or 500 mg three times a day IV.
Notes:
Course length is based on clinical assessment: minimum of 7 days and up to 6 weeks for osteomyelitis (use oral antibiotics for prolonged treatment).
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics if possible.
Other antibiotics may be appropriate based on microbiological results and specialist advice.
Skin takes some time to return to normal, and full resolution of symptoms after a course of antibiotics is not expected. Review the need for continued antibiotics regularly.
Antibiotic
Dosage
See BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding, and administering intravenous (IV; or, where appropriate, intramuscular) antibiotics.
Oral doses are for immediate-release medicines.
Piperacillin with tazobactam
g three times a day IV (can be increased to 4.5 g four times a day).
Clindamycin with
to 300 mg four times a day orally (can be increased to 450 mg four times a day) or 600 mg to 2.7 g daily IV in two to four divided doses, increased if necessary in life-threatening infection to 4.8 g daily (maximum per dose 1.2 g).
Ciprofloxacin (consider safety issues) and/or
mg twice a day orally or 400 mg two or three times a day IV.
See Medicines and Healthcare products Regulatory Agency (MHRA) advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).
Gentamicin
Initially 5 to 7 mg/kg once a day IV, subsequent doses adjusted according to serum gentamicin concentration.
See BNF for information on therapeutic drug monitoring and monitoring of patient parameters.
Notes:
Course length is based on clinical assessment: minimum of 7 days and up to 6 weeks for osteomyelitis (use oral antibiotics for prolonged treatment).
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics if possible.
Other antibiotics may be appropriate based on microbiological results and specialist advice.
These antibiotics may also be appropriate in other situations based on microbiological results and specialist advice.
Antibiotic
Dosage
See BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding, and administering intravenous (IV; or, where appropriate, intramuscular) antibiotics.
Oral doses are for immediate-release medicines.
Vancomycin
to 20 mg/kg two or three times a day IV (maximum 2 g per dose), adjusted according to serum vancomycin concentration.
See BNF for information on therapeutic drug monitoring and monitoring of patient parameters.
Teicoplanin
Initially 6 mg/kg every 12 hours for three doses, then 6 mg/kg once a day IV.
See BNF for information on therapeutic drug monitoring and monitoring of patient parameters.
Linezolid (if vancomycin or teicoplanin cannot be used; specialist use only)
mg twice a day orally.
mg twice a day IV.
See BNF for information on monitoring of patient parameters.
Notes:
Course length is based on clinical assessment: minimum of 7 days and up to 6 weeks for osteomyelitis (use oral antibiotics for prolonged treatment).
Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics if possible.
Other antibiotics may be appropriate based on microbiological results and specialist advice.
For a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on choice of antibiotic, dose frequency, route of administration and course length .
Full details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.
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## Advice
When prescribing antibiotics for a diabetic foot infection, give advice about:
possible adverse effects of the antibiotic(s)
seeking medical help if symptoms worsen rapidly or significantly at any time, or do not start to improve within 1 to 2 days.
For a short explanation of why the committee made this 2019 recommendation and how it might affect practice, see the rationale and impact section on advice .
Full details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.
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## Reassessment
When microbiological results are available:
review the choice of antibiotic and
change the antibiotic according to results, using a narrow-spectrum antibiotic, if appropriate.
Reassess people with a suspected diabetic foot infection if symptoms worsen rapidly or significantly at any time, do not start to improve within 1 to 2 days, or the person becomes systemically very unwell or has severe pain out of proportion to the infection. Take account of:
-ther possible diagnoses, such as pressure sores, gout or non-infected ulcers
any symptoms or signs suggesting a more serious illness or condition, such as limb ischaemia, osteomyelitis, necrotising fasciitis or sepsis
previous antibiotic use.
For a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on reassessment .
Full details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.
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## Prevention
Do not offer antibiotics to prevent diabetic foot infections. Give advice about seeking medical help if symptoms of a diabetic foot infection develop.
For a short explanation of why the committee made this 2019 recommendation and how it might affect practice, see the rationale and impact section on prevention .
Full details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.
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# Charcot arthropathy
## Investigation
Be aware that if a person with diabetes fractures their foot or ankle, it may progress to Charcot arthropathy.
Suspect acute Charcot arthropathy if there is redness, warmth, swelling or deformity (in particular, when the skin is intact), especially in the presence of peripheral neuropathy or renal failure. Think about acute Charcot arthropathy even when deformity is not present or pain is not reported.
To confirm the diagnosis of acute Charcot arthropathy, refer the person within 1 working day to the multidisciplinary foot care service for triage within 1 further working day. Offer non-weight-bearing treatment until definitive treatment can be started by the multidisciplinary foot care service.
If acute Charcot arthropathy is suspected, arrange a weight-bearing X‑ray of the affected foot and ankle. Consider an MRI if the X‑ray is normal but Charcot arthropathy is still suspected.
## Treatment
If the multidisciplinary foot care service suspects acute Charcot arthropathy, offer treatment with a non-removable offloading device. If a non-removable device is not advisable because of the clinical, or the person's, circumstances, consider treatment with a removable offloading device.
Do not offer bisphosphonates to treat acute Charcot arthropathy, unless as part of a clinical trial.
Monitor the treatment of acute Charcot arthropathy using clinical assessment. This should include measuring foot–skin temperature difference and taking serial X‑rays until the acute Charcot arthropathy resolves. Acute Charcot arthropathy is likely to resolve when there is a sustained temperature difference of less than 2 degrees between both feet and when X‑ray changes show no further progression.
People who have a foot deformity that may be the result of a previous Charcot arthropathy are at high risk of ulceration and should be cared for by the foot protection service.
# Terms used in this guideline
## Diabetic foot infection
Diabetic foot infection is defined by the presence of at least 2 of the following:
local swelling or induration
erythema
local tenderness or pain
local warmth
purulent discharge.
Local infection involving only the skin and subcutaneous tissue; if erythema, must be 0.5 cm to less than 2 cm around the ulcer (exclude other causes of inflammatory response, such as trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis and venous stasis).
Local infection with erythema more than 2 cm around the ulcer or involving structures deeper than skin and subcutaneous tissues (such as abscess, osteomyelitis, septic arthritis or fasciitis), and no systemic inflammatory response signs.
Local infection with signs of systemic inflammatory response (such as temperature of more than 38°C or less than 36°C, increased heart rate or increased respiratory rate).
## Diabetic foot problem
'Diabetic foot problem' refers to any problem affecting the feet in people with diabetes that is caused by loss of sensation (peripheral sensory neuropathy) and/or circulation problems (peripheral arterial disease).
Diabetic foot problems include:
diabetic foot ulcers
soft tissue infection
destruction of the deep tissues such as heel pressure sores
-steomyelitis (bone infection)
Charcot arthropathy.
This guideline uses 'diabetic foot problem' throughout, because this is the term healthcare professionals will most commonly recognise for foot problems in people with diabetes. We do not mean to imply that people with diabetes should be blamed for their foot problems, and they should still be treated as individuals with their own needs, preferences and values.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Frequency of diabetic foot assessments
Based on clinical trial data and routinely collected real-world data, what is the clinical and cost effectiveness of annual foot assessments for people categorised as low risk, compared with checks every 2 years, in reducing diabetic foot problems (including ulcer, amputation and death)?
For a short explanation of why the committee made this recommendation for research, see the rationale section on managing the risk of developing a diabetic foot problem .
Full details of the evidence and the committee's discussion are in evidence review B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.
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## Digital and emerging technologies for assessing the risk of developing diabetic foot problems
What is the effectiveness, cost effectiveness and acceptability of digital and emerging technologies for:
assessing the risk of developing a diabetic foot problem
helping to prevent diabetic foot problems from developing.
For example, laser doppler flowmetry, infrared thermography, and devices for measuring and providing feedback on plantar pressure.
For a short explanation of why the committee made this recommendation for research, see the rationale section on managing the risk of developing a diabetic foot problem .
Full details of the evidence and the committee's discussion are in evidence review B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.
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## Referral criteria for the foot protection service and the multidisciplinary foot care service
When and with what criteria should people with diabetes be referred to the foot protection service or the multidisciplinary foot care service?
## Education and psycho-behavioural interventions for prevention
What is the role of educational models and psycho-behavioural interventions in prevention of diabetic foot complications?
## Prevention strategies for Charcot arthropathy
What strategies may be useful in the prevention of Charcot arthropathy?
## Diabetic ulcer dressings
What is the clinical effectiveness of different dressing types in treating diabetic foot problems?
# Other recommendations for research
## Referral of people who have diabetic foot problems
Within the hospital multidisciplinary team, when is it appropriate and effective to refer people with diabetes who have foot problems to specialist services such as investigative or interventional radiology, orthopaedic or vascular services, specialist pain management and specialist orthotics?
## Prevention of diabetic foot problems
What is the effectiveness of different footwear, insoles and orthoses in the prevention of foot problems?
## Review of people with diabetic foot problems
How often should people with diabetic foot problems (foot ulcers, soft tissue infections, osteomyelitis or gangrene) be reviewed?
For a short explanation of why the committee made this recommendation for research, see the rationale section on managing the risk of developing a diabetic foot problem .
Full details of the evidence and the committee's discussion are in evidence review B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.
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## Negative pressure wound therapy for treating diabetic foot ulcers
What is the clinical effectiveness of negative pressure wound therapy in the treatment of diabetic foot ulcers?
## Maggot debridement therapy for treating diabetic foot ulcers
What is the clinical effectiveness of maggot debridement therapy in the debridement of diabetic foot ulcers?
## Risk stratification tools for predicting Charcot arthropathy
Which risk stratification tools can be used to predict the likelihood of Charcot arthropathy?
## When to stop contact casting for acute Charcot arthropathy
When is it safe to stop contact casting in the treatment of acute Charcot arthropathy? # Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Assessing the risk of a diabetic foot problem
Recommendations 1.3.4 and 1.3.6
## Why the committee made the recommendations
All the risk assessment tools reviewed by the committee were able to predict ulcer occurrence with acceptable accuracy. There were no significant differences in classification accuracy (assessed using c‑statistics) between the different risk assessment tools. When considering classification accuracy, sensitivity and specificity together, the PODUS and SIGN systems were the best. PODUS had a higher c‑statistic than SIGN, but it did not report sensitivity or specificity. SIGN had the best overall sensitivity and specificity.
The committee agreed that the most important factor for an assessment tool was the ability to accurately identify people who are at high risk of developing a diabetic foot ulcer. Accurate identification allows people to be referred to appropriate services, where monitoring and preventative treatment can be started. A focus on high sensitivity over high specificity may lead to more false positives, with more people incorrectly receiving increased monitoring and referral to specialist services. However, the committee believe that this is preferable to using a system with lower sensitivity, because an increased risk of ulcer, infection and amputation is much worse than wasted resources from unnecessary monitoring or referrals. Overall, the SIGN system showed the highest sensitivity for both high-risk and combined high- and moderate-risk groups.
The committee considered recommending the PODUS clinical prediction rule because:
evidence from the prospective cohort study was high quality
it has higher classification accuracy than the SIGN system and
it is a short and simple assessment with only 3 items, and it could be completed by primary care professionals who do not have specialist knowledge of diabetic foot care.
Despite the good evidence for the PODUS system, the committee decided not to change the 2015 recommendations, because:
SIGN had good sensitivity and specificity (although this assessment was based on a study with a high risk of bias).
PODUS did not include an assessment of foot deformity in its final model (in an earlier systematic review to identify the factors that most accurately predicted foot ulceration, foot deformity was rejected for being inconsistently defined). Based on their experience and knowledge of established research, the committee believe that this is an important clinical risk factor and disagreed with it being left out of the final PODUS model.
The SIGN system is also relatively simple. It uses the same 3 items as PODUS, but also includes an assessment of foot deformity. The committee think that assessments using SIGN would only take slightly longer than assessments using PODUS, and could also be completed by primary care professionals who do not have specialist knowledge of diabetic foot care.
SIGN is recommended by the 2015 guideline. It is well established in clinical practice, and widely recognised and understood by practitioners. If the committee recommended SIGN, existing processes could be used without issue and there would be no risk of a disruptive change to practice.
If the committee recommended PODUS, staff would need training on how to use the new system. Several free online training courses for primary care professionals would need changing. Primary care electronic patient record systems would also need to be modified.
There is no evidence assessing the use of PODUS in NHS practice. Given the difficulties the NHS and primary care are currently facing, the committee did not want to introduce a potentially expensive and time-consuming change in practice without clear evidence of a significant benefit. They were particularly concerned about the impact because of current low staffing levels and the time staff will need for retraining.
NHS organisations and diabetes specialists were broadly supportive of retaining the 2015 recommendations.
The 2015 guideline recommended a modified version of SIGN that includes a check for renal disease. The committee agreed that this modification is useful and should be retained, because renal disease is a known risk factor for diabetic foot problems.
## How the recommendations might affect practice
The recommendations have not changed, so no resource impact is expected.
Return to recommendations
# Managing the risk of developing a diabetic foot problem
Recommendations 1.3.7 and 1.3.11
## Why the committee made the recommendations
The evidence showed that 95.5% of people assessed as low risk at their first clinical assessment remained in the low-risk group at their final assessment 8 years later. The ulceration rate in the low-risk group is also very low. Given this evidence, the committee discussed reducing the frequency of foot risk assessments to once every 2 years. However, they were concerned about the impact this may have on patient care.
The annual foot assessment is not just a foot examination and risk assessment. It is also a chance to teach people how to look after their feet, and to emphasise the importance of doing so. Many people with diabetes do not have good foot care routines, or do not have foot care routines at all. They may not know what to do if they have a foot problem, or who to contact. And they may benefit from regular advice about risk factors for foot problems. Reducing the frequency of foot assessments would mean reducing the number of chances to encourage good foot care and direct people to sources of support.
The committee discussed options for providing education and support outside of foot assessments (for example, remote appointments). However, it was not clear how feasible it would be to run these extra appointments in practice. Foot assessments are currently part of the annual diabetes review, so it makes sense to continue to include the foot check and risk assessment in that appointment. There are also Quality and Outcomes Framework (QOF) indicators for annual foot examination and risk classification, which further justify retaining the current system.
Given the risk of reducing access to education and support, the committee agreed to continue recommending annual foot assessments. They agreed that, for the recommendations to change, better evidence would be needed comparing annual and 2‑yearly foot assessments. The committee therefore made recommendations for research on:
frequency of diabetic foot assessments
frequency of review for people with diabetic foot problems
whether access to new technologies can improve diabetic foot assessments.
## How the recommendations might affect practice
The recommendations have not changed, so no resource impact is expected.
Return to recommendations
# Treatment
Recommendations 1.6.6 and 1.6.7
## Why the committee made the recommendations
The committee agreed that in people with diabetes, all foot wounds are likely to be colonised with bacteria. However, for people with a diabetic foot infection, prompt treatment of the infection is important to prevent complications, including limb-threatening infections.
The committee agreed to retain the recommendation from the 2015 guideline that antibiotics should be started as soon as possible if a diabetic foot infection is suspected. The choice of antibiotic would depend on the severity of infection, although the committee acknowledged that the studies they looked at did not always differentiate between severities. The committee accepted the Infectious Diseases Society of America's definitions of mild, moderate and severe infection, and recommended that this should be taken into account when choosing an antibiotic.
The committee retained the 2015 recommendation that samples should be taken for microbiological testing before, or as close as possible to, the start of antibiotic treatment. This would allow empirical antibiotic treatment to be changed if needed when results are available.
## How the recommendations might affect practice
These recommendations are consistent with current practice.
Return to recommendations
# Choice of antibiotic, dose frequency, route of administration and course length
Recommendations 1.6.8 to 1.6.12
## Why the committee made the recommendations
The committee agreed that in their experience, the incidence of diabetic foot infections in children and young people is rare. The mean age of participants in the evidence considered ranged from 54 to 64 years. Based on these factors, the committee included an antibiotic prescribing table for adults, but not for children and young people. They recommended that if a diabetic foot infection is suspected or confirmed in children or young people, specialist advice should be sought regarding antibiotic choice and regimen.
The evidence showed no difference in clinical outcomes for most antibiotics. But the antibiotics used in the studies were not wholly representative of UK practice, with some not being available in the UK and others not widely used. There were no differences in adverse events for many antibiotic comparisons. However, there were differences between some antibiotic classes, with lower rates of adverse effects generally for beta-lactam antibiotics.
The committee agreed that the choice of antibiotic in adults should be based on severity of infection (mild, moderate or severe) and the risk of complications, while minimising adverse effects and antibiotic resistance. This means using narrow-spectrum antibiotics first where possible, and using microbiological results, when available, to guide treatment.
The antibiotics recommended have good activity against many of the pathogens that cause diabetic foot infection, have good penetration for skin and soft tissue infections, and can be used in the different settings where treatment may take place, including ambulatory care. Based on evidence, their experience and resistance data, the committee agreed that flucloxacillin is an effective empirical antibiotic for mild diabetic foot infections (with dosing taking account of a person's body weight and renal function). The committee agreed that flucloxacillin has poor oral bioavailability and in people with diabetes who could have impaired circulation, a higher (off‑label dose) of up to 1 g four times a day may be needed to adequately treat diabetic foot infection.
For adults with a moderate or severe diabetic foot infection, a choice of antibiotics (or combinations of antibiotics) should be available. This enables selection based on individual patient factors, likely pathogens, and guided by microbiological results where available. In moderate and severe infection (which includes osteomyelitis), broader cover is needed because aerobic and anaerobic bacteria may be present. Severe infections can become limb-threatening quickly so antibiotic choices with the broadest spectrum of cover are appropriate; this can be changed to a narrower-spectrum antibiotic based on microbiological results when available, in line with principles of good antimicrobial stewardship. For moderate or severe infection, the committee recommended flucloxacillin at a dose of 1 g four times a day.
Patient preference is also important, particularly for treatment that will involve a hospital stay or be prolonged. Diabetes is a chronic condition and people may have had previous foot infections, with previous courses of antibiotics, that will influence their preferences.
No evidence was identified comparing antibiotic dose, frequency or route of administration. However, the committee acknowledged that a person with a diabetic foot infection may already be on a number of other medications, and this should be taken into account when deciding on dose, frequency and route of administration of an antibiotic.
In line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that oral antibiotics should be used in preference to intravenous antibiotics where possible. Intravenous antibiotics should only be used for people who are severely ill, unable to tolerate oral treatment, or where oral treatment would not provide adequate coverage or tissue penetration. The use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.
The committee agreed that a shorter course was generally as effective as a longer course for adults with a mild diabetic foot infection, and a 7‑day course was sufficient for most people. However, it agreed that a longer course (up to a further 7 days) may be needed for some people based on a clinical assessment of their symptoms and history. They discussed the limited evidence on antibiotic course length, which compared 6 weeks with 12 weeks in adults with diabetic foot osteomyelitis. The committee agreed that for adults with a moderate or severe diabetic foot infection (which includes osteomyelitis), a 7‑day course would be a minimum, with antibiotic treatment for up to 6 weeks if they have osteomyelitis. When prolonged antibiotic treatment is given, oral options should be used and treatment should be reviewed regularly, taking into account the need for continued antibiotics. The committee discussed antibiotic choices for osteomyelitis and agreed that the empirical choices for moderate and severe diabetic foot infection are also effective empirical choices for osteomyelitis.
## How the recommendations might affect practice
The recommendations aim to optimise antibiotic use and reduce antibiotic resistance.
Return to recommendations
# Advice
Recommendation 1.6.13
## Why the committee made the recommendation
The committee based the recommendation on their experience and safety netting advice from the NICE guideline on antimicrobial stewardship. They agreed that if symptoms worsened rapidly or significantly at any time, or did not improve within 1 to 2 days, people with a diabetic foot infection should be advised to seek medical help.
## How the recommendation might affect practice
The recommendation should ensure that appropriate safety netting is in place.
Return to recommendation
# Reassessment
Recommendations 1.6.14 and 1.6.15
## Why the committee made the recommendations
The committee agreed that when microbiological results are available, they should be used to guide antibiotic choice. The committee recognised the complexity around interpreting microbiological results, and agreed that the quality and type of specimen should be taken into account when making decisions around whether to change an antibiotic. The committee also discussed factors that would indicate that a person with a diabetic foot infection would need to be reassessed. These included if an infection was rapidly or significantly worsening or not improving, if other diagnoses were possible, or symptoms suggested a more serious illness or condition.
## How the recommendations might affect practice
These recommendations should ensure that appropriate reassessment is in place.
Return to recommendations
# Prevention
Recommendation 1.6.16
## Why the committee made the recommendation
The committee agreed to retain the 2015 recommendation that antibiotics should not be given to prevent diabetic foot infections. No evidence was identified for antibiotic prophylaxis and the committee agreed that antibiotic prophylaxis is not appropriate because of concerns about antimicrobial resistance. People should be advised to seek medical help if symptoms of a diabetic foot infection develop.
## How the recommendation might affect practice
This recommendation is consistent with current practice.
Return to recommendation# Context
Diabetes is one of the most common chronic diseases in the UK and its prevalence is increasing. More than 4.9 million people in the UK have diabetes. Around 90% of these people have type 2 diabetes, around 8% have type 1 diabetes, and about 2% have rarer types of diabetes. By 2030, it is estimated that more than 5.5 million people in the UK will have diabetes. In England, the number of people diagnosed with diabetes increased between 2006 and 2019 from 1.9 million to 3.3 million. The life expectancy of people with diabetes is shortened by up to 15 years, and 75% die of macrovascular complications.
The risk of foot problems in people with diabetes is increased, largely because of either diabetic neuropathy (nerve damage or degeneration) or peripheral arterial disease (poor blood supply due to diseased large- and medium-sized blood vessels in the legs), or both. Peripheral arterial disease affects 1 in 3 people with diabetes over the age of 50 and can also increase the risk of heart attack and stroke. For more information, see the NICE guideline on peripheral arterial disease.
Foot complications are common in people with diabetes. It is estimated that 10% of people with diabetes will have a diabetic foot ulcer at some point in their lives. A foot ulcer can be defined as a localised injury to the skin and/or underlying tissue, below the ankle, in a person with diabetes.
Diabetes is the most common cause of non-traumatic limb amputation, with diabetic foot ulcers preceding more than 80% of amputations in people with diabetes. More than 7,000 diabetes-related amputations are reported in the UK per year. People are at higher risk of diabetes-related major and minor limb amputations if they are male, from the most deprived areas, aged over 65, or of white European family background. After a first amputation, people with diabetes are twice as likely to have a subsequent amputation as people without diabetes. Mortality rates after diabetic foot ulceration and amputation are high, with up to 70% of people dying within 5 years of having an amputation and around 50% dying within 5 years of developing a diabetic foot ulcer. This high mortality rate is believed to be associated with cardiovascular disease, and emphasises the importance of good diabetic and cardiovascular risk management. Although people of South Asian, African and African Caribbean family origin are more at risk of diabetes, there is no evidence that the prevalence of diabetic foot ulceration and amputation is higher in these subgroups than in the general population of people with diabetes in the UK.
Foot problems in people with diabetes have a significant financial impact on the NHS through primary care, community care, outpatient costs, increased bed occupancy and prolonged stays in hospital. The NHS spends at least £10 billion a year on diabetes, equivalent to 10% of its budget. Of this, 80% is spent on treating complications, and diabetic foot care is estimated to cost the NHS in England over £1 billion per year. Diabetic foot care accounts for more healthcare costs in England than breast, prostate and lung cancer combined. Much of these costs come from treating prolonged and severe ulceration.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Care within 24\xa0hours of a person with diabetic foot problems being admitted to hospital, or the detection of diabetic foot problems (if the person is already in hospital)\n\nEach hospital should have a care pathway for people with diabetic foot problems who need inpatient care. \n\nA named consultant should be accountable for the overall care of the person, and for ensuring that healthcare professionals provide timely care. \n\nRefer the person to the multidisciplinary foot care service within 24\xa0hours of the initial examination of the person's feet. Transfer the responsibility of care to a consultant member of the multidisciplinary foot care service if a diabetic foot problem is the dominant clinical factor for inpatient care. \n\nThe named consultant and the healthcare professionals from the existing team should remain accountable for the care of the person unless their care is transferred to the multidisciplinary foot care service. \n\n# Care across all settings\n\nCommissioners and service providers should ensure that the following are in place:\n\nA foot protection service for preventing diabetic foot problems, and for treating and managing diabetic foot problems in the community.\n\nA multidisciplinary foot care service for managing diabetic foot problems in hospital and in the community that cannot be managed by the foot protection service. This may also be known as an interdisciplinary foot care service.\n\nRobust protocols and clear local pathways for the continued and integrated care of people across all settings including emergency care and general practice. The protocols should set out the relationship between the foot protection service and the multidisciplinary foot care service.\n\nRegular reviews of treatment and patient outcomes, in line with the National Diabetes Foot Care Audit. \n\nThe foot protection service should be led by a podiatrist with specialist training in diabetic foot problems, and should have access to healthcare professionals with skills in the following areas:\n\nDiabetology.\n\nBiomechanics and orthoses.\n\nWound care. \n\nThe multidisciplinary foot care service should be led by a named healthcare professional, and consist of specialists with skills in the following areas:\n\nDiabetology.\n\nPodiatry.\n\nDiabetes specialist nursing.\n\nVascular surgery.\n\nMicrobiology.\n\nOrthopaedic surgery.\n\nBiomechanics and orthoses.\n\nInterventional radiology.\n\nCasting.\n\nWound care. \n\nThe multidisciplinary foot care service should have access to rehabilitation services, plastic surgery, psychological services and nutritional services. \n\nHealthcare professionals may need to discuss, agree and make special arrangements for disabled people and people who are housebound or living in care settings, to ensure equality of access to foot care assessments and treatments for people with diabetes. \n\nTake into account any disabilities, including visual impairment, when planning and delivering care for people with diabetes. \n\n# Assessing the risk of developing a diabetic foot problem\n\n## Frequency of assessments\n\nFor children with diabetes who are under 12\xa0years, give them, and their family members or carers (as appropriate), basic foot care advice. \n\nFor young people with diabetes who are 12\xa0to 17\xa0years, the paediatric care team or the transitional care team should assess the young person's feet as part of their annual assessment, and provide information about foot care. If a diabetic foot problem is found or suspected, the paediatric care team or the transitional care team should refer the young person to an appropriate specialist. \n\nFor adults with diabetes, assess their risk of developing a diabetic foot problem at the following times:\n\nWhen diabetes is diagnosed, and at least annually thereafter (see the recommendation\xa0on carrying out reassessments at intervals, depending on the person's risk of developing a diabetic foot problem).\n\nIf any foot problems arise.\n\nOn any admission to hospital, and if there is any change in their status while they are in hospital. \n\n## Assessing the risk of developing a diabetic foot problem\n\nWhen examining the feet of a person with diabetes, remove their shoes, socks, bandages and dressings, and examine both feet for evidence of the following risk factors:\n\nneuropathy (use a 10\xa0g monofilament as part of a foot sensory examination)\n\nlimb ischaemia (see the NICE guideline on peripheral arterial disease)\n\nulceration\n\ncallus\n\ninfection and/or inflammation\n\ndeformity\n\ngangrene\n\nCharcot arthropathy. \n\nUse ankle brachial pressure index in line with the NICE guideline on peripheral arterial disease. Interpret results carefully in people with diabetes because calcified arteries may falsely elevate results. \n\nAssess the person's current risk of developing a diabetic foot problem or needing an amputation using the following risk stratification:\n\nLow risk:\n\n\n\nno risk factors present except callus alone.\n\n\n\nModerate risk:\n\n\n\ndeformity or\n\nneuropathy or\n\nperipheral arterial disease.\n\n\n\nHigh risk:\n\n\n\nprevious ulceration or\n\nprevious amputation or\n\non renal replacement therapy or\n\nneuropathy and peripheral arterial disease together or\n\nneuropathy in combination with callus and/or deformity or\n\nperipheral arterial disease in combination with callus and/or deformity.\n\n\n\nActive diabetic foot problem:\n\n\n\nulceration or\n\ninfection or\n\nchronic limb-threatening ischaemia or\n\ngangrene or\n\nsuspicion of an acute Charcot arthropathy, or an unexplained hot, swollen foot with a change in colour, with or without pain. \n\n\n\nFor a short explanation of why the committee did not change the recommendations that were reviewed in 2023, and how this might affect practice, see the rationale and impact section on assessing the risk of developing a diabetic foot problem\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.\n\nLoading. Please wait.\n\n## Managing the risk of developing a diabetic foot problem\n\nFor people who are at low risk of developing a diabetic foot problem:\n\ncontinue to carry out foot assessments at their annual diabetes review\n\nemphasise the importance of foot care (see the section on patient information about the risk of developing a diabetic foot problem)\n\nadvise them that they could progress to moderate or high risk. \n\nRefer people who are at moderate or high risk of developing a diabetic foot problem to the foot protection service. \n\nThe foot protection service should assess newly referred people as follows:\n\nWithin 2 to 4\xa0weeks for people who are at high risk of developing a diabetic foot problem.\n\nWithin 6 to 8\xa0weeks for people who are at moderate risk of developing a diabetic foot problem. \n\nFor people at moderate or high risk of developing a diabetic foot problem, the foot protection service should:\n\nAssess the feet.\n\nGive advice about, and provide, skin and nail care of the feet.\n\nAssess the biomechanical status of the feet, including the need to provide specialist footwear and orthoses.\n\nAssess the vascular status of the lower limbs.\n\nLiaise with other healthcare professionals, for example, the person's GP, about the person's diabetes management and risk of cardiovascular disease. \n\nDepending on the person's risk of developing a diabetic foot problem, carry out reassessments at the following intervals:\n\nAnnually for people who are at low risk, as part of their annual diabetes review.\n\nFrequently (for example, every 3\xa0to 6\xa0months) for people who are at moderate risk.\n\nMore frequently (for example, every 1\xa0to 2\xa0months) for people who are at high risk, if there is no immediate concern.\n\nVery frequently (for example, every 1\xa0to 2\xa0weeks) for people who are at high risk, if there is immediate concern.\n\nConsider more frequent reassessments for people who are at moderate or high risk, and for people who are unable to check their own feet. \n\nPeople in hospital who are at moderate or high risk of developing a diabetic foot problem should be given a pressure redistribution device to offload heel pressure. On discharge they should be referred or notified to the foot protection service. \n\nFor a short explanation of why the committee did not change the recommendations that were reviewed in 2023, and how this might affect practice, see the rationale and impact section on managing the risk of developing a diabetic foot problem\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.\n\nLoading. Please wait.\n\n## Patient information about the risk of developing a diabetic foot problem\n\nProvide information and clear explanations to people with diabetes and/or their family members or carers (as appropriate) when diabetes is diagnosed, during assessments, and if problems arise. Information should be oral and written, and include the following:\n\nBasic foot care advice and the importance of foot care.\n\nFoot emergencies and who to contact.\n\nFootwear advice.\n\nThe person's current individual risk of developing a foot problem.\n\nInformation about diabetes and the importance of blood glucose control (also see recommendation\xa01.3.14). \n\nFor guidance on education programmes and information about diabetes, see the education and information section in the NICE guideline on type\xa01 diabetes in adults, the education section in the NICE guideline on type\xa02 diabetes in adults, and the sections on education and information for children and young people with type\xa01 diabetes and education and information for children and young people with type\xa02 diabetes in the NICE guideline on diabetes (type\xa01 and type\xa02) in children and young people. \n\n# Diabetic foot problems\n\n## Referral\n\nIf a person has a limb-threatening or life-threatening diabetic foot problem, refer them immediately to acute services and inform the multidisciplinary foot care service (according to local protocols and pathways; also see the recommendation on services and protocols commissioners and service providers should ensure are in place), so they can be assessed and an individualised treatment plan put in place. Examples of limb-threatening and life-threatening diabetic foot problems include the following:\n\nUlceration with fever or any signs of sepsis.\n\nUlceration with limb ischaemia (see the NICE guideline on peripheral arterial disease).\n\nClinical concern that there is a deep-seated soft tissue or bone infection (with or without ulceration).\n\nGangrene (with or without ulceration). \n\nFor all other active diabetic foot problems, refer the person within 1\xa0working day to the multidisciplinary foot care service or foot protection service (according to local protocols and pathways; also see the recommendation on services and protocols commissioners and service providers should ensure are in place) for triage within 1\xa0further working day. \n\n## Patient information about diabetic foot problems\n\nProvide information and clear explanations as part of the individualised treatment plan for people with a diabetic foot problem. Information should be oral and written, and include the following:\n\nA clear explanation of the person's foot problem.\n\nPictures of diabetic foot problems.\n\nCare of the other foot and leg.\n\nFoot emergencies and who to contact.\n\nFootwear advice.\n\nWound care.\n\nInformation about diabetes and the importance of blood glucose control (also see the recommendation\xa0on additional guidance on education programmes and information about diabetes). \n\nIf a person presents with a diabetic foot problem, take into account that they may have an undiagnosed, increased risk of cardiovascular disease that may need further investigation and treatment. For guidance on the primary prevention of cardiovascular disease, see the NICE guideline on cardiovascular disease: risk assessment and reduction, including lipid modification. \n\n# Diabetic foot ulcer\n\n## Investigation\n\nIf a person has a diabetic foot ulcer, assess and document the size, depth and position of the ulcer. \n\nUse a standardised system to document the severity of the foot ulcer, such as the SINBAD (Site, Ischaemia, Neuropathy, Bacterial Infection, Area and Depth) or the University of Texas classification system. \n\nDo not use the Wagner classification system to assess the severity of a diabetic foot ulcer. \n\n## Treatment\n\nOffer 1\xa0or more of the following as standard care for treating diabetic foot ulcers:\n\nOffloading.\n\nControl of foot infection.\n\nControl of ischaemia.\n\nWound debridement.\n\nWound dressings. \n\nOffer non‑removable casting to offload plantar neuropathic, non-ischaemic, uninfected forefoot and midfoot diabetic ulcers. Offer an alternative offloading device until casting can be provided. \n\nIn line with the NICE guideline on pressure ulcers, use pressure-redistributing devices and strategies to minimise the risk of pressure ulcers developing. \n\nWhen treating diabetic foot ulcers, debridement in hospital should only be done by healthcare professionals from the multidisciplinary foot care service, using the technique that best matches their specialist expertise and clinical experience, the site of the diabetic foot ulcer and the person's preference. \n\nWhen treating diabetic foot ulcers, debridement in the community should only be done by healthcare professionals with the relevant training and skills, continuing the care described in the person's treatment plan. \n\nConsider negative pressure wound therapy after surgical debridement for diabetic foot ulcers, on the advice of the multidisciplinary foot care service. \n\nWhen deciding about wound dressings and offloading when treating diabetic foot ulcers, take into account the clinical assessment of the wound and the person's preference, and use devices and dressings with the lowest acquisition cost appropriate to the clinical circumstances. \n\nConsider dermal or skin substitutes as an adjunct to standard care when treating diabetic foot ulcers, only when healing has not progressed and on the advice of the multidisciplinary foot care service. \n\nDo not offer the following to treat diabetic foot ulcers, unless as part of a clinical trial:\n\nElectrical stimulation therapy, autologous platelet-rich plasma gel, regenerative wound matrices and dalteparin.\n\nGrowth factors (granulocyte colony-stimulating factor [G‑CSF], platelet-derived growth factor [PDGF], epidermal growth factor [EGF] and transforming growth factor beta [TGF‑β]).\n\nHyperbaric oxygen therapy. \n\nWhen deciding the frequency of follow‑up as part of the treatment plan, take into account the overall health of the person with diabetes, how healing has progressed, and any deterioration. \n\nEnsure that the frequency of monitoring set out in the person's individualised treatment plan is maintained whether the person with diabetes is being treated in hospital or in the community. \n\n# Diabetic foot infection\n\n## Investigation\n\nIf a diabetic foot infection is suspected and a wound is present, send a soft tissue or bone sample from the base of the debrided wound for microbiological examination. If this cannot be obtained, take a deep swab because it may provide useful information on the choice of antibiotic treatment. \n\nConsider an X‑ray of the person's affected foot (or feet) to determine the extent of the diabetic foot problem. \n\nThink about osteomyelitis if the person with diabetes has a local infection, a deep foot wound or a chronic foot wound. \n\nBe aware that osteomyelitis may be present in a person with diabetes despite normal inflammatory markers, X‑rays or probe-to-bone testing. \n\nIf osteomyelitis is suspected in a person with diabetes but is not confirmed by initial X‑ray, consider an MRI to confirm the diagnosis. \n\n## Treatment\n\nStart antibiotic treatment for people with suspected diabetic foot infection as soon as possible. Take samples for microbiological testing before, or as close as possible to, the start of antibiotic treatment. \n\nWhen choosing an antibiotic for people with a suspected diabetic foot infection (see recommendations\xa01.6.8 and\xa01.6.9), take account of:\n\nthe severity of diabetic foot infection (mild, moderate or severe)\n\nthe risk of developing complications\n\nprevious microbiological results\n\nprevious antibiotic use\n\npatient preferences. \n\nFor a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.\n\nLoading. Please wait.\n\n## Choice of antibiotic\n\nWhen prescribing antibiotics for a suspected diabetic foot infection in adults aged 18\xa0years and over, follow table\xa01 for a mild infection or table\xa02 for a moderate or severe infection. \n\nSeek specialist advice when prescribing antibiotics for a suspected diabetic foot infection in children and young people under 18\xa0years. \n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics. \n\nIf intravenous antibiotics are given, review by 48\xa0hours and consider switching to oral antibiotics if possible. \n\nBase antibiotic course length on the severity of the infection and a clinical assessment of response to treatment. Review the need for continued antibiotics regularly. \n\nAntibiotic\n\nDosage and course length\n\nSee BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding.\n\nOral doses are for immediate-release medicines.\n\nFlucloxacillin\n\nmg to 1\xa0g four times a day for 7\xa0days.\n\nA longer course (up to a further 7\xa0days) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 7\xa0days is not expected.\n\nIn August 2015, the upper dose of 1\xa0g four times a day was off label. See NICE's information on prescribing medicines.\n\nAntibiotic\n\nDosage and course length\n\nSee BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding.\n\nOral doses are for immediate-release medicines.\n\nClarithromycin\n\nmg twice a day for 7\xa0days.\n\nA longer course (up to a further 7\xa0days) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 7\xa0days is not expected.\n\nErythromycin (in pregnancy)\n\nmg four times a day for 7\xa0days.\n\nA longer course (up to a further 7\xa0days) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 7\xa0days is not expected.\n\nDoxycycline\n\nmg on first day, then 100\xa0mg once a day (can be increased to 200\xa0mg daily) for 7\xa0days.\n\nA longer course (up to a further 7\xa0days) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 7\xa0days is not expected.\n\nAntibiotic\n\nDosage\n\nSee BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding, and administering intravenous (IV; or, where appropriate, intramuscular) antibiotics.\n\nOral doses are for immediate-release medicines.\n\nFlucloxacillin with or without\n\ng four times a day orally or 1 to 2\xa0g four times a day IV.\n\nIn August 2015, the dose of 1\xa0g four times a day was off label. See NICE's information on prescribing medicines.\n\nGentamicin and/or\n\nInitially 5 to 7\xa0mg/kg once a day IV, subsequent doses adjusted according to serum gentamicin concentration.\n\nSee BNF for information on therapeutic drug monitoring and monitoring of patient parameters.\n\nMetronidazole\n\nmg three times a day orally or 500\xa0mg three times a day IV.\n\nCo-amoxiclav with or without\n\n/125\xa0mg three times a day orally or 1.2\xa0g three times a day IV\n\nGentamicin\n\nInitially 5 to 7\xa0mg/kg once a day IV, subsequent doses adjusted according to serum gentamicin concentration.\n\nSee BNF for information on therapeutic drug monitoring and monitoring of patient parameters.\n\nCo-trimoxazole (in penicillin allergy) with or without\n\nmg twice a day orally or 960\xa0mg twice a day IV (can be increased to 1.44\xa0g twice a day).\n\nSee BNF for information on monitoring of patient parameters.\n\nIn August 2015, this was not licensed for diabetic foot infection, so was off‑label. See NICE's information on prescribing medicines.\n\nGentamicin and/or\n\nInitially 5 to 7\xa0mg/kg once a day IV, subsequent doses adjusted according to serum gentamicin concentration.\n\nSee BNF for information on therapeutic drug monitoring and monitoring of patient parameters.\n\nMetronidazole\n\nmg three times a day orally or 500\xa0mg three times a day IV.\n\nCeftriaxone with\n\ng once a day IV.\n\nMetronidazole\n\nmg three times a day orally or 500\xa0mg three times a day IV.\n\nNotes:\n\nCourse length is based on clinical assessment: minimum of 7\xa0days and up to 6\xa0weeks for osteomyelitis (use oral antibiotics for prolonged treatment).\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nOther antibiotics may be appropriate based on microbiological results and specialist advice.\n\nSkin takes some time to return to normal, and full resolution of symptoms after a course of antibiotics is not expected. Review the need for continued antibiotics regularly.\n\nAntibiotic\n\nDosage\n\nSee BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding, and administering intravenous (IV; or, where appropriate, intramuscular) antibiotics.\n\nOral doses are for immediate-release medicines.\n\nPiperacillin with tazobactam\n\ng three times a day IV (can be increased to 4.5\xa0g four times a day).\n\nClindamycin with\n\nto 300\xa0mg four times a day orally (can be increased to 450\xa0mg four times a day) or 600\xa0mg to 2.7\xa0g daily IV in two to four divided doses, increased if necessary in life-threatening infection to 4.8\xa0g daily (maximum per dose 1.2\xa0g).\n\nCiprofloxacin (consider safety issues) and/or\n\nmg twice a day orally or 400\xa0mg two or three times a day IV.\n\nSee Medicines and Healthcare products Regulatory Agency (MHRA) advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60\xa0years and avoiding coadministration with a corticosteroid (March\xa02019).\n\nGentamicin\n\nInitially 5 to 7\xa0mg/kg once a day IV, subsequent doses adjusted according to serum gentamicin concentration.\n\nSee BNF for information on therapeutic drug monitoring and monitoring of patient parameters.\n\nNotes:\n\nCourse length is based on clinical assessment: minimum of 7\xa0days and up to 6\xa0weeks for osteomyelitis (use oral antibiotics for prolonged treatment).\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nOther antibiotics may be appropriate based on microbiological results and specialist advice.\n\nThese antibiotics may also be appropriate in other situations based on microbiological results and specialist advice.\n\nAntibiotic\n\nDosage\n\nSee BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, or who are pregnant or breastfeeding, and administering intravenous (IV; or, where appropriate, intramuscular) antibiotics.\n\nOral doses are for immediate-release medicines.\n\nVancomycin\n\nto 20\xa0mg/kg two or three times a day IV (maximum 2\xa0g per dose), adjusted according to serum vancomycin concentration.\n\nSee BNF for information on therapeutic drug monitoring and monitoring of patient parameters.\n\nTeicoplanin\n\nInitially 6\xa0mg/kg every 12\xa0hours for three\xa0doses, then 6\xa0mg/kg once a day IV.\n\nSee BNF for information on therapeutic drug monitoring and monitoring of patient parameters.\n\nLinezolid (if vancomycin or teicoplanin cannot be used; specialist use only)\n\nmg twice a day orally.\n\nmg twice a day IV.\n\nSee BNF for information on monitoring of patient parameters.\n\nNotes:\n\nCourse length is based on clinical assessment: minimum of 7\xa0days and up to 6\xa0weeks for osteomyelitis (use oral antibiotics for prolonged treatment).\n\nReview intravenous antibiotics by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nOther antibiotics may be appropriate based on microbiological results and specialist advice.\n\nFor a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on choice of antibiotic, dose frequency, route of administration and course length\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.\n\nLoading. Please wait.\n\n## Advice\n\nWhen prescribing antibiotics for a diabetic foot infection, give advice about:\n\npossible adverse effects of the antibiotic(s)\n\nseeking medical help if symptoms worsen rapidly or significantly at any time, or do not start to improve within 1\xa0to\xa02\xa0days. \n\nFor a short explanation of why the committee made this 2019 recommendation and how it might affect practice, see the rationale and impact section on advice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.\n\nLoading. Please wait.\n\n## Reassessment\n\nWhen microbiological results are available:\n\nreview the choice of antibiotic and\n\nchange the antibiotic according to results, using a narrow-spectrum antibiotic, if appropriate. \n\nReassess people with a suspected diabetic foot infection if symptoms worsen rapidly or significantly at any time, do not start to improve within 1\xa0to 2\xa0days, or the person becomes systemically very unwell or has severe pain out of proportion to the infection. Take account of:\n\nother possible diagnoses, such as pressure sores, gout or non-infected ulcers\n\nany symptoms or signs suggesting a more serious illness or condition, such as limb ischaemia, osteomyelitis, necrotising fasciitis or sepsis\n\nprevious antibiotic use. \n\nFor a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on reassessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.\n\nLoading. Please wait.\n\n## Prevention\n\nDo not offer antibiotics to prevent diabetic foot infections. Give advice about seeking medical help if symptoms of a diabetic foot infection develop. \n\nFor a short explanation of why the committee made this 2019 recommendation and how it might affect practice, see the rationale and impact section on prevention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: diabetic foot infection: antimicrobial prescribing.\n\nLoading. Please wait.\n\n# Charcot arthropathy\n\n## Investigation\n\nBe aware that if a person with diabetes fractures their foot or ankle, it may progress to Charcot arthropathy. \n\nSuspect acute Charcot arthropathy if there is redness, warmth, swelling or deformity (in particular, when the skin is intact), especially in the presence of peripheral neuropathy or renal failure. Think about acute Charcot arthropathy even when deformity is not present or pain is not reported. \n\nTo confirm the diagnosis of acute Charcot arthropathy, refer the person within 1\xa0working day to the multidisciplinary foot care service for triage within 1\xa0further working day. Offer non-weight-bearing treatment until definitive treatment can be started by the multidisciplinary foot care service. \n\nIf acute Charcot arthropathy is suspected, arrange a weight-bearing X‑ray of the affected foot and ankle. Consider an MRI if the X‑ray is normal but Charcot arthropathy is still suspected. \n\n## Treatment\n\nIf the multidisciplinary foot care service suspects acute Charcot arthropathy, offer treatment with a non-removable offloading device. If a non-removable device is not advisable because of the clinical, or the person's, circumstances, consider treatment with a removable offloading device. \n\nDo not offer bisphosphonates to treat acute Charcot arthropathy, unless as part of a clinical trial. \n\nMonitor the treatment of acute Charcot arthropathy using clinical assessment. This should include measuring foot–skin temperature difference and taking serial X‑rays until the acute Charcot arthropathy resolves. Acute Charcot arthropathy is likely to resolve when there is a sustained temperature difference of less than 2\xa0degrees between both feet and when X‑ray changes show no further progression. \n\nPeople who have a foot deformity that may be the result of a previous Charcot arthropathy are at high risk of ulceration and should be cared for by the foot protection service. \n\n# Terms used in this guideline\n\n## Diabetic foot infection\n\nDiabetic foot infection is defined by the presence of at least 2\xa0of the following:\n\nlocal swelling or induration\n\nerythema\n\nlocal tenderness or pain\n\nlocal warmth\n\npurulent discharge.\n\nLocal infection involving only the skin and subcutaneous tissue; if erythema, must be 0.5\xa0cm to less than 2\xa0cm around the ulcer (exclude other causes of inflammatory response, such as trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis and venous stasis).\n\nLocal infection with erythema more than 2\xa0cm around the ulcer or involving structures deeper than skin and subcutaneous tissues (such as abscess, osteomyelitis, septic arthritis or fasciitis), and no systemic inflammatory response signs.\n\nLocal infection with signs of systemic inflammatory response (such as temperature of more than 38°C or less than 36°C, increased heart rate or increased respiratory rate).\n\n## Diabetic foot problem\n\n'Diabetic foot problem' refers to any problem affecting the feet in people with diabetes that is caused by loss of sensation (peripheral sensory neuropathy) and/or circulation problems (peripheral arterial disease).\n\nDiabetic foot problems include:\n\ndiabetic foot ulcers\n\nsoft tissue infection\n\ndestruction of the deep tissues such as heel pressure sores\n\nosteomyelitis (bone infection)\n\nCharcot arthropathy.\n\nThis guideline uses 'diabetic foot problem' throughout, because this is the term healthcare professionals will most commonly recognise for foot problems in people with diabetes. We do not mean to imply that people with diabetes should be blamed for their foot problems, and they should still be treated as individuals with their own needs, preferences and values.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Frequency of diabetic foot assessments\n\nBased on clinical trial data and routinely collected real-world data, what is the clinical and cost effectiveness of annual foot assessments for people categorised as low risk, compared with checks every 2\xa0years, in reducing diabetic foot problems (including ulcer, amputation and death)? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing the risk of developing a diabetic foot problem\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.\n\nLoading. Please wait.\n\n## Digital and emerging technologies for assessing the risk of developing diabetic foot problems\n\nWhat is the effectiveness, cost effectiveness and acceptability of digital and emerging technologies for:\n\nassessing the risk of developing a diabetic foot problem\n\nhelping to prevent diabetic foot problems from developing.\n\nFor example, laser doppler flowmetry, infrared thermography, and devices for measuring and providing feedback on plantar pressure. \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing the risk of developing a diabetic foot problem\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.\n\nLoading. Please wait.\n\n## Referral criteria for the foot protection service and the multidisciplinary foot care service\n\nWhen and with what criteria should people with diabetes be referred to the foot protection service or the multidisciplinary foot care service? \n\n## Education and psycho-behavioural interventions for prevention\n\nWhat is the role of educational models and psycho-behavioural interventions in prevention of diabetic foot complications? \n\n## Prevention strategies for Charcot arthropathy\n\nWhat strategies may be useful in the prevention of Charcot arthropathy? \n\n## Diabetic ulcer dressings\n\nWhat is the clinical effectiveness of different dressing types in treating diabetic foot problems? \n\n# Other recommendations for research\n\n## Referral of people who have diabetic foot problems\n\nWithin the hospital multidisciplinary team, when is it appropriate and effective to refer people with diabetes who have foot problems to specialist services such as investigative or interventional radiology, orthopaedic or vascular services, specialist pain management and specialist orthotics? \n\n## Prevention of diabetic foot problems\n\nWhat is the effectiveness of different footwear, insoles and orthoses in the prevention of foot problems? \n\n## Review of people with diabetic foot problems\n\nHow often should people with diabetic foot problems (foot ulcers, soft tissue infections, osteomyelitis or gangrene) be reviewed? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing the risk of developing a diabetic foot problem\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: risk assessment models and tools for predicting the development of diabetic foot problems and foot review frequency.\n\nLoading. Please wait.\n\n## Negative pressure wound therapy for treating diabetic foot ulcers\n\nWhat is the clinical effectiveness of negative pressure wound therapy in the treatment of diabetic foot ulcers? \n\n## Maggot debridement therapy for treating diabetic foot ulcers\n\nWhat is the clinical effectiveness of maggot debridement therapy in the debridement of diabetic foot ulcers? \n\n## Risk stratification tools for predicting Charcot arthropathy\n\nWhich risk stratification tools can be used to predict the likelihood of Charcot arthropathy? \n\n## When to stop contact casting for acute Charcot arthropathy\n\nWhen is it safe to stop contact casting in the treatment of acute Charcot arthropathy? ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Assessing the risk of a diabetic foot problem\n\nRecommendations 1.3.4 and 1.3.6\n\n## Why the committee made the recommendations\n\nAll the risk assessment tools reviewed by the committee were able to predict ulcer occurrence with acceptable accuracy. There were no significant differences in classification accuracy (assessed using c‑statistics) between the different risk assessment tools. When considering classification accuracy, sensitivity and specificity together, the PODUS and SIGN systems were the best. PODUS had a higher c‑statistic than SIGN, but it did not report sensitivity or specificity. SIGN had the best overall sensitivity and specificity.\n\nThe committee agreed that the most important factor for an assessment tool was the ability to accurately identify people who are at high risk of developing a diabetic foot ulcer. Accurate identification allows people to be referred to appropriate services, where monitoring and preventative treatment can be started. A focus on high sensitivity over high specificity may lead to more false positives, with more people incorrectly receiving increased monitoring and referral to specialist services. However, the committee believe that this is preferable to using a system with lower sensitivity, because an increased risk of ulcer, infection and amputation is much worse than wasted resources from unnecessary monitoring or referrals. Overall, the SIGN system showed the highest sensitivity for both high-risk and combined high- and moderate-risk groups.\n\nThe committee considered recommending the PODUS clinical prediction rule because:\n\nevidence from the prospective cohort study was high quality\n\nit has higher classification accuracy than the SIGN system and\n\nit is a short and simple assessment with only 3\xa0items, and it could be completed by primary care professionals who do not have specialist knowledge of diabetic foot care.\n\nDespite the good evidence for the PODUS system, the committee decided not to change the 2015 recommendations, because:\n\nSIGN had good sensitivity and specificity (although this assessment was based on a study with a high risk of bias).\n\nPODUS did not include an assessment of foot deformity in its final model (in an earlier systematic review to identify the factors that most accurately predicted foot ulceration, foot deformity was rejected for being inconsistently defined). Based on their experience and knowledge of established research, the committee believe that this is an important clinical risk factor and disagreed with it being left out of the final PODUS model.\n\nThe SIGN system is also relatively simple. It uses the same 3\xa0items as PODUS, but also includes an assessment of foot deformity. The committee think that assessments using SIGN would only take slightly longer than assessments using PODUS, and could also be completed by primary care professionals who do not have specialist knowledge of diabetic foot care.\n\nSIGN is recommended by the 2015 guideline. It is well established in clinical practice, and widely recognised and understood by practitioners. If the committee recommended SIGN, existing processes could be used without issue and there would be no risk of a disruptive change to practice.\n\nIf the committee recommended PODUS, staff would need training on how to use the new system. Several free online training courses for primary care professionals would need changing. Primary care electronic patient record systems would also need to be modified.\n\nThere is no evidence assessing the use of PODUS in NHS practice. Given the difficulties the NHS and primary care are currently facing, the committee did not want to introduce a potentially expensive and time-consuming change in practice without clear evidence of a significant benefit. They were particularly concerned about the impact because of current low staffing levels and the time staff will need for retraining.\n\nNHS organisations and diabetes specialists were broadly supportive of retaining the 2015 recommendations.\n\nThe 2015 guideline recommended a modified version of SIGN that includes a check for renal disease. The committee agreed that this modification is useful and should be retained, because renal disease is a known risk factor for diabetic foot problems.\n\n## How the recommendations might affect practice\n\nThe recommendations have not changed, so no resource impact is expected.\n\nReturn to recommendations\n\n# Managing the risk of developing a diabetic foot problem\n\nRecommendations 1.3.7 and 1.3.11\n\n## Why the committee made the recommendations\n\nThe evidence showed that 95.5% of people assessed as low risk at their first clinical assessment remained in the low-risk group at their final assessment 8\xa0years later. The ulceration rate in the low-risk group is also very low. Given this evidence, the committee discussed reducing the frequency of foot risk assessments to once every 2\xa0years. However, they were concerned about the impact this may have on patient care.\n\nThe annual foot assessment is not just a foot examination and risk assessment. It is also a chance to teach people how to look after their feet, and to emphasise the importance of doing so. Many people with diabetes do not have good foot care routines, or do not have foot care routines at all. They may not know what to do if they have a foot problem, or who to contact. And they may benefit from regular advice about risk factors for foot problems. Reducing the frequency of foot assessments would mean reducing the number of chances to encourage good foot care and direct people to sources of support.\n\nThe committee discussed options for providing education and support outside of foot assessments (for example, remote appointments). However, it was not clear how feasible it would be to run these extra appointments in practice. Foot assessments are currently part of the annual diabetes review, so it makes sense to continue to include the foot check and risk assessment in that appointment. There are also Quality and Outcomes Framework (QOF) indicators for annual foot examination and risk classification, which further justify retaining the current system.\n\nGiven the risk of reducing access to education and support, the committee agreed to continue recommending annual foot assessments. They agreed that, for the recommendations to change, better evidence would be needed comparing annual and 2‑yearly foot assessments. The committee therefore made recommendations for research on:\n\nfrequency of diabetic foot assessments\n\nfrequency of review for people with diabetic foot problems\n\nwhether access to new technologies can improve diabetic foot assessments.\n\n## How the recommendations might affect practice\n\nThe recommendations have not changed, so no resource impact is expected.\n\nReturn to recommendations\n\n# Treatment\n\nRecommendations 1.6.6 and 1.6.7\n\n## Why the committee made the recommendations\n\nThe committee agreed that in people with diabetes, all foot wounds are likely to be colonised with bacteria. However, for people with a diabetic foot infection, prompt treatment of the infection is important to prevent complications, including limb-threatening infections.\n\nThe committee agreed to retain the recommendation from the 2015 guideline that antibiotics should be started as soon as possible if a diabetic foot infection is suspected. The choice of antibiotic would depend on the severity of infection, although the committee acknowledged that the studies they looked at did not always differentiate between severities. The committee accepted the Infectious Diseases Society of America's definitions of mild, moderate and severe infection, and recommended that this should be taken into account when choosing an antibiotic.\n\nThe committee retained the 2015 recommendation that samples should be taken for microbiological testing before, or as close as possible to, the start of antibiotic treatment. This would allow empirical antibiotic treatment to be changed if needed when results are available.\n\n## How the recommendations might affect practice\n\nThese recommendations are consistent with current practice.\n\nReturn to recommendations\n\n# Choice of antibiotic, dose frequency, route of administration and course length\n\nRecommendations 1.6.8 to 1.6.12\n\n## Why the committee made the recommendations\n\nThe committee agreed that in their experience, the incidence of diabetic foot infections in children and young people is rare. The mean age of participants in the evidence considered ranged from 54\xa0to 64\xa0years. Based on these factors, the committee included an antibiotic prescribing table for adults, but not for children and young people. They recommended that if a diabetic foot infection is suspected or confirmed in children or young people, specialist advice should be sought regarding antibiotic choice and regimen.\n\nThe evidence showed no difference in clinical outcomes for most antibiotics. But the antibiotics used in the studies were not wholly representative of UK practice, with some not being available in the UK and others not widely used. There were no differences in adverse events for many antibiotic comparisons. However, there were differences between some antibiotic classes, with lower rates of adverse effects generally for beta-lactam antibiotics.\n\nThe committee agreed that the choice of antibiotic in adults should be based on severity of infection (mild, moderate or severe) and the risk of complications, while minimising adverse effects and antibiotic resistance. This means using narrow-spectrum antibiotics first where possible, and using microbiological results, when available, to guide treatment.\n\nThe antibiotics recommended have good activity against many of the pathogens that cause diabetic foot infection, have good penetration for skin and soft tissue infections, and can be used in the different settings where treatment may take place, including ambulatory care. Based on evidence, their experience and resistance data, the committee agreed that flucloxacillin is an effective empirical antibiotic for mild diabetic foot infections (with dosing taking account of a person's body weight and renal function). The committee agreed that flucloxacillin has poor oral bioavailability and in people with diabetes who could have impaired circulation, a higher (off‑label dose) of up to 1\xa0g four times a day may be needed to adequately treat diabetic foot infection.\n\nFor adults with a moderate or severe diabetic foot infection, a choice of antibiotics (or combinations of antibiotics) should be available. This enables selection based on individual patient factors, likely pathogens, and guided by microbiological results where available. In moderate and severe infection (which includes osteomyelitis), broader cover is needed because aerobic and anaerobic bacteria may be present. Severe infections can become limb-threatening quickly so antibiotic choices with the broadest spectrum of cover are appropriate; this can be changed to a narrower-spectrum antibiotic based on microbiological results when available, in line with principles of good antimicrobial stewardship. For moderate or severe infection, the committee recommended flucloxacillin at a dose of 1\xa0g four times a day.\n\nPatient preference is also important, particularly for treatment that will involve a hospital stay or be prolonged. Diabetes is a chronic condition and people may have had previous foot infections, with previous courses of antibiotics, that will influence their preferences.\n\nNo evidence was identified comparing antibiotic dose, frequency or route of administration. However, the committee acknowledged that a person with a diabetic foot infection may already be on a number of other medications, and this should be taken into account when deciding on dose, frequency and route of administration of an antibiotic.\n\nIn line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that oral antibiotics should be used in preference to intravenous antibiotics where possible. Intravenous antibiotics should only be used for people who are severely ill, unable to tolerate oral treatment, or where oral treatment would not provide adequate coverage or tissue penetration. The use of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.\n\nThe committee agreed that a shorter course was generally as effective as a longer course for adults with a mild diabetic foot infection, and a 7‑day course was sufficient for most people. However, it agreed that a longer course (up to a further 7\xa0days) may be needed for some people based on a clinical assessment of their symptoms and history. They discussed the limited evidence on antibiotic course length, which compared 6\xa0weeks with 12\xa0weeks in adults with diabetic foot osteomyelitis. The committee agreed that for adults with a moderate or severe diabetic foot infection (which includes osteomyelitis), a 7‑day course would be a minimum, with antibiotic treatment for up to 6\xa0weeks if they have osteomyelitis. When prolonged antibiotic treatment is given, oral options should be used and treatment should be reviewed regularly, taking into account the need for continued antibiotics. The committee discussed antibiotic choices for osteomyelitis and agreed that the empirical choices for moderate and severe diabetic foot infection are also effective empirical choices for osteomyelitis.\n\n## How the recommendations might affect practice\n\nThe recommendations aim to optimise antibiotic use and reduce antibiotic resistance.\n\nReturn to recommendations\n\n# Advice\n\nRecommendation 1.6.13\n\n## Why the committee made the recommendation\n\nThe committee based the recommendation on their experience and safety netting advice from the NICE guideline on antimicrobial stewardship. They agreed that if symptoms worsened rapidly or significantly at any time, or did not improve within 1\xa0to 2\xa0days, people with a diabetic foot infection should be advised to seek medical help.\n\n## How the recommendation might affect practice\n\nThe recommendation should ensure that appropriate safety netting is in place.\n\nReturn to recommendation\n\n# Reassessment\n\nRecommendations 1.6.14 and 1.6.15\n\n## Why the committee made the recommendations\n\nThe committee agreed that when microbiological results are available, they should be used to guide antibiotic choice. The committee recognised the complexity around interpreting microbiological results, and agreed that the quality and type of specimen should be taken into account when making decisions around whether to change an antibiotic. The committee also discussed factors that would indicate that a person with a diabetic foot infection would need to be reassessed. These included if an infection was rapidly or significantly worsening or not improving, if other diagnoses were possible, or symptoms suggested a more serious illness or condition.\n\n## How the recommendations might affect practice\n\nThese recommendations should ensure that appropriate reassessment is in place.\n\nReturn to recommendations\n\n# Prevention\n\nRecommendation 1.6.16\n\n## Why the committee made the recommendation\n\nThe committee agreed to retain the 2015 recommendation that antibiotics should not be given to prevent diabetic foot infections. No evidence was identified for antibiotic prophylaxis and the committee agreed that antibiotic prophylaxis is not appropriate because of concerns about antimicrobial resistance. People should be advised to seek medical help if symptoms of a diabetic foot infection develop.\n\n## How the recommendation might affect practice\n\nThis recommendation is consistent with current practice.\n\nReturn to recommendation", 'Context': 'Diabetes is one\xa0of the most common chronic diseases in the UK and its prevalence is increasing. More than 4.9\xa0million people in the UK have diabetes. Around 90% of these people have type\xa02 diabetes, around 8% have type\xa01 diabetes, and about 2% have rarer types of diabetes. By 2030, it is estimated that more than 5.5\xa0million people in the UK will have diabetes. In England, the number of people diagnosed with diabetes increased between 2006 and 2019 from 1.9\xa0million to 3.3\xa0million. The life expectancy of people with diabetes is shortened by up to 15\xa0years, and 75% die of macrovascular complications.\n\nThe risk of foot problems in people with diabetes is increased, largely because of either diabetic neuropathy (nerve damage or degeneration) or peripheral arterial disease (poor blood supply due to diseased large- and medium-sized blood vessels in the legs), or both. Peripheral arterial disease affects 1\xa0in 3\xa0people with diabetes over the age of\xa050 and can also increase the risk of heart attack and stroke. For more information, see the NICE guideline on peripheral arterial disease.\n\nFoot complications are common in people with diabetes. It is estimated that 10% of people with diabetes will have a diabetic foot ulcer at some point in their lives. A foot ulcer can be defined as a localised injury to the skin and/or underlying tissue, below the ankle, in a person with diabetes.\n\nDiabetes is the most common cause of non-traumatic limb amputation, with diabetic foot ulcers preceding more than 80% of amputations in people with diabetes. More than 7,000\xa0diabetes-related amputations are reported in the UK per year. People are at higher risk of diabetes-related major and minor limb amputations if they are male, from the most deprived areas, aged over\xa065, or of white European family background. After a first amputation, people with diabetes are twice as likely to have a subsequent amputation as people without diabetes. Mortality rates after diabetic foot ulceration and amputation are high, with up to 70% of people dying within 5\xa0years of having an amputation and around 50% dying within 5\xa0years of developing a diabetic foot ulcer. This high mortality rate is believed to be associated with cardiovascular disease, and emphasises the importance of good diabetic and cardiovascular risk management. Although people of South Asian, African and African Caribbean family origin are more at risk of diabetes, there is no evidence that the prevalence of diabetic foot ulceration and amputation is higher in these subgroups than in the general population of people with diabetes in the UK.\n\nFoot problems in people with diabetes have a significant financial impact on the NHS through primary care, community care, outpatient costs, increased bed occupancy and prolonged stays in hospital. The NHS spends at least £10\xa0billion a year on diabetes, equivalent to 10% of its budget. Of this, 80% is spent on treating complications, and diabetic foot care is estimated to cost the NHS in England over £1\xa0billion per year. Diabetic foot care accounts for more healthcare costs in England than breast, prostate and lung cancer combined. Much of these costs come from treating prolonged and severe ulceration.'}
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https://www.nice.org.uk/guidance/ng19
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This guideline covers preventing and managing foot problems in children, young people and adults with diabetes. It aims to reduce variation in practice, including antibiotic prescribing for diabetic foot infections.
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08330ddd6e2f5b410147e9fbe590185fe3aa9c0e
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nice
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Gastro-oesophageal reflux disease in children and young people: diagnosis and management
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Gastro-oesophageal reflux disease in children and young people: diagnosis and management
This guideline covers diagnosing and managing gastro-oesophageal reflux disease in children and young people (under 18s). It aims to raise awareness of symptoms that need investigating and treating, and to reassure parents and carers that regurgitation is common in infants under 1 year.
# Introduction
Gastro‑oesophageal reflux (GOR) is a normal physiological process that usually happens after eating in healthy infants, children, young people and adults. In contrast, gastro‑oesophageal reflux disease (GORD) occurs when the effect of GOR leads to symptoms severe enough to merit medical treatment. GOR is more common in infants than in older children and young people, and it is noticeable by the effortless regurgitation of feeds in young babies.
In clinical practice, it is difficult to differentiate between GOR and GORD, and the terms are used interchangeably by health professionals and families alike. There is no simple, reliable and accurate diagnostic test to confirm whether the condition is GOR or GORD, and this in turn affects research and clinical decisions. Furthermore, the term GORD covers a number of specific conditions that have different effects and present in different ways. This makes it difficult to identify the person who genuinely has GORD, and to estimate the real prevalence and burden of the problem. Nevertheless, regardless of the definition used, GORD affects many children and families in the UK, who commonly seek medical advice and as a result, it constitutes a health burden for the NHS.
Generally, experts suggest that groups of children most affected by GORD are otherwise healthy infants, children with identifiable risk factors, and pubescent young people who acquire the problem in the same way as adults. The 2 other specific populations of children affected by GORD are premature infants and children with complex, severe neurodisabilities. In the latter group, the diagnosis is complicated further by a tendency to confuse vomiting with or without gut dysmotility with severe GORD. In addition, for a child with neurodisabilities, a diagnosis of GORD often fails to recognise a number of distinct problems that may coexist and combine to produce a very complicated feeding problem in an individual with already very complex health needs. For example, a child with severe cerebral palsy may be dependent on enteral tube feeding, have severe chronic vomiting, be constipated, have marked kyphoscoliosis, possess a poor swallow mechanism and be unable to safely protect their airway resulting in a risk of regular aspiration pneumonia.
This guideline focuses on signs and symptoms and interventions for GORD. Commonly observed events, such as infant regurgitation, are covered as well as much rarer but potentially more serious problems, such as apnoea. Where appropriate, clear recommendations are given as to when and how reassurance should be offered. The guideline also advises healthcare professionals about when to think about investigations, and what treatments to offer. Finally, it is emphasised that other, and on occasion more serious, conditions that need different management can be confused with some of the relatively common manifestations of GOR or GORD. These warning signs are defined under the headings of 'red flags' along with recommended initial actions.
# Safeguarding children
Remember that child maltreatment:
is common
can present anywhere
may co‑exist with other health problems, including GORD.
For more information see the NICE guideline on child maltreatment.
# Medicines
The guideline will assume that prescribers will use a medicine's summary of product characteristics to inform decisions made with individual patients.# Recommendations
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Terms used in this guideline
Infants, children and young people are defined as follows:
infants: under 1 year
children: 1 to under 12 years
young people: 12 to under 18 years.
Gastro‑oesophageal reflux (GOR) is the passage of gastric contents into the oesophagus. It is a common physiological event that can happen at all ages from infancy to old age, and is often asymptomatic. It occurs more frequently after feeds/meals. In many infants, GOR is associated with a tendency to 'overt regurgitation' – the visible regurgitation of feeds.
Gastro‑oesophageal reflux disease (GORD) refers to gastro‑oesophageal reflux that causes symptoms (for example, discomfort or pain) severe enough to merit medical treatment, or to gastro‑oesophageal reflux‑associated complications (such as oesophagitis or pulmonary aspiration). In adults, the term GORD is often used more narrowly, referring specifically to reflux oesophagitis.
Marked distress There is very limited evidence, and no objective or widely accepted clinical definition, for what constitutes 'marked distress' in infants and children who are unable to adequately communicate (expressively) their sensory emotions. In this guideline, 'marked distress' refers to an outward demonstration of pain or unhappiness that is outside what is considered to be the normal range by an appropriately trained, competent healthcare professional, based on a thorough assessment. This assessment should include a careful analysis of the description offered by the parents or carers in the clinical context of the individual child.
Occult reflux refers to the movement of part or all of the stomach contents up the oesophagus, but not to the extent that it enters the mouth or is obvious to the child, parents or carers, or observing healthcare professional. There is no obvious, visible regurgitation or vomiting. It is sometimes referred to as silent reflux.
Overt regurgitation refers tothe voluntary or involuntary movement of part or all of the stomach contents up the oesophagus at least to the mouth, and often emerging from the mouth. Regurgitation is in principle clinically observable, so is an overt phenomenon, although lesser degrees of regurgitation into the mouth might be overlooked.
Specialist refers to a paediatrician with the skills, experience and competency necessary to deal with the particular clinical concern that has been identified by the referring healthcare professional. In this guideline this is most likely to be a consultant general paediatrician. Depending on the clinical circumstances, 'specialist' may also refer to a paediatric surgeon, paediatric gastroenterologist or a doctor with the equivalent skills and competency.
# Diagnosing and investigating GORD
Recognise regurgitation of feeds as a common and normal occurrence in infants that:
is due to gastro‑oesophageal reflux (GOR) – a normal physiological process in infancy
does not usually need any investigation or treatment
is managed by advising and reassuring parents and carers.
Be aware that in a small proportion of infants, GOR may be associated with signs of distress or may lead to certain recognised complications that need clinical management. This is known as gastro‑oesophageal reflux disease (GORD).
Give advice about GOR and reassure parents and carers that in well infants, effortless regurgitation of feeds:
is very common (it affects at least 40% of infants)
usually begins before the infant is 8 weeks old
may be frequent (5% of those affected have 6 or more episodes each day)
usually becomes less frequent with time (it resolves in 90% of affected infants before they are 1 year old)
does not usually need further investigation or treatment.
When reassuring parents and carers about regurgitation, advise them that they should return for review if any of the following occur:
the regurgitation becomes persistently projectile
there is bile‑stained (green or yellow‑green) vomiting or haematemesis (blood in vomit)
there are new concerns, such as signs of marked distress, feeding difficulties or faltering growth
there is persistent, frequent regurgitation beyond the first year of life.
In infants, children and young people with vomiting or regurgitation, look out for the 'red flags' in table 1, which may suggest disorders other than GOR. Investigate or refer using clinical judgement.
## Table 1 'Red flag' symptoms suggesting disorders other than GOR
Gastrointestinal symptoms and signs
Possible diagnostic implications
Suggested actions
Frequent, forceful (projectile) vomiting
May suggest hypertrophic pyloric stenosis in infants up to 2 months old
Paediatric surgery referral
Bile‑stained (green or yellow‑green) vomit
May suggest intestinal obstruction
Paediatric surgery referral
Haematemesis (blood in vomit) with the exception of swallowed blood, for example, following a nose bleed or ingested blood from a cracked nipple in some breast‑fed infants
May suggest an important and potentially serious bleed from the oesophagus, stomach or upper gut
Specialist referral
Onset of regurgitation and/or vomiting after 6 months old or persisting after 1 year old
Late onset suggests a cause other than reflux, for example a urinary tract infection (also see the NICE guideline on urinary tract infection in under 16s)
Persistence suggests an alternative diagnosis
Urine microbiology investigation
Specialist referral
Blood in stool
May suggest a variety of conditions, including bacterial gastroenteritis, infant cows' milk protein allergy (also see the NICE guideline on food allergy in under 19s) or an acute surgical condition
Stool microbiology investigation
Specialist referral
Abdominal distension, tenderness or palpable mass
May suggest intestinal obstruction or another acute surgical condition
Paediatric surgery referral
Chronic diarrhoea
May suggest cows' milk protein allergy (also see the NICE guideline on food allergy in under 19s)
Specialist referral
Systemic symptoms and signs
Possible diagnostic implications
Suggested actions
Appearing unwell
Fever
May suggest infection (also see the NICE guideline on fever in under 5s)
Clinical assessment and urine microbiology investigation
Specialist referral
Dysuria
May suggest urinary tract infection (also see the NICE guideline on urinary tract infection in under 16s)
Clinical assessment and urine microbiology investigation
Specialist referral
Bulging fontanelle
May suggest raised intracranial pressure, for example, due to meningitis (also see the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s)
Specialist referral
Rapidly increasing head circumference (more than 1 cm per week)
Persistent morning headache, and vomiting worse in the morning
May suggest raised intracranial pressure, for example, due to hydrocephalus or a brain tumour
Specialist referral
Altered responsiveness, for example, lethargy or irritability
May suggest an illness such as meningitis (also see the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s)
Specialist referral
Infants and children with, or at high risk of, atopy
May suggest cows' milk protein allergy (also see the NICE guideline on food allergy in under 19s)
Specialist referral
Do not routinely investigate or treat for GOR if an infant or child without overt regurgitation presents with only 1 of the following:
unexplained feeding difficulties (for example, refusing to feed, gagging or choking)
distressed behaviour
faltering growth
chronic cough
hoarseness
a single episode of pneumonia.
Consider referring infants and children with persistent back arching or features of Sandifer's syndrome (episodic torticollis with neck extension and rotation) for specialist assessment.
Recognise the following as possible complications of GOR in infants, children and young people:
reflux oesophagitis
recurrent aspiration pneumonia
frequent otitis media (for example, more than 3 episodes in 6 months)
dental erosion in a child or young person with a neurodisability, in particular cerebral palsy.
Recognise the following as possible symptoms of GOR in children and young people:
heartburn
retrosternal pain
epigastric pain.
Be aware that GOR is more common in children and young people with asthma, but it has not been shown to cause or worsen it.
Be aware that some symptoms of a non‑IgE‑mediated cows' milk protein allergy can be similar to the symptoms of GORD, especially in infants with atopic symptoms, signs and/or a family history. If a non‑IgE‑mediated cows' milk protein allergy is suspected, see the NICE guideline on food allergy in under 19s.
When deciding whether to investigate or treat, take into account that the following are associated with an increased prevalence of GORD:
premature birth
parental history of heartburn or acid regurgitation
-besity
hiatus hernia
history of congenital diaphragmatic hernia (repaired)
history of congenital oesophageal atresia (repaired)
a neurodisability.
GOR only rarely causes episodes of apnoea or apparent life‑threatening events (ALTEs), but consider referral for specialist investigations if it is suspected as a possible factor following a general paediatric assessment.
For children and young people who are obese and have heartburn or acid regurgitation, advise them and their parents or carers (as appropriate) that losing weight may improve their symptoms (also see the NICE guideline on obesity).
Do not offer an upper gastrointestinal (GI) contrast study to diagnose or assess the severity of GORD in infants, children and young people.
Perform an urgent (same day) upper GI contrast study for infants with unexplained bile‑stained vomiting. Explain to the parents and carers that this is needed to rule out serious disorders such as intestinal obstruction due to mid‑gut volvulus.
Consider an upper GI contrast study for children and young people with a history of bile‑stained vomiting, particularly if it is persistent or recurrent.
Offer an upper GI contrast study for children and young people with a history of GORD presenting with dysphagia.
Arrange an urgent specialist hospital assessment to take place on the same day for infants younger than 2 months with progressively worsening or forceful vomiting of feeds, to assess them for possible hypertrophic pyloric stenosis.
Arrange a specialist hospital assessment for infants, children and young people for a possible upper GI endoscopy with biopsies if there is:
haematemesis (blood‑stained vomit) not caused by swallowed blood (assessment to take place on the same day if clinically indicated; also see table 1)
melaena (black, foul‑smelling stool; assessment to take place on the same day if clinically indicated; also see table 1)
dysphagia (assessment to take place on the same day if clinically indicated)
no improvement in regurgitation after 1 year old
persistent, faltering growth associated with overt regurgitation
unexplained distress in children and young people with communication difficulties
retrosternal, epigastric or upper abdominal pain that needs ongoing medical therapy or is refractory to medical therapy
feeding aversion and a history of regurgitation
unexplained iron‑deficiency anaemia
a suspected diagnosis of Sandifer's syndrome.
Consider performing an oesophageal pH study (or combined oesophageal pH and impedance monitoring if available) in infants, children and young people with:
suspected recurrent aspiration pneumonia
unexplained apnoeas
unexplained non‑epileptic seizure‑like events
unexplained upper airway inflammation
dental erosion associated with a neurodisability
frequent otitis media
a possible need for fundoplication (see the recommendations in the section on surgery for GORD)
a suspected diagnosis of Sandifer's syndrome.
Consider performing an oesophageal pH study without impedance monitoring in infants, children and young people if, using clinical judgement, it is thought necessary to ensure effective acid suppression.
Investigate the possibility of a urinary tract infection in infants with regurgitation if there is:
faltering growth
late onset (after the infant is 8 weeks old)
frequent regurgitation and marked distress.
# Initial management of GOR and GORD
Do not use positional management to treat GOR in sleeping infants. In line with NHS advice on sudden infant death syndrome (SIDS), infants should be placed on their back when sleeping.
In breast‑fed infants with frequent regurgitation associated with marked distress, ensure that a person with appropriate expertise and training carries out a breastfeeding assessment.
In formula‑fed infants with frequent regurgitation associated with marked distress, use the following stepped‑care approach:
review the feeding history, then
reduce the feed volumes only if excessive for the infant's weight, then
-ffer a trial of smaller, more frequent feeds (while maintaining an appropriate total daily amount of milk) unless the feeds are already small and frequent, then
-ffer a trial of thickened formula (for example, containing rice starch, cornstarch, locust bean gum or carob bean gum).
In breast‑fed infants with frequent regurgitation associated with marked distress that continues despite a breastfeeding assessment and advice, consider alginate therapy for a trial period of 1 to 2 weeks. If the alginate therapy is successful continue with it, but try stopping it at intervals to see if the infant has recovered.
In formula‑fed infants, if the stepped‑care approach is unsuccessful (see the recommendation on stepped-care approach for formula-fed infants with frequent regurgitation associated with marked distress), stop the thickened formula and offer alginate therapy for a trial period of 1 to 2 weeks. If the alginate therapy is successful continue with it, but try stopping it at intervals to see if the infant has recovered.
# Pharmacological treatment of GORD
Not all PPIs and H2RAs are licensed for use in children and those that are licensed vary in the age that they are licensed from. For licensing and prescribing information see the individual SPCs and BNF for children. MHRA drug safety updates have been issued for PPIs, covering hypomagnesaemia, the increased risk of fracture with long-term use and very low risk of subacute cutaneous lupus erythematosus.
Do not offer acid‑suppressing drugs, such as proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs), to treat overt regurgitation in infants and children occurring as an isolated symptom.
Consider a 4‑week trial of a PPI or H2RA for those who are unable to tell you about their symptoms (for example, infants and young children, and those with a neurodisability associated with expressive communication difficulties) who have overt regurgitation with 1 or more of the following:
unexplained feeding difficulties (for example, refusing feeds, gagging or choking)
distressed behaviour
faltering growth.
Consider a 4‑week trial of a PPI or H2RA for children and young people with persistent heartburn, retrosternal or epigastric pain.
Assess the response to the 4‑week trial of the PPI or H2RA, and consider referral to a specialist for possible endoscopy if the symptoms:
do not resolve or
recur after stopping the treatment.
When choosing between PPIs and H2RAs, take into account:
the availability of age‑appropriate preparations
the preference of the parent (or carer), child or young person (as appropriate)
local procurement costs.
Offer PPI or H2RA treatment to infants, children and young people with endoscopy‑proven reflux oesophagitis, and consider repeat endoscopic examinations as necessary to guide subsequent treatment.
Do not offer metoclopramide, domperidone or erythromycin to treat GOR or GORD unless all the following conditions are met:
the potential benefits outweigh the risk of adverse events
-ther interventions have been tried
there is specialist paediatric healthcare professional agreement for its use.Metoclopramide, domperidone and erythromycin are not licensed for use in children. Metoclopramide is contraindicated in infants, and should only be prescribed for short-term use (up to 5 days). For licensing and prescribing information see the individual SPCs and BNF for children. MHRA drug safety updates have been issued covering risk of cardiac side effects with domperidone and:
risk of neurological adverse events with metoclopramide
risk of infantile hypertrophic pyloric stenosis with erythromycin
cardiac risks (QT interval prolongation) with erythromycin and potential drug interaction of erythromycin with rivaroxaban.
# Enteral tube feeding for GORD
Only consider enteral tube feeding to promote weight gain in infants and children with overt regurgitation and faltering growth if:
-ther explanations for poor weight gain have been explored and/or
recommended feeding and medical management of overt regurgitation is unsuccessful.
Before starting enteral tube feeding for infants and children with faltering growth associated with overt regurgitation, agree in advance:
a specific, individualised nutrition plan
a strategy to reduce it as soon as possible
an exit strategy, if appropriate, to stop it as soon as possible.
In infants and children receiving enteral tube feeding for faltering growth associated with overt regurgitation:
provide oral stimulation, continuing oral feeding as tolerated
follow the nutrition plan, ensuring that the intended target weight is achieved and that appropriate weight gain is sustained
reduce and stop enteral tube feeding as soon as possible.
Consider jejunal feeding for infants, children and young people:
who need enteral tube feeding but who cannot tolerate intragastric feeds because of regurgitation or
if reflux‑related pulmonary aspiration is a concern.
# Surgery for GORD
Offer an upper GI endoscopy with oesophageal biopsies for infants, children and young people before deciding whether to offer fundoplication for presumed GORD.
Consider performing other investigations such as an oesophageal pH study (or combined oesophageal pH and impedance monitoring if available) and an upper GI contrast study for infants, children and young people before deciding whether to offer fundoplication.
Consider fundoplication in infants, children and young people with severe, intractable GORD if:
appropriate medical treatment has been unsuccessful or
feeding regimens to manage GORD prove impractical, for example, in the case of long‑term, continuous, thickened enteral tube feeding.# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Symptoms of gastro-oesophageal reflux disease (GORD) in infants, children and young people with a neurodisability
What are the symptoms of GORD in infants, children and young people with a neurodisability?
## Why this is important
The evidence reviewed on the symptoms associated with GORD in children and young people with a neurodisability was limited to 3 studies and graded as low‑ to very low‑quality. The lack of a set of clearly defined features makes GORD difficult to recognise and differentiate from other vomiting problems. The proposed study would use objective measures of reflux (such as oesophageal pH monitoring) to assess GORD symptoms in infants, children and young people with a neurodisability.
# Cows' milk protein elimination in formula-fed infants
What is the effectiveness and cost effectiveness of a trial of hydrolysed formula in formula‑fed infants with frequent regurgitation associated with marked distress?
## Why this is important
There is a widespread belief that GOR and/or GORD in formula‑fed infants is often caused by intolerance to cows' milk. As a result, health professionals often prescribe a trial of hydrolysed formula as a substitute for cows' milk formula. This has resource implications because hydrolysed formula is more expensive than cows' milk formula. Additionally, there is no evidence on the clinical or cost effectiveness of this approach. Therefore, it is proposed that a randomised controlled trial is undertaken to explore this question. It is important to consider 2 population subgroups:
infants with a personal or family history of atopic conditions
infants whose GOR and/or GORD has not responded to the initial management outlined in this guideline (up to and including alginates).
# Fundoplication and oesophageal pH monitoring
In infants, children and young people with overt or occult reflux, is fundoplication effective in reducing acid reflux as determined by oesophageal pH monitoring?
## Why this is important
Fundoplication is used to manage severe GORD. At present, there is limited evidence that overt regurgitation is reduced after surgery. However, this has not been objectively measured. In addition, the effect of surgery on occult reflux has not been assessed. This is important because surgery may be masking a continuing problem. The proposed study would monitor regurgitation before and after fundoplication using oesophageal pH monitoring. This may help health professionals identify which infants, children and young people will benefit from surgery.# Finding more information and resources
You can see everything NICE says on this topic in the NICE Pathway on dyspepsia and gastro-oesophageal reflux disease.
To find NICE guidance on related topics, including guidance in development, see the NICE webpage on gastro-oesophageal reflux, including Barrett's oesophagus.
For full details of the evidence and the guideline committee's discussions, see the full guideline. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.
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{'Introduction': "Gastro‑oesophageal reflux (GOR) is a normal physiological process that usually happens after eating in healthy infants, children, young people and adults. In contrast, gastro‑oesophageal reflux disease (GORD) occurs when the effect of GOR leads to symptoms severe enough to merit medical treatment. GOR is more common in infants than in older children and young people, and it is noticeable by the effortless regurgitation of feeds in young babies.\n\nIn clinical practice, it is difficult to differentiate between GOR and GORD, and the terms are used interchangeably by health professionals and families alike. There is no simple, reliable and accurate diagnostic test to confirm whether the condition is GOR or GORD, and this in turn affects research and clinical decisions. Furthermore, the term GORD covers a number of specific conditions that have different effects and present in different ways. This makes it difficult to identify the person who genuinely has GORD, and to estimate the real prevalence and burden of the problem. Nevertheless, regardless of the definition used, GORD affects many children and families in the UK, who commonly seek medical advice and as a result, it constitutes a health burden for the NHS.\n\nGenerally, experts suggest that groups of children most affected by GORD are otherwise healthy infants, children with identifiable risk factors, and pubescent young people who acquire the problem in the same way as adults. The 2\xa0other specific populations of children affected by GORD are premature infants and children with complex, severe neurodisabilities. In the latter group, the diagnosis is complicated further by a tendency to confuse vomiting with or without gut dysmotility with severe GORD. In addition, for a child with neurodisabilities, a diagnosis of GORD often fails to recognise a number of distinct problems that may coexist and combine to produce a very complicated feeding problem in an individual with already very complex health needs. For example, a child with severe cerebral palsy may be dependent on enteral tube feeding, have severe chronic vomiting, be constipated, have marked kyphoscoliosis, possess a poor swallow mechanism and be unable to safely protect their airway resulting in a risk of regular aspiration pneumonia.\n\nThis guideline focuses on signs and symptoms and interventions for GORD. Commonly observed events, such as infant regurgitation, are covered as well as much rarer but potentially more serious problems, such as apnoea. Where appropriate, clear recommendations are given as to when and how reassurance should be offered. The guideline also advises healthcare professionals about when to think about investigations, and what treatments to offer. Finally, it is emphasised that other, and on occasion more serious, conditions that need different management can be confused with some of the relatively common manifestations of GOR or GORD. These warning signs are defined under the headings of 'red flags' along with recommended initial actions.\n\n# Safeguarding children\n\nRemember that child maltreatment:\n\nis common\n\ncan present anywhere\n\nmay co‑exist with other health problems, including GORD.\n\nFor more information see the NICE guideline on child maltreatment.\n\n# Medicines\n\nThe guideline will assume that prescribers will use a medicine's summary of product characteristics to inform decisions made with individual patients.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Terms used in this guideline\n\nInfants, children and young people are defined as follows:\n\ninfants: under 1\xa0year\n\nchildren: 1 to under 12\xa0years\n\nyoung people: 12 to under 18\xa0years.\n\nGastro‑oesophageal reflux (GOR) is the passage of gastric contents into the oesophagus. It is a common physiological event that can happen at all ages from infancy to old age, and is often asymptomatic. It occurs more frequently after feeds/meals. In many infants, GOR is associated with a tendency to 'overt regurgitation' – the visible regurgitation of feeds.\n\nGastro‑oesophageal reflux disease (GORD) refers to gastro‑oesophageal reflux that causes symptoms (for example, discomfort or pain) severe enough to merit medical treatment, or to gastro‑oesophageal reflux‑associated complications (such as oesophagitis or pulmonary aspiration). In adults, the term GORD is often used more narrowly, referring specifically to reflux oesophagitis.\n\nMarked distress There is very limited evidence, and no objective or widely accepted clinical definition, for what constitutes 'marked distress' in infants and children who are unable to adequately communicate (expressively) their sensory emotions. In this guideline, 'marked distress' refers to an outward demonstration of pain or unhappiness that is outside what is considered to be the normal range by an appropriately trained, competent healthcare professional, based on a thorough assessment. This assessment should include a careful analysis of the description offered by the parents or carers in the clinical context of the individual child.\n\nOccult reflux refers to the movement of part or all of the stomach contents up the oesophagus, but not to the extent that it enters the mouth or is obvious to the child, parents or carers, or observing healthcare professional. There is no obvious, visible regurgitation or vomiting. It is sometimes referred to as silent reflux.\n\nOvert regurgitation refers tothe voluntary or involuntary movement of part or all of the stomach contents up the oesophagus at least to the mouth, and often emerging from the mouth. Regurgitation is in principle clinically observable, so is an overt phenomenon, although lesser degrees of regurgitation into the mouth might be overlooked.\n\nSpecialist refers to a paediatrician with the skills, experience and competency necessary to deal with the particular clinical concern that has been identified by the referring healthcare professional. In this guideline this is most likely to be a consultant general paediatrician. Depending on the clinical circumstances, 'specialist' may also refer to a paediatric surgeon, paediatric gastroenterologist or a doctor with the equivalent skills and competency.\n\n# Diagnosing and investigating GORD\n\nRecognise regurgitation of feeds as a common and normal occurrence in infants that:\n\nis due to gastro‑oesophageal reflux (GOR) – a normal physiological process in infancy\n\ndoes not usually need any investigation or treatment\n\nis managed by advising and reassuring parents and carers.\n\nBe aware that in a small proportion of infants, GOR may be associated with signs of distress or may lead to certain recognised complications that need clinical management. This is known as gastro‑oesophageal reflux disease (GORD).\n\nGive advice about GOR and reassure parents and carers that in well infants, effortless regurgitation of feeds:\n\nis very common (it affects at least 40% of infants)\n\nusually begins before the infant is 8\xa0weeks old\n\nmay be frequent (5% of those affected have 6 or more episodes each day)\n\nusually becomes less frequent with time (it resolves in 90% of affected infants before they are 1\xa0year old)\n\ndoes not usually need further investigation or treatment.\n\nWhen reassuring parents and carers about regurgitation, advise them that they should return for review if any of the following occur:\n\nthe regurgitation becomes persistently projectile\n\nthere is bile‑stained (green or yellow‑green) vomiting or haematemesis (blood in vomit)\n\nthere are new concerns, such as signs of marked distress, feeding difficulties or faltering growth\n\nthere is persistent, frequent regurgitation beyond the first year of life.\n\nIn infants, children and young people with vomiting or regurgitation, look out for the 'red flags' in table\xa01, which may suggest disorders other than GOR. Investigate or refer using clinical judgement.\n\n## Table 1 'Red flag' symptoms suggesting disorders other than GOR\n\nGastrointestinal symptoms and signs\n\nPossible diagnostic implications\n\nSuggested actions\n\nFrequent, forceful (projectile) vomiting\n\nMay suggest hypertrophic pyloric stenosis in infants up to 2\xa0months old\n\nPaediatric surgery referral\n\nBile‑stained (green or yellow‑green) vomit\n\nMay suggest intestinal obstruction\n\nPaediatric surgery referral\n\nHaematemesis (blood in vomit) with the exception of swallowed blood, for example, following a nose bleed or ingested blood from a cracked nipple in some breast‑fed infants\n\nMay suggest an important and potentially serious bleed from the oesophagus, stomach or upper gut\n\nSpecialist referral\n\nOnset of regurgitation and/or vomiting after 6\xa0months old or persisting after 1\xa0year old\n\nLate onset suggests a cause other than reflux, for example a urinary tract infection (also see the NICE guideline on urinary tract infection in under 16s)\n\nPersistence suggests an alternative diagnosis\n\nUrine microbiology investigation\n\n\n\nSpecialist referral\n\nBlood in stool\n\nMay suggest a variety of conditions, including bacterial gastroenteritis, infant cows' milk protein allergy (also see the NICE guideline on food allergy in under 19s) or an acute surgical condition\n\nStool microbiology investigation\n\n\n\nSpecialist referral\n\nAbdominal distension, tenderness or palpable mass\n\nMay suggest intestinal obstruction or another acute surgical condition\n\nPaediatric surgery referral\n\nChronic diarrhoea\n\nMay suggest cows' milk protein allergy (also see the NICE guideline on food allergy in under 19s)\n\nSpecialist referral\n\nSystemic symptoms and signs\n\nPossible diagnostic implications\n\nSuggested actions\n\nAppearing unwell\n\nFever\n\nMay suggest infection (also see the NICE guideline on fever in under 5s)\n\nClinical assessment and urine microbiology investigation\n\n\n\nSpecialist referral\n\nDysuria\n\nMay suggest urinary tract infection (also see the NICE guideline on urinary tract infection in under 16s)\n\nClinical assessment and urine microbiology investigation\n\n\n\nSpecialist referral\n\nBulging fontanelle\n\nMay suggest raised intracranial pressure, for example, due to meningitis (also see the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s)\n\nSpecialist referral\n\nRapidly increasing head circumference (more than 1\xa0cm per week)\n\n\n\nPersistent morning headache, and vomiting worse in the morning\n\nMay suggest raised intracranial pressure, for example, due to hydrocephalus or a brain tumour\n\nSpecialist referral\n\nAltered responsiveness, for example, lethargy or irritability\n\nMay suggest an illness such as meningitis (also see the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s)\n\nSpecialist referral\n\nInfants and children with, or at high risk of, atopy\n\nMay suggest cows' milk protein allergy (also see the NICE guideline on food allergy in under 19s)\n\nSpecialist referral\n\nDo not routinely investigate or treat for GOR if an infant or child without overt regurgitation presents with only 1 of the following:\n\nunexplained feeding difficulties (for example, refusing to feed, gagging or choking)\n\ndistressed behaviour\n\nfaltering growth\n\nchronic cough\n\nhoarseness\n\na single episode of pneumonia.\n\nConsider referring infants and children with persistent back arching or features of Sandifer's syndrome (episodic torticollis with neck extension and rotation) for specialist assessment.\n\nRecognise the following as possible complications of GOR in infants, children and young people:\n\nreflux oesophagitis\n\nrecurrent aspiration pneumonia\n\nfrequent otitis media (for example, more than 3\xa0episodes in 6\xa0months)\n\ndental erosion in a child or young person with a neurodisability, in particular cerebral palsy.\n\nRecognise the following as possible symptoms of GOR in children and young people:\n\nheartburn\n\nretrosternal pain\n\nepigastric pain.\n\nBe aware that GOR is more common in children and young people with asthma, but it has not been shown to cause or worsen it.\n\nBe aware that some symptoms of a non‑IgE‑mediated cows' milk protein allergy can be similar to the symptoms of GORD, especially in infants with atopic symptoms, signs and/or a family history. If a non‑IgE‑mediated cows' milk protein allergy is suspected, see the NICE guideline on food allergy in under 19s.\n\nWhen deciding whether to investigate or treat, take into account that the following are associated with an increased prevalence of GORD:\n\npremature birth\n\nparental history of heartburn or acid regurgitation\n\nobesity\n\nhiatus hernia\n\nhistory of congenital diaphragmatic hernia (repaired)\n\nhistory of congenital oesophageal atresia (repaired)\n\na neurodisability.\n\nGOR only rarely causes episodes of apnoea or apparent life‑threatening events (ALTEs), but consider referral for specialist investigations if it is suspected as a possible factor following a general paediatric assessment.\n\nFor children and young people who are obese and have heartburn or acid regurgitation, advise them and their parents or carers (as appropriate) that losing weight may improve their symptoms (also see the NICE guideline on obesity).\n\nDo not offer an upper gastrointestinal (GI) contrast study to diagnose or assess the severity of GORD in infants, children and young people.\n\nPerform an urgent (same day) upper GI contrast study for infants with unexplained bile‑stained vomiting. Explain to the parents and carers that this is needed to rule out serious disorders such as intestinal obstruction due to mid‑gut volvulus.\n\nConsider an upper GI contrast study for children and young people with a history of bile‑stained vomiting, particularly if it is persistent or recurrent.\n\nOffer an upper GI contrast study for children and young people with a history of GORD presenting with dysphagia.\n\nArrange an urgent specialist hospital assessment to take place on the same day for infants younger than 2\xa0months with progressively worsening or forceful vomiting of feeds, to assess them for possible hypertrophic pyloric stenosis.\n\nArrange a specialist hospital assessment for infants, children and young people for a possible upper GI endoscopy with biopsies if there is:\n\nhaematemesis (blood‑stained vomit) not caused by swallowed blood (assessment to take place on the same day if clinically indicated; also see table\xa01)\n\nmelaena (black, foul‑smelling stool; assessment to take place on the same day if clinically indicated; also see table\xa01)\n\ndysphagia (assessment to take place on the same day if clinically indicated)\n\nno improvement in regurgitation after 1\xa0year old\n\npersistent, faltering growth associated with overt regurgitation\n\nunexplained distress in children and young people with communication difficulties\n\nretrosternal, epigastric or upper abdominal pain that needs ongoing medical therapy or is refractory to medical therapy\n\nfeeding aversion and a history of regurgitation\n\nunexplained iron‑deficiency anaemia\n\na suspected diagnosis of Sandifer's syndrome.\n\nConsider performing an oesophageal pH study (or combined oesophageal pH and impedance monitoring if available) in infants, children and young people with:\n\nsuspected recurrent aspiration pneumonia\n\nunexplained apnoeas\n\nunexplained non‑epileptic seizure‑like events\n\nunexplained upper airway inflammation\n\ndental erosion associated with a neurodisability\n\nfrequent otitis media\n\na possible need for fundoplication (see the recommendations in the section on surgery for GORD)\n\na suspected diagnosis of Sandifer's syndrome.\n\nConsider performing an oesophageal pH study without impedance monitoring in infants, children and young people if, using clinical judgement, it is thought necessary to ensure effective acid suppression.\n\nInvestigate the possibility of a urinary tract infection in infants with regurgitation if there is:\n\nfaltering growth\n\nlate onset (after the infant is 8\xa0weeks old)\n\nfrequent regurgitation and marked distress.\n\n# Initial management of GOR and GORD\n\nDo not use positional management to treat GOR in sleeping infants. In line with NHS advice on sudden infant death syndrome (SIDS), infants should be placed on their back when sleeping.\n\nIn breast‑fed infants with frequent regurgitation associated with marked distress, ensure that a person with appropriate expertise and training carries out a breastfeeding assessment.\n\nIn formula‑fed infants with frequent regurgitation associated with marked distress, use the following stepped‑care approach:\n\nreview the feeding history, then\n\nreduce the feed volumes only if excessive for the infant's weight, then\n\noffer a trial of smaller, more frequent feeds (while maintaining an appropriate total daily amount of milk) unless the feeds are already small and frequent, then\n\noffer a trial of thickened formula (for example, containing rice starch, cornstarch, locust bean gum or carob bean gum).\n\nIn breast‑fed infants with frequent regurgitation associated with marked distress that continues despite a breastfeeding assessment and advice, consider alginate therapy for a trial period of 1 to 2\xa0weeks. If the alginate therapy is successful continue with it, but try stopping it at intervals to see if the infant has recovered.\n\nIn formula‑fed infants, if the stepped‑care approach is unsuccessful (see the recommendation on stepped-care approach for formula-fed infants with frequent regurgitation associated with marked distress), stop the thickened formula and offer alginate therapy for a trial period of 1 to 2\xa0weeks. If the alginate therapy is successful continue with it, but try stopping it at intervals to see if the infant has recovered.\n\n# Pharmacological treatment of GORD\n\nNot all PPIs and H2RAs are licensed for use in children and those that are licensed vary in the age that they are licensed from. For licensing and prescribing information see the individual SPCs and BNF for children. MHRA drug safety updates have been issued for PPIs, covering hypomagnesaemia, the increased risk of fracture with long-term use and very low risk of subacute cutaneous lupus erythematosus.\n\nDo not offer acid‑suppressing drugs, such as proton pump inhibitors (PPIs) or H2\xa0receptor antagonists (H2RAs), to treat overt regurgitation in infants and children occurring as an isolated symptom.\n\nConsider a 4‑week trial of a PPI or H2RA for those who are unable to tell you about their symptoms (for example, infants and young children, and those with a neurodisability associated with expressive communication difficulties) who have overt regurgitation with 1\xa0or more of the following:\n\nunexplained feeding difficulties (for example, refusing feeds, gagging or choking)\n\ndistressed behaviour\n\nfaltering growth.\n\nConsider a 4‑week trial of a PPI or H2RA for children and young people with persistent heartburn, retrosternal or epigastric pain.\n\nAssess the response to the 4‑week trial of the PPI or H2RA, and consider referral to a specialist for possible endoscopy if the symptoms:\n\ndo not resolve or\n\nrecur after stopping the treatment.\n\nWhen choosing between PPIs and H2RAs, take into account:\n\nthe availability of age‑appropriate preparations\n\nthe preference of the parent (or carer), child or young person (as appropriate)\n\nlocal procurement costs.\n\nOffer PPI or H2RA treatment to infants, children and young people with endoscopy‑proven reflux oesophagitis, and consider repeat endoscopic examinations as necessary to guide subsequent treatment.\n\nDo not offer metoclopramide, domperidone or erythromycin to treat GOR or GORD unless all the following conditions are met:\n\nthe potential benefits outweigh the risk of adverse events\n\nother interventions have been tried\n\nthere is specialist paediatric healthcare professional agreement for its use.Metoclopramide, domperidone and erythromycin are not licensed for use in children. Metoclopramide is contraindicated in infants, and should only be prescribed for short-term use (up to 5\xa0days). For licensing and prescribing information see the individual SPCs and BNF for children. MHRA drug safety updates have been issued covering risk of cardiac side effects with domperidone and:\n\n\n\nrisk of neurological adverse events with metoclopramide\n\nrisk of infantile hypertrophic pyloric stenosis with erythromycin\n\ncardiac risks (QT interval prolongation) with erythromycin and potential drug interaction of erythromycin with rivaroxaban.\n\n\n\n# Enteral tube feeding for GORD\n\nOnly consider enteral tube feeding to promote weight gain in infants and children with overt regurgitation and faltering growth if:\n\nother explanations for poor weight gain have been explored and/or\n\nrecommended feeding and medical management of overt regurgitation is unsuccessful.\n\nBefore starting enteral tube feeding for infants and children with faltering growth associated with overt regurgitation, agree in advance:\n\na specific, individualised nutrition plan\n\na strategy to reduce it as soon as possible\n\nan exit strategy, if appropriate, to stop it as soon as possible.\n\nIn infants and children receiving enteral tube feeding for faltering growth associated with overt regurgitation:\n\nprovide oral stimulation, continuing oral feeding as tolerated\n\nfollow the nutrition plan, ensuring that the intended target weight is achieved and that appropriate weight gain is sustained\n\nreduce and stop enteral tube feeding as soon as possible.\n\nConsider jejunal feeding for infants, children and young people:\n\nwho need enteral tube feeding but who cannot tolerate intragastric feeds because of regurgitation or\n\nif reflux‑related pulmonary aspiration is a concern.\n\n# Surgery for GORD\n\nOffer an upper GI endoscopy with oesophageal biopsies for infants, children and young people before deciding whether to offer fundoplication for presumed GORD.\n\nConsider performing other investigations such as an oesophageal\xa0pH study (or combined oesophageal\xa0pH and impedance monitoring if available) and an upper\xa0GI contrast study for infants, children and young people before deciding whether to offer fundoplication.\n\nConsider fundoplication in infants, children and young people with severe, intractable GORD if:\n\nappropriate medical treatment has been unsuccessful or\n\nfeeding regimens to manage GORD prove impractical, for example, in the case of long‑term, continuous, thickened enteral tube feeding.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Symptoms of gastro-oesophageal reflux disease (GORD) in infants, children and young people with a neurodisability\n\nWhat are the symptoms of GORD in infants, children and young people with a neurodisability?\n\n## Why this is important\n\nThe evidence reviewed on the symptoms associated with GORD in children and young people with a neurodisability was limited to 3\xa0studies and graded as low‑ to very low‑quality. The lack of a set of clearly defined features makes GORD difficult to recognise and differentiate from other vomiting problems. The proposed study would use objective measures of reflux (such as oesophageal\xa0pH monitoring) to assess GORD symptoms in infants, children and young people with a neurodisability.\n\n# Cows' milk protein elimination in formula-fed infants\n\nWhat is the effectiveness and cost effectiveness of a trial of hydrolysed formula in formula‑fed infants with frequent regurgitation associated with marked distress?\n\n## Why this is important\n\nThere is a widespread belief that GOR and/or GORD in formula‑fed infants is often caused by intolerance to cows' milk. As a result, health professionals often prescribe a trial of hydrolysed formula as a substitute for cows' milk formula. This has resource implications because hydrolysed formula is more expensive than cows' milk formula. Additionally, there is no evidence on the clinical or cost effectiveness of this approach. Therefore, it is proposed that a randomised controlled trial is undertaken to explore this question. It is important to consider 2\xa0population subgroups:\n\ninfants with a personal or family history of atopic conditions\n\ninfants whose GOR and/or GORD has not responded to the initial management outlined in this guideline (up to and including alginates).\n\n# Fundoplication and oesophageal pH monitoring\n\nIn infants, children and young people with overt or occult reflux, is fundoplication effective in reducing acid reflux as determined by oesophageal\xa0pH monitoring?\n\n## Why this is important\n\nFundoplication is used to manage severe GORD. At present, there is limited evidence that overt regurgitation is reduced after surgery. However, this has not been objectively measured. In addition, the effect of surgery on occult reflux has not been assessed. This is important because surgery may be masking a continuing problem. The proposed study would monitor regurgitation before and after fundoplication using oesophageal pH monitoring. This may help health professionals identify which infants, children and young people will benefit from surgery.", 'Finding more information and resources': "You can see everything NICE says on this topic in the NICE Pathway on dyspepsia and gastro-oesophageal reflux disease.\n\nTo find NICE guidance on related topics, including guidance in development, see the NICE webpage on gastro-oesophageal reflux, including Barrett's oesophagus.\n\nFor full details of the evidence and the guideline committee's discussions, see the full guideline. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see\xa0resources to help you put NICE guidance into practice."}
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https://www.nice.org.uk/guidance/ng1
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This guideline covers diagnosing and managing gastro-oesophageal reflux disease in children and young people (under 18s). It aims to raise awareness of symptoms that need investigating and treating, and to reassure parents and carers that regurgitation is common in infants under 1 year.
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91f7a77a0d607878f45ff40203cf59a16afc78e1
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nice
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Xeomin (botulinum neurotoxin type A) for treating chronic sialorrhoea
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Xeomin (botulinum neurotoxin type A) for treating chronic sialorrhoea
Evidence-based recommendations on Xeomin (botulinum neurotoxin type A) for treating chronic sialorrhoea (excessive salivation and drooling) caused by neurological conditions in adults.
# Recommendations
Xeomin (botulinum neurotoxin type A) is recommended, within its marketing authorisation, as an option for treating chronic sialorrhoea caused by neurological conditions in adults. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Chronic sialorrhoea (excessive salivation and drooling) happens when neurological conditions cause problems with swallowing. Treatment is usually standard (non-drug) care such as using bibs, speech and language therapy, and occupational therapy. But some people may take anticholinergic drugs to reduce the amount of saliva produced.
Randomised controlled trial evidence shows that Xeomin reduces the amount of saliva produced. The evidence suggests that this does not improve quality of life. However, it seems that the benefit of Xeomin on quality of life might not have been fully captured in the trial because of the way that quality of life was assessed.
Taking into account the unmeasured benefits in the evidence means that the cost-effectiveness estimates are within the range that NICE usually considers a cost-effective use of NHS resources. Therefore, Xeomin is recommended.# Information about Xeomin (botulinum neurotoxin type A)
Marketing authorisation indication
Xeomin (botulinum neurotoxin type A, Merz) is intended for 'chronic sialorrhoea due to neurological disorders in adults'.
Dosage in the marketing authorisation
A reconstituted solution at a concentration of 5 units/0.1 ml should be used.
Xeomin is injected into the parotid and submandibular glands on both sides (4 injections per treatment in total). The dose is divided in a ratio of 3:2 between the parotid and submandibular glands as follows:
parotid glands: 30 units per side, 0.6 ml per injection
submandibular glands: 20 units per side, 0.4 ml per injection.
The injection site should be close to the centre of the gland.
The recommended dose per treatment session is 100 units. This maximum dose should not be exceeded.
Treatment intervals should be determined based on the actual clinical need of the individual patient.
Repeat treatment more frequent than every 16 weeks is not recommended.
Because of unit differences in the potency assay, unit doses for Xeomin are not interchangeable with those for other preparations of botulinum toxin type A.
Price
£129.90 per 100‑unit powder for solution for injection vial (excluding VAT; BNF accessed online July 2019).
The company has a commercial arrangement. This makes Xeomin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Merz Pharma UK, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that none of the issues were fully resolved after the technical engagement stage.
It discussed the following issues: comparator and treatment choice; outcomes in the pivotal trial; health-related quality of life and utility value assumptions; ultrasound guidance prevalence; implementation and resource use within the trial (new since technical engagement; see technical report, issues 1 to 6), which were outstanding after the technical engagement stage.
# Clinical need
## Chronic sialorrhoea can affect the quality of life of patients and their carers
Chronic sialorrhoea and excessive saliva accumulation can occur because of dysfunction or weakness of the muscles in the mouth and face. It is a common secondary symptom of many neurological conditions such as Parkinson's disease, cerebral palsy, stroke and traumatic brain injury and is often caused by swallowing issues and poor lip seal. Complications of sialorrhoea may include poor oral hygiene, bad breath, perioral dermatitis, dehydration, eating and speaking difficulties, sleep disturbance and fatigue. Sialorrhoea may also increase the risk of aspiration pneumonia if the saliva is inhaled. This may affect mortality and is more prevalent in older people. Sialorrhoea, and the resulting excessive drooling, also has a psychosocial effect on patients including embarrassment, decreased self-esteem and the potential for social isolation. It can also increase the burden on caregivers who may already be helping the patient manage their neurological condition. For example, the patient may need more frequent changes of clothing or bibs, and this extra care can lead to depression and anxiety for the caregivers. The clinical experts stated that the burden of sialorrhoea may depend on the underlying neurological condition, the age and social activity of the person with sialorrhoea and their view of the severity of the drooling. They also said that results from a survey of people with Parkinson's disease showed that sialorrhoea was considered the third most troublesome symptom of Parkinson's disease. The committee considered that sialorrhoea affects the quality of life of patients and their caregivers, but the extent of this is uncertain and depends on a number of factors.
## People with chronic sialorrhoea would welcome better access to botulinum toxin type A as a first-line treatment
Botulinum toxin type A products are recommended (albeit outside of their marketing authorisations) as a second- or third-line treatment option for sialorrhoea in NICE's guidelines on motor neurone disease, Parkinson's disease and cerebral palsy in under 25s. However, referral for treatment does not always occur because of the variable availability of botulinum toxin clinics across England. The 3 clinical guidelines all recommend that anticholinergics are tried first, and that botulinum toxin products should be offered if the anticholinergics are not effective, not tolerated or contraindicated. The clinical experts highlighted a need for a targeted treatment such as botulinum toxin type A that avoids the side effects of anticholinergics. This is because people with chronic sialorrhoea caused by an underlying neurological condition often have other systemic treatments for the condition and may be taking other medications too. The committee agreed that people with chronic sialorrhoea would welcome earlier use of botulinum toxin type A and better access to it in the treatment pathway.
# Comparators
## Standard care and anticholinergics are appropriate comparators
The company positioned Xeomin (its preparation of botulinum neurotoxin type A) as both a first- and second-line treatment option. The committee therefore considered it as:
an alternative first-line treatment to non-pharmacological management such as bibs, speech and language therapy and occupational therapy (referred to as standard care by the company) and to anticholinergics and
as an alternative second-line treatment to standard care (in line with the 3 NICE guidelines).The clinical experts stated that anticholinergic treatments may be considered as a treatment option for some patients (particularly for younger people) but they are poorly tolerated. The choice of pharmacological treatment depends on comorbidities, the severity of the sialorrhoea, the efficacy of previous treatment and the patient and clinician's views. Glycopyrronium bromide is the most commonly used anticholinergic because it does not cross the blood-brain barrier. The committee noted that glycopyrronium bromide's summary of product characteristics specifies that treatment duration should be as short as possible, and it should be used on an intermittent rather than a continuous basis. Chronic use of anticholinergics can be associated with cognitive problems such as memory loss. The committee accepted that anticholinergics may be appropriate for a small number of people. However, it considered there to be unmet need (see section 3.2) for a large proportion of people with sialorrhoea who are not able to tolerate anticholinergics. Therefore, the committee concluded that standard care was the most relevant comparator, but that it was also appropriate to consider short-term anticholinergics such as glycopyrronium bromide as a comparator.
## There are no standard measures for sialorrhoea severity in clinical practice
The marketing authorisation for Xeomin, unlike the marketing authorisation for glycopyrronium bromide, does not specify the severity of sialorrhoea for treatment. However, the committee was aware that severity is an important factor for both patients and clinicians when considering treatment options (see section 3.3). There are no standardised measures for sialorrhoea severity used in NHS clinical practice. Severity is typically determined by physical assessment and patient history. Also, because patients have underlying neurological conditions, sialorrhoea is often measured as part of neurological disease-specific questionnaires in NHS clinical practice in England. The company identified the drooling severity and frequency score (DSFS) to measure severity in the pivotal trial (SIAXI; see section 3.5). The inclusion criteria in SIAXI included patients with a DSFS score of 6 or more, which included people with 'moderate' sialorrhoea by the company definition. The clinical experts stated that severe sialorrhoea is not a distinct subgroup and severity can fluctuate. The committee concluded it was appropriate to consider Xeomin for people with chronic sialorrhoea, and that severity should be based on clinical judgement rather than the DSFS score.
# Clinical evidence
## The SIAXI trial provides the main clinical evidence for Xeomin
The main evidence for Xeomin came from SIAXI, a randomised placebo-controlled trial. The population included 110 patients with chronic sialorrhoea who had either Xeomin (n=74) or placebo (n=36). The inclusion criteria specified a DSFS of 6 or more and the mean age of the patients was 65. The population included patients with Parkinson's related diseases (79%), stroke-related diseases (18%) and traumatic brain injury (3%). The co-primary outcomes were unstimulated salivary flow rate and global impression of change scale, 4 weeks after an injection with Xeomin. Secondary outcomes included health-related quality of life as measured by the EQ-5D questionnaire, safety data and the DSFS. The trial also included an extension period that measured these outcomes over 3 further injection cycles of 16 weeks. The results showed a statistically significant decrease in salivary flow rate and increase in global impression of change score at 4 weeks compared with placebo. The committee agreed that SIAXI was a well-designed study and appropriate for decision making. But it noted that it did not include aspiration pneumonia as an outcome measure, which it considered to be an important complication of sialorrhoea (see section 3.1).
## The results from the SIAXI trial are generalisable to people seen in clinical practice with chronic sialorrhoea
The company stated that the reduction in saliva output in SIAXI was independent of the underlying neurological condition. Therefore, the results from SIAXI would be generalisable to everyone with chronic sialorrhoea caused by a neurological condition. The clinical experts agreed but noted that the trial largely included patients with Parkinson's disease who were younger than those who would be expected to be seen in routine NHS clinical practice. They were unable to comment on Xeomin's efficacy for populations not included in SIAXI. The committee recalled that anticholinergic therapy is more likely to be associated with systemic adverse effects in an older population so targeted treatment for sialorrhoea may have additional advantages in the population more often seen in routine clinical practice. The committee concluded that the results of SIAXI were generalisable to the population with chronic sialorrhoea seen in NHS clinical practice and that Xeomin would reduce saliva output regardless of the underlying neurological condition.
## The most relevant outcomes for decision making are the EQ‑5D, global impression of change scale and the DSFS score
The committee was aware that there was no survival benefit associated with treating sialorrhoea so all the benefits of Xeomin must result from increased quality of life. Although the results of the trial suggested a statistically significant reduction in unstimulated salivary flow rate and an improvement in the global impression of change scale at 4 weeks for Xeomin compared with placebo, this did not translate into a statistically significant increase in quality of life as measured by the EQ‑5D. The relationship between unstimulated salivary flow rate, global impression of change scale and DSFS to quality of life were uncertain. The committee considered unstimulated salivary flow rate to be unsuitable because the ability of a treatment to reduce saliva is not an entirely appropriate way of estimating clinical effectiveness. For example, dry mouth is a common adverse event of anticholinergic treatments, so it is inappropriate to assume that a reduction in salivary flow translates to improved clinical outcomes. The committee instead preferred direct quality-of-life measurements such as the EQ‑5D questionnaire and the global impression of change scale. The committee noted that the DSFS is likely to correlate with the burden of the disease because drooling and its consequences form a large part of the symptom burden of sialorrhoea. The committee therefore concluded that the most relevant outcomes for its decision making were the EQ‑5D questionnaire and the global impression of change scale and agreed to consider these further (see section 3.9). It also concluded that, although the DSFS score is not used in clinical practice (see section 3.4), it was appropriate for defining the severity of health states in the economic model (see section 3.11).
## There are no robust sources of evidence for comparing Xeomin with anticholinergic treatments
The committee acknowledged that anticholinergic treatments for sialorrhoea are used outside their marketing authorisations. Therefore, there is a lack of data on their effectiveness and safety in the population with chronic sialorrhoea. The company assumed that all anticholinergic treatments were 75% as effective as Xeomin based on an assumption in NICE's guideline on cerebral palsy in under 25s. The committee considered that this may not be the case because a common adverse event of anticholinergics is dry mouth, so the drying effect would be dose related and would depend on whether the patient could tolerate dose escalation (see section 3.7). However, the clinical experts stated that glycopyrronium bromide is likely to be more effective than other anticholinergics. Therefore, the committee accepted that, because there was no evidence, equal efficacy in reducing saliva production should be assumed.
## Quality of life as measured by the EQ‑5D‑3L in the SIAXI trial may not fully capture the consequences of sialorrhoea and the benefits of treatment
The company measured health-related quality of life using the EQ‑5D‑3L questionnaire. It considered that this questionnaire was not sensitive to measuring sialorrhoea symptoms because it was measuring health-related quality of life in a population with debilitating underlying neurological conditions. The EQ‑5D‑3L measures 5 domains including mobility, self-care, usual activities, pain and anxiety or depression using 3 levels ranging from extreme problems, some problems and no problems. It can only register a change in health state when a patient indicates a step change in at least 1 domain. Many patients answered with a score of 2 ('some problems') for multiple domains and would therefore need to answer 1 ('no problems') to register any improvement. The company considered this unlikely because every domain would be affected in some way by the underlying neurological condition. The clinical experts stated that none of the specific consequences of sialorrhoea would be reliably detected by a non-sialorrhoea specific questionnaire. The committee agreed that there was uncertainty about the extent to which the EQ‑5D‑3L fully captures the consequences of sialorrhoea and the benefits of any treatment and it would consider this in its decision making (see section 3.17).
## The adverse effects of Xeomin can be managed in clinical practice
The committee acknowledged the SIAXI results showed that there may be a low risk of major clinical events including dysphagia. The clinical experts commented that Xeomin is unlikely to lead to an overly dry mouth as an adverse event of treatment because it is possible to titrate the dose and reduce the number of injection sites. The committee concluded that the adverse effects of Xeomin can be managed in clinical practice.
# The company's economic model
## The model structure is appropriate for decision making
The company developed a Markov state-transition model that included 3 health states to represent different sialorrhoea severity: severe (DSFS score of 7 to 9); moderate (DSFS score of 4 to 6) and mild or resolved (DSFS score of 2 to 3). In the model, patients who stop treatment are assumed to continue having standard care alone. Any patient could independently transition to death at the rate of the general population, although a standardised mortality rate to represent increased mortality from Parkinson's disease was explored in a scenario analysis. The committee was concerned about anticholinergic use over the full-time horizon of the model given the short-term or intermittent use of anticholinergics and the high drop-out rates (see section 3.3). The committee also noted that the company had assumed no adverse events for either arm in the economic model. This was because of the lack of data available to do a comparison of the adverse events of Xeomin with those of the anticholinergics. The committee agreed with the company that the assumption of no adverse events was conservative, given the severe side effect burden of anticholinergics. However, it considered that the company should have included adverse events in its economic modelling. Nevertheless, the committee concluded that the economic model structure was acceptable for decision making.
# Utility values in the economic model
## Utility values derived from the population in the SIAXI trial are the most appropriate values to use in the economic modelling
Because of the problems with measuring health-related quality of life (see section 3.9), the company preferred to use utility values from NICE's guideline for cerebral palsy in under 25s, stratified into 3 severity groups (mild or resolved , moderate and severe ). The committee was aware that these utility values were from a hypothetical model in the guideline because there were no data available. The company stated that the psychosocial impact of social isolation, the impact on caregivers and the potential for aspiration pneumonia were not captured in the model, and that the guideline-derived utility values were more plausible than those derived in SIAXI. The ERG considered this modelling inappropriate because the utility values were from a very different population to the SIAXI trial population, and from a hypothetical model. The ERG preferred to use utility values derived from SIAXI (mild or resolved , moderate and severe ). It considered that the small health-related quality-of-life gain in SIAXI may be an accurate translation of utility gain associated with Xeomin. The ERG calculated the effect associated with a neurological condition in the company's model (average utility for a person of 65 minus the mild or resolved state utility value) as a disutility of 0.28 and the effect of severe sialorrhoea (utility of the mild or resolved state minus the severe state utility value) as a disutility of 0.23. The ERG and clinical experts were not convinced that sialorrhoea would have a similar magnitude of disutility to the neurological condition. The committee agreed that SIAXI was the most appropriate data source for deriving utility values. But it acknowledged the substantial uncertainty for utility values associated with sialorrhoea because of the lack of data.
## Utility values derived from the SIAXI trial are likely to underestimate utility gain
The committee agreed that SIAXI was the most appropriate data source for the utility data (see section 3.12). But it concluded that the EQ‑5D‑3L data and the derived utility value were unlikely to fully capture the health-related quality-of-life benefit (see section 3.9). Additionally, the EQ‑5D‑3L may not fully capture the psychosocial impact of sialorrhoea, including social isolation (see section 3.1). The committee also considered that the impact of carer quality of life was not captured, including workload and potential further social isolation of caregivers. It considered that, because the cost-effectiveness results were very sensitive to the utility values chosen and there was a lack of data for sialorrhoea, a qualitative assessment of the direction of uncertainty of the utility values in SIAXI was appropriate. The committee concluded that the EQ‑5D‑3L results from SIAXI were likely to underestimate utility gain from the treatment and that it would consider this in its decision making (see section 3.17).
# Costs in the economic model
## Using ultrasound imaging to guide injections is less frequent in NHS clinical practice than in the SIAXI trial
Ultrasound imaging is sometimes used to guide the needle into the correct injection site for administering Xeomin. Alternatively, anatomical landmarks are used as guides. The company assumed in its base case that the frequency of using ultrasound guidance in SIAXI (56% of injections) was equivalent to NHS clinical practice. The ERG provided a scenario analysis that assumed 100% of procedures involved ultrasound-guided injections. The committee noted that the summary of product characteristics for Xeomin states that ultrasound-guided application showed superior results to the anatomical landmarks method. However, the clinical experts stated that, although it may vary across centres, using ultrasound guidance for administering injections is infrequent in current NHS clinical practice in England. The committee agreed that ultrasound may be used less in clinical practice than in SIAXI. Therefore, the company's assumption may have overestimated the costs of ultrasound guidance, which would have reduced the cost-effectiveness estimates (see section 3.17).
## Assuming more speech and language and occupational therapy consultations for severe than for moderate sialorrhoea is inappropriate
In SIAXI no data were collected on the resource use of standard care, which the committee considered to be the most relevant comparator (see section 3.3). Standard care was also used alongside all active treatments. The company assumed that speech and language consultations and occupational therapy consultations would be once every 16 weeks for the severe sialorrhoea group, once every 32 weeks for the moderate group, and there would be none for the mild or resolved group. The committee noted that the costs of these consultations were applied for the entire duration of the time horizon. The ERG provided a scenario exploring no associated costs for standard care for each treatment option. The clinical experts stated that speech, language and occupational therapy consultations would start with an initial assessment for all sialorrhoea severity groups. This would include training for head positioning, posture, swallow timers and speech assessment. The frequency of follow-up consultations would vary by underlying neurological condition, for example people with stroke and traumatic brain injury may have more frequent assessments. However, in general, most patients would not have follow-up consultations as often as every 16 weeks; it would depend on individual patient needs and access to these services. The committee concluded that the speech and language and occupational therapy resource use in the model did not reflect clinical practice.
# Cost-effectiveness estimates
## The cost-effectiveness results are highly sensitive to assumptions about utility value
The committee considered whether Xeomin would be a cost-effective use of NHS resources for chronic sialorrhoea. The company provided base-case incremental cost-effectiveness ratios (ICERs) and scenario analyses based on the list price of Xeomin and based on a confidential commercial arrangement. Because the ICERs based on the commercial arrangement are confidential, only the list-price ICERs are presented here.
The company's base-case deterministic ICER was £9,583 per quality-adjusted life year (QALY) gained for Xeomin compared with standard care. Xeomin dominated glycopyrronium bromide.
The ERG's exploratory analyses provided both a deterministic ICER and a probabilistic ICER for Xeomin compared with standard care; £47,309 and £45,423 per QALY gained respectively. Xeomin continued to dominate glycopyrronium bromide.The committee noted that the main driver of the difference in ICERs was the source of the utility values, and that the ICER was very sensitive to small changes in assumptions about utility values. It recalled that the most appropriate source of data for the utility values was the EQ‑5D‑3L from SIAXI (see section 3.9), which was used in the ERG's analyses. The committee also agreed that standard care was the most appropriate comparator (see section 3.3). Therefore, it concluded that the most appropriate ICER for decision making was the ERG's exploratory probabilistic ICER of £45,423 per QALY gained for Xeomin compared with standard care.
## Xeomin is recommended as a treatment option
Having considered that the ERG's probabilistic ICER is in line with its preferred assumptions, the committee recalled that it would take into account these factors in its decision making:
The EQ‑5D‑3L may not fully capture the health-related quality-of-life gain associated with sialorrhoea; this would increase QALY gains and lower the ICER (see section 3.9).
The health-related quality of life of carers is not considered in SIAXI and the economic model; this would increase QALY gains and lower the ICER (see section 3.13).
Ultrasound guidance is not as prevalent in NHS clinical practice as in SIAXI; using the percentage from the NHS in the economic model would reduce the costs and lower the ICER (see section 3.14).
Resource use was inappropriately modelled; it is unclear how a more appropriate model would affect the ICER (see section 3.15).The committee noted that when these factors and the commercial arrangement were taken into account, the ICER would reduce to within the range usually considered to be a cost-effective use of NHS resources. Therefore, the committee recommended Xeomin as a treatment option.
# Other factors
## There are no equalities considerations, but stigma associated with drooling may not be captured by routine quality assessments
The committee considered whether there were any equalities considerations for this appraisal, as suggested by Parkinson's UK. Potential equalities issues were age, physical disability, communication difficulties and mental health problems. The committee agreed that the increased prevalence of drooling in older people with neurological conditions is a feature of sialorrhoea. Any recommendation resulting from this appraisal will apply to all people, so age, as defined by the Equalities Act, is not a relevant equalities issue. Similarly, physical disability, communication difficulties and mental health problems vary by underlying neurological condition and will apply to all people so are not relevant equalities issues. The committee also considered whether there is stigma associated with drooling, as a social value judgement. It concluded that many of the issues associated with drooling should be picked up as part of measuring social isolation and other psychosocial symptoms (see section 3.1), although these were not captured with the chosen assessment tools. However, there may be additional relief of stigma as a result of treatment that would not be captured in routine quality-of-life assessments.
## The technology is not innovative
The company considers the drug to be innovative. However, when focusing specifically on relevant benefits associated with innovation, the committee considered that these were adequately captured in the model.
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{'Recommendations': 'Xeomin (botulinum neurotoxin type\xa0A) is recommended, within its marketing authorisation, as an option for treating chronic sialorrhoea caused by neurological conditions in adults. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nChronic sialorrhoea (excessive salivation and drooling) happens when neurological conditions cause problems with swallowing. Treatment is usually standard (non-drug) care such as using bibs, speech and language therapy, and occupational therapy. But some people may take anticholinergic drugs to reduce the amount of saliva produced.\n\nRandomised controlled trial evidence shows that Xeomin reduces the amount of saliva produced. The evidence suggests that this does not improve quality of life. However, it seems that the benefit of Xeomin on quality of life might not have been fully captured in the trial because of the way that quality of life was assessed.\n\nTaking into account the unmeasured benefits in the evidence means that the cost-effectiveness estimates are within the range that NICE usually considers a cost-effective use of NHS resources. Therefore, Xeomin is recommended.', 'Information about Xeomin (botulinum neurotoxin type\xa0A)': "Marketing authorisation indication\n\nXeomin (botulinum neurotoxin type\xa0A, Merz) is intended for 'chronic sialorrhoea due to neurological disorders in adults'.\n\nDosage in the marketing authorisation\n\nA reconstituted solution at a concentration of 5\xa0units/0.1\xa0ml should be used.\n\nXeomin is injected into the parotid and submandibular glands on both sides (4\xa0injections per treatment in total). The dose is divided in a ratio of 3:2 between the parotid and submandibular glands as follows:\n\nparotid glands: 30\xa0units per side, 0.6\xa0ml per injection\n\nsubmandibular glands: 20\xa0units per side, 0.4\xa0ml per injection.\n\nThe injection site should be close to the centre of the gland.\n\nThe recommended dose per treatment session is 100\xa0units. This maximum dose should not be exceeded.\n\nTreatment intervals should be determined based on the actual clinical need of the individual patient.\n\nRepeat treatment more frequent than every 16\xa0weeks is not recommended.\n\nBecause of unit differences in the potency assay, unit doses for Xeomin are not interchangeable with those for other preparations of botulinum toxin type\xa0A.\n\nPrice\n\n£129.90 per 100‑unit powder for solution for injection vial (excluding VAT; BNF accessed online July 2019).\n\n\n\nThe company has a commercial arrangement. This makes Xeomin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Merz Pharma UK, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that none of the issues were fully resolved after the technical engagement stage.\n\nIt discussed the following issues: comparator and treatment choice; outcomes in the pivotal trial; health-related quality of life and utility value assumptions; ultrasound guidance prevalence; implementation and resource use within the trial (new since technical engagement; see technical report, issues 1 to 6), which were outstanding after the technical engagement stage.\n\n# Clinical need\n\n## Chronic sialorrhoea can affect the quality of life of patients and their carers\n\nChronic sialorrhoea and excessive saliva accumulation can occur because of dysfunction or weakness of the muscles in the mouth and face. It is a common secondary symptom of many neurological conditions such as Parkinson's disease, cerebral palsy, stroke and traumatic brain injury and is often caused by swallowing issues and poor lip seal. Complications of sialorrhoea may include poor oral hygiene, bad breath, perioral dermatitis, dehydration, eating and speaking difficulties, sleep disturbance and fatigue. Sialorrhoea may also increase the risk of aspiration pneumonia if the saliva is inhaled. This may affect mortality and is more prevalent in older people. Sialorrhoea, and the resulting excessive drooling, also has a psychosocial effect on patients including embarrassment, decreased self-esteem and the potential for social isolation. It can also increase the burden on caregivers who may already be helping the patient manage their neurological condition. For example, the patient may need more frequent changes of clothing or bibs, and this extra care can lead to depression and anxiety for the caregivers. The clinical experts stated that the burden of sialorrhoea may depend on the underlying neurological condition, the age and social activity of the person with sialorrhoea and their view of the severity of the drooling. They also said that results from a survey of people with Parkinson's disease showed that sialorrhoea was considered the third most troublesome symptom of Parkinson's disease. The committee considered that sialorrhoea affects the quality of life of patients and their caregivers, but the extent of this is uncertain and depends on a number of factors.\n\n## People with chronic sialorrhoea would welcome better access to botulinum toxin type\xa0A as a first-line treatment\n\nBotulinum toxin type\xa0A products are recommended (albeit outside of their marketing authorisations) as a second- or third-line treatment option for sialorrhoea in NICE's guidelines on motor neurone disease, Parkinson's disease and cerebral palsy in under\xa025s. However, referral for treatment does not always occur because of the variable availability of botulinum toxin clinics across England. The 3\xa0clinical guidelines all recommend that anticholinergics are tried first, and that botulinum toxin products should be offered if the anticholinergics are not effective, not tolerated or contraindicated. The clinical experts highlighted a need for a targeted treatment such as botulinum toxin type\xa0A that avoids the side effects of anticholinergics. This is because people with chronic sialorrhoea caused by an underlying neurological condition often have other systemic treatments for the condition and may be taking other medications too. The committee agreed that people with chronic sialorrhoea would welcome earlier use of botulinum toxin type\xa0A and better access to it in the treatment pathway.\n\n# Comparators\n\n## Standard care and anticholinergics are appropriate comparators\n\nThe company positioned Xeomin (its preparation of botulinum neurotoxin type\xa0A) as both a first- and second-line treatment option. The committee therefore considered it as:\n\nan alternative first-line treatment to non-pharmacological management such as bibs, speech and language therapy and occupational therapy (referred to as standard care by the company) and to anticholinergics and\n\nas an alternative second-line treatment to standard care (in line with the 3\xa0NICE guidelines).The clinical experts stated that anticholinergic treatments may be considered as a treatment option for some patients (particularly for younger people) but they are poorly tolerated. The choice of pharmacological treatment depends on comorbidities, the severity of the sialorrhoea, the efficacy of previous treatment and the patient and clinician's views. Glycopyrronium bromide is the most commonly used anticholinergic because it does not cross the blood-brain barrier. The committee noted that glycopyrronium bromide's summary of product characteristics specifies that treatment duration should be as short as possible, and it should be used on an intermittent rather than a continuous basis. Chronic use of anticholinergics can be associated with cognitive problems such as memory loss. The committee accepted that anticholinergics may be appropriate for a small number of people. However, it considered there to be unmet need (see section\xa03.2) for a large proportion of people with sialorrhoea who are not able to tolerate anticholinergics. Therefore, the committee concluded that standard care was the most relevant comparator, but that it was also appropriate to consider short-term anticholinergics such as glycopyrronium bromide as a comparator.\n\n## There are no standard measures for sialorrhoea severity in clinical practice\n\nThe marketing authorisation for Xeomin, unlike the marketing authorisation for glycopyrronium bromide, does not specify the severity of sialorrhoea for treatment. However, the committee was aware that severity is an important factor for both patients and clinicians when considering treatment options (see section\xa03.3). There are no standardised measures for sialorrhoea severity used in NHS clinical practice. Severity is typically determined by physical assessment and patient history. Also, because patients have underlying neurological conditions, sialorrhoea is often measured as part of neurological disease-specific questionnaires in NHS clinical practice in England. The company identified the drooling severity and frequency score (DSFS) to measure severity in the pivotal trial (SIAXI; see section\xa03.5). The inclusion criteria in SIAXI included patients with a DSFS score of\xa06 or more, which included people with 'moderate' sialorrhoea by the company definition. The clinical experts stated that severe sialorrhoea is not a distinct subgroup and severity can fluctuate. The committee concluded it was appropriate to consider Xeomin for people with chronic sialorrhoea, and that severity should be based on clinical judgement rather than the DSFS score.\n\n# Clinical evidence\n\n## The SIAXI trial provides the main clinical evidence for Xeomin\n\nThe main evidence for Xeomin came from SIAXI, a randomised placebo-controlled trial. The population included 110\xa0patients with chronic sialorrhoea who had either Xeomin (n=74) or placebo (n=36). The inclusion criteria specified a DSFS of\xa06 or more and the mean age of the patients was\xa065. The population included patients with Parkinson's related diseases (79%), stroke-related diseases (18%) and traumatic brain injury (3%). The co-primary outcomes were unstimulated salivary flow rate and global impression of change scale, 4\xa0weeks after an injection with Xeomin. Secondary outcomes included health-related quality of life as measured by the EQ-5D questionnaire, safety data and the DSFS. The trial also included an extension period that measured these outcomes over 3\xa0further injection cycles of 16\xa0weeks. The results showed a statistically significant decrease in salivary flow rate and increase in global impression of change score at 4\xa0weeks compared with placebo. The committee agreed that SIAXI was a well-designed study and appropriate for decision making. But it noted that it did not include aspiration pneumonia as an outcome measure, which it considered to be an important complication of sialorrhoea (see section\xa03.1).\n\n## The results from the SIAXI trial are generalisable to people seen in clinical practice with chronic sialorrhoea\n\nThe company stated that the reduction in saliva output in SIAXI was independent of the underlying neurological condition. Therefore, the results from SIAXI would be generalisable to everyone with chronic sialorrhoea caused by a neurological condition. The clinical experts agreed but noted that the trial largely included patients with Parkinson's disease who were younger than those who would be expected to be seen in routine NHS clinical practice. They were unable to comment on Xeomin's efficacy for populations not included in SIAXI. The committee recalled that anticholinergic therapy is more likely to be associated with systemic adverse effects in an older population so targeted treatment for sialorrhoea may have additional advantages in the population more often seen in routine clinical practice. The committee concluded that the results of SIAXI were generalisable to the population with chronic sialorrhoea seen in NHS clinical practice and that Xeomin would reduce saliva output regardless of the underlying neurological condition.\n\n## The most relevant outcomes for decision making are the EQ‑5D, global impression of change scale and the DSFS score\n\nThe committee was aware that there was no survival benefit associated with treating sialorrhoea so all the benefits of Xeomin must result from increased quality of life. Although the results of the trial suggested a statistically significant reduction in unstimulated salivary flow rate and an improvement in the global impression of change scale at 4\xa0weeks for Xeomin compared with placebo, this did not translate into a statistically significant increase in quality of life as measured by the EQ‑5D. The relationship between unstimulated salivary flow rate, global impression of change scale and DSFS to quality of life were uncertain. The committee considered unstimulated salivary flow rate to be unsuitable because the ability of a treatment to reduce saliva is not an entirely appropriate way of estimating clinical effectiveness. For example, dry mouth is a common adverse event of anticholinergic treatments, so it is inappropriate to assume that a reduction in salivary flow translates to improved clinical outcomes. The committee instead preferred direct quality-of-life measurements such as the EQ‑5D questionnaire and the global impression of change scale. The committee noted that the DSFS is likely to correlate with the burden of the disease because drooling and its consequences form a large part of the symptom burden of sialorrhoea. The committee therefore concluded that the most relevant outcomes for its decision making were the EQ‑5D questionnaire and the global impression of change scale and agreed to consider these further (see section\xa03.9). It also concluded that, although the DSFS score is not used in clinical practice (see section\xa03.4), it was appropriate for defining the severity of health states in the economic model (see section\xa03.11).\n\n## There are no robust sources of evidence for comparing Xeomin with anticholinergic treatments\n\nThe committee acknowledged that anticholinergic treatments for sialorrhoea are used outside their marketing authorisations. Therefore, there is a lack of data on their effectiveness and safety in the population with chronic sialorrhoea. The company assumed that all anticholinergic treatments were 75% as effective as Xeomin based on an assumption in NICE's guideline on cerebral palsy in under 25s. The committee considered that this may not be the case because a common adverse event of anticholinergics is dry mouth, so the drying effect would be dose related and would depend on whether the patient could tolerate dose escalation (see section\xa03.7). However, the clinical experts stated that glycopyrronium bromide is likely to be more effective than other anticholinergics. Therefore, the committee accepted that, because there was no evidence, equal efficacy in reducing saliva production should be assumed.\n\n## Quality of life as measured by the EQ‑5D‑3L in the SIAXI trial may not fully capture the consequences of sialorrhoea and the benefits of treatment\n\nThe company measured health-related quality of life using the EQ‑5D‑3L questionnaire. It considered that this questionnaire was not sensitive to measuring sialorrhoea symptoms because it was measuring health-related quality of life in a population with debilitating underlying neurological conditions. The EQ‑5D‑3L measures 5\xa0domains including mobility, self-care, usual activities, pain and anxiety or depression using 3\xa0levels ranging from extreme problems, some problems and no problems. It can only register a change in health state when a patient indicates a step change in at least 1\xa0domain. Many patients answered with a score of\xa02 ('some problems') for multiple domains and would therefore need to answer\xa01 ('no problems') to register any improvement. The company considered this unlikely because every domain would be affected in some way by the underlying neurological condition. The clinical experts stated that none of the specific consequences of sialorrhoea would be reliably detected by a non-sialorrhoea specific questionnaire. The committee agreed that there was uncertainty about the extent to which the EQ‑5D‑3L fully captures the consequences of sialorrhoea and the benefits of any treatment and it would consider this in its decision making (see section\xa03.17).\n\n## The adverse effects of Xeomin can be managed in clinical practice\n\nThe committee acknowledged the SIAXI results showed that there may be a low risk of major clinical events including dysphagia. The clinical experts commented that Xeomin is unlikely to lead to an overly dry mouth as an adverse event of treatment because it is possible to titrate the dose and reduce the number of injection sites. The committee concluded that the adverse effects of Xeomin can be managed in clinical practice.\n\n# The company's economic model\n\n## The model structure is appropriate for decision making\n\nThe company developed a Markov state-transition model that included 3\xa0health states to represent different sialorrhoea severity: severe (DSFS score of 7\xa0to\xa09); moderate (DSFS score of 4\xa0to\xa06) and mild or resolved (DSFS score of 2\xa0to\xa03). In the model, patients who stop treatment are assumed to continue having standard care alone. Any patient could independently transition to death at the rate of the general population, although a standardised mortality rate to represent increased mortality from Parkinson's disease was explored in a scenario analysis. The committee was concerned about anticholinergic use over the full-time horizon of the model given the short-term or intermittent use of anticholinergics and the high drop-out rates (see section\xa03.3). The committee also noted that the company had assumed no adverse events for either arm in the economic model. This was because of the lack of data available to do a comparison of the adverse events of Xeomin with those of the anticholinergics. The committee agreed with the company that the assumption of no adverse events was conservative, given the severe side effect burden of anticholinergics. However, it considered that the company should have included adverse events in its economic modelling. Nevertheless, the committee concluded that the economic model structure was acceptable for decision making.\n\n# Utility values in the economic model\n\n## Utility values derived from the population in the SIAXI trial are the most appropriate values to use in the economic modelling\n\nBecause of the problems with measuring health-related quality of life (see section\xa03.9), the company preferred to use utility values from NICE's guideline for cerebral palsy in under\xa025s, stratified into 3\xa0severity groups (mild or resolved [0.5346], moderate [0.4283] and severe [0.3008]). The committee was aware that these utility values were from a hypothetical model in the guideline because there were no data available. The company stated that the psychosocial impact of social isolation, the impact on caregivers and the potential for aspiration pneumonia were not captured in the model, and that the guideline-derived utility values were more plausible than those derived in SIAXI. The ERG considered this modelling inappropriate because the utility values were from a very different population to the SIAXI trial population, and from a hypothetical model. The ERG preferred to use utility values derived from SIAXI (mild or resolved [0.6227], moderate [0.5983] and severe [0.5774]). It considered that the small health-related quality-of-life gain in SIAXI may be an accurate translation of utility gain associated with Xeomin. The ERG calculated the effect associated with a neurological condition in the company's model (average utility for a person of 65\xa0minus the mild or resolved state utility value) as a disutility of\xa00.28 and the effect of severe sialorrhoea (utility of the mild or resolved state minus the severe state utility value) as a disutility of\xa00.23. The ERG and clinical experts were not convinced that sialorrhoea would have a similar magnitude of disutility to the neurological condition. The committee agreed that SIAXI was the most appropriate data source for deriving utility values. But it acknowledged the substantial uncertainty for utility values associated with sialorrhoea because of the lack of data.\n\n## Utility values derived from the SIAXI trial are likely to underestimate utility gain\n\nThe committee agreed that SIAXI was the most appropriate data source for the utility data (see section\xa03.12). But it concluded that the EQ‑5D‑3L data and the derived utility value were unlikely to fully capture the health-related quality-of-life benefit (see section\xa03.9). Additionally, the EQ‑5D‑3L may not fully capture the psychosocial impact of sialorrhoea, including social isolation (see section\xa03.1). The committee also considered that the impact of carer quality of life was not captured, including workload and potential further social isolation of caregivers. It considered that, because the cost-effectiveness results were very sensitive to the utility values chosen and there was a lack of data for sialorrhoea, a qualitative assessment of the direction of uncertainty of the utility values in SIAXI was appropriate. The committee concluded that the EQ‑5D‑3L results from SIAXI were likely to underestimate utility gain from the treatment and that it would consider this in its decision making (see section\xa03.17).\n\n# Costs in the economic model\n\n## Using ultrasound imaging to guide injections is less frequent in NHS clinical practice than in the SIAXI trial\n\nUltrasound imaging is sometimes used to guide the needle into the correct injection site for administering Xeomin. Alternatively, anatomical landmarks are used as guides. The company assumed in its base case that the frequency of using ultrasound guidance in SIAXI (56% of injections) was equivalent to NHS clinical practice. The ERG provided a scenario analysis that assumed 100% of procedures involved ultrasound-guided injections. The committee noted that the summary of product characteristics for Xeomin states that ultrasound-guided application showed superior results to the anatomical landmarks method. However, the clinical experts stated that, although it may vary across centres, using ultrasound guidance for administering injections is infrequent in current NHS clinical practice in England. The committee agreed that ultrasound may be used less in clinical practice than in SIAXI. Therefore, the company's assumption may have overestimated the costs of ultrasound guidance, which would have reduced the cost-effectiveness estimates (see section\xa03.17).\n\n## Assuming more speech and language and occupational therapy consultations for severe than for moderate sialorrhoea is inappropriate\n\nIn SIAXI no data were collected on the resource use of standard care, which the committee considered to be the most relevant comparator (see section\xa03.3). Standard care was also used alongside all active treatments. The company assumed that speech and language consultations and occupational therapy consultations would be once every 16\xa0weeks for the severe sialorrhoea group, once every 32\xa0weeks for the moderate group, and there would be none for the mild or resolved group. The committee noted that the costs of these consultations were applied for the entire duration of the time horizon. The ERG provided a scenario exploring no associated costs for standard care for each treatment option. The clinical experts stated that speech, language and occupational therapy consultations would start with an initial assessment for all sialorrhoea severity groups. This would include training for head positioning, posture, swallow timers and speech assessment. The frequency of follow-up consultations would vary by underlying neurological condition, for example people with stroke and traumatic brain injury may have more frequent assessments. However, in general, most patients would not have follow-up consultations as often as every 16\xa0weeks; it would depend on individual patient needs and access to these services. The committee concluded that the speech and language and occupational therapy resource use in the model did not reflect clinical practice.\n\n# Cost-effectiveness estimates\n\n## The cost-effectiveness results are highly sensitive to assumptions about utility value\n\nThe committee considered whether Xeomin would be a cost-effective use of NHS resources for chronic sialorrhoea. The company provided base-case incremental cost-effectiveness ratios (ICERs) and scenario analyses based on the list price of Xeomin and based on a confidential commercial arrangement. Because the ICERs based on the commercial arrangement are confidential, only the list-price ICERs are presented here.\n\nThe company's base-case deterministic ICER was £9,583 per quality-adjusted life year (QALY) gained for Xeomin compared with standard care. Xeomin dominated glycopyrronium bromide.\n\nThe ERG's exploratory analyses provided both a deterministic ICER and a probabilistic ICER for Xeomin compared with standard care; £47,309 and £45,423 per QALY gained respectively. Xeomin continued to dominate glycopyrronium bromide.The committee noted that the main driver of the difference in ICERs was the source of the utility values, and that the ICER was very sensitive to small changes in assumptions about utility values. It recalled that the most appropriate source of data for the utility values was the EQ‑5D‑3L from SIAXI (see section\xa03.9), which was used in the ERG's analyses. The committee also agreed that standard care was the most appropriate comparator (see section\xa03.3). Therefore, it concluded that the most appropriate ICER for decision making was the ERG's exploratory probabilistic ICER of £45,423 per QALY gained for Xeomin compared with standard care.\n\n## Xeomin is recommended as a treatment option\n\nHaving considered that the ERG's probabilistic ICER is in line with its preferred assumptions, the committee recalled that it would take into account these factors in its decision making:\n\nThe EQ‑5D‑3L may not fully capture the health-related quality-of-life gain associated with sialorrhoea; this would increase QALY gains and lower the ICER (see section\xa03.9).\n\nThe health-related quality of life of carers is not considered in SIAXI and the economic model; this would increase QALY gains and lower the ICER (see section\xa03.13).\n\nUltrasound guidance is not as prevalent in NHS clinical practice as in SIAXI; using the percentage from the NHS in the economic model would reduce the costs and lower the ICER (see section\xa03.14).\n\nResource use was inappropriately modelled; it is unclear how a more appropriate model would affect the ICER (see section\xa03.15).The committee noted that when these factors and the commercial arrangement were taken into account, the ICER would reduce to within the range usually considered to be a cost-effective use of NHS resources. Therefore, the committee recommended Xeomin as a treatment option.\n\n# Other factors\n\n## There are no equalities considerations, but stigma associated with drooling may not be captured by routine quality assessments\n\nThe committee considered whether there were any equalities considerations for this appraisal, as suggested by Parkinson's UK. Potential equalities issues were age, physical disability, communication difficulties and mental health problems. The committee agreed that the increased prevalence of drooling in older people with neurological conditions is a feature of sialorrhoea. Any recommendation resulting from this appraisal will apply to all people, so age, as defined by the Equalities Act, is not a relevant equalities issue. Similarly, physical disability, communication difficulties and mental health problems vary by underlying neurological condition and will apply to all people so are not relevant equalities issues. The committee also considered whether there is stigma associated with drooling, as a social value judgement. It concluded that many of the issues associated with drooling should be picked up as part of measuring social isolation and other psychosocial symptoms (see section\xa03.1), although these were not captured with the chosen assessment tools. However, there may be additional relief of stigma as a result of treatment that would not be captured in routine quality-of-life assessments.\n\n## The technology is not innovative\n\nThe company considers the drug to be innovative. However, when focusing specifically on relevant benefits associated with innovation, the committee considered that these were adequately captured in the model."}
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https://www.nice.org.uk/guidance/ta605
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Evidence-based recommendations on Xeomin (botulinum neurotoxin type A) for treating chronic sialorrhoea (excessive salivation and drooling) caused by neurological conditions in adults.
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4bae8b8400f9ada84022969647c61e05119cbece
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nice
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EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing
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EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing
Evidence-based recommendations on EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.
The case for adopting the EXOGEN ultrasound bone healing system to treat long bone fractures with non-union (failure to heal after 9 months) is supported by the clinical evidence, which shows high rates of fracture healing.
The EXOGEN ultrasound bone healing system to treat long bone fractures with non-union is associated with an estimated cost saving of £2,407 per patient compared with current management, through avoiding surgery.
There is some radiological evidence of improved healing when the EXOGEN ultrasound bone healing system is used for long bone fractures with delayed healing (no radiological evidence of healing after approximately 3 months). There are substantial uncertainties about the rate at which bone healing progresses without adjunctive treatment between 3 and 9 months after fracture, and about whether or not surgery would be necessary. These uncertainties result in a range of cost consequences, some cost saving and others that are more costly than current management (see sections 5.12, 5.19 and 5.26).# The technology
# Description of the technology
The EXOGEN ultrasound bone healing system (Smith & Nephew), referred to in this document as EXOGEN, delivers low-intensity pulsed ultrasound waves with the aim of stimulating bone healing. It is thought that healing is promoted by stimulating the production of growth factors and proteins that increase the removal of old bone, increase the production of new bone and increase the rate at which fibrous matrix at a fracture site is converted to mineralised bone. Long bone fractures are suitable for treatment if the fracture is stable and well-aligned. EXOGEN is not indicated for use in fractures of the skull or vertebrae, or in children or adolescents because of their skeletal immaturity.
The EXOGEN system is a single hand-held device with 2 treatment options: EXOGEN 150 and EXOGEN 250. These are equivalent to the former versions EXOGEN Express and EXOGEN 4000+ respectively. The device has a visual treatment-tracking calendar and treatment history log aimed at improving compliance. EXOGEN controls the number of treatments performed using an SD card. The device operates on a low lithium battery and has a battery door and charger. The device also has a smartphone app, EXOGEN Connects, which enables adherence by providing information such as treatment reminders, information on fracture healing and videos on how to use EXOGEN. The phone app has not been assessed as part of the evaluation.
The EXOGEN device consists of a main operating unit with a permanently connected transducer and a separate fixture strap. The strap is placed around the fractured bone, coupling gel is applied to the transducer head (to aid conduction of ultrasound) and the transducer is secured directly over the fracture site by a fixture on the strap. The ultrasound signal emitted by the device is derived from a combination of defined electrical signal parameters and the proprietary transducer design, which generate an acoustic wave pattern specific to EXOGEN. If the patient's limb is immobilised in a cast then a hole is cut in the cast to allow access of the transducer to the skin. The device is programmed to deliver ultrasound in 20‑minute sessions and these are self-administered by the patient each day. It is intended to be used in the patient's home.
The cost of the EXOGEN 4000+ stated in the sponsor's submission was £2,562.50 (excluding VAT) and the cost of the EXOGEN Express device was £999.38 (excluding VAT).
The claimed benefits of EXOGEN for long bone fractures with non-union or delayed healing presented in the case for adoption by the sponsor are:
reduced healing time compared with surgery
avoidance of surgery and achievement of comparable clinical outcomes
quicker return to weight bearing and normal daily living compared with surgery
improved treatment accessibility with a therapy that can be self-administered in a home environment
reduced need for high-cost surgical intervention
reduced cost because of a reduction in outpatient care, quicker recovery and return to work and normal living.
# Current management
Long bone fractures are usually treated immediately by closed or open reduction (realignment of the bone ends, which can involve surgery). The affected limb is immobilised using a cast or by internal or external fixation. X‑rays are used to verify alignment of the bone. Progress towards fracture healing is usually assessed by X‑ray demonstration of bridging of the gap between the fractured bone ends with new bone cortex.
Patients with delayed fracture healing at 3 months do not usually have surgery at this time unless the fracture is complex (for example, an unstable or misaligned fracture or an inter-fragment gap of more than 10 mm). Surgery may take place between 3 and 9 months after fracture, but clinical practice varies and decisions about the timing of surgery are made on an individual patient basis. If surgery is considered necessary, it usually involves internal or external fixation and bone grafting (with harvesting from the patient's iliac crest).# Clinical evidence
# Summary of clinical evidence
Full details of all clinical outcomes considered by the Committee are available in the assessment report overview. Reference to EXOGEN in the context of non-union should be taken to mean the EXOGEN 4000+ device and in the context of delayed healing to be the EXOGEN Express device, unless otherwise stated.
The key clinical outcomes for EXOGEN for long bone fractures with non-union or delayed healing presented in the decision problem were:
evidence of bridging on radiograph (3 out of 4 cortices bridged)
fracture healing time
return to painless weight bearing
avoidance of further surgery
device-related adverse events.
The sponsor presented clinical evidence from 18 studies in its submission. Of these, the External Assessment Centre excluded one because it did not report any outcomes defined in the scope. The clinical evidence for EXOGEN is therefore based on 17 clinical studies (total of 1,710 patients), including 3 randomised controlled trials, 13 case series and 1 prospective comparison. Of these, 13 studies reported on non-union fractures, 2 reported on delayed healing and 2 reported on both types of fracture. There were no controlled or randomised studies in which EXOGEN and surgery were compared directly in the treatment of either non-union or delayed fractures. However, independent estimates of healing rates for EXOGEN and surgery were available from non-comparative case series for non-union fractures. The age of study participants ranged from 13 to 92 years and follow-up across the studies ranged from 2 months to 6 years. None of the studies were carried out in the UK.
## Non-union long bone fracture
Mayr et al. (2000) described 256 patients with non-union fractures (failure to heal 9 months after fracture) from an international register of patients treated with EXOGEN. Healing was defined as 3 cortices bridged in 3 X‑ray planes or trabecular bridging of at least 80% of the fracture in the case of cancellous fractures. The mean healing rate across all long bone fractures (humerus, radius/ulna, femur, tibia-fibula) was 84% (216/256), with a mean healing time of 5.3 months.
Gebauer et al. (2005) described a case series of 51 patients with non-union fractures (defined as minimum fracture age 8 months, radiographic indication that the healing process had stopped for at least 3 months, and a minimum of 4 months without surgical intervention before EXOGEN). A healing rate (healing defined as no pain or motion upon gentle stress and weight bearing if applicable, and radiographic healing defined as 3 of 4 cortices bridged) of 90% (46/51) for all long bone fractures (not otherwise described) was reported with a mean healing time of 178 days (range 86 to 375 days).
In a case series of 32 patients with non-union fractures (defined on the basis that surgery was otherwise deemed to be indicated), Jingushi et al. (2007) reported a healing rate (defined as clinical and radiographic healing as determined by experienced orthopaedic surgeons) of 66% (21/32); analyses by individual long bone were not included. A mean healing time of 219 days (range 56 to 588 days) was reported for a mixed group of 72 patients with non-union and delayed healing fractures. When treatment with EXOGEN was started within 6 months of the most recent operation, the union rate was approximately 90%. When treatment was started after 12 months, the union rate was less than 65% (follow‑up not reported).
Nolte et al. (2001) evaluated a case series of 22 patients with non‑union fractures (defined as failure of the fracture to unite at a minimum of 6 months from fracture, no progression towards radiographic healing or healing had stopped for a minimum period of 3 months before EXOGEN). Healing rates (healing defined as absence of pain, weight bearing without pain or normal function of the limb, 3 or 4 cortices bridged on radiograph) of 100% (10/10) for tibia-tibia/fibula (mean healing time 144 days), 80% (4/5) for femur (mean healing time 185 days), 80% (4/5) for radius-radius/ulna (mean healing time 139 days) and 100% (2/2) for other long bone fractures (mean healing time 153 days) were reported.
Romano et al. (1999) studied 13 patients with non-union fractures of long bones (tibia, humerus and femur) and septic pseudoarthrosis. Healing was reported in 62% (8/13) of patients (no further details reported).
Data were identified by the sponsor on the rates of healing for non-union long bone fractures treated by surgery. Healing rates ranged from 62% to 100%, and healing time ranged from 9 weeks (Livani et al. 2010) to 24 weeks (Ring et al. 1997). Across 3 case series and 1 cohort study, including a total of 166 patients with non-union fractures treated by surgery, 10 patients needed further surgery (follow-up not reported; Birjandinejad et al. 2009, Khalil et al. 2010, Lin et al. 2010 and Ring et al. 1997). These studies reported on fractures of different long bones, including distal femur, femur, tibia and ulna/radius.
## Delayed healing long bone fracture
Schofer et al. (2010) carried out a randomised controlled trial of 101 patients with delayed healing of tibial shaft fractures (defined as lack of clinical and radiologic evidence of union, bony continuity or bone reaction at the fracture site no less than 16 weeks from the index injury or the most recent intervention) treated by EXOGEN (n=51) or placebo (n=50). No significant difference was reported between the groups in healing rate (judged by clinician, not otherwise described) over a 4-month follow-up period (65% for EXOGEN compared with 46% for placebo, HR 1.69, p=0.07).
Mayr et al. (2000) reported on a total of 696 patients from the international register for EXOGEN (see section 3.4) who received treatment for fractures with delayed healing (defined as failure to heal 3 to 9 months after fracture). In this case series, 90% (586/654) of all long bone fractures healed (as defined in section 3.4) in a mean time of 4.4 months. The authors presented healing rates separately for the different types of fracture. Healing rates ranged from 76% (41/54) with a mean healing time of 125 days for fractures of the humerus to 96% (26/27) with a mean healing time of 113 days for fractures of the fibula.
The case series reported by Jingushi et al. (2007) included 40 patients with delayed healing fractures (defined as union or radiological bone reaction not being observed more than 3 months after the most recent operation). A healing rate (healing defined in section 3.4) for fractures of the femur, tibia, humerus, radius and ulna of 83% (33/40) was reported (follow-up not stated).
In a case series of 16 patients with delayed healing (defined as no radiological evidence of fracture callus 4 to 38 months after surgical insertion of an intramedullary nail or the Ilizarov procedure ), Lerner et al. (2004) reported a healing rate (as determined by an experienced orthopaedic surgeon) of 94% (15/16) over a mean follow-up of 17 months (fractures included femur, tibia, radius/ulna and humerus).
No studies that reported healing rates after surgery in patients with delayed healing long bone fractures were presented by the sponsor.
## Adverse events
The US Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database reported 3 cases of skin irritation caused by skin sensitivity to the coupling gel (resolved by change of coupling medium) and 1 report of increased chest pain, possibly caused by interference with a cardiac pacemaker, during a 1‑year period (the sponsor stated that approximately 55,000 EXOGEN devices were used by patients in the USA over this time period).
None of the clinical studies reported device-related adverse events and no significant safety concerns were identified by the External Assessment Centre in relation to EXOGEN in its independent search of the literature. In contrast, reports on surgical treatment of non-union and delayed healing fractures documented adverse events including postoperative wound infection, osteomyelitis and pain.
## Committee considerations
The Committee considered that although the evidence on using EXOGEN for long bone fractures with non-union was from observational studies and related to a limited number of outcomes (healing defined in various ways including weight bearing, and radiographic evidence), it suggested good clinical results after treatment with EXOGEN. The Committee judged that the observed healing rates supported the efficacy of EXOGEN in promoting healing of these fractures and that its use meant that many of these patients avoided surgery.
For long bone fractures with delayed healing, the Committee found the outcomes after treatment with EXOGEN more difficult to interpret. There were uncertainties, including the rate at which healing progresses between 3 and 9 months after fracture, both with and without EXOGEN. There were also uncertainties about the proportion of patients in whom surgery would be avoided, because some of these fractures heal spontaneously.
The Committee noted that the clinical evidence comparing the efficacy of EXOGEN with surgery was very limited. The Committee recognised the difficulties in conducting comparative studies (and specifically randomised controlled trials) to collect data on healing rates.
Clinical experts advised the Committee that the efficacy of EXOGEN may differ depending on which long bone is being treated. The experts stated that non-union most commonly occurs in fractures of the tibia.
The Committee discussed the applicability of the data from Schofer et al. (2010) in the context of delayed healing. The External Assessment Centre stated that 51 of the 101 patients in this trial had sustained fractures 9 months or more before entry to the study. According to the definition used in the scope, these would be classified as non-union fractures. The Committee was advised by the External Assessment Centre that this trial was not powered to detect differences in healing rates (one of the outcomes defined in the decision problem) and so considered the other primary clinical outcomes reported; radiographically-measured bone mineral density and gap at the fracture site (assessed by computed tomography scan). The Committee noted that there were significant improvements in these outcomes in the group treated with EXOGEN compared with placebo (sham treatment).
The Committee discussed the variation in fracture healing time among patients. It was advised that there is a considerable natural inter-patient variation in healing rates and that this could explain differences in healing rates reported across the studies. In addition, variation in healing time is more pronounced in the early stage of the healing process and that contributes to the greater complexity of interpreting outcomes for fractures with delayed healing compared against those with non-union.
The Committee recognised that there may be subgroups of patients in whom healing takes place at a slower rate than the general population. However, it considered that neither current evidence nor expert opinions provided sufficient information to model the potential impact of EXOGEN in these groups of patients.# NHS considerations
# System impact
No studies were identified that included avoiding surgery as a result of treatment with EXOGEN as an outcome measure. In addition, no studies presented data on return to weight bearing and normal daily living after EXOGEN treatment, compared with surgery.
## Committee considerations
The Committee considered that any effective treatment that avoids or reduces the need for surgery is of significant benefit to patients and also has potential advantages to the NHS in terms of resource use. Such advantages might include reducing the duration of NHS care, the number of outpatient visits or the number of X‑rays that patients need.
The Committee considered that the healing rates reported across the clinical studies indicate that surgery can be avoided and that healing time can be reduced by treatment with EXOGEN. The Committee heard persuasive comments from a patient expert about the benefits EXOGEN treatment can provide in terms of return to activity and quality of life.
The Committee discussed the proportion of patients who might avoid surgery as a result of treatment with EXOGEN. The Committee was advised by clinical experts that approximately one third of non-union tibial fractures might be suitable for treatment with EXOGEN, although estimates of the total number of non-union long bone fractures varied.
The Committee noted that treatment with EXOGEN is self-administered, and therefore some patients may need help when using the device. The Committee was told by the patient expert and clinical experts that the device is easy to use and can be administered by a carer instead of the patient.# Cost considerations
# Cost evidence
The sponsor identified 3 economic studies, all in UK settings. Taylor et al. (2009) carried out a cost-effectiveness analysis on non-union tibial fractures treated by EXOGEN or by surgery (intramedullary nailing). The model developed for this study was adapted for use in the sponsor's submission. Kanakaris et al. (2007) presented a non-comparative analysis of the cost of compression plate fixation and bone grafting to treat aseptic non-union long bone fractures, and Patil et al. (2006) reported a similar analysis for the Ilizarov surgical procedure to treat complex non-union tibia or femur fractures.
The sponsor submitted a de novo cost analysis for EXOGEN. Full details of all cost evidence and modelling considered by the Committee are available in the assessment report overview.
Two cost models were submitted by the sponsor – 1 for non-union and 1 for delayed healing (both adapted from the model by Taylor et al. 2009). Markov models with a 1‑year time horizon and monthly cycles were used to carry out each cost analysis. The patient population included patients with fractures of the tibia initially treated by surgical insertion of an intramedullary nail.
For non-union fractures, the cost model evaluated the costs and consequences associated with the use of the EXOGEN 4000+ at diagnosis of non-union, followed by further surgery if the fracture did not heal within 6 months, compared with surgery at diagnosis, followed by repeat surgery if the fracture did not heal within 6 months.
The non-union model had 4 health states: 'non-union fracture', 'healed fracture', 'infection' and 'post infection'. All patients began in the 'non-union fracture' health state. Patients in the EXOGEN arm had treatment with EXOGEN 4000+ from baseline, whereas patients in the control arm had surgery at baseline. In both arms, if healing had not occurred after 6 months in the non-union fracture health state, it was assumed that further surgery was needed. In the surgery arm, patients were at risk of infection as a complication of surgery from the time of diagnosis of non-union, and also if they had further revision surgery after 6 months in the non-union state. The model assumed that no infection would occur in the EXOGEN arm.
In the sponsor's base case for non-union fracture, the key assumptions were cited as follows:
Healing rates and healing times are equivalent for both the EXOGEN 4000+ and surgery in the case of stable, well-aligned fractures.
Average length of bed stay for surgery is 4.9 days (Hospital episode statistics online 2010/11).
Average theatre time for non-union surgery is 3 hours.
All initial non-union surgical management includes autologous iliac crest bone graft.
In the EXOGEN 4000+ group, in most cases, only 1 additional operation will be offered over 1 year if the fracture has not healed.
Non-procedure-related costs (for example, physiotherapy, X‑ray) are the same in both treatment arms.
Infection rates in the EXOGEN 4000+ and control groups are assumed to be 0% and 1.4% per month (Health Protection Agency, 2011) respectively.
Infection lasts for a maximum of 2 months, but all costs associated with its treatment are incurred in the first month.
In the case of osteomyelitis, staged revision surgery is carried out.
Patients with osteomyelitis are given intravenous antibiotics in hospital over a minimum of 3 weeks.
For delayed healing, the costs and consequences associated with the use of the EXOGEN Express at diagnosis of delayed healing followed by surgery if the fracture did not heal within 6 months (9 months after fracture), were compared with no intervention at diagnosis followed by surgery if the fracture did not heal within 6 months.
The delayed healing model had 5 health states: 'delayed union', 'healed fracture', 'non-union', 'infection' and 'post infection'. All patients begin in the delayed union state. It was assumed that surgical intervention (intramedullary nailing) had been carried out before delayed healing was diagnosed, shortly after the fracture occurred. The model for delayed union was run twice; once for the EXOGEN arm, when patients started using the EXOGEN Express device at the beginning of the modelling period; and once for the control arm, when patients were assumed to have no further treatment (observation only) until non-union was diagnosed. In subsequent cycles, patients could move to 'healed fracture' (an absorbing state), 'infection', or after 6 months in the model, to 'non-union'. After infection, a staged revision surgery process began, with the administration of intravenous antibiotics and removal of metalwork. It was considered that the infection would take 2 months to clear, at which point revision surgery would take place. Patients could become re-infected having previously moved into the post-infection state. After 6 months of delayed healing, and no infection occurring, the patient could progress to 'non-union fracture', when further surgery would take place. In subsequent cycles, non-union fractures may have healed or become infected.
In the sponsor's base case for delayed healing the key assumptions were as follows:
For both arms in the model, patient treatment pathways start with a surgical intervention (insertion of an intramedullary nail) to treat a fresh fracture.
On diagnosis of delayed union, the patient will either have treatment with the EXOGEN Express or will receive no further treatment (observation only) until either bony union is achieved or non-union is diagnosed.
Healing rates for delayed healing at 6 months are a linear progression of those reported at 4 months in the Schofer et al. (2010) study in the absence of any comparative data on healing rate from other randomised controlled trials.
The cost models were from an NHS cost perspective. The cost analyses included costs associated with surgery (including surgical intervention, theatre time, drugs, bed stay) and costs associated with GP visits, outpatient visits, treating infection (including surgery and medication), X‑rays, wheelchair, crutches and physiotherapy.
In the sponsor's base case for non-union fractures, the average cost per patient for the EXOGEN 4000+ device was £4,647 and the average cost per patient for surgery was £6,957. The EXOGEN 4000+ was therefore associated with a cost saving of £2,310 compared with surgery. The sponsor carried out a deterministic sensitivity analysis to vary the rates of healing and infection. The analysis showed that the model is not sensitive to changes in rates of healing and infection, and the EXOGEN 4000+ remained cost saving for non-union fractures in all scenarios tested.
For delayed healing, the sponsor's base case presented an average cost per patient of £4,290 for the EXOGEN Express and £4,974 for current management (observation followed by surgery at non-union if needed). The EXOGEN Express was therefore associated with a cost saving of £684 per patient on early use compared with current management. The sponsor varied the rates of healing and infection in a sensitivity analysis and showed that the model is sensitive to changes in these parameters.
For the non-union model, the External Assessment Centre considered that a number of the assumptions were not justified and it made several changes to the sponsor's base-case model. These were as follows:
applying the healing rate for EXOGEN from Mayr et al. (2000)
allowing for infection in the EXOGEN arm following surgery at 6 months
applying a one-off rate of infection following any surgery
adjusting the post-surgical infection rate
correcting minor errors in the model.
For the non-union model, the External Assessment Centre's additional analysis showed average costs per patient for the EXOGEN 4000+ of £5,688 and for surgery of £6,852. The EXOGEN 4000+ was therefore associated with a cost saving of £1,164 compared with immediate surgery for non-union. Sensitivity analysis showed that the model is relatively insensitive to changes in assumptions about the relative effectiveness of surgery compared with EXOGEN. The External Assessment Centre considered that the EXOGEN 4000+ is significantly cheaper than surgery.
In a 2‑way sensitivity analysis, varying the baseline healing rate with EXOGEN, and the relative risk of healing with surgery compared with EXOGEN, showed stable results. Only if the healing rate with EXOGEN was reduced to its lower limit and the relative risk of healing with surgery increased to its upper limit did EXOGEN become more expensive than surgery. The External Assessment Centre also carried out sensitivity analyses to apply no delay to the onset of healing, add VAT on devices and consumables, and use healthcare resource group costs for infection and surgery. The EXOGEN 4000+ remained cost saving for all scenarios tested.
For the delayed healing model, the External Assessment Centre considered that several of the sponsor's assumptions were not justified and made a number of changes to the base-case model. These changes included:
allowing for infection in the EXOGEN arm following further surgery for patients who have not healed after 6 months (9 months after fracture)
changing costs to apply to delayed healing resource use (as per model) at baseline, not fresh fracture
adjusting the infection rate and associated costs as for non-union.
After applying these changes, the External Assessment Centre estimated results for 8 scenarios that reflected different sources of healing rates (Mayr et al. 2000 for the EXOGEN Express arm and relative risk from Schofer et al. 2010 compared with Schofer et al. 2010 alone), different assumptions about the minimum time to healing following surgery and EXOGEN (no delay compared with 2‑month delay before healing is observed), and the persistence of relative benefits of EXOGEN (persistence of enhanced healing rate compared with no persistence between the end of EXOGEN treatment at 4 months and further surgery if needed at 6 months).
For delayed healing the External Assessment Centre's preferred scenario from among the 8 in its report applied the following key assumptions:
The best estimate of the healing rate with EXOGEN is from the register data reported by Mayr et al. (2000).
The best estimate of relative healing rates with the EXOGEN Express compared with no further treatment until non-union is provided by Schofer et al. (2010).
It is reasonable to assume that healing following either surgery or the start of treatment with the EXOGEN Express will not usually be observed within 2 months (expert opinion).
It is conservative to assume that EXOGEN does not continue to enhance the background healing rate once ultrasound treatment has finished after 4 months (the duration of follow-up in Schofer et al. 2010).
The External Assessment Centre's preferred scenario for the treatment of long bone fractures with delayed healing showed a total cost for the EXOGEN Express of £3,033 and a total cost for current management of £2,529. The EXOGEN Express was therefore associated with a cost increase of £504 per patient compared with observation followed by surgery at non-union if necessary.
The External Assessment Centre carried out a 2‑way sensitivity analysis in which the baseline healing rate was varied with the EXOGEN Express and the relative risk of healing compared with control using the preferred scenario. They found that the results were not sensitive to varying these estimates: the EXOGEN Express remained more costly than waiting to see if fractures healed without further intervention. The External Assessment Centre carried out further sensitivity analyses to vary the risk of infection, applying VAT on devices and consumables, using healthcare resource group costs for surgery and for the treatment of infection. The EXOGEN Express remained more expensive than the comparator for delayed healing under all of the scenarios tested.
## Committee considerations
For long bone fractures with non-union the Committee accepted that treatment with the EXOGEN 4000+ results in cost savings. It was advised by clinical experts that the costs associated with surgery in the cost models might well be underestimates and so the cost savings could be even greater in practice.
The Committee discussed the healing rates applied in the sponsor's base case for delayed healing. It was advised by the External Assessment Centre that the methods by which healing rates were extracted from the clinical studies (Mayr et al. 2000 and Schofer et al. 2010) and converted to monthly rates were likely to represent an overestimate of the relative effectiveness of EXOGEN Express compared with the control arms. Clinical experts stated that the patient group suitable for treatment with EXOGEN is heterogeneous and treatment strategies are made on an individual patient basis. On the basis of all this information, the Committee considered that the External Assessment Centre's approach to scenario analyses was reasonable.
For long bone fractures with delayed healing, the Committee discussed the scenarios presented by the External Assessment Centre and accepted the External Assessment Centre's preferred scenario as the most likely. However, as for non-union fractures, it considered that the costs associated with surgery might have been underestimated.
The Committee considered that it was acceptable for the cost models to be limited to tibial fractures (as opposed to fractures of other long bones) because the tibia is the most common long bone for which treatment of non-union is needed.
The Committee questioned whether the 12‑month time horizon used in the cost models might be too short. However, it was advised by the External Assessment Centre that it is likely that extending the time horizon would have little impact on the results, because most fractures would have healed by the end of the 12 months, regardless of the intervention.
The External Assessment Centre applied the updated cost of the device and other costs to the cost model for non-union healing and reported net savings increased from £1,164 to £2,407 per patient compared with current management, through avoiding surgery. The increase in savings is primarily because length of hospital stay if a patient has surgery has increased from 4.9 days to 7 days. The External Assessment Centre also applied updated costs to delayed healing. It reported an estimated cost increase of £628 (was £504) per patient compared with current management. The increase in incremental costs is primarily due to the increase in the cost of the EXOGEN 150 device. # Conclusions
The Committee recognised that the available clinical data on the effectiveness of EXOGEN for treating long bone fractures with non-union show high rates of fracture healing and it judged them sufficient to support the efficacy and utility of EXOGEN treatment. Despite the absence of direct evidence on avoiding surgery, the Committee considered that the assumptions in the cost model were plausible and that EXOGEN is cost saving compared with current management for the treatment of non-union. Overall, therefore, the case for adoption of EXOGEN in the treatment of long bone fractures with non-union was found to be supported by the evidence.
For long bone fractures with delayed healing the Committee considered that the clinical evidence was more limited. In addition there were significant uncertainties about the rate at which healing progresses between 3 and 9 months after fracture, both with and without EXOGEN, and about whether or not surgery would be required if EXOGEN was not used. These and other considerations influenced the Committee's views about the most appropriate assumptions for cost modelling: the model considered to be most appropriate estimated that EXOGEN treatment would be more costly than current management. The Committee therefore judged that the case for adoption of EXOGEN to treat long bone fractures with delayed healing was not supported by the current evidence.
|
{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.\n\nThe case for adopting the EXOGEN ultrasound bone healing system to treat long bone fractures with non-union (failure to heal after 9\xa0months) is supported by the clinical evidence, which shows high rates of fracture healing.\n\nThe EXOGEN ultrasound bone healing system to treat long bone fractures with non-union is associated with an estimated cost saving of £2,407 per patient compared with current management, through avoiding surgery. \n\nThere is some radiological evidence of improved healing when the EXOGEN ultrasound bone healing system is used for long bone fractures with delayed healing (no radiological evidence of healing after approximately 3\xa0months). There are substantial uncertainties about the rate at which bone healing progresses without adjunctive treatment between 3 and 9\xa0months after fracture, and about whether or not surgery would be necessary. These uncertainties result in a range of cost consequences, some cost saving and others that are more costly than current management (see sections 5.12, 5.19 and 5.26).", 'The technology': "# Description of the technology\n\nThe EXOGEN ultrasound bone healing system (Smith & Nephew), referred to in this document as EXOGEN, delivers low-intensity pulsed ultrasound waves with the aim of stimulating bone healing. It is thought that healing is promoted by stimulating the production of growth factors and proteins that increase the removal of old bone, increase the production of new bone and increase the rate at which fibrous matrix at a fracture site is converted to mineralised bone. Long bone fractures are suitable for treatment if the fracture is stable and well-aligned. EXOGEN is not indicated for use in fractures of the skull or vertebrae, or in children or adolescents because of their skeletal immaturity.\n\nThe EXOGEN system is a single hand-held device with 2\xa0treatment options: EXOGEN\xa0150 and EXOGEN\xa0250. These are equivalent to the former versions EXOGEN Express and EXOGEN\xa04000+ respectively. The device has a visual treatment-tracking calendar and treatment history log aimed at improving compliance. EXOGEN controls the number of treatments performed using an SD\xa0card. The device operates on a low lithium battery and has a battery door and charger. The device also has a smartphone app, EXOGEN Connects, which enables adherence by providing information such as treatment reminders, information on fracture healing and videos on how to use EXOGEN. The phone app has not been assessed as part of the evaluation. \n\nThe EXOGEN device consists of a main operating unit with a permanently connected transducer and a separate fixture strap. The strap is placed around the fractured bone, coupling gel is applied to the transducer head (to aid conduction of ultrasound) and the transducer is secured directly over the fracture site by a fixture on the strap. The ultrasound signal emitted by the device is derived from a combination of defined electrical signal parameters and the proprietary transducer design, which generate an acoustic wave pattern specific to EXOGEN. If the patient's limb is immobilised in a cast then a hole is cut in the cast to allow access of the transducer to the skin. The device is programmed to deliver ultrasound in 20‑minute sessions and these are self-administered by the patient each day. It is intended to be used in the patient's home.\n\nThe cost of the EXOGEN\xa04000+ stated in the sponsor's submission was £2,562.50 (excluding VAT) and the cost of the EXOGEN Express device was £999.38 (excluding VAT).\n\nThe claimed benefits of EXOGEN for long bone fractures with non-union or delayed healing presented in the case for adoption by the sponsor are:\n\nreduced healing time compared with surgery\n\navoidance of surgery and achievement of comparable clinical outcomes\n\nquicker return to weight bearing and normal daily living compared with surgery\n\nimproved treatment accessibility with a therapy that can be self-administered in a home environment\n\nreduced need for high-cost surgical intervention\n\nreduced cost because of a reduction in outpatient care, quicker recovery and return to work and normal living.\n\n# Current management\n\nLong bone fractures are usually treated immediately by closed or open reduction (realignment of the bone ends, which can involve surgery). The affected limb is immobilised using a cast or by internal or external fixation. X‑rays are used to verify alignment of the bone. Progress towards fracture healing is usually assessed by X‑ray demonstration of bridging of the gap between the fractured bone ends with new bone cortex.\n\nPatients with delayed fracture healing at 3\xa0months do not usually have surgery at this time unless the fracture is complex (for example, an unstable or misaligned fracture or an inter-fragment gap of more than 10\xa0mm). Surgery may take place between 3 and 9\xa0months after fracture, but clinical practice varies and decisions about the timing of surgery are made on an individual patient basis. If surgery is considered necessary, it usually involves internal or external fixation and bone grafting (with harvesting from the patient's iliac crest).", 'Clinical evidence': '# Summary of clinical evidence\n\nFull details of all clinical outcomes considered by the Committee are available in the assessment report overview. Reference to EXOGEN in the context of non-union should be taken to mean the EXOGEN\xa04000+ device and in the context of delayed healing to be the EXOGEN Express device, unless otherwise stated.\n\nThe key clinical outcomes for EXOGEN for long bone fractures with non-union or delayed healing presented in the decision problem were:\n\nevidence of bridging on radiograph (3 out of 4 cortices bridged)\n\nfracture healing time\n\nreturn to painless weight bearing\n\navoidance of further surgery\n\ndevice-related adverse events.\n\nThe sponsor presented clinical evidence from 18\xa0studies in its submission. Of these, the External Assessment Centre excluded one because it did not report any outcomes defined in the scope. The clinical evidence for EXOGEN is therefore based on 17\xa0clinical studies (total of 1,710\xa0patients), including 3\xa0randomised controlled trials, 13\xa0case series and 1\xa0prospective comparison. Of these, 13\xa0studies reported on non-union fractures, 2 reported on delayed healing and 2 reported on both types of fracture. There were no controlled or randomised studies in which EXOGEN and surgery were compared directly in the treatment of either non-union or delayed fractures. However, independent estimates of healing rates for EXOGEN and surgery were available from non-comparative case series for non-union fractures. The age of study participants ranged from 13\xa0to 92\xa0years and follow-up across the studies ranged from 2\xa0months to 6\xa0years. None of the studies were carried out in the UK.\n\n## Non-union long bone fracture\n\nMayr et al. (2000) described 256\xa0patients with non-union fractures (failure to heal 9\xa0months after fracture) from an international register of patients treated with EXOGEN. Healing was defined as 3\xa0cortices bridged in 3\xa0X‑ray planes or trabecular bridging of at least 80% of the fracture in the case of cancellous fractures. The mean healing rate across all long bone fractures (humerus, radius/ulna, femur, tibia-fibula) was 84% (216/256), with a mean healing time of 5.3\xa0months.\n\nGebauer et al. (2005) described a case series of 51\xa0patients with non-union fractures (defined as minimum fracture age 8\xa0months, radiographic indication that the healing process had stopped for at least 3\xa0months, and a minimum of 4\xa0months without surgical intervention before EXOGEN). A healing rate (healing defined as no pain or motion upon gentle stress and weight bearing if applicable, and radiographic healing defined as 3\xa0of 4\xa0cortices bridged) of 90% (46/51) for all long bone fractures (not otherwise described) was reported with a mean healing time of 178\xa0days (range 86 to 375\xa0days).\n\nIn a case series of 32\xa0patients with non-union fractures (defined on the basis that surgery was otherwise deemed to be indicated), Jingushi et al. (2007) reported a healing rate (defined as clinical and radiographic healing as determined by experienced orthopaedic surgeons) of 66% (21/32); analyses by individual long bone were not included. A mean healing time of 219\xa0days (range 56 to 588\xa0days) was reported for a mixed group of 72\xa0patients with non-union and delayed healing fractures. When treatment with EXOGEN was started within 6\xa0months of the most recent operation, the union rate was approximately 90%. When treatment was started after 12\xa0months, the union rate was less than 65% (follow‑up not reported).\n\nNolte et al. (2001) evaluated a case series of 22\xa0patients with non‑union fractures (defined as failure of the fracture to unite at a minimum of 6\xa0months from fracture, no progression towards radiographic healing or healing had stopped for a minimum period of 3\xa0months before EXOGEN). Healing rates (healing defined as absence of pain, weight bearing without pain or normal function of the limb, 3 or 4\xa0cortices bridged on radiograph) of 100% (10/10) for tibia-tibia/fibula (mean healing time 144\xa0days), 80% (4/5) for femur (mean healing time 185\xa0days), 80% (4/5) for radius-radius/ulna (mean healing time 139\xa0days) and 100% (2/2) for other long bone fractures (mean healing time 153\xa0days) were reported.\n\nRomano et al. (1999) studied 13\xa0patients with non-union fractures of long bones (tibia, humerus and femur) and septic pseudoarthrosis. Healing was reported in 62% (8/13) of patients (no further details reported).\n\nData were identified by the sponsor on the rates of healing for non-union long bone fractures treated by surgery. Healing rates ranged from 62% to 100%, and healing time ranged from 9\xa0weeks (Livani et al. 2010) to 24\xa0weeks (Ring et al. 1997). Across 3\xa0case series and 1\xa0cohort study, including a total of 166\xa0patients with non-union fractures treated by surgery, 10\xa0patients needed further surgery (follow-up not reported; Birjandinejad et al. 2009, Khalil et al. 2010, Lin et al. 2010 and Ring et al. 1997). These studies reported on fractures of different long bones, including distal femur, femur, tibia and ulna/radius.\n\n## Delayed healing long bone fracture\n\nSchofer et al. (2010) carried out a randomised controlled trial of 101\xa0patients with delayed healing of tibial shaft fractures (defined as lack of clinical and radiologic evidence of union, bony continuity or bone reaction at the fracture site no less than 16\xa0weeks from the index injury or the most recent intervention) treated by EXOGEN (n=51) or placebo (n=50). No significant difference was reported between the groups in healing rate (judged by clinician, not otherwise described) over a 4-month follow-up period (65% [33/51] for EXOGEN compared with 46% [23/50] for placebo, HR\xa01.69, p=0.07).\n\nMayr et al. (2000) reported on a total of 696\xa0patients from the international register for EXOGEN (see section 3.4) who received treatment for fractures with delayed healing (defined as failure to heal 3 to 9\xa0months after fracture). In this case series, 90% (586/654) of all long bone fractures healed (as defined in section 3.4) in a mean time of 4.4\xa0months. The authors presented healing rates separately for the different types of fracture. Healing rates ranged from 76% (41/54) with a mean healing time of 125\xa0days for fractures of the humerus to 96% (26/27) with a mean healing time of 113\xa0days for fractures of the fibula.\n\nThe case series reported by Jingushi et al. (2007) included 40\xa0patients with delayed healing fractures (defined as union or radiological bone reaction not being observed more than 3\xa0months after the most recent operation). A healing rate (healing defined in section 3.4) for fractures of the femur, tibia, humerus, radius and ulna of 83% (33/40) was reported (follow-up not stated).\n\nIn a case series of 16\xa0patients with delayed healing (defined as no radiological evidence of fracture callus 4 to 38\xa0months after surgical insertion of an intramedullary nail or the Ilizarov procedure [external fixator]), Lerner et al. (2004) reported a healing rate (as determined by an experienced orthopaedic surgeon) of 94% (15/16) over a mean follow-up of 17\xa0months (fractures included femur, tibia, radius/ulna and humerus).\n\nNo studies that reported healing rates after surgery in patients with delayed healing long bone fractures were presented by the sponsor.\n\n## Adverse events\n\nThe US Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database reported 3\xa0cases of skin irritation caused by skin sensitivity to the coupling gel (resolved by change of coupling medium) and 1\xa0report of increased chest pain, possibly caused by interference with a cardiac pacemaker, during a 1‑year period (the sponsor stated that approximately 55,000\xa0EXOGEN devices were used by patients in the USA over this time period).\n\nNone of the clinical studies reported device-related adverse events and no significant safety concerns were identified by the External Assessment Centre in relation to EXOGEN in its independent search of the literature. In contrast, reports on surgical treatment of non-union and delayed healing fractures documented adverse events including postoperative wound infection, osteomyelitis and pain.\n\n## Committee considerations\n\nThe Committee considered that although the evidence on using EXOGEN for long bone fractures with non-union was from observational studies and related to a limited number of outcomes (healing defined in various ways including weight bearing, and radiographic evidence), it suggested good clinical results after treatment with EXOGEN. The Committee judged that the observed healing rates supported the efficacy of EXOGEN in promoting healing of these fractures and that its use meant that many of these patients avoided surgery.\n\nFor long bone fractures with delayed healing, the Committee found the outcomes after treatment with EXOGEN more difficult to interpret. There were uncertainties, including the rate at which healing progresses between 3 and 9\xa0months after fracture, both with and without EXOGEN. There were also uncertainties about the proportion of patients in whom surgery would be avoided, because some of these fractures heal spontaneously.\n\nThe Committee noted that the clinical evidence comparing the efficacy of EXOGEN with surgery was very limited. The Committee recognised the difficulties in conducting comparative studies (and specifically randomised controlled trials) to collect data on healing rates.\n\nClinical experts advised the Committee that the efficacy of EXOGEN may differ depending on which long bone is being treated. The experts stated that non-union most commonly occurs in fractures of the tibia.\n\nThe Committee discussed the applicability of the data from Schofer et al. (2010) in the context of delayed healing. The External Assessment Centre stated that 51 of the 101\xa0patients in this trial had sustained fractures 9\xa0months or more before entry to the study. According to the definition used in the scope, these would be classified as non-union fractures. The Committee was advised by the External Assessment Centre that this trial was not powered to detect differences in healing rates (one of the outcomes defined in the decision problem) and so considered the other primary clinical outcomes reported; radiographically-measured bone mineral density and gap at the fracture site (assessed by computed tomography scan). The Committee noted that there were significant improvements in these outcomes in the group treated with EXOGEN compared with placebo (sham treatment).\n\nThe Committee discussed the variation in fracture healing time among patients. It was advised that there is a considerable natural inter-patient variation in healing rates and that this could explain differences in healing rates reported across the studies. In addition, variation in healing time is more pronounced in the early stage of the healing process and that contributes to the greater complexity of interpreting outcomes for fractures with delayed healing compared against those with non-union.\n\nThe Committee recognised that there may be subgroups of patients in whom healing takes place at a slower rate than the general population. However, it considered that neither current evidence nor expert opinions provided sufficient information to model the potential impact of EXOGEN in these groups of patients.', 'NHS considerations': '# System impact\n\nNo studies were identified that included avoiding surgery as a result of treatment with EXOGEN as an outcome measure. In addition, no studies presented data on return to weight bearing and normal daily living after EXOGEN treatment, compared with surgery.\n\n## Committee considerations\n\nThe Committee considered that any effective treatment that avoids or reduces the need for surgery is of significant benefit to patients and also has potential advantages to the NHS in terms of resource use. Such advantages might include reducing the duration of NHS care, the number of outpatient visits or the number of X‑rays that patients need.\n\nThe Committee considered that the healing rates reported across the clinical studies indicate that surgery can be avoided and that healing time can be reduced by treatment with EXOGEN. The Committee heard persuasive comments from a patient expert about the benefits EXOGEN treatment can provide in terms of return to activity and quality of life.\n\nThe Committee discussed the proportion of patients who might avoid surgery as a result of treatment with EXOGEN. The Committee was advised by clinical experts that approximately one third of non-union tibial fractures might be suitable for treatment with EXOGEN, although estimates of the total number of non-union long bone fractures varied.\n\nThe Committee noted that treatment with EXOGEN is self-administered, and therefore some patients may need help when using the device. The Committee was told by the patient expert and clinical experts that the device is easy to use and can be administered by a carer instead of the patient.', 'Cost considerations': "# Cost evidence\n\nThe sponsor identified 3 economic studies, all in UK settings. Taylor et al. (2009) carried out a cost-effectiveness analysis on non-union tibial fractures treated by EXOGEN or by surgery (intramedullary nailing). The model developed for this study was adapted for use in the sponsor's submission. Kanakaris et al. (2007) presented a non-comparative analysis of the cost of compression plate fixation and bone grafting to treat aseptic non-union long bone fractures, and Patil et al. (2006) reported a similar analysis for the Ilizarov surgical procedure to treat complex non-union tibia or femur fractures.\n\nThe sponsor submitted a de novo cost analysis for EXOGEN. Full details of all cost evidence and modelling considered by the Committee are available in the assessment report overview.\n\nTwo cost models were submitted by the sponsor – 1 for non-union and 1 for delayed healing (both adapted from the model by Taylor et al. 2009). Markov models with a 1‑year time horizon and monthly cycles were used to carry out each cost analysis. The patient population included patients with fractures of the tibia initially treated by surgical insertion of an intramedullary nail.\n\nFor non-union fractures, the cost model evaluated the costs and consequences associated with the use of the EXOGEN\xa04000+ at diagnosis of non-union, followed by further surgery if the fracture did not heal within 6\xa0months, compared with surgery at diagnosis, followed by repeat surgery if the fracture did not heal within 6\xa0months.\n\nThe non-union model had 4 health states: 'non-union fracture', 'healed fracture', 'infection' and 'post infection'. All patients began in the 'non-union fracture' health state. Patients in the EXOGEN arm had treatment with EXOGEN\xa04000+ from baseline, whereas patients in the control arm had surgery at baseline. In both arms, if healing had not occurred after 6\xa0months in the non-union fracture health state, it was assumed that further surgery was needed. In the surgery arm, patients were at risk of infection as a complication of surgery from the time of diagnosis of non-union, and also if they had further revision surgery after 6\xa0months in the non-union state. The model assumed that no infection would occur in the EXOGEN arm.\n\nIn the sponsor's base case for non-union fracture, the key assumptions were cited as follows:\n\nHealing rates and healing times are equivalent for both the EXOGEN\xa04000+ and surgery in the case of stable, well-aligned fractures.\n\nAverage length of bed stay for surgery is 4.9\xa0days (Hospital episode statistics online 2010/11).\n\nAverage theatre time for non-union surgery is 3\xa0hours.\n\nAll initial non-union surgical management includes autologous iliac crest bone graft.\n\nIn the EXOGEN\xa04000+ group, in most cases, only 1 additional operation will be offered over 1\xa0year if the fracture has not healed.\n\nNon-procedure-related costs (for example, physiotherapy, X‑ray) are the same in both treatment arms.\n\nInfection rates in the EXOGEN\xa04000+ and control groups are assumed to be 0% and 1.4% per month (Health Protection Agency, 2011) respectively.\n\nInfection lasts for a maximum of 2\xa0months, but all costs associated with its treatment are incurred in the first month.\n\nIn the case of osteomyelitis, staged revision surgery is carried out.\n\nPatients with osteomyelitis are given intravenous antibiotics in hospital over a minimum of 3\xa0weeks.\n\nFor delayed healing, the costs and consequences associated with the use of the EXOGEN Express at diagnosis of delayed healing followed by surgery if the fracture did not heal within 6\xa0months (9\xa0months after fracture), were compared with no intervention at diagnosis followed by surgery if the fracture did not heal within 6\xa0months.\n\nThe delayed healing model had 5 health states: 'delayed union', 'healed fracture', 'non-union', 'infection' and 'post infection'. All patients begin in the delayed union state. It was assumed that surgical intervention (intramedullary nailing) had been carried out before delayed healing was diagnosed, shortly after the fracture occurred. The model for delayed union was run twice; once for the EXOGEN arm, when patients started using the EXOGEN Express device at the beginning of the modelling period; and once for the control arm, when patients were assumed to have no further treatment (observation only) until non-union was diagnosed. In subsequent cycles, patients could move to 'healed fracture' (an absorbing state), 'infection', or after 6\xa0months in the model, to 'non-union'. After infection, a staged revision surgery process began, with the administration of intravenous antibiotics and removal of metalwork. It was considered that the infection would take 2\xa0months to clear, at which point revision surgery would take place. Patients could become re-infected having previously moved into the post-infection state. After 6\xa0months of delayed healing, and no infection occurring, the patient could progress to 'non-union fracture', when further surgery would take place. In subsequent cycles, non-union fractures may have healed or become infected.\n\nIn the sponsor's base case for delayed healing the key assumptions were as follows:\n\nFor both arms in the model, patient treatment pathways start with a surgical intervention (insertion of an intramedullary nail) to treat a fresh fracture.\n\nOn diagnosis of delayed union, the patient will either have treatment with the EXOGEN Express or will receive no further treatment (observation only) until either bony union is achieved or non-union is diagnosed.\n\nHealing rates for delayed healing at 6\xa0months are a linear progression of those reported at 4\xa0months in the Schofer et al. (2010) study in the absence of any comparative data on healing rate from other randomised controlled trials.\n\nThe cost models were from an NHS cost perspective. The cost analyses included costs associated with surgery (including surgical intervention, theatre time, drugs, bed stay) and costs associated with GP visits, outpatient visits, treating infection (including surgery and medication), X‑rays, wheelchair, crutches and physiotherapy.\n\nIn the sponsor's base case for non-union fractures, the average cost per patient for the EXOGEN\xa04000+ device was £4,647 and the average cost per patient for surgery was £6,957. The EXOGEN\xa04000+ was therefore associated with a cost saving of £2,310 compared with surgery. The sponsor carried out a deterministic sensitivity analysis to vary the rates of healing and infection. The analysis showed that the model is not sensitive to changes in rates of healing and infection, and the EXOGEN\xa04000+ remained cost saving for non-union fractures in all scenarios tested.\n\nFor delayed healing, the sponsor's base case presented an average cost per patient of £4,290 for the EXOGEN Express and £4,974 for current management (observation followed by surgery at non-union if needed). The EXOGEN Express was therefore associated with a cost saving of £684 per patient on early use compared with current management. The sponsor varied the rates of healing and infection in a sensitivity analysis and showed that the model is sensitive to changes in these parameters.\n\nFor the non-union model, the External Assessment Centre considered that a number of the assumptions were not justified and it made several changes to the sponsor's base-case model. These were as follows:\n\napplying the healing rate for EXOGEN from Mayr et al. (2000)\n\nallowing for infection in the EXOGEN arm following surgery at 6\xa0months\n\napplying a one-off rate of infection following any surgery\n\nadjusting the post-surgical infection rate\n\ncorrecting minor errors in the model.\n\nFor the non-union model, the External Assessment Centre's additional analysis showed average costs per patient for the EXOGEN\xa04000+ of £5,688 and for surgery of £6,852. The EXOGEN\xa04000+ was therefore associated with a cost saving of £1,164 compared with immediate surgery for non-union. Sensitivity analysis showed that the model is relatively insensitive to changes in assumptions about the relative effectiveness of surgery compared with EXOGEN. The External Assessment Centre considered that the EXOGEN\xa04000+ is significantly cheaper than surgery.\n\nIn a 2‑way sensitivity analysis, varying the baseline healing rate with EXOGEN, and the relative risk of healing with surgery compared with EXOGEN, showed stable results. Only if the healing rate with EXOGEN was reduced to its lower limit and the relative risk of healing with surgery increased to its upper limit did EXOGEN become more expensive than surgery. The External Assessment Centre also carried out sensitivity analyses to apply no delay to the onset of healing, add VAT on devices and consumables, and use healthcare resource group costs for infection and surgery. The EXOGEN\xa04000+ remained cost saving for all scenarios tested.\n\nFor the delayed healing model, the External Assessment Centre considered that several of the sponsor's assumptions were not justified and made a number of changes to the base-case model. These changes included:\n\nallowing for infection in the EXOGEN arm following further surgery for patients who have not healed after 6\xa0months (9\xa0months after fracture)\n\nchanging costs to apply to delayed healing resource use (as per model) at baseline, not fresh fracture\n\nadjusting the infection rate and associated costs as for non-union.\n\nAfter applying these changes, the External Assessment Centre estimated results for 8 scenarios that reflected different sources of healing rates (Mayr et al. 2000 for the EXOGEN Express arm and relative risk from Schofer et al. 2010 compared with Schofer et al. 2010 alone), different assumptions about the minimum time to healing following surgery and EXOGEN (no delay compared with 2‑month delay before healing is observed), and the persistence of relative benefits of EXOGEN (persistence of enhanced healing rate compared with no persistence between the end of EXOGEN treatment at 4\xa0months and further surgery if needed at 6\xa0months).\n\nFor delayed healing the External Assessment Centre's preferred scenario from among the 8 in its report applied the following key assumptions:\n\nThe best estimate of the healing rate with EXOGEN is from the register data reported by Mayr et al. (2000).\n\nThe best estimate of relative healing rates with the EXOGEN Express compared with no further treatment until non-union is provided by Schofer et al. (2010).\n\nIt is reasonable to assume that healing following either surgery or the start of treatment with the EXOGEN Express will not usually be observed within 2\xa0months (expert opinion).\n\nIt is conservative to assume that EXOGEN does not continue to enhance the background healing rate once ultrasound treatment has finished after 4\xa0months (the duration of follow-up in Schofer et al. 2010).\n\nThe External Assessment Centre's preferred scenario for the treatment of long bone fractures with delayed healing showed a total cost for the EXOGEN Express of £3,033 and a total cost for current management of £2,529. The EXOGEN Express was therefore associated with a cost increase of £504 per patient compared with observation followed by surgery at non-union if necessary.\n\nThe External Assessment Centre carried out a 2‑way sensitivity analysis in which the baseline healing rate was varied with the EXOGEN Express and the relative risk of healing compared with control using the preferred scenario. They found that the results were not sensitive to varying these estimates: the EXOGEN Express remained more costly than waiting to see if fractures healed without further intervention. The External Assessment Centre carried out further sensitivity analyses to vary the risk of infection, applying VAT on devices and consumables, using healthcare resource group costs for surgery and for the treatment of infection. The EXOGEN Express remained more expensive than the comparator for delayed healing under all of the scenarios tested.\n\n## Committee considerations\n\nFor long bone fractures with non-union the Committee accepted that treatment with the EXOGEN\xa04000+ results in cost savings. It was advised by clinical experts that the costs associated with surgery in the cost models might well be underestimates and so the cost savings could be even greater in practice.\n\nThe Committee discussed the healing rates applied in the sponsor's base case for delayed healing. It was advised by the External Assessment Centre that the methods by which healing rates were extracted from the clinical studies (Mayr et al. 2000 and Schofer et al. 2010) and converted to monthly rates were likely to represent an overestimate of the relative effectiveness of EXOGEN Express compared with the control arms. Clinical experts stated that the patient group suitable for treatment with EXOGEN is heterogeneous and treatment strategies are made on an individual patient basis. On the basis of all this information, the Committee considered that the External Assessment Centre's approach to scenario analyses was reasonable.\n\nFor long bone fractures with delayed healing, the Committee discussed the scenarios presented by the External Assessment Centre and accepted the External Assessment Centre's preferred scenario as the most likely. However, as for non-union fractures, it considered that the costs associated with surgery might have been underestimated.\n\nThe Committee considered that it was acceptable for the cost models to be limited to tibial fractures (as opposed to fractures of other long bones) because the tibia is the most common long bone for which treatment of non-union is needed.\n\nThe Committee questioned whether the 12‑month time horizon used in the cost models might be too short. However, it was advised by the External Assessment Centre that it is likely that extending the time horizon would have little impact on the results, because most fractures would have healed by the end of the 12\xa0months, regardless of the intervention.\n\nThe External Assessment Centre applied the updated cost of the device and other costs to the cost model for non-union healing and reported net savings increased from £1,164 to £2,407 per patient compared with current management, through avoiding surgery. The increase in savings is primarily because length of hospital stay if a patient has surgery has increased from 4.9\xa0days to 7\xa0days. The External Assessment Centre also applied updated costs to delayed healing. It reported an estimated cost increase of £628 (was £504) per patient compared with current management. The increase in incremental costs is primarily due to the increase in the cost of the EXOGEN\xa0150 device. ", 'Conclusions': "The Committee recognised that the available clinical data on the effectiveness of EXOGEN for treating long bone fractures with non-union show high rates of fracture healing and it judged them sufficient to support the efficacy and utility of EXOGEN treatment. Despite the absence of direct evidence on avoiding surgery, the Committee considered that the assumptions in the cost model were plausible and that EXOGEN is cost saving compared with current management for the treatment of non-union. Overall, therefore, the case for adoption of EXOGEN in the treatment of long bone fractures with non-union was found to be supported by the evidence.\n\nFor long bone fractures with delayed healing the Committee considered that the clinical evidence was more limited. In addition there were significant uncertainties about the rate at which healing progresses between 3 and 9\xa0months after fracture, both with and without EXOGEN, and about whether or not surgery would be required if EXOGEN was not used. These and other considerations influenced the Committee's views about the most appropriate assumptions for cost modelling: the model considered to be most appropriate estimated that EXOGEN treatment would be more costly than current management. The Committee therefore judged that the case for adoption of EXOGEN to treat long bone fractures with delayed healing was not supported by the current evidence."}
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https://www.nice.org.uk/guidance/mtg12
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Evidence-based recommendations on EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing.
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3b3a9cf2847dc2138be401f14135f515b37576ac
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nice
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Familial hypercholesterolaemia: identification and management
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Familial hypercholesterolaemia: identification and management
This guideline covers identifying and managing familial hypercholesterolaemia (FH), a specific type of high cholesterol that runs in the family, in children, young people and adults. It aims to help identify people at increased risk of coronary heart disease as a result of having FH.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Case finding and diagnosis
See also the section on information needs and support.
Suspect familial hypercholesterolaemia (FH) as a possible diagnosis in adults with:
a total cholesterol level greater than 7.5 mmol/l or
a personal or family history of premature coronary heart disease (an event before 60 years in an index individual or first-degree relative).
Systematically search primary care records for people:
younger than 30 years, with a total cholesterol concentration greater than 7.5 mmol/l and
years or older, with a total cholesterol concentration greater than 9.0 mmol/las these are the people who are at highest risk of FH.
For people with a personal or family history of premature coronary heart disease (an event before 60 years in an index individual or first-degree relative), but whose total cholesterol is unknown, offer to measure their total cholesterol.
Healthcare professionals should exclude secondary causes of hypercholesterolaemia before a diagnosis of FH is considered.
Use the Simon Broome criteria (see appendix F of the full guideline) or Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH in primary care settings. This should be done by a healthcare professional competent in using the criteria.
Refer the person to an FH specialist service for DNA testing if they meet the Simon Broome criteria for possible or definite FH, or they have a DLCN score greater than 5.
Healthcare professionals should be aware that the absence of clinical signs (for example, tendon xanthomata) in adults and children/young people does not exclude a diagnosis of FH.
Healthcare professionals should consider a clinical diagnosis of homozygous FH in adults with a low-density lipoprotein cholesterol (LDL‑C) concentration greater than 13 mmol/l and in children/young people with an LDL‑C concentration greater than 11 mmol/l. All people with a clinical diagnosis of homozygous FH should be offered referral to a specialist centre.
To confirm a diagnosis of FH, healthcare professionals should undertake two measurements of LDL‑C concentration because biological and analytical variability occurs.
When considering a diagnosis of FH, healthcare professionals with expertise in FH should use standardised pedigree terminology to document, when possible, at least a three-generation pedigree. This should include relatives' age of onset of coronary heart disease, lipid concentrations and smoking history. For deceased relatives, the age and cause of death, and smoking history should be documented. If possible, the index individual should verify this information with other family members.
Ultrasonography of the Achilles tendon is not recommended in the diagnosis of FH.
Coronary heart disease risk estimation tools, such as QRISK2 and those based on the Framingham algorithm, should not be used because people with FH are already at a high risk of premature coronary heart disease.
Inform all people who have an identified mutation diagnostic of FH that they have an unequivocal diagnosis of FH even if their LDL‑C concentration does not meet the diagnostic criteria (see recommendation 1.1.5).
In a family where a DNA mutation is identified, not all family members may have inherited the mutation. When DNA testing has excluded FH in a member of a family, healthcare professionals should manage the person's coronary heart disease risk as in the general population (see NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification).
In children aged 0–10 years at risk of FH because of 1 affected parent, offer a DNA test at the earliest opportunity. If testing of a child at risk has not been undertaken by the age of 10 years, offer an additional opportunity for a DNA test.
In children at risk of homozygous FH because of two affected parents or because of the presence of clinical signs, for example, cutaneous lipid deposits (xanthomata), LDL‑C concentration should be measured before the age of 5 years or at the earliest opportunity thereafter. If the LDL‑C concentration is greater than 11 mmol/l then a clinical diagnosis of homozygous FH should be considered.
# Identifying people with FH using cascade testing
Carry out cascade testing using DNA testing to identify affected first- and second- and, when possible, third-degree biological relatives of people with a genetic diagnosis of FH.
Healthcare professionals should offer all people with FH a referral to a specialist with expertise in FH for confirmation of diagnosis and initiation of cascade testing.
Healthcare professionals with expertise in FH should explain what is meant by cascade testing, and discuss its implications with all people with FH.
Healthcare professionals should be aware of the latest guidance on data protection when undertaking cascade testing.
# Management
## Drug treatment
Recommendations 1.3.1.4 to 1.3.1.9 have been adapted from NICE's technology appraisal guidance on ezetimibe for treating primary (heterozygous-familial and non-familial) hypercholesterolaemia.
When offering lipid-modifying drug therapy to adults with FH, healthcare professionals should inform the person that this treatment should be lifelong. .
Offer a high-intensity statin with the lowest acquisition cost as the initial treatment for all adults with FH and aim for at least a 50% reduction in LDL‑C concentration from the baseline measurement.
The dose of statin should be increased to the maximum licensed or tolerated dose to achieve a recommended reduction in LDL‑C concentration of greater than 50% from baseline (that is, LDL‑C concentration before treatment).
Ezetimibe monotherapy is recommended as an option for treating primary heterozygous‑familial hypercholesterolaemia in adults in whom initial statin therapy is contraindicated.
Ezetimibe monotherapy is recommended as an option for treating primary heterozygous‑familial hypercholesterolaemia in adults who cannot tolerate statin therapy (as defined in recommendation 1.3.1.9).
Ezetimibe, co‑administered with initial statin therapy, is recommended as an option for treating primary (heterozygous‑familial) hypercholesterolaemia in adults who have started statin therapy when:
serum total or low‑density lipoprotein (LDL) cholesterol concentration is not appropriately controlled (as defined in recommendation 1.3.1.8) either after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy (as defined in recommendation 1.3.1.9) and
a change from initial statin therapy to an alternative statin is being considered.
When prescribing ezetimibe co-administered with a statin, ezetimibe should be prescribed on the basis of lowest acquisition cost.
For the purposes of this guidance, appropriate control of cholesterol concentrations should be based on individualised risk assessment according to national guidance on managing cardiovascular disease in the relevant populations.
For the purposes of this guidance, intolerance to initial statin therapy is defined as the presence of clinically significant adverse effects that represent an unacceptable risk to the patient or that may reduce compliance with therapy.
Prescribing of drug therapy for adults with homozygous FH should be undertaken within a specialist centre.
Healthcare professionals should offer adults with FH a referral to a specialist with expertise in FH if treatment with the maximum tolerated dose of a high-intensity statin and ezetimibe does not achieve a recommended reduction in LDL‑C concentration of greater than 50% from baseline (that is, LDL‑C concentration before treatment).
Healthcare professionals should offer adults with FH a referral to a specialist with expertise in FH for consideration for further treatment if they are assessed to be at very high risk of a coronary event, that is, if they have any of the following.
Established coronary heart disease.
A family history of premature coronary heart disease.
Two or more other cardiovascular risk factors (for example, they are male, they smoke, or they have hypertension or diabetes).
For recommendations on managing primary heterozygous familial hypercholesterolaemia in people whose LDL‑C levels are not adequately controlled despite maximal tolerated lipid-lowering therapy, see the NICE technology appraisal guidance on alirocumab and evolocumab.
Adults with FH with intolerance or contraindications to statins or ezetimibe should be offered a referral to a specialist with expertise in FH for consideration for treatment with either a bile acid sequestrant (resin) or a fibrate to reduce their LDL‑C concentration.
The decision to offer treatment with a bile acid sequestrant (resin) or a fibrate in addition to initial statin therapy should be taken by a specialist with expertise in FH.
Healthcare professionals should exercise caution when adding a fibrate to a statin because of the risk of muscle-related side effects (including rhabdomyolysis). Gemfibrozil and statins should not be used together.
Healthcare professionals should offer all children and young people diagnosed with, or being investigated for, a diagnosis of FH a referral to a specialist with expertise in FH in children and young people. This should be in an appropriate child/young person-focused setting that meets the standards within the National service framework for children, young people and maternity services.
Lipid-modifying drug therapy for a child or young person with FH should usually be considered by the age of 10 years. The decision to defer or offer lipid-modifying drug therapy for a child or young person should take into account:
their age
the age of onset of coronary heart disease within the family, and
the presence of other cardiovascular risk factors, including their LDL‑C concentration.
When offering lipid-modifying drug therapy for children or young people, healthcare professionals should inform the child/young person and their parent/carer that this treatment should be lifelong.
Offer statins to children with FH by the age of 10 years or at the earliest opportunity thereafter.
For children and young people with FH, consider a statin that is licensed for use in the appropriate age group.
Statin therapy for children and young people should be initiated by a healthcare professional with expertise in treating children and young people with FH, and in a child-focused setting.
Statin therapy for children and young people with FH should usually be prescribed at the doses specified in the 'British national formulary (BNF) for children'.
In exceptional instances, for example, when there is a family history of coronary heart disease in early adulthood, healthcare professionals with expertise in FH in children and young people should consider offering:
a higher dose of statin than is licensed for use in the appropriate age group, and/or
more than one lipid-modifying drug therapy, and/or
lipid-modifying drug therapy before the age of 10 years.
In children and young people with homozygous FH, LDL‑C concentration may be lowered by lipid-modifying drug therapy and this should be considered before LDL apheresis (see section 1.3.3).
In children and young people with FH who are intolerant of statins, healthcare professionals should consider offering other lipid-modifying drug therapies capable of reducing LDL‑C concentration (such as bile acid sequestrants , fibrates or ezetimibe).
Routine monitoring of growth and pubertal development in children and young people with FH is recommended.
Decisions about the choice of treatment should be made following discussion with the adult or child/young person and their parent/carer, and be informed by consideration of concomitant medication, comorbidities, safety and tolerability.
Healthcare professionals should consider offering fat-soluble vitamin (vitamins A, D and K) and folic acid supplementation for adults or children/young people with FH who are receiving long-term treatment with bile acid sequestrants (resins).
Healthcare professionals should offer people with FH a referral to a specialist with expertise in FH if they are experiencing side effects that compromise concordance with lipid-modifying drug therapy.
When the decision has been made to offer adults or children/young people with FH treatment with a statin, baseline liver and muscle enzymes (including transaminases and creatine kinase, respectively) should be measured before initiation of therapy. However, people with raised liver or muscle enzymes should not routinely be excluded from statin therapy.
Routine monitoring of creatine kinase is not recommended in asymptomatic adults or children/young people with FH who are receiving treatment with a statin.
## Lifestyle interventions
Healthcare professionals should regard lifestyle advice as a component of medical management, and not as a substitute for lipid-modifying drug therapy.
All people with FH should be offered individualised nutritional advice from a healthcare professional with specific expertise in nutrition.
People with FH should be advised to consume a diet in which:
total fat intake is 30% or less of total energy intake
saturated fats are 10% or less of total energy intake
intake of dietary cholesterol is less than 300 mg/day
saturated fats are replaced by increasing the intake of monounsaturated and polyunsaturated fats. It may be helpful to suggest they look at Live Well for further practical advice.
Healthcare professionals should advise people with FH to eat at least five portions of fruit and vegetables a day, in line with national guidance for the general population. Examples of what constitutes a portion can be found at Live Well.
Healthcare professionals should advise people with FH to consume at least two portions of fish a week (one of which should be oily fish). Pregnant women with FH should be advised to limit their oily fish to two portions a week. Further information and advice on healthy cooking methods can be found at Live Well.
Healthcare professionals should advise people with FH that if they wish to consume food products containing stanols and sterols these need to be taken consistently to be effective.
People with FH should not routinely be recommended to take omega-3 fatty acid supplements. For people with FH who have already had a myocardial infarction (MI), refer to the NICE guideline on myocardial infarction.
Healthcare professionals should advise people with FH to undertake physical activity in line with national guidance for the general population (see the UK Chief Medical Officers' physical activity guidelines for more information).
Healthcare professionals should encourage people who are unable to perform moderate-intensity physical activity because of comorbidity, medical conditions or personal circumstances to exercise at their maximum safe capacity (see the UK Chief Medical Officers' physical activity guidelines for more information).
Recommended types of physical activity include those that can be incorporated into everyday life, such as brisk walking, using stairs and cycling (see the UK Chief Medical Officers' physical activity guidelines for more information).
Healthcare professionals should offer people with FH who are overweight or obese appropriate advice and support to achieve and maintain a healthy weight in line with NICE's guideline on obesity prevention.
As for the general population, alcohol consumption for adult men with FH should be limited to up to 3–4 units a day, and for adult women with FH up to 2–3 units of alcohol a day. Binge drinking should be avoided. Further information can be found at Live Well.
People with FH, especially children, who do not smoke should be strongly discouraged from starting because of their already greatly increased risk of coronary heart disease.
People with FH who smoke should be advised that, because of their already greatly increased risk of coronary heart disease, they should stop.
Healthcare professionals should offer people who want to stop smoking support and advice, and referral to an intensive support service, in line with the NICE guidance on smoking cessation.
People with FH who are unwilling or unable to accept a referral to an intensive support service should be offered pharmacotherapy in line with NICE guidance on nicotine replacement therapy and bupropion, and varenicline. See NICE guidance on smoking cessation, including NICE's technology appraisal guidance on varenicline for smoking cessation.
## Specialist treatment
Healthcare professionals should consider offering LDL apheresis for the treatment of adults and children/young people with homozygous FH (see recommendations 1.1.8 and 1.1.16). The timing of initiation of LDL apheresis should depend on factors such as the person's response to lipid-modifying drug therapy and presence of coronary heart disease.
In exceptional instances (such as when there is progressive, symptomatic coronary heart disease, despite maximal tolerated lipid-modifying drug therapy and optimal medical and surgical therapy), healthcare professionals should consider offering LDL apheresis for the treatment of people with heterozygous FH. This should take place in a specialist centre on a case-by-case basis and data recorded in an appropriate registry.
Healthcare professionals should recommend arterio-venous fistulae as the preferred method of access for people with FH who are offered treatment with LDL apheresis. People should be counselled about possible benefits and complications of this procedure.
Routine monitoring of the person's iron status should be carried out and iron supplementation initiated as required for people with FH who are receiving treatment with LDL apheresis.
Angiotensin-converting enzyme (ACE) inhibitors should not be used in people with FH who are being treated with LDL apheresis. Instead, ACE inhibitors should be substituted with angiotensin-receptor blocking agents.
People with FH who are receiving blood pressure-lowering drug therapy should have this reviewed and considered for discontinuation on the morning of the day of LDL apheresis.
People with FH who are taking warfarin should have this discontinued approximately 4 days before LDL apheresis and substituted with low molecular weight heparin.
People with FH who are receiving anti-platelet therapy should have this continued if they are receiving treatment with LDL apheresis.
Healthcare professionals should consider offering liver transplantation as an option for the treatment of people with homozygous FH after treatment with lipid-modifying drug therapy and LDL apheresis.
The decision to refer for liver transplantation should take place in partnership with the patient and/or their relatives in an appropriate specialist setting, following a discussion of the benefits and potential harms of undertaking or declining transplantation.
# Information needs and support
## General information and support
During the assessment and communication of familial risk, people should receive clear and appropriate educational information about FH, the process of family testing, DNA testing and the measurement of LDL‑C concentration.
A healthcare professional with expertise in FH should provide information to people with FH on their specific level of risk of coronary heart disease, its implications for them and their families, lifestyle advice and treatment options.
Healthcare professionals with expertise in FH should encourage people with FH to contact their relatives to inform them of their potential risk and so that cascade testing can take place.
When considering cascade testing, a healthcare professional with expertise in FH should offer to facilitate the sharing of information about FH with family members.
Healthcare professionals should offer people with FH and their families written advice and information about patient support groups.
## Information and counselling on contraception for women and girls with FH
When lipid-modifying drug therapy is first considered for women and girls, the risks for future pregnancy and the fetus while taking lipid-modifying drug therapy should be discussed. This discussion should be revisited at least annually.
Healthcare professionals should give women and girls with FH specific information tailored to their needs and should offer a choice of effective contraceptive methods.
Combined oral contraceptives (COCs) are not generally contraindicated for women and girls being treated with lipid-modifying drug therapy. However, because there is a potential small increased risk of cardiovascular events with the use of COCs, healthcare professionals should consider other forms of contraception. Prescribers should refer to the summary of product characteristics of COCs and the relevant lipid-modifying drugs for their specific contraindications.
## Information for pregnant women with FH
Healthcare professionals should be aware that, in general, there is no reason to advise against pregnancy or breastfeeding in women with FH.
Healthcare professionals should advise women with FH that lipid-modifying drug therapy should not be taken if they are planning to conceive or during pregnancy, because of the potential risk of fetal abnormality. Women should be advised that lipid-modifying drug therapy should be stopped 3 months before they attempt to conceive.
Women with FH who conceive while taking statins or other systemically absorbed lipid-modifying drug therapy should be advised to stop treatment immediately and they should be offered an urgent referral to an obstetrician for a fetal assessment. Women should be fully informed about the nature and purpose of the assessment.
Women with FH who have conceived while taking statins or other systemically absorbed lipid-modifying drug therapy and have had a fetal assessment should be given time, opportunity and full information to consider their options (including the advantages and disadvantages) of continuing with their pregnancy.
Shared-care arrangements, to include expertise in cardiology and obstetrics, should be made for women with FH who are considering pregnancy or are pregnant. Such care should include an assessment of coronary heart disease risk, particularly to exclude aortic stenosis. This is essential for women with homozygous FH.
Serum cholesterol concentrations should not be measured routinely during pregnancy.
Women with FH who are pregnant should be advised on the potential risks and benefits of re-starting lipid-modifying drug therapy for the mother and breastfed infant. Resins are the only lipid-modifying drug therapy that should be considered during lactation.
# Ongoing assessment and monitoring
## Review
All people with FH should be offered a regular structured review that is carried out at least annually.
A baseline electrocardiogram (ECG) should be considered for adults with FH.
Healthcare professionals should record the progress of cascade testing among the relatives of a person with FH as part of the structured review. This should include at least the first- and second-degree relatives- and, when possible, third-degree biological relatives. If there are still relatives who have not been tested, further action should be discussed.
Healthcare professionals should update the family pedigree of a person with FH and note any changes in the coronary heart disease status of their relatives as part of the structured review. This should include at least the first- and second- and, when possible, third-degree biological relatives.
Structured review should include assessment of any symptoms of coronary heart disease and smoking status, a fasting lipid profile, and discussion about concordance with medication, possible side effects of treatment the patient may be experiencing, and any changes in lifestyle or lipid-modifying drug therapy that may be required to achieve the recommended LDL‑C concentration (see the section on management).
## Referral for evaluation of coronary heart disease
Healthcare professionals should offer people with FH an urgent referral to a specialist with expertise in cardiology for evaluation if they have symptoms or signs of possible coronary heart disease which are not immediately life-threatening. A low threshold for referral is recommended.
A person with FH with symptoms or signs of possible coronary heart disease which are immediately life-threatening (for example, acute coronary syndrome) should be referred to hospital as an emergency in line with advice for the general population.
Healthcare professionals should consider offering people with FH a referral for evaluation of coronary heart disease if they have a family history of coronary heart disease in early adulthood, or two or more other cardiovascular risk factors (for example, they are male, they smoke, or they have hypertension or diabetes).
Upon diagnosis, healthcare professionals should offer all adults and children/young people with homozygous FH a referral for an evaluation of coronary heart disease.
In asymptomatic children and young people with heterozygous FH, evaluation of coronary heart disease is unlikely to detect clinically significant disease and referral should not be routinely offered.
# Terms used in this guideline
## Adults with FH
For the purposes of this guideline, 'adults' includes all persons with familial hypercholesterolaemia (FH; heterozygous or homozygous) who are 16 years and older.
## Cascade testing
Cascade testing is a mechanism for identifying people at risk of a genetic condition by a process of family tracing. For FH the test employed is a DNA test where a disease-causing mutation has been identified in the index individual/proband.
## Children/young people
For the purposes of this guideline, 'children' refers to persons younger than 10 years; 'young people' refers to persons from 10 years of age up to the age of 15 years. The definitions used here are not prescriptive and healthcare professionals are expected to exercise their judgement and consider the wishes of the patients, and their families or carers when interpreting these terms in individual instances.
## Child-focused setting
Child-focused refers to valuing the child's view and validating their voice in making decisions impacting their lives. A child-focused facility or space is one designed from the viewpoint of the service recipients.
## Coronary heart disease
An event is defined as angina, acute coronary syndrome, myocardial infarction, need for coronary artery bypass grafting, need for percutaneous coronary intervention or definite coronary artery disease on coronary angiography.
## Dutch Lipid Clinic Network (DLCN) criteria/score
A method of assessing whether a person has FH. It is based on personal and family medical history, clinical signs, LDL‑C concentration and DNA testing. A score is attributed to each component; the higher the score, the higher the likelihood of the person having FH.
## Family history
The structure and relationships within the family that relates information about diseases in family members.
## First-degree relative
A person's biological parents, brothers and sisters, and children.
## Heterozygous FH
High LDL‑C concentration in the blood caused by an inherited mutation from one parent only. People with FH are at increased risk of cardiovascular disease.
## High-intensity statin
Statins are classified as high intensity if they produce average reductions in LDL-C greater than 40%. See appendix A of NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification.
## Homozygous FH
Very high LDL‑C concentration in the blood caused by an inherited mutation from both parents. When a person inherits exactly the same affected gene from both parents this is called truly 'homozygous' FH. When the mutations in the LDL receptor gene (or equivalent) are different, this state is called 'compound heterozygous'. In general, the overall effect in both states is similar, in that LDL‑C concentrations are very high. Both groups of patients have the same clinical pattern and high risk of cardiovascular disease.
For clinical purposes, both homozygous FH and compound heterozygous FH can be regarded as behaving in a similar manner. Therefore, for the purposes of this guideline the term 'homozygous FH' is used to also encompass compound heterozygous FH.
## Index individual (synonymous with 'proband')
The original patient who is the starting point for follow-up of other members of a family when investigating for possible causative genetic factors of the presenting condition.
## Lipid measurements/concentrations/levels
These terms refer to the measurement of total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL‑C), and LDL‑C. LDL‑C is not usually measured directly but calculated from the TC, TGs and HDL‑C, ideally using a fasting sample.
Such tests are usually done in a clinical biochemistry laboratory.
## Mutation
An identified change in the DNA sequence of a gene that is predicted to damage the normal function of the gene and so cause disease.
## Pedigree
A method of characterising the relatives of an index individual/case and their family relationship as well as problems or illnesses within the family. This information, often represented graphically as a family tree, facilitates analysis of inheritance patterns. Study of a trait or disease begins with the affected person (the index individual). The pedigree is drawn as the relatives are described. One begins with the siblings of the index individual and proceeds to the parents; relatives of the parents, including brothers, sisters, nephews, nieces, grandparents, and so on. At least three generations are usually included. Illnesses, hospitalisations, causes of death, miscarriages, abortions, congenital anomalies, and any other unusual features are recorded.
## Premature coronary heart disease
For the purpose of this guideline, this refers to a coronary event that has occurred before 60 years of age in an index individual or first-degree relative.
## Proband
The affected (index) individual through whom a family with a genetic disorder is ascertained.
## Second-degree relative
A person's biological grandparent, grandchild, uncle, aunt, niece, nephew, half sister or half brother.
## Secondary causes of hypercholesterolaemia
Causes of hyperlipidaemia other than familial, including uncontrolled diabetes mellitus, obesity, excess alcohol consumption, untreated hypothyroidism and some medications, for example, thiazide diuretics and ciclosporin.
## Specialist centre
The definition of a specialist centre is not rigid and is based on a combination of patient treatment services, numbers and ages of people attending there, the presence of a multi-disciplinary team (which may include, for example, physicians, lipidologists, specialist nurses, pharmacists and dietitians), the ability to manage the more unusual manifestations of the condition and the additional functions such as research, education and standard setting. Care is supervised by expert healthcare professionals but shared with local hospitals and primary care teams. Although details of the model may vary between patients and areas, the key is that specialist supervision oversees local provision with the patient seen at diagnosis for initial assessment and then at least annually for review.
## Tendon xanthomata
A clinically detectable nodularity and/or thickening of the tendons caused by infiltration with lipid-laden histiocytes (macrophages in connective tissue).
A distinctive feature of FH that most frequently affects the Achilles tendons but can also involve tendons on the back of the hands, elbows and knees.
## Third-degree biological relative
A person's biological great grandparent, great grandchild, great aunt, great uncle, first cousin, grand nephew or grand niece.
## Urgent referral
For the purposes of this guideline, urgent referral is as soon as possible with a maximum of 14 days.# Context
In some people, a high cholesterol concentration in the blood is caused by an inherited genetic defect known as familial hypercholesterolaemia (FH). A raised cholesterol concentration in the blood is present from birth and may lead to early development of atherosclerotic disease like coronary heart disease. The disease shows an autosomal dominant pattern of inheritance, being transmitted from generation to generation in such a way that siblings and children of a person with FH have a 50% risk of inheriting FH.
Most people with FH have inherited a defective gene for FH from only one parent and are therefore heterozygous. Rarely, a person will inherit a genetic defect from both parents and will have homozygous FH or compound heterozygous FH, which will be collectively termed homozygous FH for the purpose of this guideline.
The prevalence of heterozygous FH in the UK population is estimated to be somewhere between 1 in 250 and 1 in 500, which means that between approximately 130,000 and 260,000 people are affected. The elevated serum cholesterol concentration that characterises heterozygous FH leads to a greater than 50% risk of coronary heart disease in men by the age of 50 years and at least 30% in women by the age of 60 years.
Homozygous FH is rare, with symptoms appearing in childhood, and is associated with early death from coronary heart disease. Homozygous FH has an incidence of approximately one case per one million.
The guideline will assume that prescribers will use a drug's summary of product characteristics to inform their decisions for individual patients.
In 2017 the areas on case-finding, diagnosis and pharmacological monotherapy (statin v placebo) were updated. Since the original guideline was published in 2008, cascade testing may now be more cost-effective, and DNA diagnosis technology has changed greatly. In addition, more evidence has been identified on the use of high-intensity statins, and on the safety profile of statins in children and young people.# Recommendations for research
The guideline committee has made the following recommendations for research.
As part of the 2017 update, the standing committee made research recommendations on using different thresholds of low-density lipoprotein cholesterol (LDL‑C) concentration in primary care case finding and on long-term monitoring of sub-clinical atherosclerosis in children with familial hypercholesterolaemia (FH) who are treated with statins (see below). The committee also made 3 other research recommendations, on secondary care case finding, cascade testing and the use of clinical scoring criteria. One research recommendation on identification using clinical registers was removed. Details can be found in the evidence reviews.
# Using different thresholds of low-density lipoprotein cholesterol concentration in primary care case finding
What is the clinical and cost effectiveness of using different thresholds of LDL‑C concentration in primary care case finding?
## Why this is important
The clinical community recognises that FH is underdiagnosed, with prevalence more likely to be approximately 1 in 250 rather than the widely cited 1 in 500. Searching electronic primary care databases is an effective way of identifying people with FH. One of the ways in which people are identified through electronic primary care database searching is to search using total cholesterol or LDL‑C concentration. Currently, the entire evidence base for identifying cohorts of people with FH through primary care case finding uses a total cholesterol concentration cut-off of 9.3 mmol/l. This is a very high concentration and anecdotal evidence suggests that this identifies older people but may miss younger people with FH. This could lead to missed opportunities to identify and treat people with FH at an earlier age. Research is needed to identify whether using different total cholesterol and LDL‑C concentrations to identify people with FH through primary care database searching affects the diagnostic yield of FH. Additionally, there is a lack of data on the ethnicity, age and triglyceride concentration of people with FH identified through primary care database searching. These should be included as outcomes in future research.
# Long-term monitoring of sub-clinical atherosclerosis in children with FH who are treated with statin therapy
What are the long-term effects of statin therapy on sub-clinical atherosclerosis in children with FH who are treated with statin therapy?
## Why this is important
Although statins are increasing in use, there is still a lack of data on the long-term effects of statins in children. It is particularly important to determine any long-term adverse effects of statin treatment in a population with FH, as people generally take statins for the rest of their lives once treatment starts.
# Lipid-modifying drug therapy in children
What is the clinical effectiveness and safety of differing doses of lipid-modifying therapy in children with FH?
## Why this is important
There have been no published studies to establish target serum LDL‑C concentration in treated children with FH receiving lipid-modifying drug therapy. Treatment is recommended from 10 years onwards, however this lack of data prevents a recommendation regarding the aim of pharmacological treatment on serum LDL‑C concentrations.
Research (both cross-sectional and longitudinal) should assess the evidence of end-organ involvement (for example, carotid intima medial thickness ) to determine at which age abnormalities can first be seen in children. The aim would be to identify a threshold effect, with an LDL‑C concentration below which carotid IMT is normal and where thickening is absent, and above which it is abnormal and where thickening is observed. Outcomes should include fasting serum total and LDL‑C concentration, carotid artery IMT, and growth and pubertal development.
# LDL apheresis for people with heterozygous FH
What are the appropriate indications, effectiveness and safety of LDL apheresis in people with heterozygous FH?
## Why this is important
There is limited evidence to inform specific indications for LDL apheresis in people with heterozygous FH. In addition, there is limited published evidence on the cardiovascular outcome of such patients treated with LDL apheresis.
Evidence on the value of investigations (various measures of vascular status, considered to reflect the extent or activity of atherosclerotic vascular disease of the coronary arteries) in predicting outcome from LDL apheresis should ideally be based on evidence from randomised controlled trials with clinical outcomes. It is difficult to identify a suitable alternative treatment because LDL apheresis is generally only considered in people for whom no other treatment is available. One comparator may be novel therapies with antisense oligonucleotides (ApoB).
A national register should be established for all people with FH who are referred for and/or are undergoing LDL apheresis. Data should be collected on the natural history of FH and the temporal relationship of clinical and vascular features in relation to treatments and other parameters.
# Pregnancy in women with FH
What are the implications of FH for the safety of a mother during pregnancy and what are the risks of fetal malformations attributable to pharmacological therapies?
## Why this is important
There is little information on the outcomes of pregnancy in women with FH. A small number of conflicting studies have suggested a small increase in fetal abnormalities if the mother has taken statins during the first trimester, but there are not sufficient data to provide an accurate estimate of the level of risk. There is also limited information on the risk of pregnancy (including cardiac death) in a woman with FH.
Data on the incidence of cardiac problems in pregnancy and incidence of fetal malformation would inform future recommendations. This could reduce uncertainty for women, and help to identify risks during the pregnancy that could be better managed. The only feasible research method to address these questions is an observational longitudinal study following women with FH and other women (not diagnosed with FH) using statins through their pregnancies using a national register.
# Cardiovascular evaluation for people with FH
What is the utility of routine cardiovascular evaluation for asymptomatic people with FH?
## Why this is important
Because of their inherent high risk of developing premature coronary heart disease, a low threshold of suspicion for coronary disease is recommended for people with FH. Routine monitoring to detect sub-clinical atherosclerosis should be non-invasive, sensitive, specific and cost effective. Research to assess the prevalence of both asymptomatic coronary and non-coronary atherosclerosis in people with definite heterozygous FH is required.
As well as exercise ECG testing followed by stress echocardiography before possible angiography in people with an abnormal exercise test and ankle brachial pressure measures, research should include magnetic resonance imaging (MRI) in addition to other modalities such as carotid IMT and coronary calcification. Outcomes should include changes in exercise ECG/ankle brachial pressure testing/IMT/calcification over time.
Consideration should also be given to the feasibility of conducting a long-term randomised trial to compare the differences in morbidity or mortality attributable to early diagnosis using routine monitoring or symptom-based investigation.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Case finding and diagnosis\n\nSee also the section on information needs and support.\n\nSuspect familial hypercholesterolaemia (FH) as a possible diagnosis in adults with:\n\na total cholesterol level greater than 7.5\xa0mmol/l or\n\na personal or family history of premature coronary heart disease (an event before 60\xa0years in an index individual or first-degree relative). [2008, amended 2019]\n\nSystematically search primary care records for people:\n\nyounger than 30\xa0years, with a total cholesterol concentration greater than 7.5\xa0mmol/l and\n\nyears or older, with a total cholesterol concentration greater than 9.0\xa0mmol/las these are the people who are at highest risk of FH. \n\nFor people with a personal or family history of premature coronary heart disease (an event before 60\xa0years in an index individual or first-degree relative), but whose total cholesterol is unknown, offer to measure their total cholesterol. \n\nHealthcare professionals should exclude secondary causes of hypercholesterolaemia before a diagnosis of FH is considered. \n\nUse the Simon Broome criteria (see appendix F of the full guideline) or Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH in primary care settings. This should be done by a healthcare professional competent in using the criteria. \n\nRefer the person to an FH specialist service for DNA testing if they meet the Simon Broome criteria for possible or definite FH, or they have a DLCN score greater than 5. \n\nHealthcare professionals should be aware that the absence of clinical signs (for example, tendon xanthomata) in adults and children/young people does not exclude a diagnosis of FH. \n\nHealthcare professionals should consider a clinical diagnosis of homozygous FH in adults with a low-density lipoprotein cholesterol (LDL‑C) concentration greater than 13\xa0mmol/l and in children/young people with an LDL‑C concentration greater than 11\xa0mmol/l. All people with a clinical diagnosis of homozygous FH should be offered referral to a specialist centre. \n\nTo confirm a diagnosis of FH, healthcare professionals should undertake two measurements of LDL‑C concentration because biological and analytical variability occurs. \n\nWhen considering a diagnosis of FH, healthcare professionals with expertise in FH should use standardised pedigree terminology to document, when possible, at least a three-generation pedigree. This should include relatives' age of onset of coronary heart disease, lipid concentrations and smoking history. For deceased relatives, the age and cause of death, and smoking history should be documented. If possible, the index individual should verify this information with other family members. \n\nUltrasonography of the Achilles tendon is not recommended in the diagnosis of FH. \n\nCoronary heart disease risk estimation tools, such as QRISK2 and those based on the Framingham algorithm, should not be used because people with FH are already at a high risk of premature coronary heart disease. [2008, amended 2017]\n\nInform all people who have an identified mutation diagnostic of FH that they have an unequivocal diagnosis of FH even if their LDL‑C concentration does not meet the diagnostic criteria (see recommendation 1.1.5). [2008, amended 2017]\n\nIn a family where a DNA mutation is identified, not all family members may have inherited the mutation. When DNA testing has excluded FH in a member of a family, healthcare professionals should manage the person's coronary heart disease risk as in the general population (see NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification). \n\nIn children aged 0–10\xa0years at risk of FH because of 1 affected parent, offer a DNA test at the earliest opportunity. If testing of a child at risk has not been undertaken by the age of 10\xa0years, offer an additional opportunity for a DNA test. \n\nIn children at risk of homozygous FH because of two affected parents or because of the presence of clinical signs, for example, cutaneous lipid deposits (xanthomata), LDL‑C concentration should be measured before the age of 5\xa0years or at the earliest opportunity thereafter. If the LDL‑C concentration is greater than 11\xa0mmol/l then a clinical diagnosis of homozygous FH should be considered. \n\n# Identifying people with FH using cascade testing\n\nCarry out cascade testing using DNA testing to identify affected first- and second- and, when possible, third-degree biological relatives of people with a genetic diagnosis of FH. \n\nHealthcare professionals should offer all people with FH a referral to a specialist with expertise in FH for confirmation of diagnosis and initiation of cascade testing. \n\nHealthcare professionals with expertise in FH should explain what is meant by cascade testing, and discuss its implications with all people with FH. \n\nHealthcare professionals should be aware of the latest guidance on data protection when undertaking cascade testing. \n\n# Management\n\n## Drug treatment\n\nRecommendations 1.3.1.4 to 1.3.1.9 have been adapted from NICE's technology appraisal guidance on ezetimibe for treating primary (heterozygous-familial and non-familial) hypercholesterolaemia.\n\nWhen offering lipid-modifying drug therapy to adults with FH, healthcare professionals should inform the person that this treatment should be lifelong. .\n\nOffer a high-intensity statin with the lowest acquisition cost as the initial treatment for all adults with FH and aim for at least a 50% reduction in LDL‑C concentration from the baseline measurement. \n\nThe dose of statin should be increased to the maximum licensed or tolerated dose to achieve a recommended reduction in LDL‑C concentration of greater than 50% from baseline (that is, LDL‑C concentration before treatment). \n\nEzetimibe monotherapy is recommended as an option for treating primary heterozygous‑familial hypercholesterolaemia in adults in whom initial statin therapy is contraindicated. \n\nEzetimibe monotherapy is recommended as an option for treating primary heterozygous‑familial hypercholesterolaemia in adults who cannot tolerate statin therapy (as defined in recommendation\xa01.3.1.9). \n\nEzetimibe, co‑administered with initial statin therapy, is recommended as an option for treating primary (heterozygous‑familial) hypercholesterolaemia in adults who have started statin therapy when:\n\nserum total or low‑density lipoprotein (LDL) cholesterol concentration is not appropriately controlled (as defined in recommendation 1.3.1.8) either after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy (as defined in recommendation 1.3.1.9) and\n\na change from initial statin therapy to an alternative statin is being considered. \n\nWhen prescribing ezetimibe co-administered with a statin, ezetimibe should be prescribed on the basis of lowest acquisition cost. \n\nFor the purposes of this guidance, appropriate control of cholesterol concentrations should be based on individualised risk assessment according to national guidance on managing cardiovascular disease in the relevant populations. \n\nFor the purposes of this guidance, intolerance to initial statin therapy is defined as the presence of clinically significant adverse effects that represent an unacceptable risk to the patient or that may reduce compliance with therapy. \n\nPrescribing of drug therapy for adults with homozygous FH should be undertaken within a specialist centre. \n\nHealthcare professionals should offer adults with FH a referral to a specialist with expertise in FH if treatment with the maximum tolerated dose of a high-intensity statin and ezetimibe does not achieve a recommended reduction in LDL‑C concentration of greater than 50% from baseline (that is, LDL‑C concentration before treatment). \n\nHealthcare professionals should offer adults with FH a referral to a specialist with expertise in FH for consideration for further treatment if they are assessed to be at very high risk of a coronary event, that is, if they have any of the following.\n\nEstablished coronary heart disease.\n\nA family history of premature coronary heart disease.\n\nTwo or more other cardiovascular risk factors (for example, they are male, they smoke, or they have hypertension or diabetes). \n\nFor recommendations on managing primary heterozygous familial hypercholesterolaemia in people whose LDL‑C levels are not adequately controlled despite maximal tolerated lipid-lowering therapy, see the NICE technology appraisal guidance on alirocumab and evolocumab. \n\nAdults with FH with intolerance or contraindications to statins or ezetimibe should be offered a referral to a specialist with expertise in FH for consideration for treatment with either a bile acid sequestrant (resin) or a fibrate to reduce their LDL‑C concentration. [2008, amended 2017]\n\nThe decision to offer treatment with a bile acid sequestrant (resin) or a fibrate in addition to initial statin therapy should be taken by a specialist with expertise in FH. [2008, amended 2017]\n\nHealthcare professionals should exercise caution when adding a fibrate to a statin because of the risk of muscle-related side effects (including rhabdomyolysis). Gemfibrozil and statins should not be used together. [2008, amended 2017]\n\nHealthcare professionals should offer all children and young people diagnosed with, or being investigated for, a diagnosis of FH a referral to a specialist with expertise in FH in children and young people. This should be in an appropriate child/young person-focused setting that meets the standards within the National service framework for children, young people and maternity services. \n\nLipid-modifying drug therapy for a child or young person with FH should usually be considered by the age of 10\xa0years. The decision to defer or offer lipid-modifying drug therapy for a child or young person should take into account:\n\ntheir age\n\nthe age of onset of coronary heart disease within the family, and\n\nthe presence of other cardiovascular risk factors, including their LDL‑C concentration. \n\nWhen offering lipid-modifying drug therapy for children or young people, healthcare professionals should inform the child/young person and their parent/carer that this treatment should be lifelong. \n\nOffer statins to children with FH by the age of 10\xa0years or at the earliest opportunity thereafter. \n\nFor children and young people with FH, consider a statin that is licensed for use in the appropriate age group. \n\nStatin therapy for children and young people should be initiated by a healthcare professional with expertise in treating children and young people with FH, and in a child-focused setting. [2008, amended 2017]\n\nStatin therapy for children and young people with FH should usually be prescribed at the doses specified in the 'British national formulary (BNF) for children'. \n\nIn exceptional instances, for example, when there is a family history of coronary heart disease in early adulthood, healthcare professionals with expertise in FH in children and young people should consider offering:\n\na higher dose of statin than is licensed for use in the appropriate age group, and/or\n\nmore than one lipid-modifying drug therapy, and/or\n\nlipid-modifying drug therapy before the age of 10\xa0years. \n\nIn children and young people with homozygous FH, LDL‑C concentration may be lowered by lipid-modifying drug therapy and this should be considered before LDL apheresis (see section\xa01.3.3). \n\nIn children and young people with FH who are intolerant of statins, healthcare professionals should consider offering other lipid-modifying drug therapies capable of reducing LDL‑C concentration (such as bile acid sequestrants [resins], fibrates or ezetimibe). \n\nRoutine monitoring of growth and pubertal development in children and young people with FH is recommended. \n\nDecisions about the choice of treatment should be made following discussion with the adult or child/young person and their parent/carer, and be informed by consideration of concomitant medication, comorbidities, safety and tolerability. \n\nHealthcare professionals should consider offering fat-soluble vitamin (vitamins A, D and K) and folic acid supplementation for adults or children/young people with FH who are receiving long-term treatment with bile acid sequestrants (resins). \n\nHealthcare professionals should offer people with FH a referral to a specialist with expertise in FH if they are experiencing side effects that compromise concordance with lipid-modifying drug therapy. \n\nWhen the decision has been made to offer adults or children/young people with FH treatment with a statin, baseline liver and muscle enzymes (including transaminases and creatine kinase, respectively) should be measured before initiation of therapy. However, people with raised liver or muscle enzymes should not routinely be excluded from statin therapy. \n\nRoutine monitoring of creatine kinase is not recommended in asymptomatic adults or children/young people with FH who are receiving treatment with a statin. \n\n## Lifestyle interventions\n\nHealthcare professionals should regard lifestyle advice as a component of medical management, and not as a substitute for lipid-modifying drug therapy. \n\nAll people with FH should be offered individualised nutritional advice from a healthcare professional with specific expertise in nutrition. \n\nPeople with FH should be advised to consume a diet in which:\n\ntotal fat intake is 30% or less of total energy intake\n\nsaturated fats are 10% or less of total energy intake\n\nintake of dietary cholesterol is less than 300\xa0mg/day\n\nsaturated fats are replaced by increasing the intake of monounsaturated and polyunsaturated fats. It may be helpful to suggest they look at Live Well for further practical advice. \n\nHealthcare professionals should advise people with FH to eat at least five portions of fruit and vegetables a day, in line with national guidance for the general population. Examples of what constitutes a portion can be found at Live Well. \n\nHealthcare professionals should advise people with FH to consume at least two portions of fish a week (one of which should be oily fish). Pregnant women with FH should be advised to limit their oily fish to two portions a week. Further information and advice on healthy cooking methods can be found at Live Well. \n\nHealthcare professionals should advise people with FH that if they wish to consume food products containing stanols and sterols these need to be taken consistently to be effective. \n\nPeople with FH should not routinely be recommended to take omega-3 fatty acid supplements. For people with FH who have already had a myocardial infarction (MI), refer to the NICE guideline on myocardial infarction. \n\nHealthcare professionals should advise people with FH to undertake physical activity in line with national guidance for the general population (see the UK Chief Medical Officers' physical activity guidelines for more information). \n\nHealthcare professionals should encourage people who are unable to perform moderate-intensity physical activity because of comorbidity, medical conditions or personal circumstances to exercise at their maximum safe capacity (see the UK Chief Medical Officers' physical activity guidelines for more information). \n\nRecommended types of physical activity include those that can be incorporated into everyday life, such as brisk walking, using stairs and cycling (see the UK Chief Medical Officers' physical activity guidelines for more information). \n\nHealthcare professionals should offer people with FH who are overweight or obese appropriate advice and support to achieve and maintain a healthy weight in line with NICE's guideline on obesity prevention. \n\nAs for the general population, alcohol consumption for adult men with FH should be limited to up to 3–4\xa0units a day, and for adult women with FH up to 2–3\xa0units of alcohol a day. Binge drinking should be avoided. Further information can be found at Live Well. \n\nPeople with FH, especially children, who do not smoke should be strongly discouraged from starting because of their already greatly increased risk of coronary heart disease. \n\nPeople with FH who smoke should be advised that, because of their already greatly increased risk of coronary heart disease, they should stop. \n\nHealthcare professionals should offer people who want to stop smoking support and advice, and referral to an intensive support service, in line with the NICE guidance on smoking cessation. \n\nPeople with FH who are unwilling or unable to accept a referral to an intensive support service should be offered pharmacotherapy in line with NICE guidance on nicotine replacement therapy and bupropion, and varenicline. See NICE guidance on smoking cessation, including NICE's technology appraisal guidance on varenicline for smoking cessation. \n\n## Specialist treatment\n\nHealthcare professionals should consider offering LDL apheresis for the treatment of adults and children/young people with homozygous FH (see recommendations 1.1.8 and 1.1.16). The timing of initiation of LDL apheresis should depend on factors such as the person's response to lipid-modifying drug therapy and presence of coronary heart disease. \n\nIn exceptional instances (such as when there is progressive, symptomatic coronary heart disease, despite maximal tolerated lipid-modifying drug therapy and optimal medical and surgical therapy), healthcare professionals should consider offering LDL apheresis for the treatment of people with heterozygous FH. This should take place in a specialist centre on a case-by-case basis and data recorded in an appropriate registry. \n\nHealthcare professionals should recommend arterio-venous fistulae as the preferred method of access for people with FH who are offered treatment with LDL apheresis. People should be counselled about possible benefits and complications of this procedure. \n\nRoutine monitoring of the person's iron status should be carried out and iron supplementation initiated as required for people with FH who are receiving treatment with LDL apheresis. \n\nAngiotensin-converting enzyme (ACE) inhibitors should not be used in people with FH who are being treated with LDL apheresis. Instead, ACE inhibitors should be substituted with angiotensin-receptor blocking agents. \n\nPeople with FH who are receiving blood pressure-lowering drug therapy should have this reviewed and considered for discontinuation on the morning of the day of LDL apheresis. \n\nPeople with FH who are taking warfarin should have this discontinued approximately 4\xa0days before LDL apheresis and substituted with low molecular weight heparin. \n\nPeople with FH who are receiving anti-platelet therapy should have this continued if they are receiving treatment with LDL apheresis. \n\nHealthcare professionals should consider offering liver transplantation as an option for the treatment of people with homozygous FH after treatment with lipid-modifying drug therapy and LDL apheresis. \n\nThe decision to refer for liver transplantation should take place in partnership with the patient and/or their relatives in an appropriate specialist setting, following a discussion of the benefits and potential harms of undertaking or declining transplantation. \n\n# Information needs and support\n\n## General information and support\n\nDuring the assessment and communication of familial risk, people should receive clear and appropriate educational information about FH, the process of family testing, DNA testing and the measurement of LDL‑C concentration. \n\nA healthcare professional with expertise in FH should provide information to people with FH on their specific level of risk of coronary heart disease, its implications for them and their families, lifestyle advice and treatment options. \n\nHealthcare professionals with expertise in FH should encourage people with FH to contact their relatives to inform them of their potential risk and so that cascade testing can take place. \n\nWhen considering cascade testing, a healthcare professional with expertise in FH should offer to facilitate the sharing of information about FH with family members. \n\nHealthcare professionals should offer people with FH and their families written advice and information about patient support groups. \n\n## Information and counselling on contraception for women and girls with FH\n\nWhen lipid-modifying drug therapy is first considered for women and girls, the risks for future pregnancy and the fetus while taking lipid-modifying drug therapy should be discussed. This discussion should be revisited at least annually. \n\nHealthcare professionals should give women and girls with FH specific information tailored to their needs and should offer a choice of effective contraceptive methods. \n\nCombined oral contraceptives (COCs) are not generally contraindicated for women and girls being treated with lipid-modifying drug therapy. However, because there is a potential small increased risk of cardiovascular events with the use of COCs, healthcare professionals should consider other forms of contraception. Prescribers should refer to the summary of product characteristics of COCs and the relevant lipid-modifying drugs for their specific contraindications. \n\n## Information for pregnant women with FH\n\nHealthcare professionals should be aware that, in general, there is no reason to advise against pregnancy or breastfeeding in women with FH. \n\nHealthcare professionals should advise women with FH that lipid-modifying drug therapy should not be taken if they are planning to conceive or during pregnancy, because of the potential risk of fetal abnormality. Women should be advised that lipid-modifying drug therapy should be stopped 3\xa0months before they attempt to conceive. \n\nWomen with FH who conceive while taking statins or other systemically absorbed lipid-modifying drug therapy should be advised to stop treatment immediately and they should be offered an urgent referral to an obstetrician for a fetal assessment. Women should be fully informed about the nature and purpose of the assessment. \n\nWomen with FH who have conceived while taking statins or other systemically absorbed lipid-modifying drug therapy and have had a fetal assessment should be given time, opportunity and full information to consider their options (including the advantages and disadvantages) of continuing with their pregnancy. \n\nShared-care arrangements, to include expertise in cardiology and obstetrics, should be made for women with FH who are considering pregnancy or are pregnant. Such care should include an assessment of coronary heart disease risk, particularly to exclude aortic stenosis. This is essential for women with homozygous FH. \n\nSerum cholesterol concentrations should not be measured routinely during pregnancy. \n\nWomen with FH who are pregnant should be advised on the potential risks and benefits of re-starting lipid-modifying drug therapy for the mother and breastfed infant. Resins are the only lipid-modifying drug therapy that should be considered during lactation. \n\n# Ongoing assessment and monitoring\n\n## Review\n\nAll people with FH should be offered a regular structured review that is carried out at least annually. \n\nA baseline electrocardiogram (ECG) should be considered for adults with FH. \n\nHealthcare professionals should record the progress of cascade testing among the relatives of a person with FH as part of the structured review. This should include at least the first- and second-degree relatives- and, when possible, third-degree biological relatives. If there are still relatives who have not been tested, further action should be discussed. \n\nHealthcare professionals should update the family pedigree of a person with FH and note any changes in the coronary heart disease status of their relatives as part of the structured review. This should include at least the first- and second- and, when possible, third-degree biological relatives. \n\nStructured review should include assessment of any symptoms of coronary heart disease and smoking status, a fasting lipid profile, and discussion about concordance with medication, possible side effects of treatment the patient may be experiencing, and any changes in lifestyle or lipid-modifying drug therapy that may be required to achieve the recommended LDL‑C concentration (see the section\xa0on management). \n\n## Referral for evaluation of coronary heart disease\n\nHealthcare professionals should offer people with FH an urgent referral to a specialist with expertise in cardiology for evaluation if they have symptoms or signs of possible coronary heart disease which are not immediately life-threatening. A low threshold for referral is recommended. \n\nA person with FH with symptoms or signs of possible coronary heart disease which are immediately life-threatening (for example, acute coronary syndrome) should be referred to hospital as an emergency in line with advice for the general population. \n\nHealthcare professionals should consider offering people with FH a referral for evaluation of coronary heart disease if they have a family history of coronary heart disease in early adulthood, or two or more other cardiovascular risk factors (for example, they are male, they smoke, or they have hypertension or diabetes). \n\nUpon diagnosis, healthcare professionals should offer all adults and children/young people with homozygous FH a referral for an evaluation of coronary heart disease. \n\nIn asymptomatic children and young people with heterozygous FH, evaluation of coronary heart disease is unlikely to detect clinically significant disease and referral should not be routinely offered. \n\n# Terms used in this guideline\n\n## Adults with FH\n\nFor the purposes of this guideline, 'adults' includes all persons with familial hypercholesterolaemia (FH; heterozygous or homozygous) who are 16 years and older.\n\n## Cascade testing\n\nCascade testing is a mechanism for identifying people at risk of a genetic condition by a process of family tracing. For FH the test employed is a DNA test where a disease-causing mutation has been identified in the index individual/proband.\n\n## Children/young people\n\nFor the purposes of this guideline, 'children' refers to persons younger than 10\xa0years; 'young people' refers to persons from 10\xa0years of age up to the age of 15\xa0years. The definitions used here are not prescriptive and healthcare professionals are expected to exercise their judgement and consider the wishes of the patients, and their families or carers when interpreting these terms in individual instances.\n\n## Child-focused setting\n\nChild-focused refers to valuing the child's view and validating their voice in making decisions impacting their lives. A child-focused facility or space is one designed from the viewpoint of the service recipients.\n\n## Coronary heart disease\n\nAn event is defined as angina, acute coronary syndrome, myocardial infarction, need for coronary artery bypass grafting, need for percutaneous coronary intervention or definite coronary artery disease on coronary angiography.\n\n## Dutch Lipid Clinic Network (DLCN) criteria/score\n\nA method of assessing whether a person has FH. It is based on personal and family medical history, clinical signs, LDL‑C concentration and DNA testing. A score is attributed to each component; the higher the score, the higher the likelihood of the person having FH.\n\n## Family history\n\nThe structure and relationships within the family that relates information about diseases in family members.\n\n## First-degree relative\n\nA person's biological parents, brothers and sisters, and children.\n\n## Heterozygous FH\n\nHigh LDL‑C concentration in the blood caused by an inherited mutation from one parent only. People with FH are at increased risk of cardiovascular disease.\n\n## High-intensity statin\n\nStatins are classified as high intensity if they produce average reductions in LDL-C greater than 40%. See appendix A of NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification.\n\n## Homozygous FH\n\nVery high LDL‑C concentration in the blood caused by an inherited mutation from both parents. When a person inherits exactly the same affected gene from both parents this is called truly 'homozygous' FH. When the mutations in the LDL receptor gene (or equivalent) are different, this state is called 'compound heterozygous'. In general, the overall effect in both states is similar, in that LDL‑C concentrations are very high. Both groups of patients have the same clinical pattern and high risk of cardiovascular disease.\n\nFor clinical purposes, both homozygous FH and compound heterozygous FH can be regarded as behaving in a similar manner. Therefore, for the purposes of this guideline the term 'homozygous FH' is used to also encompass compound heterozygous FH.\n\n## Index individual (synonymous with 'proband')\n\nThe original patient who is the starting point for follow-up of other members of a family when investigating for possible causative genetic factors of the presenting condition.\n\n## Lipid measurements/concentrations/levels\n\nThese terms refer to the measurement of total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL‑C), and LDL‑C. LDL‑C is not usually measured directly but calculated from the TC, TGs and HDL‑C, ideally using a fasting sample.\n\nSuch tests are usually done in a clinical biochemistry laboratory.\n\n## Mutation\n\nAn identified change in the DNA sequence of a gene that is predicted to damage the normal function of the gene and so cause disease.\n\n## Pedigree\n\nA method of characterising the relatives of an index individual/case and their family relationship as well as problems or illnesses within the family. This information, often represented graphically as a family tree, facilitates analysis of inheritance patterns. Study of a trait or disease begins with the affected person (the index individual). The pedigree is drawn as the relatives are described. One begins with the siblings of the index individual and proceeds to the parents; relatives of the parents, including brothers, sisters, nephews, nieces, grandparents, and so on. At least three generations are usually included. Illnesses, hospitalisations, causes of death, miscarriages, abortions, congenital anomalies, and any other unusual features are recorded.\n\n## Premature coronary heart disease\n\nFor the purpose of this guideline, this refers to a coronary event that has occurred before 60 years of age in an index individual or first-degree relative.\n\n## Proband\n\nThe affected (index) individual through whom a family with a genetic disorder is ascertained.\n\n## Second-degree relative\n\nA person's biological grandparent, grandchild, uncle, aunt, niece, nephew, half sister or half brother.\n\n## Secondary causes of hypercholesterolaemia\n\nCauses of hyperlipidaemia other than familial, including uncontrolled diabetes mellitus, obesity, excess alcohol consumption, untreated hypothyroidism and some medications, for example, thiazide diuretics and ciclosporin.\n\n## Specialist centre\n\nThe definition of a specialist centre is not rigid and is based on a combination of patient treatment services, numbers and ages of people attending there, the presence of a multi-disciplinary team (which may include, for example, physicians, lipidologists, specialist nurses, pharmacists and dietitians), the ability to manage the more unusual manifestations of the condition and the additional functions such as research, education and standard setting. Care is supervised by expert healthcare professionals but shared with local hospitals and primary care teams. Although details of the model may vary between patients and areas, the key is that specialist supervision oversees local provision with the patient seen at diagnosis for initial assessment and then at least annually for review.\n\n## Tendon xanthomata\n\nA clinically detectable nodularity and/or thickening of the tendons caused by infiltration with lipid-laden histiocytes (macrophages in connective tissue).\n\nA distinctive feature of FH that most frequently affects the Achilles tendons but can also involve tendons on the back of the hands, elbows and knees.\n\n## Third-degree biological relative\n\nA person's biological great grandparent, great grandchild, great aunt, great uncle, first cousin, grand nephew or grand niece.\n\n## Urgent referral\n\nFor the purposes of this guideline, urgent referral is as soon as possible with a maximum of 14\xa0days.", 'Context': "In some people, a high cholesterol concentration in the blood is caused by an inherited genetic defect known as familial hypercholesterolaemia (FH). A raised cholesterol concentration in the blood is present from birth and may lead to early development of atherosclerotic disease like coronary heart disease. The disease shows an autosomal dominant pattern of inheritance, being transmitted from generation to generation in such a way that siblings and children of a person with FH have a 50% risk of inheriting FH.\n\nMost people with FH have inherited a defective gene for FH from only one parent and are therefore heterozygous. Rarely, a person will inherit a genetic defect from both parents and will have homozygous FH or compound heterozygous FH, which will be collectively termed homozygous FH for the purpose of this guideline.\n\nThe prevalence of heterozygous FH in the UK population is estimated to be somewhere between 1 in 250 and 1\xa0in\xa0500, which means that between approximately 130,000 and 260,000 people are affected. The elevated serum cholesterol concentration that characterises heterozygous FH leads to a greater than 50% risk of coronary heart disease in men by the age of 50\xa0years and at least 30% in women by the age of 60\xa0years.\n\nHomozygous FH is rare, with symptoms appearing in childhood, and is associated with early death from coronary heart disease. Homozygous FH has an incidence of approximately one case per one million.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform their decisions for individual patients.\n\nIn 2017 the areas on case-finding, diagnosis and pharmacological monotherapy (statin v placebo) were updated. Since the original guideline was published in 2008, cascade testing may now be more cost-effective, and DNA diagnosis technology has changed greatly. In addition, more evidence has been identified on the use of high-intensity statins, and on the safety profile of statins in children and young people.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\nAs part of the 2017 update, the standing committee made research recommendations on using different thresholds of low-density lipoprotein cholesterol (LDL‑C) concentration in primary care case finding and on long-term monitoring of sub-clinical atherosclerosis in children with familial hypercholesterolaemia (FH) who are treated with statins (see below). The committee also made 3 other research recommendations, on secondary care case finding, cascade testing and the use of clinical scoring criteria. One research recommendation on identification using clinical registers was removed. Details can be found in the evidence reviews.\n\n# Using different thresholds of low-density lipoprotein cholesterol concentration in primary care case finding\n\nWhat is the clinical and cost effectiveness of using different thresholds of LDL‑C concentration in primary care case finding?\n\n## Why this is important\n\nThe clinical community recognises that FH is underdiagnosed, with prevalence more likely to be approximately 1 in 250 rather than the widely cited 1 in 500. Searching electronic primary care databases is an effective way of identifying people with FH. One of the ways in which people are identified through electronic primary care database searching is to search using total cholesterol or LDL‑C concentration. Currently, the entire evidence base for identifying cohorts of people with FH through primary care case finding uses a total cholesterol concentration cut-off of 9.3\xa0mmol/l. This is a very high concentration and anecdotal evidence suggests that this identifies older people but may miss younger people with FH. This could lead to missed opportunities to identify and treat people with FH at an earlier age. Research is needed to identify whether using different total cholesterol and LDL‑C concentrations to identify people with FH through primary care database searching affects the diagnostic yield of FH. Additionally, there is a lack of data on the ethnicity, age and triglyceride concentration of people with FH identified through primary care database searching. These should be included as outcomes in future research. \n\n# Long-term monitoring of sub-clinical atherosclerosis in children with FH who are treated with statin therapy\n\nWhat are the long-term effects of statin therapy on sub-clinical atherosclerosis in children with FH who are treated with statin therapy?\n\n## Why this is important\n\nAlthough statins are increasing in use, there is still a lack of data on the long-term effects of statins in children. It is particularly important to determine any long-term adverse effects of statin treatment in a population with FH, as people generally take statins for the rest of their lives once treatment starts. \n\n# Lipid-modifying drug therapy in children\n\nWhat is the clinical effectiveness and safety of differing doses of lipid-modifying therapy in children with FH?\n\n## Why this is important\n\nThere have been no published studies to establish target serum LDL‑C concentration in treated children with FH receiving lipid-modifying drug therapy. Treatment is recommended from 10\xa0years onwards, however this lack of data prevents a recommendation regarding the aim of pharmacological treatment on serum LDL‑C concentrations.\n\nResearch (both cross-sectional and longitudinal) should assess the evidence of end-organ involvement (for example, carotid intima medial thickness [IMT]) to determine at which age abnormalities can first be seen in children. The aim would be to identify a threshold effect, with an LDL‑C concentration below which carotid IMT is normal and where thickening is absent, and above which it is abnormal and where thickening is observed. Outcomes should include fasting serum total and LDL‑C concentration, carotid artery IMT, and growth and pubertal development. \n\n# LDL apheresis for people with heterozygous FH\n\nWhat are the appropriate indications, effectiveness and safety of LDL apheresis in people with heterozygous FH?\n\n## Why this is important\n\nThere is limited evidence to inform specific indications for LDL apheresis in people with heterozygous FH. In addition, there is limited published evidence on the cardiovascular outcome of such patients treated with LDL apheresis.\n\nEvidence on the value of investigations (various measures of vascular status, considered to reflect the extent or activity of atherosclerotic vascular disease of the coronary arteries) in predicting outcome from LDL apheresis should ideally be based on evidence from randomised controlled trials with clinical outcomes. It is difficult to identify a suitable alternative treatment because LDL apheresis is generally only considered in people for whom no other treatment is available. One comparator may be novel therapies with antisense oligonucleotides (ApoB).\n\nA national register should be established for all people with FH who are referred for and/or are undergoing LDL apheresis. Data should be collected on the natural history of FH and the temporal relationship of clinical and vascular features in relation to treatments and other parameters. \n\n# Pregnancy in women with FH\n\nWhat are the implications of FH for the safety of a mother during pregnancy and what are the risks of fetal malformations attributable to pharmacological therapies?\n\n## Why this is important\n\nThere is little information on the outcomes of pregnancy in women with FH. A small number of conflicting studies have suggested a small increase in fetal abnormalities if the mother has taken statins during the first trimester, but there are not sufficient data to provide an accurate estimate of the level of risk. There is also limited information on the risk of pregnancy (including cardiac death) in a woman with FH.\n\nData on the incidence of cardiac problems in pregnancy and incidence of fetal malformation would inform future recommendations. This could reduce uncertainty for women, and help to identify risks during the pregnancy that could be better managed. The only feasible research method to address these questions is an observational longitudinal study following women with FH and other women (not diagnosed with FH) using statins through their pregnancies using a national register. \n\n# Cardiovascular evaluation for people with FH\n\nWhat is the utility of routine cardiovascular evaluation for asymptomatic people with FH?\n\n## Why this is important\n\nBecause of their inherent high risk of developing premature coronary heart disease, a low threshold of suspicion for coronary disease is recommended for people with FH. Routine monitoring to detect sub-clinical atherosclerosis should be non-invasive, sensitive, specific and cost effective. Research to assess the prevalence of both asymptomatic coronary and non-coronary atherosclerosis in people with definite heterozygous FH is required.\n\nAs well as exercise ECG testing followed by stress echocardiography before possible angiography in people with an abnormal exercise test and ankle brachial pressure measures, research should include magnetic resonance imaging (MRI) in addition to other modalities such as carotid IMT and coronary calcification. Outcomes should include changes in exercise ECG/ankle brachial pressure testing/IMT/calcification over time.\n\nConsideration should also be given to the feasibility of conducting a long-term randomised trial to compare the differences in morbidity or mortality attributable to early diagnosis using routine monitoring or symptom-based investigation. '}
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https://www.nice.org.uk/guidance/cg71
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This guideline covers identifying and managing familial hypercholesterolaemia (FH), a specific type of high cholesterol that runs in the family, in children, young people and adults. It aims to help identify people at increased risk of coronary heart disease as a result of having FH.
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Idelalisib for treating refractory follicular lymphoma
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Idelalisib for treating refractory follicular lymphoma
Evidence-based recommendations on idelalisib (Zydelig) for follicular lymphoma that has not responded to 2 prior lines of treatment in adults.
# Recommendations
Idelalisib is not recommended, within its marketing authorisation, for treating follicular lymphoma that has not responded to 2 prior lines of treatment in adults.
This recommendation is not intended to affect treatment with idelalisib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
The options after 2 lines of treatment for follicular lymphoma in the NHS include a range of chemotherapy treatments. The choice of the specific treatment depends on what the person has had already.
Idelalisib has not been compared directly with current individual chemotherapeutic treatments. There are several complex indirect comparisons of idelalisib, but these are based on sparse data and have other problems. So, it is unclear whether idelalisib is better than individual chemotherapeutic regimens currently offered by the NHS and, if so, by how much.
There is a wide range of cost-effectiveness estimates but, because the evidence is weak, idelalisib is not considered to represent a cost-effective use of NHS resources. Therefore, idelalisib cannot be recommended for routine use in the NHS.
Idelalisib cannot be recommended for inclusion in the Cancer Drugs Fund. This is because data collected in the Cancer Drugs Fund cannot resolve the key problems determining whether idelalisib is more effective that chemotherapy, nor document the adverse effects associated with individual chemotherapeutic regimens.# Information about idelalisib
Marketing authorisation indication
Idelalisib (Zydelig, Gilead) has a marketing authorisation 'as monotherapy for the treatment of adult patients with follicular lymphoma (FL) that is refractory to two prior lines of treatment'.
Dosage in the marketing authorisation
Idelalisib is administered orally at a dose of 150 mg, twice daily. Treatment is continued until disease progression or unacceptable toxicity.
Price
The list price for idelalisib is £3,114.75 per pack of 60 x 150 mg film-coated tablets (excluding VAT, company submission).
The company has a commercial arrangement for idelalisib, which would apply if the technology had been recommended.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Gilead and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Treatment pathway
## This appraisal focuses on idelalisib as a treatment used after an anti‑CD20 monoclonal antibody and an alkylating agent
Idelalisib is an oral treatment for follicular lymphoma. The marketing authorisation specifies a population with follicular lymphoma that is 'refractory to 2 prior lines of treatment'. However, the committee noted that the clinical evidence for idelalisib included a population in which there was a wide range in the numbers of prior chemotherapeutic regimens previously used by patients. Furthermore, the committee noted that the population considered in the company's submission was narrower than the population specified by the marketing authorisation, which is 'double-refractory'. This means that the follicular lymphoma has not responded, or showed only a limited response, to at least 2 previous treatments. The company specified that the previous treatments had to include an anti‑CD20 monoclonal antibody (rituximab or obinutuzumab) and chemotherapy containing an alkylating agent (for example, cyclophosphamide). The clinical experts considered this double-refractory population to have an unmet need for treatment options. The committee agreed with the company that idelalisib is likely to be used after an anti‑CD20 monoclonal antibody and an alkylating agent.
## There is no single standard-of-care chemotherapy for the population in this appraisal
In the population that would be offered idelalisib (see section 3.1), most people are currently offered chemotherapy including (as listed in the NICE scope) cyclophosphamide-containing regimens, fludarabine-containing regimens, bendamustine and chlorambucil. The clinical experts explained that these vary in effectiveness and toxicity. The choice of chemotherapy regimen depends on individual circumstances, and takes into account previous chemotherapy, plus clinician and patient preference. Because of this, there is no single standard-of-care chemotherapy regimen in this population. The committee concluded that all the chemotherapeutic regimens listed in the scope were appropriate comparators.
## Best supportive care is also a comparator for idelalisib
The clinical experts stated that, after second-line treatment, people who could not have chemotherapy would be offered best supportive care instead. The clinical experts stated that some of those people could take idelalisib because it has a different toxicity profile to chemotherapy. So, while people may not tolerate the specific adverse effects of chemotherapy, they may tolerate those of idelalisib. The committee concluded that best supportive care is an option and a relevant comparator for people who cannot have chemotherapy, but who can take idelalisib.
## The effect of autologous stem cell transplantation after idelalisib or chemotherapy should be considered
The clinical experts stated that response to second-line treatment is consolidated with autologous stem cell transplantation in people who are considered fit enough, in line with NICE's guideline on non-Hodgkin's lymphoma: diagnosis and management. They also noted that, if a patient was healthy, autologous stem cell transplantation would be considered at later lines of therapy, as soon as the cancer responded to treatment. The clinical experts considered that autologous stem cell transplantation can improve prognosis, and that it could be used after idelalisib. The committee concluded that autologous stem cell transplantation was not a comparator to idelalisib, but that it was possible to use idelalisib as a bridge to autologous stem cell transplantation if there was a sufficient response to idelalisib. It also understood that patients could have a transplant before disease progression. The committee further concluded that it would need to consider the effects of autologous stem cell transplantation used after idelalisib or chemotherapy in the clinical- and cost-effectiveness results provided by the company.
# Clinical evidence
## There is no trial evidence on how much better idelalisib is compared with current clinical practice
The key clinical evidence for idelalisib came from the single-arm phase II DELTA study. This study included 125 patients with indolent (slowly growing) non-Hodgkin's lymphoma, 72 of whom had follicular lymphoma refractory to 2 or more lines of treatment. The primary outcome measured overall response rate. Overall survival and progression-free survival were among the secondary outcomes. DELTA had no control group; all patients in the study had idelalisib. The committee understood that this study was designed to show that idelalisib was a safe treatment. It also understood that the company had not carried out further effectiveness trials planned to support its application for a marketing authorisation (see section 3.6), which the European Medicines Agency granted on the basis of the DELTA study. The data from DELTA first provided by the company (cut-off date June 2015) showed an overall response rate of 55.6% and a median progression-free survival of 11.0 months; median overall survival was not reached, but the company estimated it to be 38.1 months. During consultation, the company submitted updated data based on a later cut-off date (August 2018); they showed that the median overall survival result was better than the company's original estimate (results are academic in confidence). The company stated that the latest data suggested that the overall survival benefit was largely as a result of survival after the cancer had progressed. The company supplemented the DELTA study with another source of evidence for idelalisib: the Compassionate Use Programme (CUP). This provided retrospective observational data from patients with follicular lymphoma having compassionate treatment in the UK and Ireland. The company took a subset of 79 patients with relapsed or refractory follicular lymphoma that had been treated with idelalisib. In these patients, median progression-free survival was 7.1 months, and median overall survival was not reached. The committee concluded that the evidence in DELTA and the CUP was not adequate enough for using to determine how well patients on idelalisib fared compared with people who had not taken idelalisib.
## DELTA is a non-comparative safety study and is not designed to determine the clinical effectiveness of idelalisib compared with current NHS treatment
The committee discussed the lack of direct comparative evidence for idelalisib. The company explained that it had originally planned to develop a confirmatory randomised controlled trial after DELTA. However, the European Medicines Agency granted a marketing authorisation based on the non-comparative DELTA study. The company therefore chose not to pursue the planned studies of effectiveness of idelalisib in follicular lymphoma. The committee considered that this had resulted in an important gap in the evidence base for idelalisib, making it difficult to carry out an informed assessment of the effectiveness of idelalisib. It reflected that a randomised controlled trial in the intended population would help to resolve this. The committee concluded that the paucity of data, and the lack of comparative data, were key shortcomings to determining the clinical effectiveness of idelalisib compared with currently offered treatments in the NHS.
## It is unclear whether the DELTA population or the Compassionate Use Programme cohort more closely reflects clinical practice
Despite the absence of a controlled trial, the committee discussed the evidence presented by the company. The committee discussed whether the populations in DELTA and the CUP are generalisable to people who take idelalisib in clinical practice:
The committee questioned why only 79% (and not 100%) of patients in DELTA had cancer refractory to 2 or more lines of therapy. The company explained that some patients had had an anti‑CD20 monoclonal antibody and an alkylating agent together in the same line of therapy (rather than sequentially), which the company defined as a single treatment regimen. The committee accepted this.
The committee noted the difference in Eastern Cooperative Oncology Group (ECOG) performance status and Follicular Lymphoma International Prognostic Index (FLIPI) I and II scores between DELTA and the CUP. Notably, 8% of patients in DELTA had an ECOG score of 2 to 4 compared with 25% of patients in the CUP, reflecting poorer performance among patients in the CUP. The clinical experts stated that the ECOG performance status in the CUP more closely reflected clinical practice than that in DELTA.
The clinical experts noted that the time since completing the last therapy was shorter in DELTA than in the CUP, suggesting that patients in DELTA had a poorer prognosis.The committee agreed that the populations in DELTA and the CUP were different. The studies differed in design (for example, how they defined disease progression; see section 3.10). Also, patient and disease characteristics at baseline differed, with some suggesting a more favourable prognosis in DELTA than in the CUP, and others suggesting the opposite. The committee queried why the company had not chosen to combine the 2 studies. The company explained that it considered the DELTA data, being a trial, to be too different from clinical practice-based data. The company argued that the population enrolled in DELTA better reflected clinical practice. The committee did not accept the company's rationale for not combining the data and wondered why the company did not, for the same reason, find it inappropriate to compare DELTA with the Haematological Malignancy Research Network (HMRN, see section 3.8), a clinical practice-based cohort. The clinical experts suggested that the CUP cohort was more likely to reflect the intended UK treatment population because it was a 'real-world' study with patients from Britain and Ireland. However, the clinical experts acknowledged that such studies lack the methodological rigour typical of a clinical trial. The committee recognised that the company submitted data from the CUP in its original submission, but not in its response to the consultation, despite the committee having concluded that it would consider both studies in the appraisal consultation document. The committee concluded that it was unclear whether the DELTA population or the CUP cohort more closely reflected clinical practice and took both into account for decision making.
## Evidence of effectiveness for chemotherapy is limited because it does not provide enough information on individual regimens or best supportive care
Because the company had not done a controlled trial, it sourced evidence for comparators from a registry: the UK HMRN. This registry comprised a retrospective observational cohort. It included 26 patients with follicular lymphoma refractory to 2 previous lines of therapy, including rituximab and chemotherapy at first or second line, who had chemotherapy at third line. The committee noted that it was unclear whether the registry included a 'double-refractory' population and how many lines of chemotherapy each person had previously had. The committee was concerned that the HMRN population did not reflect the population defined for the current appraisal. The company did not have access to the data directly; instead, it requested analyses from the HMRN, based at the University of York. The company combined several comparators into a single chemotherapy comparator arm (see section 3.15). The original data cut (August 2013) submitted by the company for the committee's first meeting showed an estimated median progression-free survival of about 17 months, and a median overall survival of about 20 months. During consultation, the company submitted updated data based on a later data cut (August 2016), which showed that median overall survival was longer than the original data cut (detailed results are academic in confidence). The latest data cut had 34 patients, which the committee recognised as being a small number of patients; this number fell further in the matching analyses (see section 3.13 and section 3.15). The company explained that the analyses did not censor patients at transplantation. The committee understood that, because transplantation can improve prognosis (see section 3.4, not censoring patients at transplantation had the potential to invalidate clinical-effectiveness results. It acknowledged that it was likely that the HMRN was the only source of comparative data for the UK. Nevertheless, it concluded that the HMRN had limited value because it:
did not define the number of prior therapies each person had
did not provide information on individual chemotherapy regimens or best supportive care
was likely to differ from DELTA in ways that influenced patient outcomes.
## It is more likely that patients in DELTA would have a better prognosis than those in the HMRN
The company explained that it considered the DELTA population (that is, those having idelalisib) at baseline to have a worse prognosis than the HMRN population (that is, those having chemotherapy) at the time of reaching registry eligibility criteria. However, the clinical experts believed that the clinical practice-based HMRN population was likely to have a worse prognosis. The committee agreed that it was difficult to compare the 2 patient populations because of differences in baseline patient characteristics. It also agreed that the interplay of these differences made it difficult to judge which way overall population health would be biased. Either way, the committee appreciated that these differences could have confounded the association between treatment and survival. It considered the differences in how some variables had been defined between the 2 studies (see section 3.13), and that people in the HMRN had similar or worse disease in a shorter time from diagnosis. Based on these considerations, the committee concluded it more likely that patients in DELTA would have a better prognosis than those in the HMRN.
## It is appropriate to assume equal progression-free survival for chemotherapy and idelalisib, but progression-free survival should be taken from the HMRN
Based on the latest data for DELTA, idelalisib was associated with longer overall survival than was chemotherapy in the HMRN. However, these data showed that patients on idelalisib from 12 months onwards had a shorter progression-free survival than patients on chemotherapy. The committee agreed that shorter progression, then longer survival, was improbable. The company stated that it believed this counterintuitive result because of differences in the frequency with which each study measured disease progression. In both studies, progression-free survival was defined as 'time from initiation of treatment to date of first disease progression' or 'death from any cause'. However, in DELTA, patients had more regular scans compared with patients in the HMRN cohort; the company proposed that this is likely to have identified progression at an earlier stage for patients having idelalisib than having chemotherapy. The committee was not presented with data on the frequency of scanning in the HMRN cohort. The company stated that 'the HMRN dataset will systematically overpredict PFS in comparison to DELTA. Along with other issues of comparability across the two datasets, PFS comparison is rendered almost meaningless'. The ERG stated that this would have affected all methods of matching analyses submitted by the company (see section 3.12) equally because they all used progression-free survival from both samples. The company explained that the analyses did not account for stem cell transplantation before disease progression; specifically, it heard from the company that the analyses for progression-free survival did not censor patients at transplantation (see section 3.8). The committee considered that this may have biased the results. To address this issue, in some (but not all) of its analyses for cost effectiveness, the company assumed that the results for progression-free survival for chemotherapy and idelalisib were equivalent by using progression-free survival from DELTA in both treatment arms. The committee recognised that identifying progression at an earlier stage (for patients having idelalisib) was likely to have underestimated the treatment costs of idelalisib because people have idelalisib until disease progression (or unacceptable toxicities). The committee agreed that, in the absence of a trial, time to progression should reflect that seen in the NHS, that is, using data from the HMRN. The committee concluded that, in the absence of data, it was satisfied with the assumption that progression-free survival was equivalent between chemotherapy and idelalisib. However, it considered that the company should have taken estimates of progression-free survival from the HMRN, and not DELTA.
# Indirect treatment comparisons
## Comparisons with previous lines of therapy without clear methods do not give reliable estimates of effectiveness
In the absence of a head-to-head randomised comparison of idelalisib with chemotherapy, in its original submission, the company compared progression and survival on idelalisib with the last line of chemotherapy before idelalisib, for DELTA and the CUP. The company used the time to progression with the previous line of chemotherapy (second line) as a proxy for time to progression with chemotherapy at third line (that is, when idelalisib would be a treatment option). The committee heard at the first meeting that the company did not perform a paired matching analysis. The committee was aware that the company used data from the CUP to compare idelalisib with previous lines of therapy but, at the second meeting, the company stated that it did not have access to the CUP data. The committee discussed several issues around the analysis:
The ERG commented that this comparison should be considered with caution because of the potential bias from including only patients who survive to have idelalisib; these patients would have been healthier than the entire chemotherapy population that existed at the previous line of therapy. The committee also recognised that patients on second-line chemotherapy may be healthier than patients on third-line chemotherapy. The committee agreed that these were potential sources of bias.
The committee recognised that the fitness of a patient and the effectiveness of treatment could decline between 1 treatment line and the next. Therefore, comparing the idelalisib group with the group who previously had chemotherapy was not comparing like with like.
For DELTA, the data on the previous line of therapy were based on 'clinician recall' (because people entered the study at the point at which they would have idelalisib), which may have been subject to bias. The committee was aware that the definition of trial-based and historical progression may have differed, and that progression may be more quickly identified during a clinical trial when patients are actively monitored and scanned (see section 3.10). The committee recognised this would bias results against idelalisib.
The clinical experts recognised that it was difficult to draw conclusions on the comparative effect of idelalisib by looking retrospectively at previous lines of therapy, and more so in the CUP. This was because time to progression on idelalisib was already determined retrospectively, and treatment previous to that was even more distant in time.
For both studies, previous lines of therapy reflected a range of chemotherapeutic regimens, at a range of different points in the treatment pathway (up to fourteenth line). These regimens may differ from 1 another in clinical effectiveness and adverse effects, and may not be generalisable to the population in the appraisal.
The committee noted that DELTA began recruiting patients in 2011 from a range of countries. It recognised that chemotherapy options available for previous treatment in DELTA may have changed over time and may have differed in other countries. Therefore, the chemotherapy treatments used may not represent current UK clinical practice.
The committee recognised that this comparison did not compare the same patients with each other because the company had not done a paired matching analysis. The committee considered that a paired matching analysis would have minimised confounding.
The committee was aware that the company had not analysed idelalisib against the individual chemotherapy agents identified in the NICE scope. The committee was aware that many of these issues also applied to the matching comparisons with the HMRN data submitted by the company (see section 3.12). The committee concluded that, because the company's comparison with previous lines of therapy lacked clear methods and had multiple sources of bias, its results were not reliable.
## The company performed several matching indirect comparisons with the HMRN data
In response to the consultation, the company submitted the following matching indirect comparisons using updated data (see section 3.5 and section 3.8) from DELTA and the HMRN:
Unanchored matching adjusted indirect comparisons with the HMRN cohort (see section 3.8) including:
An 'updated' matching adjusted indirect comparison: the company matched individual patient-level data from the HMRN cohort to the population-level descriptive characteristics of patients in the DELTA study. This estimated the effects of chemotherapy in a DELTA-like population.
A 'reverse' matching adjusted indirect comparison: the company matched individual patient-level data from the DELTA study to the population-level descriptive characteristics of patients in the HMRN cohort. This estimated the effects of idelalisib in a HMRN-like population.
Propensity score matching analyses (see section 3.14):
With DELTA as the 'treated' group and the HMRN as the 'control' group: it matched individual patient-level data from the DELTA study to individual patient-level data from the HMRN cohort. This estimated the effects of chemotherapy in a DELTA-like population.
With the HMRN as the 'treated' group and DELTA as the 'control' group: it matched individual patient-level data from the HMRN cohort to individual patient-level data from the DELTA study. This estimated the effects of idelalisib in a HMRN-like population.The company submitted the propensity score analyses in response to the appraisal consultation document and because the committee had recognised that patient-level data were available from both the DELTA study and the HMRN cohort. The company submitted the 'reverse' matching adjusted indirect comparison in response to the statements in the appraisal consultation document from the ERG and committee, noting that estimating the effect of idelalisib in the HMRN (UK) population would provide more individual patient data, and better represent NHS clinical practice.
## The 'updated' matching adjusted indirect comparison is preferred over the 'reverse' comparison, although both are unreliable
The committee discussed the factors affecting prognosis that the 'updated' and 'reverse' matching adjusted indirect comparison analyses should have included (see section 3.12), and the sample sizes available. The committee was aware that it had not been presented with a systematic review of risk factors for progression and death. In addition to history of autologous stem cell transplantation (see section 3.4), the committee understood that there are other factors associated with progression and death. These include, but are not limited to, the components of FLIPI I and FLIPI II, notably: age, serum beta 2 microglobulin levels, bone marrow involvement, size of the largest involved lymph node, haemoglobin levels and the presence of bulky disease. Other factors include time in previous remission, time since completing the last therapy, comorbid conditions and previous chemotherapeutic agents. The clinical experts suggested that the FLIPI index is the best validated prognostic tool to use when diagnosing follicular lymphoma, but has limited value at third line. They proposed that a key prognostic indicator would be response to previous therapy, but this input was not captured in the variables chosen in the 'updated' matching adjusted indirect comparison. The company matched only 5 of 7 variables and assumed that these 5 accounted for all prognostic factors and treatment-effect modifiers. The committee was aware that a technical support document published by the Decision Support Unit recommends that, when only single-arm trial data are available, all the characteristics that could influence the outcomes of interest should be adjusted. However, increasing the number of matched characteristics reduced the effective sample size and the precision of the estimates, and the committee understood that the results were sensitive to this. For example, when the company removed the variable 'median time since diagnosis' from the analyses, estimated 2‑year overall survival fell by more than 20%. The committee also appreciated that there were unobserved differences between study populations that the analyses could not take into account. It noted that this would have biased the estimates of relative effectiveness if these unknown factors were associated with progression or death. The committee was satisfied that, in the 'reverse' matching adjusted indirect comparison, the company matched all 7 variables. However, in both 'updated' and 'reverse' comparisons, the committee noted that DELTA and the HMRN cohort defined 2 of the matched variables ('bulky disease' and 'time to diagnosis') differently, so the estimates of relative effectiveness from the 'updated' and 'reverse' comparison were likely to be biased. The committee was aware that the effective sample size for the 'reverse' matching adjusted indirect comparison was 26.7 people (26.7 represents a statistic rather than an actual number of people). The committee concluded that, although it preferred the 'updated' over the 'reverse' comparison, sparse data and potential confounding meant that the clinical-effectiveness results reflecting both were unreliable.
## Propensity score matching analysis is more reliable than the 'updated' and 'reverse' matching adjusted indirect comparisons, but all are problematic
In response to the consultation, the company submitted 2 analyses with propensity scores using individual patient-level data from both DELTA and the HMRN, and using both populations applied as the 'treated group' (see section 3.12). The company matched all 7 variables (see section 3.13). The committee considered that matching on bulky disease and 'time to diagnosis' caused problems because each study defined those variables differently (see section 3.13). The committee noted that the propensity score matching analyses excluded patients without a suitable match (50% of patients in DELTA), which reduced the idelalisib sample size to 39 (DELTA as 'treated group') and 35 (the HMRN as 'treated group'). It also noted that the company submitted only 1 of many methods that can be used for propensity score matching, the 'three-nearest-neighbour' matching method (that is, matching baseline characteristics to the 3 closest patients in the comparison group). The company did not provide a rationale for its choice, nor had it conducted sensitivity analyses using alternative methods. The ERG commented that this was an important limitation because using other methods could change the results. In addition, the ERG noted that the summary measures from DELTA and HMRN groups using propensity matching were not as similar at baseline as they were in the 'updated' and 'reverse' matching adjusted indirect comparisons. The committee recognised that propensity scoring matches individual patient-level data together, rather than matching individual patient-level data to the mean, as was done in the matching adjusted indirect comparisons. Therefore, it did not expect comparable baseline characteristics between groups after matching. The ERG explained that, although all the analyses had problems, it preferred the 'reverse' to the 'updated' matching adjusted indirect comparison and propensity score matching analyses. However, the committee noted that sample sizes in the analyses using propensity score matching were more balanced across treatment arms than in the matching adjusted indirect comparisons, although they were small. The committee agreed that, because propensity score analyses match individual patient data for both populations, they provide more precise estimates than those from matching adjusted indirect comparisons. Despite this, the committee concluded that analyses using propensity score matching were associated with high levels of uncertainty. It also concluded that the matching comparisons submitted by the company did not provide the committee with robust information to evaluate the relative effectiveness of idelalisib compared with chemotherapy or best supportive care.
## The 'blended' comparator assumes that different chemotherapeutic treatments are similarly effective and tolerated, but this assumption is not justified
The committee was aware that the NICE scope listed the chemotherapeutic agents separately, and heard from the clinical experts that the therapies are likely to differ in effectiveness and tolerability. It recognised that the company had combined treatments together, which reflected a 'blended' comparator. The committee considered that evidence for the effectiveness of separate chemotherapeutic agents might exist from the trials that provided evidence for using chemotherapy, or from registries other than the HMRN. The Cancer Drugs Fund clinical lead considered that currently used individual chemotherapy regimens would be based on controlled clinical trial evidence. However, the committee also considered that this evidence might be difficult to source. At the second meeting, the company explained that it had not identified other registries or trials providing information on individual chemotherapy regimens. It further explained that it chose not to collect this information from the HMRN cohort because the sample size was already small (n=34, based on the latest data cut). The committee recalled that clinicians did not consider the chemotherapeutic regimens to be equally effective or have the same profile of adverse effects (see section 3.2). It understood that there were practical issues associated with estimating the effects of individual chemotherapy regimens. However, it noted that it had not been presented with evidence that justified the company's 'blended' comparator assumption that chemotherapeutic agents in UK practice could be considered similarly effective and tolerated, and at the same costs.
## There are no data for best supportive care
The committee recognised that the company did not provide data to describe the natural history of disease in patients having best supportive care. The committee asked the company whether the HMRN cohort could provide this, or whether clinical trial data were available from control arms of clinical trials of chemotherapy. The committee was aware that the company did not provide clinical data with which to compare idelalisib with best supportive care. Even so, the company compared idelalisib with best supportive care in its cost-effectiveness analyses by relying on an assumption that patients would progress instantly in the absence of an active treatment (see section 3.18).
## The current analyses based on the data provided are insufficient
The committee appreciated the company's attempts to reduce uncertainty in determining the clinical effectiveness of idelalisib compared with chemotherapy. The company did this by submitting longer-term data from DELTA and the HMRN, and by conducting additional indirect analyses, in response to concerns identified by the committee in the appraisal consultation document. However, the committee noted several concerns with the additional data and indirect analyses:
The indirect analyses were sensitive to changes in assumptions, and did not confirm a difference between treatments (see section 3.13).
There were differences in the definition of key variables (see section 3.13) and outcomes (see section 3.10).
The company explained that it had not taken into account autologous stem cell transplantation before disease progression or death. The committee agreed this had the potential to invalidate results (see section 3.8).
In relation to the updated data it had submitted, the company stated that 'the HMRN dataset will systematically overpredict progression-free survival in comparison to DELTA. Along with other issues of comparability across the two datasets, progression-free survival comparison is rendered almost meaningless'. The ERG stated that the overprediction of progression-free survival would apply equally to all matching analyses because they all used progression-free survival from both samples (see section 3.10).
The committee noted its previous consideration that the company's decision not to pursue a randomised controlled trial of idelalisib in this population had left an important gap in the evidence base (see section 3.6).The committee appreciated statements from professional organisations and clinical experts that accepted the potential for idelalisib to extend life compared with current treatments for 'double-refractory' follicular lymphoma. A clinical expert suggested that idelalisib might prolong life by 12 months or more in some patients. However, a professional organisation suggested that estimating the extension to life with certainty is difficult. The committee acknowledged the efforts of the company, but noted that concerns about the comparative effectiveness evidence made it difficult to establish the benefit of idelalisib compared with chemotherapy or best supportive care (see section 3.14). It took this into account in its decision making.
# The company's economic models
## The model structures are appropriate for modelling
The company submitted 4 economic analyses using different model structures and sources of clinical data, which are summarised in table 1. In its models, the company used secondary endpoints (overall survival and progression-free survival) rather than the primary outcome from DELTA (overall response rate) to determine cost effectiveness.
Comparison
Idelalisib data source
Comparator data source
Model type
A (company base case)
DELTA
All chemotherapy combined: DELTA data from 'self-control' previous line of treatment as a proxy for current chemotherapy
Markov cohort – state transition
B
DELTA
All chemotherapy combined: matching adjusted survival data from chemotherapy regimens of the Haematological Malignancy Research Network cohort (either matching adjusted indirect comparison or propensity score matching analysis; see section 3.12)
Partitioned survival model
C
Data from the Compassionate Use Programme cohort and DELTA
All chemotherapy combined: time-to-progression data from 'self-control' previous line of treatment as a proxy for current chemotherapy
Markov cohort – state transition
D
DELTA
Best supportive care: no data (see section 3.16, company assumes instant disease progression
Markov cohort – state transition
Comparisons A, C and D reflected state transition models. In these, 'transition probabilities' determined the movements between states (clinical events) and time spent by patients in each state determined expected costs and quality-adjusted life years (QALYs). Comparison B used a 'partitioned survival analysis' approach in which survival curves (rather than transition probabilities) determined the proportion of patients in each state at each time point. The committee agreed in its first meeting that it would focus on comparisons A (the company's base case) and B; the company did not provide best supportive care data for comparison D. The committee noted that, in comparisons A and C, the company applied a 'hazard ratio' of 0.75 to adjust for the expected decline in the effectiveness of chemotherapy compared with idelalisib. This meant that, at each successive treatment line, patients would have expected their prognosis to worsen by 75% compared with the previous line of therapy. It also noted that the company had not justified its choice of the value of 0.75, which affected comparisons A and C to different extents. In its updated cost-effectiveness analysis submitted in response to the consultation, the company submitted results exclusively based on comparison B. It explained that, in its view, only this comparison could reflect the survival benefit of idelalisib after disease progression (see section 3.5). The committee preferred comparison B, but noted that all the comparisons were limited by:
sparse clinical data
no comparative evidence
no censoring for autologous stem cell transplantation
no comparison with or data on best supportive care
likely confounding (see section 3.9)
variables defined differently by study (see section 3.13)
using a blended comparator and the arbitrary choice of 0.75 to reflect the expected worsening in prognosis compared with previous line of therapy (see sections 3.8, 3.13, 3.14, 3.15 and 3.16).In response to the consultation, the company did not submit analyses for idelalisib compared with best supportive care, so the committee did not consider this further.
## The 'blended comparator' masks cost-ineffective treatments
The committee considered that using a blend of chemotherapeutic regimens (see section 3.15) as a comparator meant averaging the cost effectiveness of the treatments included, and potentially masked cost-ineffective individual treatments. The committee concluded that the cost effectiveness of idelalisib needed to reflect the comparison with each chemotherapy treatment individually.
# Utility values in the economic models
## There are no mapped utilities for the committee to consider
The company submitted utility values to reflect health-related quality of life from a published study (Wild et al. 2006), even though it had collected quality-of-life data in DELTA. The ERG submitted scenario analyses with alternative utility values from other published studies (Bec et al. 2014 and the GADOLIN trial for non-Hodgkin's indolent lymphoma). The clinical experts agreed that all values seemed reasonable because people with follicular lymphoma can expect a good quality of life once the bulk of the disease has decreased. The committee was aware that DELTA collected health-related quality-of-life data using the Functional Assessment of Cancer Therapy - Lymphoma (FACT‑Lym) instrument (an extension of FACT - General ). This has 15 questions specific to patients with lymphoma. It was also aware that there is a mapping algorithm to map from FACT‑G to EQ‑5D, which the ERG requested of the company at the clarification stage. The company did not provide the mapped utilities, arguing that it was not useful because there was no mapping algorithm that specifically matched FACT‑Lym to EQ‑5D. The company added that the mapped utilities would have been limited to the clinical symptoms captured in EQ‑5D. The committee expressed its interest in seeing the mapped utilities in the appraisal consultation document, but the company chose not to submit the values at the second meeting. The committee concluded that it would have liked to see mapped utility values to validate literature-derived values, but that this would not have overcome the other problems associated with the clinical evidence.
## Adverse effects with idelalisib are different than those with chemotherapy, but the adverse effects of individual chemotherapy regimens also differ
The committee noted the adverse effects in people having idelalisib outlined in the European Medicine Agency's risk management plan, which include severe drug-related colitis, pneumonitis and organising pneumonia, and serious infections. The company did not provide relative safety data for chemotherapy. The clinical experts commented that adverse effects with chemotherapy are qualitatively different to those with idelalisib, so it is difficult to compare the safety profiles. The clinical experts commented that idelalisib is generally well tolerated. The committee considered that the adverse effects of chemotherapy are unlikely to differ between haematological malignancies, and thought that data from other malignancies would be valuable. The company included adverse events as disutilities within all the economic models. These disutility values were based on various sources and estimating the incidence using DELTA. The company models assumed the same incidence of adverse effects for both idelalisib and chemotherapy. The committee noted that adverse event disutility is not a key driver in the model. It concluded that idelalisib is unlikely to have the same effect on quality of life because of an adverse effect as chemotherapy, which themselves differed by individual regimen, but that this is unlikely to markedly affect cost-effectiveness results.
# Cost-effectiveness estimates
## The company submitted several cost-effectiveness estimates
In its response to the consultation, the company submitted 3 deterministic incremental cost-effectiveness ratios (ICERs) for idelalisib compared with chemotherapy using comparison B (see section 3.18) incorporating a patient access scheme discount; probabilistic ICERs were broadly similar:
Using the updated matching adjusted indirect comparison data, and including the ERG's corrections to the model, resulted in an estimated ICER of £16,481 per QALY gained.
Using a propensity score matching analysis with the DELTA group as the treated group (based on updated data), and including the ERG's corrections to the model, with the assumption that progression-free survival with chemotherapy and idelalisib are equal (see section 3.10), resulted in an estimated ICER of £25,605 per QALY gained.
Using a propensity score matching analysis with the HMRN group as the treated group (based on updated data), and including the ERG's corrections to the model, with the assumption that progression-free survival with chemotherapy and idelalisib are equal (see section 3.10), resulted in an estimated ICER of £26,627 per QALY gained.
## The ERG carried out an exploratory cost-effectiveness analysis
The committee considered that all matching analyses (see section 3.13 and section 3.14) were associated with high levels of uncertainty. It therefore would have liked to see the cost-effectiveness results associated with all matching analyses, which it considered would help to explore the effect of clinical-effectiveness uncertainty on the cost-effectiveness results. The committee noted that the company had not submitted cost-effectiveness analyses using the 'reverse' matching adjusted indirect comparison (see section 3.12 and section 3.22), even after NICE requested this. The ERG was not able to estimate pseudo-patient-level data for the 'reverse' matching adjusted indirect comparison (to estimate parametric survival curves). This was because the company did not submit numbers at risk or survival curves, and declined to provide a model with the option to choose between matching characteristics. At the second committee meeting, the company stated it had not submitted cost-effectiveness results for the 'reverse' matching adjusted indirect comparison because they would have been based on clinically implausible effectiveness data, so the results would have added to the uncertainty. The company further stated that it submitted the results only for the 'updated' matching adjusted indirect comparison because it had submitted these at the first meeting. The ERG carried out an exploratory analysis to give a crude estimate of an ICER for the 'reverse' matching adjusted indirect comparison. This estimated an ICER of £86,161 per QALY gained, which is well above what NICE normally considers to be an effective use of NHS resources. The committee concluded that it would take into account the ERG's exploratory analysis in its decision making.
## The company's and ERG's estimates of cost effectiveness lack robustness
The committee stated that it considered propensity score matching analyses to be more reliable than matching adjusted indirect comparisons or 'reverse' matching adjusted indirect comparisons, but all had problems (see section 3.13). However, it would have preferred to see estimates from the company using all the submitted clinical-effectiveness estimates. The committee noted that the ERG's exploratory analysis contained all the uncertainties associated with the company's model in addition to potential confounding (see section 3.18). It also recalled all the limitations associated with propensity score matching analyses (see section 3.14). It considered that the cost-effectiveness estimates lacked robustness and concluded that it needed to account for this in its decision making.
## Idelalisib has not been shown to represent a cost-effective use of NHS resources
The committee appreciated that the company had submitted new clinical data and attempted additional indirect analyses. However, the committee noted that these additional data did not include any comparative evidence that appropriately adjusted for potential confounders. The analyses presented other problems including sparse data, matching on variables defined differently and analyses that did not censor patients having a transplant. The committee also appreciated that the ERG considered that, rather than reducing uncertainty, the company's additional data and analyses had instead increased uncertainty. The committee considered whether information from the clinical experts could inform estimates of overall survival with the new treatment (see section 3.17 and section 3.26). However, the company provided no data to support any estimates. Therefore, the committee concluded that idelalisib was not considered to represent a cost-effective use of NHS resource because of the range of ICERs presented (between £16,481 and £86,161 per QALY gained) and its concerns with the quality of the evidence.
# End of life
## End-of-life criteria are not met
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal:
The committee discussed whether the life expectancy using standard care was likely to be less than 24 months. It was aware that probabilistic analyses submitted by the company provided mean undiscounted life years for chemotherapy of more than 24 months (ranging from 6 to 87 months). Other model outputs that used different matching analyses also estimated that chemotherapy would result in a mean life expectancy of at least 2 years. Therefore, many of the company's own analyses predicted a life expectancy longer than 24 months. The committee was aware that, given the concerns it had about the economic model, any outputs would have to be interpreted with a high level of caution. In the absence of robust modelled data, the committee considered expert clinical opinion. The company reported that, according to the clinical community, life expectancy would be less than 12 months once a patient's cancer becomes refractory to chemotherapy. A letter (submitted by the company) gathering the opinion of 15 clinical experts suggested that disease progression within 24 months of first relapse is associated with an increased risk of death. Additionally, a clinical expert estimated that life expectancy for patients having idelalisib could be 12 months on average. The committee was aware that no data were offered to support these figures. Therefore, the committee went on to consider the unadjusted data from the HMRN. It noted these data showed that a high proportion of patients survived for a median of 2 years, and that mean life expectancy would be longer. The committee weighed up all the available data and considered that, currently, the most reliable source of evidence from which to make its judgement was the HMRN data. It concluded that the short life-expectancy criterion had not been met.
The committee discussed the criterion of whether the technology provided an extension to life, with a mean of at least 3 months of life compared with usual care. The committee noted that the modelled undiscounted incremental gains were more than 3 months with idelalisib compared with chemotherapy in all the analyses provided. It noted that a clinical expert suggested that it could be more than 3 months. However, no explanation or further data were given to support this figure. The committee also noted that the estimated undiscounted incremental life years in all analyses were more than 3 months with idelalisib compared with chemotherapy. However, given its concerns about the modelling and model inputs, the committee did not consider that the model generated a valid estimate of the mean extension to life with idelalisib. The committee was aware that NICE's guide to the methods of technology appraisal notes state that the appraisal committee must be satisfied that the 'the estimates of the extension to life are sufficiently robust'. Therefore, it concluded that, although idelalisib might prolong life, the magnitude of this is highly uncertain. Because the short life-expectancy criterion had not been met, the committee concluded that idelalisib could not be considered a life-extending treatment at the end of life.
# Cancer Drugs Fund
## Idelalisib is not a candidate for the Cancer Drugs Fund
Having concluded that idelalisib could not be recommended for routine use, the committee then considered whether it could be recommended for treating follicular lymphoma within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It noted that, at the second meeting, the company had expressed an interest in providing idelalisib through the Cancer Drugs Fund. The company confirmed that there are no ongoing comparative trials to provide more robust, controlled evidence. The committee highlighted that, because no evidence showed that idelalisib improved length or quality of life, it encouraged research comparing idelalisib with individual chemotherapeutic regimens. The committee appreciated that the Cancer Drugs Fund is designed to resolve uncertainties, and that the key uncertainty in this appraisal was about the assumptions surrounding the comparative effectiveness of idelalisib with chemotherapy. It was aware that the Cancer Drugs Fund could collect data on the intervention (idelalisib), but not the comparator (chemotherapy), so would not resolve this uncertainty. Also, the committee had not seen reliable evidence that demonstrated idelalisib had 'plausible potential' to be cost effective (see section 3.24). It concluded that idelalisib could not be recommended for use within the Cancer Drugs Fund as an option for follicular lymphoma that had not responded to 2 previous lines of therapy in adults.
## The Cancer Drugs Fund would not address the key uncertainty in the idelalisib appraisal
In its response to the appraisal consultation document, the company referred to NICE's technology appraisal guidance on daratumumab monotherapy, which was recommended through the Cancer Drugs Fund to treat relapsed and refractory multiple myeloma. It argued there was a parallel between the 2 appraisals because clinical evidence for daratumumab was limited to single-arm trials and an unanchored matching adjusted indirect comparison. The committee recalled that it had recommended daratumumab through the Cancer Drugs Fund because an Early Access programme is collecting data that have the potential to reduce several uncertainties identified by the committee (such as trial generalisability and place in the treatment pathway). The committee reiterated that the key uncertainty in the idelalisib appraisal was about the assumptions and analyses surrounding the comparative effectiveness, and the effectiveness and adverse effects associated with individual chemotherapeutic regimens, and that the Cancer Drugs Fund could not address these issues.
# Innovation
## Idelalisib is potentially innovative
The committee noted that idelalisib is innovative in that it has a different mechanism of action to other available treatments for 'double-refractory' follicular lymphoma, and addresses an area of unmet clinical need (see section 3.1). The committee noted comments from the clinical experts that this different mechanism of action might bring psychological benefits for people reluctant to have more chemotherapy. It also noted that no evidence had been submitted to support this. The committee agreed that it could not determine whether the model captured quality-of-life improvements. It also agreed that an oral drug was preferable to an intravenous one. The committee concluded that idelalisib potentially reflects an innovative step change in treatment, but that it had not been presented with evidence to establish this.
|
{'Recommendations': 'Idelalisib is not recommended, within its marketing authorisation, for treating follicular lymphoma that has not responded to 2\xa0prior lines of treatment in adults.\n\nThis recommendation is not intended to affect treatment with idelalisib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThe options after 2\xa0lines of treatment for follicular lymphoma in the NHS include a range of chemotherapy treatments. The choice of the specific treatment depends on what the person has had already.\n\nIdelalisib has not been compared directly with current individual chemotherapeutic treatments. There are several complex indirect comparisons of idelalisib, but these are based on sparse data and have other problems. So, it is unclear whether idelalisib is better than individual chemotherapeutic regimens currently offered by the NHS and, if so, by how much.\n\nThere is a wide range of cost-effectiveness estimates but, because the evidence is weak, idelalisib is not considered to represent a cost-effective use of NHS resources. Therefore, idelalisib cannot be recommended for routine use in the NHS.\n\nIdelalisib cannot be recommended for inclusion in the Cancer Drugs Fund. This is because data collected in the Cancer Drugs Fund cannot resolve the key problems determining whether idelalisib is more effective that chemotherapy, nor document the adverse effects associated with individual chemotherapeutic regimens.', 'Information about idelalisib': "Marketing authorisation indication\n\nIdelalisib (Zydelig, Gilead) has a marketing authorisation 'as monotherapy for the treatment of adult patients with follicular lymphoma (FL) that is refractory to two prior lines of treatment'.\n\nDosage in the marketing authorisation\n\nIdelalisib is administered orally at a dose of 150\xa0mg, twice daily. Treatment is continued until disease progression or unacceptable toxicity.\n\nPrice\n\nThe list price for idelalisib is £3,114.75 per pack of 60\xa0x 150\xa0mg film-coated tablets (excluding VAT, company submission).\n\nThe company has a commercial arrangement for idelalisib, which would apply if the technology had been recommended.", 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by Gilead and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## This appraisal focuses on idelalisib as a treatment used after an anti‑CD20 monoclonal antibody and an alkylating agent\n\nIdelalisib is an oral treatment for follicular lymphoma. The marketing authorisation specifies a population with follicular lymphoma that is 'refractory to 2\xa0prior lines of treatment'. However, the committee noted that the clinical evidence for idelalisib included a population in which there was a wide range in the numbers of prior chemotherapeutic regimens previously used by patients. Furthermore, the committee noted that the population considered in the company's submission was narrower than the population specified by the marketing authorisation, which is 'double-refractory'. This means that the follicular lymphoma has not responded, or showed only a limited response, to at least 2\xa0previous treatments. The company specified that the previous treatments had to include an anti‑CD20 monoclonal antibody (rituximab or obinutuzumab) and chemotherapy containing an alkylating agent (for example, cyclophosphamide). The clinical experts considered this double-refractory population to have an unmet need for treatment options. The committee agreed with the company that idelalisib is likely to be used after an anti‑CD20 monoclonal antibody and an alkylating agent.\n\n## There is no single standard-of-care chemotherapy for the population in this appraisal\n\nIn the population that would be offered idelalisib (see section\xa03.1), most people are currently offered chemotherapy including (as listed in the NICE scope) cyclophosphamide-containing regimens, fludarabine-containing regimens, bendamustine and chlorambucil. The clinical experts explained that these vary in effectiveness and toxicity. The choice of chemotherapy regimen depends on individual circumstances, and takes into account previous chemotherapy, plus clinician and patient preference. Because of this, there is no single standard-of-care chemotherapy regimen in this population. The committee concluded that all the chemotherapeutic regimens listed in the scope were appropriate comparators.\n\n## Best supportive care is also a comparator for idelalisib\n\nThe clinical experts stated that, after second-line treatment, people who could not have chemotherapy would be offered best supportive care instead. The clinical experts stated that some of those people could take idelalisib because it has a different toxicity profile to chemotherapy. So, while people may not tolerate the specific adverse effects of chemotherapy, they may tolerate those of idelalisib. The committee concluded that best supportive care is an option and a relevant comparator for people who cannot have chemotherapy, but who can take idelalisib.\n\n## The effect of autologous stem cell transplantation after idelalisib or chemotherapy should be considered\n\nThe clinical experts stated that response to second-line treatment is consolidated with autologous stem cell transplantation in people who are considered fit enough, in line with NICE's guideline on non-Hodgkin's lymphoma: diagnosis and management. They also noted that, if a patient was healthy, autologous stem cell transplantation would be considered at later lines of therapy, as soon as the cancer responded to treatment. The clinical experts considered that autologous stem cell transplantation can improve prognosis, and that it could be used after idelalisib. The committee concluded that autologous stem cell transplantation was not a comparator to idelalisib, but that it was possible to use idelalisib as a bridge to autologous stem cell transplantation if there was a sufficient response to idelalisib. It also understood that patients could have a transplant before disease progression. The committee further concluded that it would need to consider the effects of autologous stem cell transplantation used after idelalisib or chemotherapy in the clinical- and cost-effectiveness results provided by the company.\n\n# Clinical evidence\n\n## There is no trial evidence on how much better idelalisib is compared with current clinical practice\n\nThe key clinical evidence for idelalisib came from the single-arm phase\xa0II DELTA study. This study included 125\xa0patients with indolent (slowly growing) non-Hodgkin's lymphoma, 72\xa0of whom had follicular lymphoma refractory to 2\xa0or more lines of treatment. The primary outcome measured overall response rate. Overall survival and progression-free survival were among the secondary outcomes. DELTA had no control group; all patients in the study had idelalisib. The committee understood that this study was designed to show that idelalisib was a safe treatment. It also understood that the company had not carried out further effectiveness trials planned to support its application for a marketing authorisation (see section\xa03.6), which the European Medicines Agency granted on the basis of the DELTA study. The data from DELTA first provided by the company (cut-off date June 2015) showed an overall response rate of 55.6% and a median progression-free survival of 11.0\xa0months; median overall survival was not reached, but the company estimated it to be 38.1\xa0months. During consultation, the company submitted updated data based on a later cut-off date (August 2018); they showed that the median overall survival result was better than the company's original estimate (results are academic in confidence). The company stated that the latest data suggested that the overall survival benefit was largely as a result of survival after the cancer had progressed. The company supplemented the DELTA study with another source of evidence for idelalisib: the Compassionate Use Programme (CUP). This provided retrospective observational data from patients with follicular lymphoma having compassionate treatment in the UK and Ireland. The company took a subset of 79\xa0patients with relapsed or refractory follicular lymphoma that had been treated with idelalisib. In these patients, median progression-free survival was 7.1\xa0months, and median overall survival was not reached. The committee concluded that the evidence in DELTA and the CUP was not adequate enough for using to determine how well patients on idelalisib fared compared with people who had not taken idelalisib.\n\n## DELTA is a non-comparative safety study and is not designed to determine the clinical effectiveness of idelalisib compared with current NHS treatment\n\nThe committee discussed the lack of direct comparative evidence for idelalisib. The company explained that it had originally planned to develop a confirmatory randomised controlled trial after DELTA. However, the European Medicines Agency granted a marketing authorisation based on the non-comparative DELTA study. The company therefore chose not to pursue the planned studies of effectiveness of idelalisib in follicular lymphoma. The committee considered that this had resulted in an important gap in the evidence base for idelalisib, making it difficult to carry out an informed assessment of the effectiveness of idelalisib. It reflected that a randomised controlled trial in the intended population would help to resolve this. The committee concluded that the paucity of data, and the lack of comparative data, were key shortcomings to determining the clinical effectiveness of idelalisib compared with currently offered treatments in the NHS.\n\n## It is unclear whether the DELTA population or the Compassionate Use Programme cohort more closely reflects clinical practice\n\nDespite the absence of a controlled trial, the committee discussed the evidence presented by the company. The committee discussed whether the populations in DELTA and the CUP are generalisable to people who take idelalisib in clinical practice:\n\nThe committee questioned why only 79% (and not 100%) of patients in DELTA had cancer refractory to 2\xa0or more lines of therapy. The company explained that some patients had had an anti‑CD20 monoclonal antibody and an alkylating agent together in the same line of therapy (rather than sequentially), which the company defined as a single treatment regimen. The committee accepted this.\n\nThe committee noted the difference in Eastern Cooperative Oncology Group (ECOG) performance status and Follicular Lymphoma International Prognostic Index (FLIPI) I\xa0and\xa0II scores between DELTA and the CUP. Notably, 8% of patients in DELTA had an ECOG score of 2\xa0to\xa04 compared with 25% of patients in the CUP, reflecting poorer performance among patients in the CUP. The clinical experts stated that the ECOG performance status in the CUP more closely reflected clinical practice than that in DELTA.\n\nThe clinical experts noted that the time since completing the last therapy was shorter in DELTA than in the CUP, suggesting that patients in DELTA had a poorer prognosis.The committee agreed that the populations in DELTA and the CUP were different. The studies differed in design (for example, how they defined disease progression; see section\xa03.10). Also, patient and disease characteristics at baseline differed, with some suggesting a more favourable prognosis in DELTA than in the CUP, and others suggesting the opposite. The committee queried why the company had not chosen to combine the 2\xa0studies. The company explained that it considered the DELTA data, being a trial, to be too different from clinical practice-based data. The company argued that the population enrolled in DELTA better reflected clinical practice. The committee did not accept the company's rationale for not combining the data and wondered why the company did not, for the same reason, find it inappropriate to compare DELTA with the Haematological Malignancy Research Network (HMRN, see section\xa03.8), a clinical practice-based cohort. The clinical experts suggested that the CUP cohort was more likely to reflect the intended UK treatment population because it was a 'real-world' study with patients from Britain and Ireland. However, the clinical experts acknowledged that such studies lack the methodological rigour typical of a clinical trial. The committee recognised that the company submitted data from the CUP in its original submission, but not in its response to the consultation, despite the committee having concluded that it would consider both studies in the appraisal consultation document. The committee concluded that it was unclear whether the DELTA population or the CUP cohort more closely reflected clinical practice and took both into account for decision making.\n\n## Evidence of effectiveness for chemotherapy is limited because it does not provide enough information on individual regimens or best supportive care\n\nBecause the company had not done a controlled trial, it sourced evidence for comparators from a registry: the UK HMRN. This registry comprised a retrospective observational cohort. It included 26\xa0patients with follicular lymphoma refractory to 2\xa0previous lines of therapy, including rituximab and chemotherapy at first or second line, who had chemotherapy at third line. The committee noted that it was unclear whether the registry included a 'double-refractory' population and how many lines of chemotherapy each person had previously had. The committee was concerned that the HMRN population did not reflect the population defined for the current appraisal. The company did not have access to the data directly; instead, it requested analyses from the HMRN, based at the University of York. The company combined several comparators into a single chemotherapy comparator arm (see section\xa03.15). The original data cut (August 2013) submitted by the company for the committee's first meeting showed an estimated median progression-free survival of about 17\xa0months, and a median overall survival of about 20\xa0months. During consultation, the company submitted updated data based on a later data cut (August 2016), which showed that median overall survival was longer than the original data cut (detailed results are academic in confidence). The latest data cut had 34\xa0patients, which the committee recognised as being a small number of patients; this number fell further in the matching analyses (see section 3.13 and\xa0section 3.15). The company explained that the analyses did not censor patients at transplantation. The committee understood that, because transplantation can improve prognosis (see section\xa03.4, not censoring patients at transplantation had the potential to invalidate clinical-effectiveness results. It acknowledged that it was likely that the HMRN was the only source of comparative data for the UK. Nevertheless, it concluded that the HMRN had limited value because it:\n\ndid not define the number of prior therapies each person had\n\ndid not provide information on individual chemotherapy regimens or best supportive care\n\nwas likely to differ from DELTA in ways that influenced patient outcomes.\n\n## It is more likely that patients in DELTA would have a better prognosis than those in the HMRN\n\nThe company explained that it considered the DELTA population (that is, those having idelalisib) at baseline to have a worse prognosis than the HMRN population (that is, those having chemotherapy) at the time of reaching registry eligibility criteria. However, the clinical experts believed that the clinical practice-based HMRN population was likely to have a worse prognosis. The committee agreed that it was difficult to compare the 2\xa0patient populations because of differences in baseline patient characteristics. It also agreed that the interplay of these differences made it difficult to judge which way overall population health would be biased. Either way, the committee appreciated that these differences could have confounded the association between treatment and survival. It considered the differences in how some variables had been defined between the 2\xa0studies (see section\xa03.13), and that people in the HMRN had similar or worse disease in a shorter time from diagnosis. Based on these considerations, the committee concluded it more likely that patients in DELTA would have a better prognosis than those in the HMRN.\n\n## It is appropriate to assume equal progression-free survival for chemotherapy and idelalisib, but progression-free survival should be taken from the HMRN\n\nBased on the latest data for DELTA, idelalisib was associated with longer overall survival than was chemotherapy in the HMRN. However, these data showed that patients on idelalisib from 12\xa0months onwards had a shorter progression-free survival than patients on chemotherapy. The committee agreed that shorter progression, then longer survival, was improbable. The company stated that it believed this counterintuitive result because of differences in the frequency with which each study measured disease progression. In both studies, progression-free survival was defined as 'time from initiation of treatment to date of first disease progression' or 'death from any cause'. However, in DELTA, patients had more regular scans compared with patients in the HMRN cohort; the company proposed that this is likely to have identified progression at an earlier stage for patients having idelalisib than having chemotherapy. The committee was not presented with data on the frequency of scanning in the HMRN cohort. The company stated that 'the HMRN dataset will systematically overpredict PFS [progression-free survival] in comparison to DELTA. Along with other issues of comparability across the two datasets, PFS comparison is rendered almost meaningless'. The ERG stated that this would have affected all methods of matching analyses submitted by the company (see section\xa03.12) equally because they all used progression-free survival from both samples. The company explained that the analyses did not account for stem cell transplantation before disease progression; specifically, it heard from the company that the analyses for progression-free survival did not censor patients at transplantation (see section\xa03.8). The committee considered that this may have biased the results. To address this issue, in some (but not all) of its analyses for cost effectiveness, the company assumed that the results for progression-free survival for chemotherapy and idelalisib were equivalent by using progression-free survival from DELTA in both treatment arms. The committee recognised that identifying progression at an earlier stage (for patients having idelalisib) was likely to have underestimated the treatment costs of idelalisib because people have idelalisib until disease progression (or unacceptable toxicities). The committee agreed that, in the absence of a trial, time to progression should reflect that seen in the NHS, that is, using data from the HMRN. The committee concluded that, in the absence of data, it was satisfied with the assumption that progression-free survival was equivalent between chemotherapy and idelalisib. However, it considered that the company should have taken estimates of progression-free survival from the HMRN, and not DELTA.\n\n# Indirect treatment comparisons\n\n## Comparisons with previous lines of therapy without clear methods do not give reliable estimates of effectiveness\n\nIn the absence of a head-to-head randomised comparison of idelalisib with chemotherapy, in its original submission, the company compared progression and survival on idelalisib with the last line of chemotherapy before idelalisib, for DELTA and the CUP. The company used the time to progression with the previous line of chemotherapy (second line) as a proxy for time to progression with chemotherapy at third line (that is, when idelalisib would be a treatment option). The committee heard at the first meeting that the company did not perform a paired matching analysis. The committee was aware that the company used data from the CUP to compare idelalisib with previous lines of therapy but, at the second meeting, the company stated that it did not have access to the CUP data. The committee discussed several issues around the analysis:\n\nThe ERG commented that this comparison should be considered with caution because of the potential bias from including only patients who survive to have idelalisib; these patients would have been healthier than the entire chemotherapy population that existed at the previous line of therapy. The committee also recognised that patients on second-line chemotherapy may be healthier than patients on third-line chemotherapy. The committee agreed that these were potential sources of bias.\n\nThe committee recognised that the fitness of a patient and the effectiveness of treatment could decline between 1\xa0treatment line and the next. Therefore, comparing the idelalisib group with the group who previously had chemotherapy was not comparing like with like.\n\nFor DELTA, the data on the previous line of therapy were based on 'clinician recall' (because people entered the study at the point at which they would have idelalisib), which may have been subject to bias. The committee was aware that the definition of trial-based and historical progression may have differed, and that progression may be more quickly identified during a clinical trial when patients are actively monitored and scanned (see section\xa03.10). The committee recognised this would bias results against idelalisib.\n\nThe clinical experts recognised that it was difficult to draw conclusions on the comparative effect of idelalisib by looking retrospectively at previous lines of therapy, and more so in the CUP. This was because time to progression on idelalisib was already determined retrospectively, and treatment previous to that was even more distant in time.\n\nFor both studies, previous lines of therapy reflected a range of chemotherapeutic regimens, at a range of different points in the treatment pathway (up to fourteenth line). These regimens may differ from 1\xa0another in clinical effectiveness and adverse effects, and may not be generalisable to the population in the appraisal.\n\nThe committee noted that DELTA began recruiting patients in 2011 from a range of countries. It recognised that chemotherapy options available for previous treatment in DELTA may have changed over time and may have differed in other countries. Therefore, the chemotherapy treatments used may not represent current UK clinical practice.\n\nThe committee recognised that this comparison did not compare the same patients with each other because the company had not done a paired matching analysis. The committee considered that a paired matching analysis would have minimised confounding.\n\nThe committee was aware that the company had not analysed idelalisib against the individual chemotherapy agents identified in the NICE scope. The committee was aware that many of these issues also applied to the matching comparisons with the HMRN data submitted by the company (see section\xa03.12). The committee concluded that, because the company's comparison with previous lines of therapy lacked clear methods and had multiple sources of bias, its results were not reliable.\n\n## The company performed several matching indirect comparisons with the HMRN data\n\nIn response to the consultation, the company submitted the following matching indirect comparisons using updated data (see section 3.5 and section\xa03.8) from DELTA and the HMRN:\n\nUnanchored matching adjusted indirect comparisons with the HMRN cohort (see section\xa03.8) including:\n\n\n\nAn 'updated' matching adjusted indirect comparison: the company matched individual patient-level data from the HMRN cohort to the population-level descriptive characteristics of patients in the DELTA study. This estimated the effects of chemotherapy in a DELTA-like population.\n\nA 'reverse' matching adjusted indirect comparison: the company matched individual patient-level data from the DELTA study to the population-level descriptive characteristics of patients in the HMRN cohort. This estimated the effects of idelalisib in a HMRN-like population.\n\n\n\nPropensity score matching analyses (see section\xa03.14):\n\n\n\nWith DELTA as the 'treated' group and the HMRN as the 'control' group: it matched individual patient-level data from the DELTA study to individual patient-level data from the HMRN cohort. This estimated the effects of chemotherapy in a DELTA-like population.\n\nWith the HMRN as the 'treated' group and DELTA as the 'control' group: it matched individual patient-level data from the HMRN cohort to individual patient-level data from the DELTA study. This estimated the effects of idelalisib in a HMRN-like population.The company submitted the propensity score analyses in response to the appraisal consultation document and because the committee had recognised that patient-level data were available from both the DELTA study and the HMRN cohort. The company submitted the 'reverse' matching adjusted indirect comparison in response to the statements in the appraisal consultation document from the ERG and committee, noting that estimating the effect of idelalisib in the HMRN (UK) population would provide more individual patient data, and better represent NHS clinical practice.\n\n\n\n## The 'updated' matching adjusted indirect comparison is preferred over the 'reverse' comparison, although both are unreliable\n\nThe committee discussed the factors affecting prognosis that the 'updated' and 'reverse' matching adjusted indirect comparison analyses should have included (see section\xa03.12), and the sample sizes available. The committee was aware that it had not been presented with a systematic review of risk factors for progression and death. In addition to history of autologous stem cell transplantation (see section\xa03.4), the committee understood that there are other factors associated with progression and death. These include, but are not limited to, the components of FLIPI\xa0I and FLIPI\xa0II, notably: age, serum beta\xa02 microglobulin levels, bone marrow involvement, size of the largest involved lymph node, haemoglobin levels and the presence of bulky disease. Other factors include time in previous remission, time since completing the last therapy, comorbid conditions and previous chemotherapeutic agents. The clinical experts suggested that the FLIPI index is the best validated prognostic tool to use when diagnosing follicular lymphoma, but has limited value at third line. They proposed that a key prognostic indicator would be response to previous therapy, but this input was not captured in the variables chosen in the 'updated' matching adjusted indirect comparison. The company matched only 5\xa0of\xa07 variables and assumed that these 5\xa0accounted for all prognostic factors and treatment-effect modifiers. The committee was aware that a technical support document published by the Decision Support Unit recommends that, when only single-arm trial data are available, all the characteristics that could influence the outcomes of interest should be adjusted. However, increasing the number of matched characteristics reduced the effective sample size and the precision of the estimates, and the committee understood that the results were sensitive to this. For example, when the company removed the variable 'median time since diagnosis' from the analyses, estimated 2‑year overall survival fell by more than 20%. The committee also appreciated that there were unobserved differences between study populations that the analyses could not take into account. It noted that this would have biased the estimates of relative effectiveness if these unknown factors were associated with progression or death. The committee was satisfied that, in the 'reverse' matching adjusted indirect comparison, the company matched all 7\xa0variables. However, in both 'updated' and 'reverse' comparisons, the committee noted that DELTA and the HMRN cohort defined 2\xa0of the matched variables ('bulky disease' and 'time to diagnosis') differently, so the estimates of relative effectiveness from the 'updated' and 'reverse' comparison were likely to be biased. The committee was aware that the effective sample size for the 'reverse' matching adjusted indirect comparison was 26.7\xa0people (26.7\xa0represents a statistic rather than an actual number of people). The committee concluded that, although it preferred the 'updated' over the 'reverse' comparison, sparse data and potential confounding meant that the clinical-effectiveness results reflecting both were unreliable.\n\n## Propensity score matching analysis is more reliable than the 'updated' and 'reverse' matching adjusted indirect comparisons, but all are problematic\n\nIn response to the consultation, the company submitted 2\xa0analyses with propensity scores using individual patient-level data from both DELTA and the HMRN, and using both populations applied as the 'treated group' (see section\xa03.12). The company matched all 7\xa0variables (see section\xa03.13). The committee considered that matching on bulky disease and 'time to diagnosis' caused problems because each study defined those variables differently (see section\xa03.13). The committee noted that the propensity score matching analyses excluded patients without a suitable match (50% of patients in DELTA), which reduced the idelalisib sample size to\xa039 (DELTA as 'treated group') and\xa035 (the HMRN as 'treated group'). It also noted that the company submitted only 1\xa0of many methods that can be used for propensity score matching, the 'three-nearest-neighbour' matching method (that is, matching baseline characteristics to the 3\xa0closest patients in the comparison group). The company did not provide a rationale for its choice, nor had it conducted sensitivity analyses using alternative methods. The ERG commented that this was an important limitation because using other methods could change the results. In addition, the ERG noted that the summary measures from DELTA and HMRN groups using propensity matching were not as similar at baseline as they were in the 'updated' and 'reverse' matching adjusted indirect comparisons. The committee recognised that propensity scoring matches individual patient-level data together, rather than matching individual patient-level data to the mean, as was done in the matching adjusted indirect comparisons. Therefore, it did not expect comparable baseline characteristics between groups after matching. The ERG explained that, although all the analyses had problems, it preferred the 'reverse' to the 'updated' matching adjusted indirect comparison and propensity score matching analyses. However, the committee noted that sample sizes in the analyses using propensity score matching were more balanced across treatment arms than in the matching adjusted indirect comparisons, although they were small. The committee agreed that, because propensity score analyses match individual patient data for both populations, they provide more precise estimates than those from matching adjusted indirect comparisons. Despite this, the committee concluded that analyses using propensity score matching were associated with high levels of uncertainty. It also concluded that the matching comparisons submitted by the company did not provide the committee with robust information to evaluate the relative effectiveness of idelalisib compared with chemotherapy or best supportive care.\n\n## The 'blended' comparator assumes that different chemotherapeutic treatments are similarly effective and tolerated, but this assumption is not justified\n\nThe committee was aware that the NICE scope listed the chemotherapeutic agents separately, and heard from the clinical experts that the therapies are likely to differ in effectiveness and tolerability. It recognised that the company had combined treatments together, which reflected a 'blended' comparator. The committee considered that evidence for the effectiveness of separate chemotherapeutic agents might exist from the trials that provided evidence for using chemotherapy, or from registries other than the HMRN. The Cancer Drugs Fund clinical lead considered that currently used individual chemotherapy regimens would be based on controlled clinical trial evidence. However, the committee also considered that this evidence might be difficult to source. At the second meeting, the company explained that it had not identified other registries or trials providing information on individual chemotherapy regimens. It further explained that it chose not to collect this information from the HMRN cohort because the sample size was already small (n=34, based on the latest data cut). The committee recalled that clinicians did not consider the chemotherapeutic regimens to be equally effective or have the same profile of adverse effects (see section\xa03.2). It understood that there were practical issues associated with estimating the effects of individual chemotherapy regimens. However, it noted that it had not been presented with evidence that justified the company's 'blended' comparator assumption that chemotherapeutic agents in UK practice could be considered similarly effective and tolerated, and at the same costs.\n\n## There are no data for best supportive care\n\nThe committee recognised that the company did not provide data to describe the natural history of disease in patients having best supportive care. The committee asked the company whether the HMRN cohort could provide this, or whether clinical trial data were available from control arms of clinical trials of chemotherapy. The committee was aware that the company did not provide clinical data with which to compare idelalisib with best supportive care. Even so, the company compared idelalisib with best supportive care in its cost-effectiveness analyses by relying on an assumption that patients would progress instantly in the absence of an active treatment (see section\xa03.18).\n\n## The current analyses based on the data provided are insufficient\n\nThe committee appreciated the company's attempts to reduce uncertainty in determining the clinical effectiveness of idelalisib compared with chemotherapy. The company did this by submitting longer-term data from DELTA and the HMRN, and by conducting additional indirect analyses, in response to concerns identified by the committee in the appraisal consultation document. However, the committee noted several concerns with the additional data and indirect analyses:\n\nThe indirect analyses were sensitive to changes in assumptions, and did not confirm a difference between treatments (see section\xa03.13).\n\nThere were differences in the definition of key variables (see section\xa03.13) and outcomes (see section\xa03.10).\n\nThe company explained that it had not taken into account autologous stem cell transplantation before disease progression or death. The committee agreed this had the potential to invalidate results (see section\xa03.8).\n\nIn relation to the updated data it had submitted, the company stated that 'the HMRN dataset will systematically overpredict progression-free survival in comparison to DELTA. Along with other issues of comparability across the two datasets, progression-free survival comparison [between DELTA and the HMRN] is rendered almost meaningless'. The ERG stated that the overprediction of progression-free survival would apply equally to all matching analyses because they all used progression-free survival from both samples (see section\xa03.10).\n\nThe committee noted its previous consideration that the company's decision not to pursue a randomised controlled trial of idelalisib in this population had left an important gap in the evidence base (see section\xa03.6).The committee appreciated statements from professional organisations and clinical experts that accepted the potential for idelalisib to extend life compared with current treatments for 'double-refractory' follicular lymphoma. A clinical expert suggested that idelalisib might prolong life by 12\xa0months or more in some patients. However, a professional organisation suggested that estimating the extension to life with certainty is difficult. The committee acknowledged the efforts of the company, but noted that concerns about the comparative effectiveness evidence made it difficult to establish the benefit of idelalisib compared with chemotherapy or best supportive care (see section\xa03.14). It took this into account in its decision making.\n\n# The company's economic models\n\n## The model structures are appropriate for modelling\n\nThe company submitted 4\xa0economic analyses using different model structures and sources of clinical data, which are summarised in table\xa01. In its models, the company used secondary endpoints (overall survival and progression-free survival) rather than the primary outcome from DELTA (overall response rate) to determine cost effectiveness.\n\nComparison\n\nIdelalisib data source\n\nComparator data source\n\nModel type\n\nA (company base case)\n\nDELTA\n\nAll chemotherapy combined: DELTA data from 'self-control' previous line of treatment as a proxy for current chemotherapy\n\nMarkov cohort – state transition\n\nB\n\nDELTA\n\nAll chemotherapy combined: matching adjusted survival data from chemotherapy regimens of the Haematological Malignancy Research Network cohort (either matching adjusted indirect comparison or propensity score matching analysis; see section\xa03.12)\n\nPartitioned survival model\n\nC\n\nData from the Compassionate Use Programme cohort and DELTA\n\nAll chemotherapy combined: time-to-progression data from 'self-control' previous line of treatment as a proxy for current chemotherapy\n\nMarkov cohort – state transition\n\nD\n\nDELTA\n\nBest supportive care: no data (see section\xa03.16, company assumes instant disease progression\n\nMarkov cohort – state transition\n\nComparisons\xa0A, C\xa0and\xa0D reflected state transition models. In these, 'transition probabilities' determined the movements between states (clinical events) and time spent by patients in each state determined expected costs and quality-adjusted life years (QALYs). Comparison\xa0B used a 'partitioned survival analysis' approach in which survival curves (rather than transition probabilities) determined the proportion of patients in each state at each time point. The committee agreed in its first meeting that it would focus on comparisons\xa0A (the company's base case) and\xa0B; the company did not provide best supportive care data for comparison\xa0D. The committee noted that, in comparisons\xa0A and\xa0C, the company applied a 'hazard ratio' of 0.75 to adjust for the expected decline in the effectiveness of chemotherapy compared with idelalisib. This meant that, at each successive treatment line, patients would have expected their prognosis to worsen by 75% compared with the previous line of therapy. It also noted that the company had not justified its choice of the value of 0.75, which affected comparisons A\xa0and\xa0C to different extents. In its updated cost-effectiveness analysis submitted in response to the consultation, the company submitted results exclusively based on comparison\xa0B. It explained that, in its view, only this comparison could reflect the survival benefit of idelalisib after disease progression (see section\xa03.5). The committee preferred comparison\xa0B, but noted that all the comparisons were limited by:\n\nsparse clinical data\n\nno comparative evidence\n\nno censoring for autologous stem cell transplantation\n\nno comparison with or data on best supportive care\n\nlikely confounding (see section\xa03.9)\n\nvariables defined differently by study (see section\xa03.13)\n\nusing a blended comparator and the arbitrary choice of\xa00.75 to reflect the expected worsening in prognosis compared with previous line of therapy (see sections 3.8,\xa03.13,\xa03.14, 3.15\xa0and\xa03.16).In response to the consultation, the company did not submit analyses for idelalisib compared with best supportive care, so the committee did not consider this further.\n\n## The 'blended comparator' masks cost-ineffective treatments\n\nThe committee considered that using a blend of chemotherapeutic regimens (see section\xa03.15) as a comparator meant averaging the cost effectiveness of the treatments included, and potentially masked cost-ineffective individual treatments. The committee concluded that the cost effectiveness of idelalisib needed to reflect the comparison with each chemotherapy treatment individually.\n\n# Utility values in the economic models\n\n## There are no mapped utilities for the committee to consider\n\nThe company submitted utility values to reflect health-related quality of life from a published study (Wild et al. 2006), even though it had collected quality-of-life data in DELTA. The ERG submitted scenario analyses with alternative utility values from other published studies (Bec et al. 2014 and the GADOLIN trial for non-Hodgkin's indolent lymphoma). The clinical experts agreed that all values seemed reasonable because people with follicular lymphoma can expect a good quality of life once the bulk of the disease has decreased. The committee was aware that DELTA collected health-related quality-of-life data using the Functional Assessment of Cancer Therapy - Lymphoma (FACT‑Lym) instrument (an extension of FACT - General [G]). This has 15\xa0questions specific to patients with lymphoma. It was also aware that there is a mapping algorithm to map from FACT‑G to EQ‑5D, which the ERG requested of the company at the clarification stage. The company did not provide the mapped utilities, arguing that it was not useful because there was no mapping algorithm that specifically matched FACT‑Lym to EQ‑5D. The company added that the mapped utilities would have been limited to the clinical symptoms captured in EQ‑5D. The committee expressed its interest in seeing the mapped utilities in the appraisal consultation document, but the company chose not to submit the values at the second meeting. The committee concluded that it would have liked to see mapped utility values to validate literature-derived values, but that this would not have overcome the other problems associated with the clinical evidence.\n\n## Adverse effects with idelalisib are different than those with chemotherapy, but the adverse effects of individual chemotherapy regimens also differ\n\nThe committee noted the adverse effects in people having idelalisib outlined in the European Medicine Agency's risk management plan, which include severe drug-related colitis, pneumonitis and organising pneumonia, and serious infections. The company did not provide relative safety data for chemotherapy. The clinical experts commented that adverse effects with chemotherapy are qualitatively different to those with idelalisib, so it is difficult to compare the safety profiles. The clinical experts commented that idelalisib is generally well tolerated. The committee considered that the adverse effects of chemotherapy are unlikely to differ between haematological malignancies, and thought that data from other malignancies would be valuable. The company included adverse events as disutilities within all the economic models. These disutility values were based on various sources and estimating the incidence using DELTA. The company models assumed the same incidence of adverse effects for both idelalisib and chemotherapy. The committee noted that adverse event disutility is not a key driver in the model. It concluded that idelalisib is unlikely to have the same effect on quality of life because of an adverse effect as chemotherapy, which themselves differed by individual regimen, but that this is unlikely to markedly affect cost-effectiveness results.\n\n# Cost-effectiveness estimates\n\n## The company submitted several cost-effectiveness estimates\n\nIn its response to the consultation, the company submitted 3\xa0deterministic incremental cost-effectiveness ratios (ICERs) for idelalisib compared with chemotherapy using comparison\xa0B (see section\xa03.18) incorporating a patient access scheme discount; probabilistic ICERs were broadly similar:\n\nUsing the updated matching adjusted indirect comparison data, and including the ERG's corrections to the model, resulted in an estimated ICER of £16,481 per QALY gained.\n\nUsing a propensity score matching analysis with the DELTA group as the treated group (based on updated data), and including the ERG's corrections to the model, with the assumption that progression-free survival with chemotherapy and idelalisib are equal (see section\xa03.10), resulted in an estimated ICER of £25,605 per QALY gained.\n\nUsing a propensity score matching analysis with the HMRN group as the treated group (based on updated data), and including the ERG's corrections to the model, with the assumption that progression-free survival with chemotherapy and idelalisib are equal (see section\xa03.10), resulted in an estimated ICER of £26,627 per QALY gained.\n\n## The ERG carried out an exploratory cost-effectiveness analysis\n\nThe committee considered that all matching analyses (see section 3.13 and section\xa03.14) were associated with high levels of uncertainty. It therefore would have liked to see the cost-effectiveness results associated with all matching analyses, which it considered would help to explore the effect of clinical-effectiveness uncertainty on the cost-effectiveness results. The committee noted that the company had not submitted cost-effectiveness analyses using the 'reverse' matching adjusted indirect comparison (see section 3.12 and\xa0section 3.22), even after NICE requested this. The ERG was not able to estimate pseudo-patient-level data for the 'reverse' matching adjusted indirect comparison (to estimate parametric survival curves). This was because the company did not submit numbers at risk or survival curves, and declined to provide a model with the option to choose between matching characteristics. At the second committee meeting, the company stated it had not submitted cost-effectiveness results for the 'reverse' matching adjusted indirect comparison because they would have been based on clinically implausible effectiveness data, so the results would have added to the uncertainty. The company further stated that it submitted the results only for the 'updated' matching adjusted indirect comparison because it had submitted these at the first meeting. The ERG carried out an exploratory analysis to give a crude estimate of an ICER for the 'reverse' matching adjusted indirect comparison. This estimated an ICER of £86,161 per QALY gained, which is well above what NICE normally considers to be an effective use of NHS resources. The committee concluded that it would take into account the ERG's exploratory analysis in its decision making.\n\n## The company's and ERG's estimates of cost effectiveness lack robustness\n\nThe committee stated that it considered propensity score matching analyses to be more reliable than matching adjusted indirect comparisons or 'reverse' matching adjusted indirect comparisons, but all had problems (see section\xa03.13). However, it would have preferred to see estimates from the company using all the submitted clinical-effectiveness estimates. The committee noted that the ERG's exploratory analysis contained all the uncertainties associated with the company's model in addition to potential confounding (see section\xa03.18). It also recalled all the limitations associated with propensity score matching analyses (see section\xa03.14). It considered that the cost-effectiveness estimates lacked robustness and concluded that it needed to account for this in its decision making.\n\n## Idelalisib has not been shown to represent a cost-effective use of NHS resources\n\nThe committee appreciated that the company had submitted new clinical data and attempted additional indirect analyses. However, the committee noted that these additional data did not include any comparative evidence that appropriately adjusted for potential confounders. The analyses presented other problems including sparse data, matching on variables defined differently and analyses that did not censor patients having a transplant. The committee also appreciated that the ERG considered that, rather than reducing uncertainty, the company's additional data and analyses had instead increased uncertainty. The committee considered whether information from the clinical experts could inform estimates of overall survival with the new treatment (see section 3.17 and\xa0section 3.26). However, the company provided no data to support any estimates. Therefore, the committee concluded that idelalisib was not considered to represent a cost-effective use of NHS resource because of the range of ICERs presented (between £16,481 and £86,161 per QALY gained) and its concerns with the quality of the evidence.\n\n# End of life\n\n## End-of-life criteria are not met\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal:\n\nThe committee discussed whether the life expectancy using standard care was likely to be less than 24\xa0months. It was aware that probabilistic analyses submitted by the company provided mean undiscounted life years for chemotherapy of more than 24\xa0months (ranging from 6\xa0to 87\xa0months). Other model outputs that used different matching analyses also estimated that chemotherapy would result in a mean life expectancy of at least 2\xa0years. Therefore, many of the company's own analyses predicted a life expectancy longer than 24\xa0months. The committee was aware that, given the concerns it had about the economic model, any outputs would have to be interpreted with a high level of caution. In the absence of robust modelled data, the committee considered expert clinical opinion. The company reported that, according to the clinical community, life expectancy would be less than 12\xa0months once a patient's cancer becomes refractory to chemotherapy. A letter (submitted by the company) gathering the opinion of 15\xa0clinical experts suggested that disease progression within 24\xa0months of first relapse is associated with an increased risk of death. Additionally, a clinical expert estimated that life expectancy for patients having idelalisib could be 12\xa0months on average. The committee was aware that no data were offered to support these figures. Therefore, the committee went on to consider the unadjusted data from the HMRN. It noted these data showed that a high proportion of patients survived for a median of 2\xa0years, and that mean life expectancy would be longer. The committee weighed up all the available data and considered that, currently, the most reliable source of evidence from which to make its judgement was the HMRN data. It concluded that the short life-expectancy criterion had not been met.\n\nThe committee discussed the criterion of whether the technology provided an extension to life, with a mean of at least 3\xa0months of life compared with usual care. The committee noted that the modelled undiscounted incremental gains were more than 3\xa0months with idelalisib compared with chemotherapy in all the analyses provided. It noted that a clinical expert suggested that it could be more than 3\xa0months. However, no explanation or further data were given to support this figure. The committee also noted that the estimated undiscounted incremental life years in all analyses were more than 3\xa0months with idelalisib compared with chemotherapy. However, given its concerns about the modelling and model inputs, the committee did not consider that the model generated a valid estimate of the mean extension to life with idelalisib. The committee was aware that NICE's guide to the methods of technology appraisal notes state that the appraisal committee must be satisfied that the 'the estimates of the extension to life are sufficiently robust'. Therefore, it concluded that, although idelalisib might prolong life, the magnitude of this is highly uncertain. Because the short life-expectancy criterion had not been met, the committee concluded that idelalisib could not be considered a life-extending treatment at the end of life.\n\n# Cancer Drugs Fund\n\n## Idelalisib is not a candidate for the Cancer Drugs Fund\n\nHaving concluded that idelalisib could not be recommended for routine use, the committee then considered whether it could be recommended for treating follicular lymphoma within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It noted that, at the second meeting, the company had expressed an interest in providing idelalisib through the Cancer Drugs Fund. The company confirmed that there are no ongoing comparative trials to provide more robust, controlled evidence. The committee highlighted that, because no evidence showed that idelalisib improved length or quality of life, it encouraged research comparing idelalisib with individual chemotherapeutic regimens. The committee appreciated that the Cancer Drugs Fund is designed to resolve uncertainties, and that the key uncertainty in this appraisal was about the assumptions surrounding the comparative effectiveness of idelalisib with chemotherapy. It was aware that the Cancer Drugs Fund could collect data on the intervention (idelalisib), but not the comparator (chemotherapy), so would not resolve this uncertainty. Also, the committee had not seen reliable evidence that demonstrated idelalisib had 'plausible potential' to be cost effective (see section\xa03.24). It concluded that idelalisib could not be recommended for use within the Cancer Drugs Fund as an option for follicular lymphoma that had not responded to 2\xa0previous lines of therapy in adults.\n\n## The Cancer Drugs Fund would not address the key uncertainty in the idelalisib appraisal\n\nIn its response to the appraisal consultation document, the company referred to NICE's technology appraisal guidance on daratumumab monotherapy, which was recommended through the Cancer Drugs Fund to treat relapsed and refractory multiple myeloma. It argued there was a parallel between the 2\xa0appraisals because clinical evidence for daratumumab was limited to single-arm trials and an unanchored matching adjusted indirect comparison. The committee recalled that it had recommended daratumumab through the Cancer Drugs Fund because an Early Access programme is collecting data that have the potential to reduce several uncertainties identified by the committee (such as trial generalisability and place in the treatment pathway). The committee reiterated that the key uncertainty in the idelalisib appraisal was about the assumptions and analyses surrounding the comparative effectiveness, and the effectiveness and adverse effects associated with individual chemotherapeutic regimens, and that the Cancer Drugs Fund could not address these issues.\n\n# Innovation\n\n## Idelalisib is potentially innovative\n\nThe committee noted that idelalisib is innovative in that it has a different mechanism of action to other available treatments for 'double-refractory' follicular lymphoma, and addresses an area of unmet clinical need (see section\xa03.1). The committee noted comments from the clinical experts that this different mechanism of action might bring psychological benefits for people reluctant to have more chemotherapy. It also noted that no evidence had been submitted to support this. The committee agreed that it could not determine whether the model captured quality-of-life improvements. It also agreed that an oral drug was preferable to an intravenous one. The committee concluded that idelalisib potentially reflects an innovative step change in treatment, but that it had not been presented with evidence to establish this."}
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https://www.nice.org.uk/guidance/ta604
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Evidence-based recommendations on idelalisib (Zydelig) for follicular lymphoma that has not responded to 2 prior lines of treatment in adults.
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c4a0362c56ef267a870d74711e5c3b97cbd1dd12
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nice
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Cellulitis and erysipelas: antimicrobial prescribing
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Cellulitis and erysipelas: antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for adults, young people, children and babies aged 72 hours and over with cellulitis and erysipelas. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing cellulitis and erysipelas
## Treatment
To ensure that cellulitis and erysipelas are treated appropriately, exclude other causes of skin redness such as:
an inflammatory reaction to an immunisation or an insect bite or
a non-infectious cause such as chronic venous insufficiency.
Consider taking a swab for microbiological testing from people with cellulitis or erysipelas to guide treatment, but only if the skin is broken and:
there is a penetrating injury or
there has been exposure to water-borne organisms or
the infection was acquired outside the UK.
Before treating cellulitis or erysipelas, consider drawing around the extent of the infection with a single-use surgical marker pen to monitor progress. Be aware that redness may be less visible on darker skin tones.
Offer an antibiotic for people with cellulitis or erysipelas. When choosing an antibiotic (see the recommendations on choice of antibiotic), take account of:
the severity of symptoms
the site of infection (for example, near the eyes or nose)
the risk of uncommon pathogens (for example, from a penetrating injury, after exposure to water-borne organisms, or an infection acquired outside the UK)
previous microbiological results from a swab
the person's meticillin-resistant Staphylococcus aureus (MRSA) status if known.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
If intravenous antibiotics are given, review by 48 hours and consider switching to oral antibiotics if possible.
Manage any underlying condition that may predispose to cellulitis or erysipelas, for example:
diabetes
venous insufficiency
eczema
-edema, which may be an adverse effect of medicines such as calcium channel blockers.
## Advice
When prescribing antibiotics for cellulitis or erysipelas, give advice about:
possible adverse effects of antibiotics
the skin taking some time to return to normal after the course of antibiotics has finished
seeking medical help if symptoms worsen rapidly or significantly at any time, or do not start to improve within 2 to 3 days.
## Reassessment
Reassess people with cellulitis or erysipelas if symptoms worsen rapidly or significantly at any time, do not start to improve within 2 to 3 days, or the person:
becomes systemically very unwell or
has severe pain out of proportion to the infection or
has redness or swelling spreading beyond the initial presentation (taking into account that some initial spreading may occur, and that redness may be less visible on darker skin tones), see the recommendation on drawing around the extent of the infection in the section on treatment.
When reassessing people with cellulitis or erysipelas, take account of:
-ther possible diagnoses, such as an inflammatory reaction to an immunisation or an insect bite, gout, superficial thrombophlebitis, eczema, allergic dermatitis or deep vein thrombosis
any underlying condition that may predispose to cellulitis or erysipelas, such as oedema, diabetes, venous insufficiency or eczema
any symptoms or signs suggesting a more serious illness or condition, such as lymphangitis, orbital cellulitis, osteomyelitis, septic arthritis, necrotising fasciitis or sepsis
any results from microbiological testing
any previous antibiotic use, which may have led to resistant bacteria.
Consider taking a swab for microbiological testing from people with cellulitis or erysipelas if the skin is broken and this has not been done already.
If a swab has been sent for microbiological testing:
review the choice of antibiotic(s) when results are available and
change the antibiotic(s) according to results if symptoms or signs of the infection are not improving, using a narrow-spectrum antibiotic if possible.
## Referral and seeking specialist advice
Refer people to hospital if they have any symptoms or signs suggesting a more serious illness or condition, such as orbital cellulitis, osteomyelitis, septic arthritis, necrotising fasciitis or sepsis.
Consider referring people with cellulitis or erysipelas to hospital, or seek specialist advice, if they:
are severely unwell or
have infection near the eyes or nose (including periorbital cellulitis) or
could have uncommon pathogens, for example, after a penetrating injury, exposure to water-borne organisms, or an infection acquired outside the UK or
have spreading infection that is not responding to oral antibiotics or
lymphangitis or
cannot take oral antibiotics (exploring locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, where appropriate).
For a short explanation of why the committee made these recommendations, see the summary of the evidence on managing cellulitis and erysipelas.
# Choice of antibiotic
When prescribing an antibiotic for cellulitis or erysipelas, follow:
table 1 for adults aged 18 years and over
table 2 for children and young people under 18 years.
Treatment
Antibiotic, dosage and course length
First-choice antibiotic (give orally unless person unable to take oral or severely unwell)
Flucloxacillin (5 to 7 days):
mg to 1 g four times a day orally
-r 1 g to 2 g four times a day intravenously
In September 2019, 1 g orally four times a day was off label. See NICE's information on prescribing medicines.
Alternative first-choice antibiotics for penicillin allergy or if flucloxacillin is unsuitable (give orally unless person unable to take oral or severely unwell)
Clarithromycin (5 to 7 days):
mg twice a day orally
-r 500 mg twice a day intravenously
Erythromycin (in pregnancy; 5 to 7 days):
mg four times a day orally
Doxycycline (5 to 7 days in total):
mg on the first day then 100 mg once a day orally
First-choice antibiotic if infection is near the eyes or nose (consider seeking specialist advice; give orally unless person unable to take oral or severely unwell)
Co‑amoxiclav (7 days):
/125 mg three times a day orally
-r 1.2 g three times a day intravenously
Alternative first-choice antibiotics if infection is near the eyes or nose for penicillin allergy or if co‑amoxiclav is unsuitable (consider seeking specialist advice; give orally unless person unable to take oral or severely unwell)
Clarithromycin (7 days):
mg twice a day orally
-r 500 mg twice a day intravenously
with
Metronidazole (7 days):
mg three times a day orally
-r 500 mg three times a day intravenously
Alternative choice antibiotics for severe infection
Co‑amoxiclav (7 days):
/125 mg three times a day orally
-r 1.2 g three times a day intravenously
Cefuroxime (7 days):
mg to 1.5 g three or four times a day intravenously
Clindamycin (7 days):
mg to 300 mg four times a day (can be increased to 450 mg four times a day) orally
-r 600 mg to 2.7 g daily intravenously in two to four divided doses, increased if necessary in life-threatening infection to 4.8 g daily (maximum per dose 1.2 g)
Ceftriaxone (7 days; only for ambulatory care; other antibiotics may be appropriate based on microbiological results and specialist advice):
g once a day intravenously
Antibiotics to be added if meticillin-resistant
Staphylococcus aureus
infection is suspected or confirmed (combination therapy with an antibiotic listed above; other antibiotics may be appropriate based on microbiological results and specialist advice)
Vancomycin:
mg/kg to 20 mg/kg two or three times a day intravenously (maximum 2 g per dose), adjusted according to serum vancomycin concentration (see the British national formulary for information on monitoring)
Teicoplanin:
Initially 6 mg/kg every 12 hours for three doses, then 6 mg/kg once a day intravenously (see the BNF for information on monitoring)
Linezolid (if vancomycin or teicoplanin cannot be used; specialist use only):
mg twice a day orally or
mg twice a day intravenously (see the BNF for information on monitoring)
See the BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, where appropriate, intramuscular) antibiotics.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their symptoms does not warrant intravenous antibiotics. If intravenous antibiotics are given, review by 48 hours and consider switching to oral antibiotics, if possible.
A longer course length (up to 14 days in total) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 5 to 7 days is not expected.
Infection around the eyes or the nose (the triangle from the bridge of the nose to the corners of the mouth, or immediately around the eyes including periorbital cellulitis) is of more concern because of risk of a serious intracranial complication.
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
Treatment
Antibiotic, dosage and course length
Children under 1 month
Antibiotic choice based on specialist advice
First-choice antibiotic for children aged 1 month and over (give orally unless person unable to take oral or severely unwell)
Flucloxacillin (5 to 7 days):
month to 1 year, 62.5 mg to 125 mg four times a day orally
years to 9 years, 125 mg to 250 mg four times a day orally
years to 17 years, 250 mg to 500 mg four times a day orally
-r 1 month to 17 years, 12.5 mg/kg to 25 mg/kg four times a day intravenously (maximum 1 g four times a day)
Alternative first-choice antibiotics for penicillin allergy or if flucloxacillin unsuitable (give orally unless person unable to take oral or severely unwell)
Co‑amoxiclav (not in penicillin allergy; 5 to 7 days):
month to 11 months, 0.25 ml/kg of 125/31 suspension three times a day orally (dose doubled in severe infection)
year to 5 years, 0.25 ml/kg or 5 ml of 125/31 suspension three times a day orally (dose doubled in severe infection)
years to 11 years, 0.15 ml/kg or 5 ml of 250/62 suspension three times a day orally (dose doubled in severe infection)
years to 17 years, 250/125 mg or 500/125 mg three times a day orally
-r 1 month to 2 months, 30 mg/kg twice a day intravenously
months to 17 years, 30 mg/kg three times a day intravenously (maximum 1.2 g three times a day)
Clarithromycin (5 to 7 days):
month to 11 years:
under 8 kg, 7.5 mg/kg twice a day orally
kg to 11 kg, 62.5 mg twice a day orally
kg to 19 kg, 125 mg twice a day orally
kg to 29 kg, 187.5 mg twice a day orally
kg to 40 kg, 250 mg twice a day orally
years to 17 years, 250 mg to 500 mg twice a day orally
-r 1 month to 11 years, 7.5 mg/kg twice a day intravenously (maximum 500 mg per dose)
years to 17 years, 500 mg twice a day intravenously
Erythromycin (in pregnancy; 5 to 7 days):
years to 17 years, 250 mg to 500 mg four times a day orally
First-choice antibiotic if infection near the eyes or nose (consider seeking specialist advice; give orally unless person unable to take oral or severely unwell)
Co‑amoxiclav (7 days):
month to 11 months, 0.25 ml/kg of 125/31 suspension three times a day orally (dose doubled in severe infection)
year to 5 years, 0.25 ml/kg or 5 ml of 125/31 suspension three times a day orally (dose doubled in severe infection)
years to 11 years, 0.15 ml/kg or 5 ml of 250/62 suspension three times a day orally (dose doubled in severe infection)
years to 17 years, 250/125 mg or 500/125 mg three times a day orally
-r 1 month to 2 months, 30 mg/kg twice a day intravenously
months to 17 years, 30 mg/kg three times a day intravenously (maximum 1.2 g three times a day)
Alternative first-choice antibiotics if infection near the eyes or nose for penicillin allergy or if co‑amoxiclav unsuitable (consider seeking specialist advice; give orally unless person unable to take oral or severely unwell)
Clarithromycin (7 days):
month to 11 years:
under 8 kg, 7.5 mg/kg twice a day orally
kg to 11 kg, 62.5 mg twice a day orally
kg to 19 kg, 125 mg twice a day orally
kg to 29 kg, 187.5 mg twice a day orally
kg to 40 kg, 250 mg twice a day orally
years to 17 years, 250 mg to 500 mg twice a day orally
-r 1 month to 11 years, 7.5 mg/kg twice a day intravenously (maximum 500 mg per dose)
years to 17 years, 500 mg twice a day intravenously
with (if anaerobes suspected)
Metronidazole (7 days):
month, 7.5 mg/kg twice a day orally
months to 11 years, 7.5 mg/kg three times a day orally (maximum per dose 400 mg)
years to 17 years, 400 mg three times a day orally
-r 1 month, loading dose 15 mg/kg, then (after 8 hours) 7.5 mg/kg three times a day intravenously
months to 17 years, 7.5 mg/kg three times a day intravenously (maximum per dose 500 mg)
Alternative choice antibiotics for severe infection (other antibiotics may be appropriate based on microbiological results and specialist advice)
Co‑amoxiclav (7 days):
month to 11 months, 0.25 ml/kg of 125/31 suspension three times a day orally (dose can be doubled)
year to 5 years, 0.25 ml/kg or 5 ml of 125/31 suspension three times a day orally (dose can be doubled)
years to 11 years, 0.15 ml/kg or 5 ml of 250/62 suspension three times a day orally (dose can be doubled)
years to 17 years, 250/125 mg or 500/125 mg three times a day orally
-r 1 month to 2 months, 30 mg/kg twice a day intravenously
months to 17 years, 30 mg/kg three times a day intravenously (maximum 1.2 g three times a day)
Cefuroxime (7 days):
month to 17 years, 20 mg/kg three times a day intravenously (maximum 750 mg per dose), can be increased to 50 mg/kg to 60 mg/kg three or four times a day intravenously (maximum 1.5 g per dose)
Clindamycin (7 days):
month to 17 years, 3 mg/kg to 6 mg/kg four times a day orally (maximum per dose 450 mg)
-r 1 month to 17 years, 3.75 mg/kg to 6.25 mg/kg four times a day intravenously, increased if necessary, in life-threatening infection to 10 mg/kg four times a day intravenously (maximum per dose 1.2 g); total daily dose may alternatively be given in three divided doses (maximum per dose 1.2 g)
Antibiotics to be added if meticillin-resistant
Staphylococcus aureus
infection is suspected or confirmed (combination therapy with an antibiotic listed above; other antibiotics may be appropriate based on microbiological results and specialist advice)
Vancomycin:
month to 11 years, 10 mg/kg to 15 mg/kg four times a day intravenously, adjusted according to serum vancomycin concentration
years to 17 years, 15 mg/kg to 20 mg/kg two or three times a day intravenously (maximum 2 g per dose), adjusted according to serum vancomycin concentration
(see the British national formulary for children for information on monitoring)
Teicoplanin:
month, initially 16 mg/kg for one dose, then (after 24 hours) 8 mg/kg once a day intravenously
months to 11 years, initially 10 mg/kg every 12 hours for three doses, then 6 mg/kg to 10 mg/kg once a day intravenously
years to 17 years, initially 6 mg/kg every 12 hours for three doses, then 6 mg/kg once a day intravenously
(see the BNFC for information on monitoring)
Linezolid (if vancomycin or teicoplanin cannot be used; specialist use only):
month to 11 years, 10 mg/kg three times a day orally (maximum 600 mg per dose)
years to 17 years, 600 mg twice a day orally
-r 1 month to 11 years, 10 mg/kg three times a day intravenously (maximum 600 mg per dose)
years to 17 years, 600 mg twice a day intravenously
In September 2019, the use of linezolid in children and young people under 18 years was off label. See NICE's information on prescribing medicines.
(see the BNFC for information on monitoring)
See the BNFC for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, where appropriate, intramuscular) antibiotics.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands with other factors, such as the severity of the condition and the child's size in relation to the average size of children of the same age.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their symptoms does not warrant intravenous antibiotics. If intravenous antibiotics are given, review by 48 hours and consider switching to oral antibiotics, if possible.
A longer course length (up to 14 days in total) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 5 to 7 days is not expected.
If flucloxacillin oral solution is not tolerated because of poor palatability, consider capsules (see the Medicines for Children leaflet on helping your child to swallow tablets).
Co‑amoxiclav 400/57 suspension may also be considered to allow twice daily dosing (see the BNFC for dosing information).
Infection around the eyes or the nose (the triangle from the bridge of the nose to the corners of the mouth, or immediately around the eyes including periorbital cellulitis) is of more concern because of risk of a serious intracranial complication.
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
For a short explanation of why the committee made this recommendation, see the summary of the evidence on choice of antibiotics, antibiotic dose frequency, antibiotic course length and antibiotic route of administration.
Full details of the evidence are in the evidence review.
# Preventing recurrent cellulitis or erysipelas
Do not routinely offer antibiotic prophylaxis to prevent recurrent cellulitis or erysipelas. Give advice about seeking medical help if symptoms of cellulitis or erysipelas develop.
For adults who have had treatment in hospital, or under specialist advice, for at least 2 separate episodes of cellulitis or erysipelas in the previous 12 months, specialists may consider a trial of antibiotic prophylaxis. Involve the person in a shared decision by discussing and taking account of:
the severity and frequency of previous symptoms
the risk of developing complications
underlying conditions (such as oedema, diabetes or venous insufficiency) and their management
the risk of resistance with long-term antibiotic use
the person's preference for antibiotic use.
When choosing an antibiotic for prophylaxis (see the recommendations on choice of antibiotic prophylaxis), take account of any previous microbiological results and previous antibiotic use.
When antibiotic prophylaxis is given, give advice about:
possible adverse effects of long-term antibiotics
returning for review within 6 months
seeking medical help if symptoms of cellulitis or erysipelas recur.
Review antibiotic prophylaxis for recurrent cellulitis or erysipelas at least every 6 months. The review should include:
assessing the success of prophylaxis
discussing continuing, stopping or changing prophylaxis (taking into account the person's preferences for antibiotic use and the risk of antimicrobial resistance).Stop or change the prophylactic antibiotic to an alternative if cellulitis or erysipelas recurs (see recommendation 1.1.4 in the section on treatment for treatment of acute infection).
For a short explanation of why the committee made these recommendations, see the summary of the evidence on antibiotic prophylaxis for the prevention of recurrent cellulitis and erysipelas.
Full details of the evidence are in the evidence review.
# Choice of antibiotic prophylaxis
When prescribing an antibiotic to prevent recurrent cellulitis or erysipelas in adults, specialists should follow table 3.
Prophylaxis
Antibiotic and dosage
First choice
Choose antibiotics according to recent microbiological results when possible, and avoid using the same antibiotic for treatment and prophylaxis
Phenoxymethylpenicillin:
mg orally twice a day
Alternative first choice for penicillin allergy
Choose antibiotics according to recent microbiological results when possible, and avoid using the same antibiotic for treatment and prophylaxis
Erythromycin:
mg orally twice a day
See the BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, in pregnancy and breastfeeding.
For a short explanation of why the committee made this recommendation, see the summary of the evidence on antibiotic prophylaxis for the prevention of recurrent cellulitis and erysipelas.
Full details of the evidence are in the evidence review.
# Terms used in the guideline
## Ambulatory care
Clinical care that may include diagnosis, observation, treatment and rehabilitation not provided within the traditional hospital bed base or within the traditional outpatient services that can be provided across primary/secondary care.
## Cellulitis and erysipelas
Infections of the tissues under the skin (subcutaneous), which usually result from contamination of a break in the skin. Both conditions are characterised by acute localised inflammation and oedema, with lesions more superficial in erysipelas with a well-defined, raised margin (World Health Organization, WHO model prescribing information: drugs used in skin diseases, bacterial infections, staphylococcal and streptococcal infections).# Summary of the evidence
This is a summary of the evidence. For full details, see the evidence review.
# Managing cellulitis and erysipelas
Cellulitis and erysipelas are infections of the tissues under the skin, which are treated with antibiotics.
The main bacteria causing cellulitis and erysipelas are Streptococcus pyogenes and Staphylococcus aureus, but infection can also be caused by Streptococcus pneumoniae, Haemophilus influenza, gram-negative bacilli and anaerobes (NICE clinical knowledge summary on cellulitis).
The evidence identified in this guideline was for antibiotics compared with other antibiotics for managing non-surgically acquired cellulitis or erysipelas in adults, young people and children. Most studies did not report the site of infection, but where this was reported, most cases had a lower limb infection or less frequently an upper limb infection. One systematic review excluded a study of facial cellulitis.
## Committee discussion on managing cellulitis and erysipelas
The committee discussed that to ensure the appropriate treatment of cellulitis and erysipelas, it is important to exclude other causes of skin redness (erythema). This can often be caused by an inflammatory reaction, for example, following an immunisation or an insect bite, or any other non-infective cause such as chronic venous insufficiency, which could be wrongly treated as cellulitis or erysipelas.
The committee discussed that in most cases microbiological swabbing of cellulitis or erysipelas yields negative results (particularly if the skin is intact) and in most cases the infecting organism is likely to be either Streptococcus pyogenes or Staphylococcus aureus bacteria. They therefore agreed that swabbing should not be undertaken routinely. However, the committee agreed that where the skin is broken and there is reason to believe a different organism may be involved (for example, if there is a penetrating injury, exposure to water-borne organisms, or infection acquired outside the UK), then a swab may be useful to guide antibiotic treatment.
The committee agreed based on experience that to monitor the progression of cellulitis or erysipelas, and help assess the effectiveness of antibiotic treatment, it may be useful to draw around the extent of the infected area using a single-use surgical marker pen before treatment. The committee discussed that a single-use surgical pen should be used because it is designed for this purpose (unlike other pen types that may damage skin or leave permanent marking) and would not risk cross-infection. The committee noted that in people with certain conditions (for example, lymphoedema), drawing around the infected area may be difficult or not possible because the rash may be ill-defined. Additionally, they noted that the extent of redness may be less visible on darker skin tones.
The committee agreed that it may take time for antibiotic treatment to take effect, and initially redness or swelling may extend beyond the marked line (if used).
The committee agreed that, in line with the NICE guideline on antimicrobial stewardship, prescribers should provide 'safety netting' advice to people with cellulitis or erysipelas about when to seek further help if they become more unwell or have side effects of antibiotic treatment, and also discuss that skin can take some time to return to normal even after a course of effective antibiotics. The committee was aware that the time taken for skin to return to normal appearance is variable. In their experience, it could be a number of weeks. Because no data were available to affirm this, the committee agreed not to specify a timescale.
The committee agreed that if a person's symptoms worsen rapidly or significantly at any time they should be reassessed, taking into account other possible diagnoses, the development of serious complications, such as orbital cellulitis, septic arthritis, osteomyelitis, lymphangitis, necrotising fasciitis or sepsis, and the possibility of an uncommon or resistant bacteria. The committee also agreed that reassessment should include managing any underlying condition that may predispose to cellulitis or erysipelas.
The committee agreed that taking a swab for microbiological testing should be considered if the skin is broken and this has not been done already. When microbiological results are available, the antibiotic should be reviewed and changed accordingly (for example, if bacteria are found to be resistant) if symptoms are not already improving, using a narrower-spectrum antibiotic if possible.
The committee agreed that people with cellulitis or erysipelas should be referred to hospital if they have symptoms or signs suggestive of orbital cellulitis, osteomyelitis, septic arthritis, necrotising fasciitis or sepsis.
The committee discussed and agreed that in some cases, the prescriber may need to consider referring or seeking specialist advice on inpatient treatment or locally available options for intravenous treatment at home or in a community setting. These cases include people who are severely unwell, at higher risk of complications, have infection near the eyes or nose (including periorbital cellulitis), could have uncommon pathogens, have lymphangitis, have a spreading infection that is not responding to oral antibiotics, or cannot take oral antibiotics. They discussed that children under 1 year and people who are frail or have underlying disease (such as diabetes or immunosuppression) are at a higher risk of developing complications, as are those who could have an uncommon causative organism, for example, following a penetrating injury, a wound exposed to water (surfers for example), or an infection acquired outside the UK.
# Choice of antibiotics
## Effectiveness of antibiotics versus other antibiotics in adults
There were no differences in the clinical effectiveness of the following antibiotic comparisons in adults with cellulitis or erysipelas:
an oral penicillin or cephalosporin compared with an oral macrolide or oral clindamycin (adults and children; Ferreira et al. 2016)
-ral azithromycin compared with oral cefalexin (Kilburn et al. 2010)
-ral azithromycin compared with oral erythromycin (Kilburn et al. 2010)
intravenous (IV) then oral moxifloxacin compared with IV then oral co‑amoxiclav (Vick-Fragoso et al. 2009)
IV or oral linezolid compared with IV vancomycin (Kilburn et al. 2010)
IV dalbavancin compared with IV vancomycin (Boucher et al. 2014)
IV ampicillin with sulbactam compared with IV cefazolin (Kilburn et al. 2010)
IV flucloxacillin compared with IV ceftriaxone (Kilburn et al. 2010)
IV moxifloxacin compared with IV piperacillin with tazobactam (Kilburn et al. 2010)
IV daptomycin compared with IV penicillin or IV vancomycin (Konychev et al. 2013)
IV tigecycline compared with IV ampicillin with sulbactam or IV co‑amoxiclav (Matthews et al. 2012)
newer cephalosporins compared with older cephalosporins (Kilburn et al. 2010)
IV ceftaroline compared with IV vancomycin plus aztreonam (Frampton 2013)
IV daptomycin compared with IV vancomycin (Pertel et al. 2009)
IV meropenem compared with IV imipenem with cilastatin (Kilburn et al. 2010).
Some differences were seen for some effectiveness outcomes for the following antibiotic comparison in adults with cellulitis or erysipelas:
-ral macrolides or oral streptogramins (pristinamycin: not available in the UK) improved the number of people who were symptom-free, or had reduced symptoms, at 7 to 14 days' follow‑up compared with a penicillin (Kilburn et al. 2010).
Based on 3 systematic reviews (Frampton 2013, Ferreira et al. 2016 and Kilburn et al. 2010) and 5 randomised controlled trials (RCTs; Boucher et al. 2014, Konychev et al. 2013, Matthews et al. 2012, Pertel et al. 2009 and Vick-Fragoso et al. 2009).
## Effectiveness of antibiotics versus other antibiotics in children
There was no difference in the clinical effectiveness of the following antibiotic comparison in children with cellulitis or erysipelas:
IV linezolid compared with IV vancomycin (Yogev et al. 2003).
Based on 1 RCT (Yogev et al. 2003).
## Dual therapy in adults or children
There were no differences in the clinical effectiveness of the following antibiotic comparisons in adults or children with cellulitis or erysipelas:
-ral cefalexin plus oral co‑trimoxazole compared with oral cefalexin alone (Bowen et al. 2017)
IV then oral flucloxacillin plus IV then oral benzylpenicillin compared with IV then oral flucloxacillin alone (Kilburn et al. 2010)
IV or oral flucloxacillin plus oral clindamycin compared with IV or oral flucloxacillin alone (Brindle et al. 2017)
IV ceftazidime plus IV vancomycin compared with IV ceftobiprole alone (Noel et al. 2008).
Based on 2 systematic reviews (Bowen et al. 2017 and Kilburn et al. 2010) and 2 RCTs (Brindle et al. 2017 and Noel et al. 2008).
## Safety of antibiotics
Antibiotic-associated diarrhoea is estimated to occur in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta-lactam antibiotics (British national formulary information on phenoxymethylpenicillin).
Cholestatic jaundice and hepatitis can occur with flucloxacillin up to 2 months after stopping treatment; risk factors are increasing age and use for more than 14 days (BNF information on flucloxacillin).
Cholestatic jaundice can occur with co‑amoxiclav, and is more common in people over 65 years and in men; treatment should not usually exceed 14 days (BNF information on co-amoxiclav).
Macrolides should be used with caution in people with a predisposition to QT interval prolongation. Nausea, vomiting, abdominal discomfort and diarrhoea are the most common side effects of macrolides. These are less frequent with clarithromycin than with erythromycin (BNF information on erythromycin).
Tetracyclines (for example, doxycycline), can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant or breastfeeding women, and use in children under 12 years is either contraindicated or cautioned for use only in severe or life-threatening infections where there are no alternatives (BNF information on doxycycline).
Clindamycin has been associated with colitis and diarrhoea. Although this can occur with most antibiotics, it is more frequent with clindamycin. Monitoring of liver and renal function is recommended if treatment exceeds 10 days, and in babies (BNF information on clindamycin).
Glycopeptide (for example, vancomycin and teicoplanin) doses are based on body weight. Therapeutic drug monitoring and monitoring of various patient parameters (including blood count, urinalysis, auditory function, hepatic function and renal function) is recommended depending on the particular glycopeptide (BNF information on vancomycin).
Severe optic neuropathy can occur with linezolid, particularly if used for longer than 28 days. Blood disorders have also been reported and weekly full blood counts are recommended (BNF information on linezolid).
See the EMC's summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
Data on adverse events in the included studies were limited because of cellulitis or erysipelas often being a subgroup in larger skin and skin structure infection studies, where adverse event data were presented for the whole study and not cellulitis or erysipelas subgroups.
There were no differences in the adverse events of the following antibiotic comparisons in adults or children with cellulitis or erysipelas:
-ral cefazolin compared with IV ceftriaxone (Kilburn et al. 2010)
-ral cefalexin plus oral co‑trimoxazole compared with oral cefalexin alone (Bowen et al. 2017)
-ral cefalexin or oral clindamycin compared with IV cefazolin or IV clindamycin (Aboltins et al. 2015)
-ral levofloxacin for 5 days compared with 10 days (Kilburn et al. 2010)
IV ceftriaxone compared with IV flucloxacillin (Kilburn et al. 2010)
IV daptomycin compared with IV vancomycin (Pertel et al. 2009).
Some differences were seen for some adverse event outcomes for the following antibiotic comparisons in adults or children with cellulitis or erysipelas:
flucloxacillin plus clindamycin was significantly worse for adverse events (most commonly diarrhoea) compared with flucloxacillin alone (Brindle et al. 2017)
IV penicillin was significantly worse for adverse events (no details provided) compared with intramuscular penicillin (Kilburn et al. 2010).
Based on 2 systematic reviews (Bowen et al. 2017 and Kilburn et al. 2010) and 3 RCTs (Brindle et al. 2017, Pertel et al. 2009 and Aboltins et al. 2015).
The committee noted that most antibiotics compared with another antibiotic showed no difference in clinical outcomes in adults or children. The committee also noted that dual therapy was no more effective than single antibiotic therapy in adults. Adverse event data were very limited and there were no differences in adverse events between most of the antibiotic comparisons. Given the very limited amount of evidence in children, the committee agreed that antibiotic choice for children can be extrapolated from the choice for adults.
The committee agreed based on their experience that choice of antibiotic treatment should be based on the severity of symptoms and the risk of developing complications, while minimising the risk of the development of antibiotic resistance.
The committee discussed that in practice, erysipelas can often be difficult to tell apart from cellulitis and recognised that both infections may be caused by Streptococcus pyogenes or Staphylococcus aureus, although there is uncertainty around the evidence for erysipelas, which may be more associated with streptococcus. Therefore, management of both infections, with regard to antibiotic choice, is the same.
The committee were aware that severity scoring tools (for example, Eron 2000 and 'Dundee' Koerner and Johnson 2010) have been developed and may be used in practice. However, these have not to date been used in randomised clinical trials. The committee agreed that recommendations for antibiotic treatment should reflect the available evidence and provide guidance on oral and intravenous treatment because this would fit with current severity scoring tools and the risks of developing complications without needing evidence of the effectiveness of such tools.
The committee agreed that the evidence for dual therapy (a combination of 2 antibiotics) showed no benefit over monotherapy for treating cellulitis or erysipelas, and dual therapy should not be routinely used given the increased risk of antimicrobial resistance and more adverse effects.
The committee agreed based on the evidence, their experience and resistance data that the first-choice oral antibiotic should be flucloxacillin (a relatively narrow-spectrum penicillin). The committee discussed that flucloxacillin has activity against Staphylococcus aureus (because it is not inactivated by penicillinases produced by staphylococci) and Streptococcus pyogenes. They also agreed that this would be the first-choice antibiotic for people with recurrent infection, because the risk of resistance to flucloxacillin is very low. The only exception would be people with a suspected or confirmed meticillin-resistant Staphylococcus aureus (MRSA) infection, but the committee discussed that the likelihood of such a cellulitis or erysipelas infection with MRSA is very low. The committee agreed that flucloxacillin has poor oral bioavailability and in people with cellulitis or erysipelas who could have impaired circulation (such as people with diabetes or venous insufficiency), a higher (off label) dose of up to 1 g four times a day may be needed to adequately treat the infection. The committee were aware that a narrow-spectrum penicillin with a specific antistreptococcal penicillin is sometimes prescribed for cases of cellulitis or erysipelas, because these infections can involve either streptococci or staphylococci, but there is no evidence that dual therapy is more effective than, for example, flucloxacillin alone. Additionally, the committee considered that dual therapy may increase the risk of antimicrobial resistance and adverse effects.
The committee agreed that oral macrolides, clarithromycin or erythromycin (in pregnancy), are suitable alternatives to flucloxacillin in people who have penicillin allergy or where flucloxacillin is not a suitable option. Oral macrolide antibiotics were shown to be at least as effective as an oral penicillin in studies and have a similar spectrum of activity to that of a penicillin. There was limited, very low quality, evidence that oral macrolides or oral streptogramins were more effective than a penicillin (oral or IV). However, the committee considered this evidence was limited because oral macrolides and oral streptogramins were analysed together, not as separate classes. Additionally, the oral streptogramin (pristinamycin) and the only oral penicillin (cloxacillin) used in the studies are not licensed in the UK. There was no head-to-head comparison of either oral macrolides or oral streptogramins with flucloxacillin.
The committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
The committee also discussed and agreed that doxycycline (an oral tetracycline) may be useful for people over 12 years who have penicillin allergy or if flucloxacillin is unsuitable. Despite a lack of evidence found for its use, doxycycline is commonly used as an alternative to flucloxacillin for cellulitis and erysipelas in UK practice.
The committee discussed and agreed based on limited evidence and their experience that for infection near the eyes or nose (the triangle from the bridge of the nose to the corners of the mouth, or immediately around the eyes), the first-choice oral antibiotic should be the broader-spectrum antibiotic, co‑amoxiclav (a penicillin with a beta-lactamase inhibitor). This is because of the risk of a serious intracranial complication in the event of treatment failure, and because co‑amoxiclav provides cover for Haemophilus and anaerobic bacteria. The committee agreed this extended-spectrum antibiotic was needed to prevent treatment failure and reduce complications of infection in people who are at higher risk because of the location and nature of the infection, and the possibility of uncommon pathogens. For people with infection around the eyes or nose, consulting a specialist was recommended because of the particular risk of complications with this infection site.
The committee also agreed that co‑amoxiclav could be used as an alternative first-choice antibiotic in children without penicillin allergy if flucloxacillin was unsuitable. However, if flucloxacillin is only not suitable because of poor palatability of the oral solution, the committee agreed that flucloxacillin capsules should be considered because children can often take tablets or capsules if they are supported to do this (see Medicines for Children leaflet on helping your child to swallow tablets).
The committee discussed and agreed based on their experience that although routine dual therapy was not recommended, clarithromycin (a macrolide) with metronidazole (an antibiotic with high activity against anaerobic bacteria) is a suitable alternative to co‑amoxiclav in adults with infection near the eyes or nose, if co‑amoxiclav is not suitable or there is penicillin allergy. In children, the committee discussed that anaerobic bacteria are less of a concern and that clarithromycin alone may be sufficient. However, if anaerobes are suspected, the addition of metronidazole was recommended.
The committee agreed based on evidence, their experience and resistance data that the first-choice intravenous antibiotic for people unable to take oral antibiotics or who are severely unwell should be the relatively narrow-spectrum penicillin, flucloxacillin. If flucloxacillin is unsuitable, intravenous clarithromycin is recommended, with intravenous co‑amoxiclav an option for infection near the eyes or nose or severe infection.
Based on evidence, their experience and resistance data, the committee also agreed to recommend the following alternative antibiotics for people with severe infection:
cefuroxime
clindamycin
ceftriaxone (in adults for ambulatory care only).They discussed that other antibiotics may also be appropriate, particularly in ambulatory care for specific people or populations, and prescribers should seek specialist, local advice.
In cases of suspected or confirmed MRSA infection, vancomycin, teicoplanin or if these cannot be used, for specialist use, linezolid, were recommended. They also noted that other antibiotics may be appropriate based on microbiological results and specialist advice.
# Antibiotic dose frequency
There was no difference in the clinical effectiveness of the following antibiotic comparison in adults with cellulitis or erysipelas:
-ral cefalexin four times a day compared with twice a day, using the same total daily dose.
Based on 1 systematic review (Kilburn et al. 2010).
No systematic reviews or randomised controlled trials in children met the inclusion criteria.
# Antibiotic course length
There were no differences in the clinical effectiveness of the following antibiotic comparisons in adults with cellulitis:
-ral tedizolid for 6 days compared with 10 days (Hanretty et al. 2018)
-ral levofloxacin for 5 days compared with 10 days (Kilburn et al. 2010).
Based on 2 systematic reviews (Hanretty et al. 2018 and Kilburn et al. 2010).
No systematic reviews or randomised controlled trials in children met the inclusion criteria.
# Antibiotic route of administration
There were no differences in the clinical effectiveness of the following antibiotic comparisons in adults with cellulitis:
-ral cefalexin or oral clindamycin compared with IV cefazolin or IV clindamycin (Aboltins et al. 2015)
IV benzylpenicillin compared with intramuscular benzylpenicillin (Kilburn et al. 2010).
Based on 1 systematic review (Kilburn et al. 2010) and 1 RCT (Aboltins et al. 2015).
No systematic reviews or randomised controlled trials in children met the inclusion criteria.
## Committee discussion on antibiotic dose frequency, course length and route of administration
The committee acknowledged that there was very limited evidence identified for antibiotic dose frequency.
The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of side effects.
Based on limited evidence and their experience, the committee agreed that a shorter course of antibiotics was generally as effective as a longer course of antibiotics for cellulitis or erysipelas, and a 5- to 7‑day course was sufficient for most people. However, the committee noted that only 1 RCT (Brindle et al. 2017) used flucloxacillin for 5 days and the authors expressed doubts about the quality of their data for dose and duration. Therefore, the committee discussed that the decision of whether a 5‑day or a 7‑day course was given would be based on clinical judgement of individual cases. The committee discussed that a longer course (up to 14 days in total) may be needed for some people based on a clinical assessment of their symptoms and history. However, skin does take some time to return to normal, even after an effective course of antibiotics, and a full resolution of symptoms at 5 to 7 days would not be expected.
Based on limited evidence, the committee agreed that oral antibiotics were as effective as intravenous antibiotics for treating cellulitis and erysipelas.
In line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that oral antibiotics should be used in preference to intravenous antibiotics where possible. Intravenous antibiotics should only be used for people who are severely ill, unable to tolerate oral treatment, or where oral treatment would not provide adequate coverage or tissue penetration.
The use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible, for a total of 5 to 7 days. Again, a longer course (up to 14 days in total) may be needed for some people based on clinical assessment.
# Antibiotic prophylaxis for the prevention of recurrent cellulitis and erysipelas
Antibiotic prophylaxis (with an intramuscular or oral penicillin, or oral erythromycin) significantly lowered the risk of recurrence of cellulitis or erysipelas compared with no treatment or placebo in a meta-analysis of 5 RCTs in adults (approximately 46 to 70 years) with 1 or 2 previous episodes of cellulitis or erysipelas in the past 3 months to 3 years depending on the RCT.
Antibiotic prophylaxis significantly lowered the incidence rate (episodes per person month) compared with no treatment or placebo in a meta-analysis of 4 RCTs in adults with 1 or 2 previous episodes of cellulitis or erysipelas.
Antibiotic prophylaxis significantly lowered the risk of an episode (time to next episode) of cellulitis or erysipelas compared with no treatment or placebo in a meta-analysis of 3 RCTs in adults with 1 or 2 previous episodes of cellulitis or erysipelas.
Antibiotic prophylaxis was not significantly different to no treatment or placebo for mortality or risk of hospitalisation in adults with 1 or 2 previous episodes of cellulitis or erysipelas.
There were no differences in the adverse events of antibiotic prophylaxis compared with no treatment or placebo in adults with cellulitis or erysipelas.
Based on 1 systematic review (Dalal et al. 2017).
No systematic reviews or randomised controlled trials in children met the inclusion criteria.
## Committee discussion on antibiotic prophylaxis of recurrent cellulitis or erysipelas
The committee noted that recurrence is not uncommon in people who have had cellulitis or erysipelas. The committee also noted the limitations of the evidence for antibiotic prophylaxis, which was in adults only and mainly related to lower limb cellulitis. There was variation in the populations in the included studies for the number of previous episodes (1 or 2) and the time periods over which recurrence was defined (up to 3 years).
The committee discussed the evidence for prophylactic antibiotics in adults. Overall, antibiotics reduced the risk of cellulitis or erysipelas recurring but did not reduce the risk of hospitalisation or mortality, and the long-term effects on antibiotic resistance are unknown.
The committee agreed based on evidence and experience that antibiotic prophylaxis should not be routinely offered to prevent recurrent cellulitis or erysipelas because of the balance of risks and benefits in the overall population.
However, they agreed based on evidence and experience that a trial of antibiotic prophylaxis could be considered for a higher-risk population, which the committee defined as adults who have had at least 2 separate episodes of cellulitis or erysipelas in the previous 12 months, which were managed in hospital, or where the care was under specialist advice. The populations in the antibiotic prophylaxis trials were more varied (having 1 or 2 previous episodes over up to 3 years), but the committee wanted to ensure that prophylaxis would only be considered for those at highest risk.
The committee agreed that prophylaxis should only be considered following a discussion between a specialist and the person to ensure shared decision making, and should be reviewed every 6 months. Prophylaxis may be appropriate in this higher-risk population because the benefits of prophylaxis may outweigh the risks. However, it is important to ensure that the previous episodes of cellulitis and erysipelas have been correctly diagnosed, any underlying condition (such as oedema, diabetes or venous insufficiency) is being managed optimally, and prophylaxis is reviewed at least every 6 months.
The choice of antibiotic was low-dose phenoxymethylpenicillin, which was used in most of the trials in the systematic review, or low-dose erythromycin in penicillin allergy, which was used in 1 trial in the systematic review. The committee discussed that alternative antibiotics may be appropriate with specialist advice, and that choice should be based on recent microbiological results where possible. Based on their experience and resistance data, the committee agreed that using the same antibiotic for treatment and prophylaxis should be avoided.
The committee recognised the importance of reviewing antibiotic prophylaxis, and considered that up to every 6 months was reasonable based on possible adverse effects of antibiotics, the risk of resistance with long-term antibiotics, the possible need for any further investigations if recurrence of cellulitis or erysipelas, and to allow time to assess treatment success. People should also know to seek medical help if cellulitis or erysipelas recurs despite taking prophylaxis.
To reduce the risk of antimicrobial resistance, the committee agreed that each review should include a discussion around the success of prophylaxis and whether antibiotics should be continued, stopped or changed, taking into account the person's preferences for antibiotic use and the potential risk of antimicrobial resistance with long-term use of antibiotics. If treatment failure occurs and cellulitis or erysipelas recurs, the committee agreed that antibiotic prophylaxis should be stopped or changed to an alternative prophylactic antibiotic once the acute infection has been treated.
No recommendation for antibiotic prophylaxis in children was made because there was no evidence in this population.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).
# Resource implications
Recommended antibiotics are available as generic formulations. See Drug Tariff or BNF for costs.
See the evidence review for more information.
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{'Recommendations': "# Managing cellulitis and erysipelas\n\n## Treatment\n\nTo ensure that cellulitis and erysipelas are treated appropriately, exclude other causes of skin redness such as:\n\nan inflammatory reaction to an immunisation or an insect bite or\n\na non-infectious cause such as chronic venous insufficiency.\n\nConsider taking a swab for microbiological testing from people with cellulitis or erysipelas to guide treatment, but only if the skin is broken and:\n\nthere is a penetrating injury or\n\nthere has been exposure to water-borne organisms or\n\nthe infection was acquired outside the UK.\n\nBefore treating cellulitis or erysipelas, consider drawing around the extent of the infection with a single-use surgical marker pen to monitor progress. Be aware that redness may be less visible on darker skin tones.\n\nOffer an antibiotic for people with cellulitis or erysipelas. When choosing an antibiotic (see the recommendations on choice of antibiotic), take account of:\n\nthe severity of symptoms\n\nthe site of infection (for example, near the eyes or nose)\n\nthe risk of uncommon pathogens (for example, from a penetrating injury, after exposure to water-borne organisms, or an infection acquired outside the UK)\n\nprevious microbiological results from a swab\n\nthe person's meticillin-resistant Staphylococcus aureus (MRSA) status if known.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nIf intravenous antibiotics are given, review by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nManage any underlying condition that may predispose to cellulitis or erysipelas, for example:\n\ndiabetes\n\nvenous insufficiency\n\neczema\n\noedema, which may be an adverse effect of medicines such as calcium channel blockers.\n\n## Advice\n\nWhen prescribing antibiotics for cellulitis or erysipelas, give advice about:\n\npossible adverse effects of antibiotics\n\nthe skin taking some time to return to normal after the course of antibiotics has finished\n\nseeking medical help if symptoms worsen rapidly or significantly at any time, or do not start to improve within 2\xa0to 3\xa0days.\n\n## Reassessment\n\nReassess people with cellulitis or erysipelas if symptoms worsen rapidly or significantly at any time, do not start to improve within 2\xa0to 3\xa0days, or the person:\n\nbecomes systemically very unwell or\n\nhas severe pain out of proportion to the infection or\n\nhas redness or swelling spreading beyond the initial presentation (taking into account that some initial spreading may occur, and that redness may be less visible on darker skin tones), see the recommendation on drawing around the extent of the infection in the section on treatment.\n\nWhen reassessing people with cellulitis or erysipelas, take account of:\n\nother possible diagnoses, such as an inflammatory reaction to an immunisation or an insect bite, gout, superficial thrombophlebitis, eczema, allergic dermatitis or deep vein thrombosis\n\nany underlying condition that may predispose to cellulitis or erysipelas, such as oedema, diabetes, venous insufficiency or eczema\n\nany symptoms or signs suggesting a more serious illness or condition, such as lymphangitis, orbital cellulitis, osteomyelitis, septic arthritis, necrotising fasciitis or sepsis\n\nany results from microbiological testing\n\nany previous antibiotic use, which may have led to resistant bacteria.\n\nConsider taking a swab for microbiological testing from people with cellulitis or erysipelas if the skin is broken and this has not been done already.\n\nIf a swab has been sent for microbiological testing:\n\nreview the choice of antibiotic(s) when results are available and\n\nchange the antibiotic(s) according to results if symptoms or signs of the infection are not improving, using a narrow-spectrum antibiotic if possible.\n\n## Referral and seeking specialist advice\n\nRefer people to hospital if they have any symptoms or signs suggesting a more serious illness or condition, such as orbital cellulitis, osteomyelitis, septic arthritis, necrotising fasciitis or sepsis.\n\nConsider referring people with cellulitis or erysipelas to hospital, or seek specialist advice, if they:\n\nare severely unwell or\n\nhave infection near the eyes or nose (including periorbital cellulitis) or\n\ncould have uncommon pathogens, for example, after a penetrating injury, exposure to water-borne organisms, or an infection acquired outside the UK or\n\nhave spreading infection that is not responding to oral antibiotics or\n\nlymphangitis or\n\ncannot take oral antibiotics (exploring locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, where appropriate).\n\nFor a short explanation of why the committee made these recommendations, see the summary of the evidence on managing cellulitis and erysipelas.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic for cellulitis or erysipelas, follow:\n\ntable 1 for adults aged 18\xa0years and over\n\ntable 2 for children and young people under 18\xa0years.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice antibiotic (give orally unless person unable to take oral or severely unwell)\n\nFlucloxacillin (5\xa0to 7\xa0days):\n\nmg to 1\xa0g four times a day orally\n\nor 1\xa0g to 2\xa0g four times a day intravenously\n\nIn September 2019, 1\xa0g orally four times a day was off label. See NICE's information on prescribing medicines.\n\nAlternative first-choice antibiotics for penicillin allergy or if flucloxacillin is unsuitable (give orally unless person unable to take oral or severely unwell)\n\nClarithromycin (5\xa0to 7\xa0days):\n\nmg twice a day orally\n\nor 500\xa0mg twice a day intravenously\n\n\n\nErythromycin (in pregnancy; 5\xa0to 7\xa0days):\n\nmg four times a day orally\n\n\n\nDoxycycline (5\xa0to 7\xa0days in total):\n\nmg on the first day then 100\xa0mg once a day orally\n\nFirst-choice antibiotic if infection is near the eyes or nose (consider seeking specialist advice; give orally unless person unable to take oral or severely unwell)\n\nCo‑amoxiclav (7\xa0days):\n\n/125\xa0mg three times a day orally\n\nor 1.2\xa0g three times a day intravenously\n\nAlternative first-choice antibiotics if infection is near the eyes or nose for penicillin allergy or if co‑amoxiclav is unsuitable (consider seeking specialist advice; give orally unless person unable to take oral or severely unwell)\n\nClarithromycin (7\xa0days):\n\nmg twice a day orally\n\nor 500\xa0mg twice a day intravenously\n\nwith\n\nMetronidazole (7\xa0days):\n\nmg three times a day orally\n\nor 500\xa0mg three times a day intravenously\n\nAlternative choice antibiotics for severe infection\n\nCo‑amoxiclav (7\xa0days):\n\n/125\xa0mg three times a day orally\n\nor 1.2\xa0g three times a day intravenously\n\n\n\nCefuroxime (7\xa0days):\n\nmg to 1.5\xa0g three or four times a day intravenously\n\n\n\nClindamycin (7\xa0days):\n\nmg to 300\xa0mg four times a day (can be increased to 450\xa0mg four times a day) orally\n\nor 600\xa0mg to 2.7\xa0g daily intravenously in two to four divided doses, increased if necessary in life-threatening infection to 4.8\xa0g daily (maximum per dose 1.2\xa0g)\n\n\n\nCeftriaxone (7\xa0days; only for ambulatory care; other antibiotics may be appropriate based on microbiological results and specialist advice):\n\ng once a day intravenously\n\nAntibiotics to be added if meticillin-resistant \n \n Staphylococcus aureus\n \n infection is suspected or confirmed (combination therapy with an antibiotic listed above; other antibiotics may be appropriate based on microbiological results and specialist advice)\n\nVancomycin:\n\nmg/kg to 20\xa0mg/kg two or three times a day intravenously (maximum 2\xa0g per dose), adjusted according to serum vancomycin concentration (see the British national formulary [BNF] for information on monitoring)\n\n\n\nTeicoplanin:\n\nInitially 6\xa0mg/kg every 12\xa0hours for three doses, then 6\xa0mg/kg once a day intravenously (see the BNF for information on monitoring)\n\n\n\nLinezolid (if vancomycin or teicoplanin cannot be used; specialist use only):\n\nmg twice a day orally or\n\nmg twice a day intravenously (see the BNF for information on monitoring)\n\nSee the BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, where appropriate, intramuscular) antibiotics.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their symptoms does not warrant intravenous antibiotics. If intravenous antibiotics are given, review by 48\xa0hours and consider switching to oral antibiotics, if possible.\n\nA longer course length (up to 14\xa0days in total) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 5\xa0to 7\xa0days is not expected.\n\nInfection around the eyes or the nose (the triangle from the bridge of the nose to the corners of the mouth, or immediately around the eyes including periorbital cellulitis) is of more concern because of risk of a serious intracranial complication.\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nChildren under 1\xa0month\n\nAntibiotic choice based on specialist advice\n\nFirst-choice antibiotic for children aged 1\xa0month and over (give orally unless person unable to take oral or severely unwell)\n\nFlucloxacillin (5\xa0to 7\xa0days):\n\nmonth to 1\xa0year, 62.5\xa0mg to 125\xa0mg four times a day orally\n\nyears to 9\xa0years, 125\xa0mg to 250\xa0mg four times a day orally\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg four times a day orally\n\nor 1\xa0month to 17\xa0years, 12.5\xa0mg/kg to 25\xa0mg/kg four times a day intravenously (maximum 1\xa0g four times a day)\n\nAlternative first-choice antibiotics for penicillin allergy or if flucloxacillin unsuitable (give orally unless person unable to take oral or severely unwell)\n\nCo‑amoxiclav (not in penicillin allergy; 5\xa0to 7\xa0days):\n\nmonth to 11\xa0months, 0.25\xa0ml/kg of 125/31 suspension three times a day orally (dose doubled in severe infection)\n\nyear to 5\xa0years, 0.25\xa0ml/kg or 5\xa0ml of 125/31 suspension three times a day orally (dose doubled in severe infection)\n\nyears to 11\xa0years, 0.15\xa0ml/kg or 5\xa0ml of 250/62 suspension three times a day orally (dose doubled in severe infection)\n\nyears to 17\xa0years, 250/125 mg or 500/125 mg three times a day orally\n\nor 1\xa0month to 2\xa0months, 30\xa0mg/kg twice a day intravenously\n\nmonths to 17\xa0years, 30\xa0mg/kg three times a day intravenously (maximum 1.2\xa0g three times a day)\n\n\n\nClarithromycin (5 to 7 days):\n\nmonth to 11\xa0years:\n\nunder 8\xa0kg, 7.5\xa0mg/kg twice a day orally\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day orally\n\nkg to 19\xa0kg, 125\xa0mg twice a day orally\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day orally\n\nkg to 40\xa0kg, 250\xa0mg twice a day orally\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg twice a day orally\n\nor 1\xa0month to 11\xa0years, 7.5\xa0mg/kg twice a day intravenously (maximum 500\xa0mg per dose)\n\nyears to 17\xa0years, 500\xa0mg twice a day intravenously\n\n\n\nErythromycin (in pregnancy; 5\xa0to 7\xa0days):\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg four times a day orally\n\nFirst-choice antibiotic if infection near the eyes or nose (consider seeking specialist advice; give orally unless person unable to take oral or severely unwell)\n\nCo‑amoxiclav (7\xa0days):\n\nmonth to 11\xa0months, 0.25\xa0ml/kg of 125/31 suspension three times a day orally (dose doubled in severe infection)\n\nyear to 5\xa0years, 0.25\xa0ml/kg or 5\xa0ml of 125/31 suspension three times a day orally (dose doubled in severe infection)\n\nyears to 11\xa0years, 0.15\xa0ml/kg or 5\xa0ml of 250/62 suspension three times a day orally (dose doubled in severe infection)\n\nyears to 17\xa0years, 250/125\xa0mg or 500/125\xa0mg three times a day orally\n\nor 1\xa0month to 2\xa0months, 30\xa0mg/kg twice a day intravenously\n\nmonths to 17\xa0years, 30\xa0mg/kg three times a day intravenously (maximum 1.2\xa0g three times a day)\n\nAlternative first-choice antibiotics if infection near the eyes or nose for penicillin allergy or if co‑amoxiclav unsuitable (consider seeking specialist advice; give orally unless person unable to take oral or severely unwell)\n\nClarithromycin (7\xa0days):\n\nmonth to 11\xa0years:\n\nunder 8\xa0kg, 7.5\xa0mg/kg twice a day orally\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day orally\n\nkg to 19\xa0kg, 125\xa0mg twice a day orally\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day orally\n\nkg to 40\xa0kg, 250\xa0mg twice a day orally\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg twice a day orally\n\nor 1\xa0month to 11\xa0years, 7.5\xa0mg/kg twice a day intravenously (maximum 500\xa0mg per dose)\n\nyears to 17\xa0years, 500\xa0mg twice a day intravenously\n\nwith (if anaerobes suspected)\n\nMetronidazole (7\xa0days):\n\nmonth, 7.5\xa0mg/kg twice a day orally\n\nmonths to 11\xa0years, 7.5\xa0mg/kg three times a day orally (maximum per dose 400\xa0mg)\n\nyears to 17\xa0years, 400\xa0mg three times a day orally\n\nor 1\xa0month, loading dose 15\xa0mg/kg, then (after 8\xa0hours) 7.5\xa0mg/kg three times a day intravenously\n\nmonths to 17\xa0years, 7.5\xa0mg/kg three times a day intravenously (maximum per dose 500\xa0mg)\n\nAlternative choice antibiotics for severe infection (other antibiotics may be appropriate based on microbiological results and specialist advice)\n\nCo‑amoxiclav (7\xa0days):\n\nmonth to 11\xa0months, 0.25\xa0ml/kg of 125/31 suspension three times a day orally (dose can be doubled)\n\nyear to 5\xa0years, 0.25\xa0ml/kg or 5\xa0ml of 125/31 suspension three times a day orally (dose can be doubled)\n\nyears to 11\xa0years, 0.15\xa0ml/kg or 5\xa0ml of 250/62 suspension three times a day orally (dose can be doubled)\n\nyears to 17\xa0years, 250/125\xa0mg or 500/125\xa0mg three times a day orally\n\nor 1\xa0month to 2\xa0months, 30\xa0mg/kg twice a day intravenously\n\nmonths to 17\xa0years, 30\xa0mg/kg three times a day intravenously (maximum 1.2\xa0g three times a day)\n\n\n\nCefuroxime (7\xa0days):\n\nmonth to 17\xa0years, 20\xa0mg/kg three times a day intravenously (maximum 750\xa0mg per dose), can be increased to 50\xa0mg/kg to 60\xa0mg/kg three or four times a day intravenously (maximum 1.5\xa0g per dose)\n\n\n\nClindamycin (7\xa0days):\n\nmonth to 17\xa0years, 3\xa0mg/kg to 6\xa0mg/kg four times a day orally (maximum per dose 450\xa0mg)\n\nor 1\xa0month to 17\xa0years, 3.75\xa0mg/kg to 6.25\xa0mg/kg four times a day intravenously, increased if necessary, in life-threatening infection to 10\xa0mg/kg four times a day intravenously (maximum per dose 1.2\xa0g); total daily dose may alternatively be given in three divided doses (maximum per dose 1.2\xa0g)\n\nAntibiotics to be added if meticillin-resistant \n \n Staphylococcus aureus\n \n infection is suspected or confirmed (combination therapy with an antibiotic listed above; other antibiotics may be appropriate based on microbiological results and specialist advice)\n\nVancomycin:\n\nmonth to 11\xa0years, 10\xa0mg/kg to 15\xa0mg/kg four times a day intravenously, adjusted according to serum vancomycin concentration\n\nyears to 17\xa0years, 15\xa0mg/kg to 20\xa0mg/kg two or three times a day intravenously (maximum 2\xa0g per dose), adjusted according to serum vancomycin concentration\n\n(see the British national formulary for children [BNFC] for information on monitoring)\n\n\n\nTeicoplanin:\n\nmonth, initially 16\xa0mg/kg for one dose, then (after 24\xa0hours) 8\xa0mg/kg once a day intravenously\n\nmonths to 11\xa0years, initially 10\xa0mg/kg every 12\xa0hours for three\xa0doses, then 6\xa0mg/kg to 10\xa0mg/kg once a day intravenously\n\nyears to 17\xa0years, initially 6\xa0mg/kg every 12\xa0hours for three doses, then 6\xa0mg/kg once a day intravenously\n\n(see the BNFC for information on monitoring)\n\n\n\nLinezolid (if vancomycin or teicoplanin cannot be used; specialist use only):\n\nmonth to 11\xa0years, 10\xa0mg/kg three times a day orally (maximum 600\xa0mg per dose)\n\nyears to 17\xa0years, 600\xa0mg twice a day orally\n\nor 1\xa0month to 11\xa0years, 10\xa0mg/kg three times a day intravenously (maximum 600\xa0mg per dose)\n\nyears to 17\xa0years, 600\xa0mg twice a day intravenously\n\nIn September 2019, the use of linezolid in children and young people under 18\xa0years was off label. See NICE's information on prescribing medicines.\n\n(see the BNFC for information on monitoring)\n\nSee the BNFC for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, where appropriate, intramuscular) antibiotics.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands with other factors, such as the severity of the condition and the child's size in relation to the average size of children of the same age.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their symptoms does not warrant intravenous antibiotics. If intravenous antibiotics are given, review by 48\xa0hours and consider switching to oral antibiotics, if possible.\n\nA longer course length (up to 14\xa0days in total) may be needed based on clinical assessment. However, skin does take some time to return to normal, and full resolution of symptoms at 5\xa0to 7\xa0days is not expected.\n\nIf flucloxacillin oral solution is not tolerated because of poor palatability, consider capsules (see the Medicines for Children leaflet on helping your child to swallow tablets).\n\nCo‑amoxiclav 400/57\xa0suspension may also be considered to allow twice daily dosing (see the BNFC for dosing information).\n\nInfection around the eyes or the nose (the triangle from the bridge of the nose to the corners of the mouth, or immediately around the eyes including periorbital cellulitis) is of more concern because of risk of a serious intracranial complication.\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nFor a short explanation of why the committee made this recommendation, see the summary of the evidence on choice of antibiotics, antibiotic dose frequency, antibiotic course length and antibiotic route of administration.\n\nFull details of the evidence are in the evidence review.\n\n# Preventing recurrent cellulitis or erysipelas\n\nDo not routinely offer antibiotic prophylaxis to prevent recurrent cellulitis or erysipelas. Give advice about seeking medical help if symptoms of cellulitis or erysipelas develop.\n\nFor adults who have had treatment in hospital, or under specialist advice, for at least 2\xa0separate episodes of cellulitis or erysipelas in the previous 12\xa0months, specialists may consider a trial of antibiotic prophylaxis. Involve the person in a shared decision by discussing and taking account of:\n\nthe severity and frequency of previous symptoms\n\nthe risk of developing complications\n\nunderlying conditions (such as oedema, diabetes or venous insufficiency) and their management\n\nthe risk of resistance with long-term antibiotic use\n\nthe person's preference for antibiotic use.\n\nWhen choosing an antibiotic for prophylaxis (see the recommendations on choice of antibiotic prophylaxis), take account of any previous microbiological results and previous antibiotic use.\n\nWhen antibiotic prophylaxis is given, give advice about:\n\npossible adverse effects of long-term antibiotics\n\nreturning for review within 6\xa0months\n\nseeking medical help if symptoms of cellulitis or erysipelas recur.\n\nReview antibiotic prophylaxis for recurrent cellulitis or erysipelas at least every 6\xa0months. The review should include:\n\nassessing the success of prophylaxis\n\ndiscussing continuing, stopping or changing prophylaxis (taking into account the person's preferences for antibiotic use and the risk of antimicrobial resistance).Stop or change the prophylactic antibiotic to an alternative if cellulitis or erysipelas recurs (see recommendation\xa01.1.4 in the section on treatment for treatment of acute infection).\n\nFor a short explanation of why the committee made these recommendations, see the summary of the evidence on antibiotic prophylaxis for the prevention of recurrent cellulitis and erysipelas.\n\nFull details of the evidence are in the evidence review.\n\n# Choice of antibiotic prophylaxis\n\nWhen prescribing an antibiotic to prevent recurrent cellulitis or erysipelas in adults, specialists should follow table\xa03.\n\nProphylaxis\n\nAntibiotic and dosage\n\nFirst choice\n\nChoose antibiotics according to recent microbiological results when possible, and avoid using the same antibiotic for treatment and prophylaxis\n\nPhenoxymethylpenicillin:\n\nmg orally twice a day\n\nAlternative first choice for penicillin allergy\n\nChoose antibiotics according to recent microbiological results when possible, and avoid using the same antibiotic for treatment and prophylaxis\n\nErythromycin:\n\nmg orally twice a day\n\nSee the BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, in pregnancy and breastfeeding.\n\nFor a short explanation of why the committee made this recommendation, see the summary of the evidence on antibiotic prophylaxis for the prevention of recurrent cellulitis and erysipelas.\n\nFull details of the evidence are in the evidence review.\n\n# Terms used in the guideline\n\n## Ambulatory care\n\nClinical care that may include diagnosis, observation, treatment and rehabilitation not provided within the traditional hospital bed base or within the traditional outpatient services that can be provided across primary/secondary care.\n\n## Cellulitis and erysipelas\n\nInfections of the tissues under the skin (subcutaneous), which usually result from contamination of a break in the skin. Both conditions are characterised by acute localised inflammation and oedema, with lesions more superficial in erysipelas with a well-defined, raised margin (World Health Organization, WHO model prescribing information: drugs used in skin diseases, bacterial infections, staphylococcal and streptococcal infections).", 'Summary of the evidence': "This is a summary of the evidence. For full details, see the evidence review.\n\n# Managing cellulitis and erysipelas\n\nCellulitis and erysipelas are infections of the tissues under the skin, which are treated with antibiotics.\n\nThe main bacteria causing cellulitis and erysipelas are Streptococcus pyogenes and Staphylococcus aureus, but infection can also be caused by Streptococcus pneumoniae, Haemophilus influenza, gram-negative bacilli and anaerobes (NICE clinical knowledge summary on cellulitis).\n\nThe evidence identified in this guideline was for antibiotics compared with other antibiotics for managing non-surgically acquired cellulitis or erysipelas in adults, young people and children. Most studies did not report the site of infection, but where this was reported, most cases had a lower limb infection or less frequently an upper limb infection. One systematic review excluded a study of facial cellulitis.\n\n## Committee discussion on managing cellulitis and erysipelas\n\nThe committee discussed that to ensure the appropriate treatment of cellulitis and erysipelas, it is important to exclude other causes of skin redness (erythema). This can often be caused by an inflammatory reaction, for example, following an immunisation or an insect bite, or any other non-infective cause such as chronic venous insufficiency, which could be wrongly treated as cellulitis or erysipelas.\n\nThe committee discussed that in most cases microbiological swabbing of cellulitis or erysipelas yields negative results (particularly if the skin is intact) and in most cases the infecting organism is likely to be either Streptococcus pyogenes or Staphylococcus aureus bacteria. They therefore agreed that swabbing should not be undertaken routinely. However, the committee agreed that where the skin is broken and there is reason to believe a different organism may be involved (for example, if there is a penetrating injury, exposure to water-borne organisms, or infection acquired outside the UK), then a swab may be useful to guide antibiotic treatment.\n\nThe committee agreed based on experience that to monitor the progression of cellulitis or erysipelas, and help assess the effectiveness of antibiotic treatment, it may be useful to draw around the extent of the infected area using a single-use surgical marker pen before treatment. The committee discussed that a single-use surgical pen should be used because it is designed for this purpose (unlike other pen types that may damage skin or leave permanent marking) and would not risk cross-infection. The committee noted that in people with certain conditions (for example, lymphoedema), drawing around the infected area may be difficult or not possible because the rash may be ill-defined. Additionally, they noted that the extent of redness may be less visible on darker skin tones.\n\nThe committee agreed that it may take time for antibiotic treatment to take effect, and initially redness or swelling may extend beyond the marked line (if used).\n\nThe committee agreed that, in line with the NICE guideline on antimicrobial stewardship, prescribers should provide 'safety netting' advice to people with cellulitis or erysipelas about when to seek further help if they become more unwell or have side effects of antibiotic treatment, and also discuss that skin can take some time to return to normal even after a course of effective antibiotics. The committee was aware that the time taken for skin to return to normal appearance is variable. In their experience, it could be a number of weeks. Because no data were available to affirm this, the committee agreed not to specify a timescale.\n\nThe committee agreed that if a person's symptoms worsen rapidly or significantly at any time they should be reassessed, taking into account other possible diagnoses, the development of serious complications, such as orbital cellulitis, septic arthritis, osteomyelitis, lymphangitis, necrotising fasciitis or sepsis, and the possibility of an uncommon or resistant bacteria. The committee also agreed that reassessment should include managing any underlying condition that may predispose to cellulitis or erysipelas.\n\nThe committee agreed that taking a swab for microbiological testing should be considered if the skin is broken and this has not been done already. When microbiological results are available, the antibiotic should be reviewed and changed accordingly (for example, if bacteria are found to be resistant) if symptoms are not already improving, using a narrower-spectrum antibiotic if possible.\n\nThe committee agreed that people with cellulitis or erysipelas should be referred to hospital if they have symptoms or signs suggestive of orbital cellulitis, osteomyelitis, septic arthritis, necrotising fasciitis or sepsis.\n\nThe committee discussed and agreed that in some cases, the prescriber may need to consider referring or seeking specialist advice on inpatient treatment or locally available options for intravenous treatment at home or in a community setting. These cases include people who are severely unwell, at higher risk of complications, have infection near the eyes or nose (including periorbital cellulitis), could have uncommon pathogens, have lymphangitis, have a spreading infection that is not responding to oral antibiotics, or cannot take oral antibiotics. They discussed that children under 1\xa0year and people who are frail or have underlying disease (such as diabetes or immunosuppression) are at a higher risk of developing complications, as are those who could have an uncommon causative organism, for example, following a penetrating injury, a wound exposed to water (surfers for example), or an infection acquired outside the UK.\n\n# Choice of antibiotics\n\n## Effectiveness of antibiotics versus other antibiotics in adults\n\nThere were no differences in the clinical effectiveness of the following antibiotic comparisons in adults with cellulitis or erysipelas:\n\n\n\nan oral penicillin or cephalosporin compared with an oral macrolide or oral clindamycin (adults and children; Ferreira et al. 2016)\n\noral azithromycin compared with oral cefalexin (Kilburn et al. 2010)\n\noral azithromycin compared with oral erythromycin (Kilburn et al. 2010)\n\nintravenous (IV) then oral moxifloxacin compared with IV then oral co‑amoxiclav (Vick-Fragoso et al. 2009)\n\nIV or oral linezolid compared with IV vancomycin (Kilburn et al. 2010)\n\nIV dalbavancin compared with IV vancomycin (Boucher et al. 2014)\n\nIV ampicillin with sulbactam compared with IV cefazolin (Kilburn et al. 2010)\n\nIV flucloxacillin compared with IV ceftriaxone (Kilburn et al. 2010)\n\nIV moxifloxacin compared with IV piperacillin with tazobactam (Kilburn et al. 2010)\n\nIV daptomycin compared with IV penicillin or IV vancomycin (Konychev et al. 2013)\n\nIV tigecycline compared with IV ampicillin with sulbactam or IV co‑amoxiclav (Matthews et al. 2012)\n\nnewer cephalosporins compared with older cephalosporins (Kilburn et al. 2010)\n\nIV ceftaroline compared with IV vancomycin plus aztreonam (Frampton 2013)\n\nIV daptomycin compared with IV vancomycin (Pertel et al. 2009)\n\nIV meropenem compared with IV imipenem with cilastatin (Kilburn et al. 2010).\n\n\n\nSome differences were seen for some effectiveness outcomes for the following antibiotic comparison in adults with cellulitis or erysipelas:\n\n\n\noral macrolides or oral streptogramins (pristinamycin: not available in the UK) improved the number of people who were symptom-free, or had reduced symptoms, at 7\xa0to 14\xa0days' follow‑up compared with a penicillin (Kilburn et al. 2010).\n\n\n\nBased on 3\xa0systematic reviews (Frampton 2013, Ferreira et al. 2016 and Kilburn et al. 2010) and 5\xa0randomised controlled trials (RCTs; Boucher et al. 2014, Konychev et al. 2013, Matthews et al. 2012, Pertel et al. 2009 and Vick-Fragoso et al. 2009).\n\n## Effectiveness of antibiotics versus other antibiotics in children\n\nThere was no difference in the clinical effectiveness of the following antibiotic comparison in children with cellulitis or erysipelas:\n\n\n\nIV linezolid compared with IV vancomycin (Yogev et al. 2003).\n\n\n\nBased on 1\xa0RCT (Yogev et al. 2003).\n\n## Dual therapy in adults or children\n\nThere were no differences in the clinical effectiveness of the following antibiotic comparisons in adults or children with cellulitis or erysipelas:\n\n\n\noral cefalexin plus oral co‑trimoxazole compared with oral cefalexin alone (Bowen et al. 2017)\n\nIV then oral flucloxacillin plus IV then oral benzylpenicillin compared with IV then oral flucloxacillin alone (Kilburn et al. 2010)\n\nIV or oral flucloxacillin plus oral clindamycin compared with IV or oral flucloxacillin alone (Brindle et al. 2017)\n\nIV ceftazidime plus IV vancomycin compared with IV ceftobiprole alone (Noel et al. 2008).\n\n\n\nBased on 2\xa0systematic reviews (Bowen et al. 2017 and Kilburn et al. 2010) and 2\xa0RCTs (Brindle et al. 2017 and Noel et al. 2008).\n\n## Safety of antibiotics\n\nAntibiotic-associated diarrhoea is estimated to occur in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta-lactam antibiotics (British national formulary [BNF] information on phenoxymethylpenicillin).\n\nCholestatic jaundice and hepatitis can occur with flucloxacillin up to 2\xa0months after stopping treatment; risk factors are increasing age and use for more than 14\xa0days (BNF information on flucloxacillin).\n\nCholestatic jaundice can occur with co‑amoxiclav, and is more common in people over 65\xa0years and in men; treatment should not usually exceed 14\xa0days (BNF information on co-amoxiclav).\n\nMacrolides should be used with caution in people with a predisposition to QT interval prolongation. Nausea, vomiting, abdominal discomfort and diarrhoea are the most common side effects of macrolides. These are less frequent with clarithromycin than with erythromycin (BNF information on erythromycin).\n\nTetracyclines (for example, doxycycline), can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant or breastfeeding women, and use in children under 12\xa0years is either contraindicated or cautioned for use only in severe or life-threatening infections where there are no alternatives (BNF information on doxycycline).\n\nClindamycin has been associated with colitis and diarrhoea. Although this can occur with most antibiotics, it is more frequent with clindamycin. Monitoring of liver and renal function is recommended if treatment exceeds 10\xa0days, and in babies (BNF information on clindamycin).\n\nGlycopeptide (for example, vancomycin and teicoplanin) doses are based on body weight. Therapeutic drug monitoring and monitoring of various patient parameters (including blood count, urinalysis, auditory function, hepatic function and renal function) is recommended depending on the particular glycopeptide (BNF information on vancomycin).\n\nSevere optic neuropathy can occur with linezolid, particularly if used for longer than 28\xa0days. Blood disorders have also been reported and weekly full blood counts are recommended (BNF information on linezolid).\n\nSee the EMC's summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\nData on adverse events in the included studies were limited because of cellulitis or erysipelas often being a subgroup in larger skin and skin structure infection studies, where adverse event data were presented for the whole study and not cellulitis or erysipelas subgroups.\n\nThere were no differences in the adverse events of the following antibiotic comparisons in adults or children with cellulitis or erysipelas:\n\n\n\noral cefazolin compared with IV ceftriaxone (Kilburn et al. 2010)\n\noral cefalexin plus oral co‑trimoxazole compared with oral cefalexin alone (Bowen et al. 2017)\n\noral cefalexin or oral clindamycin compared with IV cefazolin or IV clindamycin (Aboltins et al. 2015)\n\noral levofloxacin for 5\xa0days compared with 10\xa0days (Kilburn et al. 2010)\n\nIV ceftriaxone compared with IV flucloxacillin (Kilburn et al. 2010)\n\nIV daptomycin compared with IV vancomycin (Pertel et al. 2009).\n\n\n\nSome differences were seen for some adverse event outcomes for the following antibiotic comparisons in adults or children with cellulitis or erysipelas:\n\n\n\nflucloxacillin plus clindamycin was significantly worse for adverse events (most commonly diarrhoea) compared with flucloxacillin alone (Brindle et al. 2017)\n\nIV penicillin was significantly worse for adverse events (no details provided) compared with intramuscular penicillin (Kilburn et al. 2010).\n\n\n\nBased on 2\xa0systematic reviews (Bowen et al. 2017 and Kilburn et al. 2010) and 3\xa0RCTs (Brindle et al. 2017, Pertel et al. 2009 and Aboltins et al. 2015).\n\nThe committee noted that most antibiotics compared with another antibiotic showed no difference in clinical outcomes in adults or children. The committee also noted that dual therapy was no more effective than single antibiotic therapy in adults. Adverse event data were very limited and there were no differences in adverse events between most of the antibiotic comparisons. Given the very limited amount of evidence in children, the committee agreed that antibiotic choice for children can be extrapolated from the choice for adults.\n\nThe committee agreed based on their experience that choice of antibiotic treatment should be based on the severity of symptoms and the risk of developing complications, while minimising the risk of the development of antibiotic resistance.\n\nThe committee discussed that in practice, erysipelas can often be difficult to tell apart from cellulitis and recognised that both infections may be caused by Streptococcus pyogenes or Staphylococcus aureus, although there is uncertainty around the evidence for erysipelas, which may be more associated with streptococcus. Therefore, management of both infections, with regard to antibiotic choice, is the same.\n\nThe committee were aware that severity scoring tools (for example, Eron 2000 and 'Dundee' Koerner and Johnson 2010) have been developed and may be used in practice. However, these have not to date been used in randomised clinical trials. The committee agreed that recommendations for antibiotic treatment should reflect the available evidence and provide guidance on oral and intravenous treatment because this would fit with current severity scoring tools and the risks of developing complications without needing evidence of the effectiveness of such tools.\n\nThe committee agreed that the evidence for dual therapy (a combination of 2\xa0antibiotics) showed no benefit over monotherapy for treating cellulitis or erysipelas, and dual therapy should not be routinely used given the increased risk of antimicrobial resistance and more adverse effects.\n\nThe committee agreed based on the evidence, their experience and resistance data that the first-choice oral antibiotic should be flucloxacillin (a relatively narrow-spectrum penicillin). The committee discussed that flucloxacillin has activity against Staphylococcus aureus (because it is not inactivated by penicillinases produced by staphylococci) and Streptococcus pyogenes. They also agreed that this would be the first-choice antibiotic for people with recurrent infection, because the risk of resistance to flucloxacillin is very low. The only exception would be people with a suspected or confirmed meticillin-resistant Staphylococcus aureus (MRSA) infection, but the committee discussed that the likelihood of such a cellulitis or erysipelas infection with MRSA is very low. The committee agreed that flucloxacillin has poor oral bioavailability and in people with cellulitis or erysipelas who could have impaired circulation (such as people with diabetes or venous insufficiency), a higher (off label) dose of up to 1\xa0g four times a day may be needed to adequately treat the infection. The committee were aware that a narrow-spectrum penicillin with a specific antistreptococcal penicillin is sometimes prescribed for cases of cellulitis or erysipelas, because these infections can involve either streptococci or staphylococci, but there is no evidence that dual therapy is more effective than, for example, flucloxacillin alone. Additionally, the committee considered that dual therapy may increase the risk of antimicrobial resistance and adverse effects.\n\nThe committee agreed that oral macrolides, clarithromycin or erythromycin (in pregnancy), are suitable alternatives to flucloxacillin in people who have penicillin allergy or where flucloxacillin is not a suitable option. Oral macrolide antibiotics were shown to be at least as effective as an oral penicillin in studies and have a similar spectrum of activity to that of a penicillin. There was limited, very low quality, evidence that oral macrolides or oral streptogramins were more effective than a penicillin (oral or IV). However, the committee considered this evidence was limited because oral macrolides and oral streptogramins were analysed together, not as separate classes. Additionally, the oral streptogramin (pristinamycin) and the only oral penicillin (cloxacillin) used in the studies are not licensed in the UK. There was no head-to-head comparison of either oral macrolides or oral streptogramins with flucloxacillin.\n\nThe committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.\n\nThe committee also discussed and agreed that doxycycline (an oral tetracycline) may be useful for people over 12\xa0years who have penicillin allergy or if flucloxacillin is unsuitable. Despite a lack of evidence found for its use, doxycycline is commonly used as an alternative to flucloxacillin for cellulitis and erysipelas in UK practice.\n\nThe committee discussed and agreed based on limited evidence and their experience that for infection near the eyes or nose (the triangle from the bridge of the nose to the corners of the mouth, or immediately around the eyes), the first-choice oral antibiotic should be the broader-spectrum antibiotic, co‑amoxiclav (a penicillin with a beta-lactamase inhibitor). This is because of the risk of a serious intracranial complication in the event of treatment failure, and because co‑amoxiclav provides cover for Haemophilus and anaerobic bacteria. The committee agreed this extended-spectrum antibiotic was needed to prevent treatment failure and reduce complications of infection in people who are at higher risk because of the location and nature of the infection, and the possibility of uncommon pathogens. For people with infection around the eyes or nose, consulting a specialist was recommended because of the particular risk of complications with this infection site.\n\nThe committee also agreed that co‑amoxiclav could be used as an alternative first-choice antibiotic in children without penicillin allergy if flucloxacillin was unsuitable. However, if flucloxacillin is only not suitable because of poor palatability of the oral solution, the committee agreed that flucloxacillin capsules should be considered because children can often take tablets or capsules if they are supported to do this (see Medicines for Children leaflet on helping your child to swallow tablets).\n\nThe committee discussed and agreed based on their experience that although routine dual therapy was not recommended, clarithromycin (a macrolide) with metronidazole (an antibiotic with high activity against anaerobic bacteria) is a suitable alternative to co‑amoxiclav in adults with infection near the eyes or nose, if co‑amoxiclav is not suitable or there is penicillin allergy. In children, the committee discussed that anaerobic bacteria are less of a concern and that clarithromycin alone may be sufficient. However, if anaerobes are suspected, the addition of metronidazole was recommended.\n\nThe committee agreed based on evidence, their experience and resistance data that the first-choice intravenous antibiotic for people unable to take oral antibiotics or who are severely unwell should be the relatively narrow-spectrum penicillin, flucloxacillin. If flucloxacillin is unsuitable, intravenous clarithromycin is recommended, with intravenous co‑amoxiclav an option for infection near the eyes or nose or severe infection.\n\nBased on evidence, their experience and resistance data, the committee also agreed to recommend the following alternative antibiotics for people with severe infection:\n\n\n\ncefuroxime\n\nclindamycin\n\nceftriaxone (in adults for ambulatory care only).They discussed that other antibiotics may also be appropriate, particularly in ambulatory care for specific people or populations, and prescribers should seek specialist, local advice.\n\n\n\nIn cases of suspected or confirmed MRSA infection, vancomycin, teicoplanin or if these cannot be used, for specialist use, linezolid, were recommended. They also noted that other antibiotics may be appropriate based on microbiological results and specialist advice.\n\n# Antibiotic dose frequency\n\nThere was no difference in the clinical effectiveness of the following antibiotic comparison in adults with cellulitis or erysipelas:\n\n\n\noral cefalexin four times a day compared with twice a day, using the same total daily dose.\n\n\n\nBased on 1\xa0systematic review (Kilburn et al. 2010).\n\nNo systematic reviews or randomised controlled trials in children met the inclusion criteria.\n\n# Antibiotic course length\n\nThere were no differences in the clinical effectiveness of the following antibiotic comparisons in adults with cellulitis:\n\n\n\noral tedizolid for 6\xa0days compared with 10\xa0days (Hanretty et al. 2018)\n\noral levofloxacin for 5\xa0days compared with 10\xa0days (Kilburn et al. 2010).\n\n\n\nBased on 2\xa0systematic reviews (Hanretty et al. 2018 and Kilburn et al. 2010).\n\nNo systematic reviews or randomised controlled trials in children met the inclusion criteria.\n\n# Antibiotic route of administration\n\nThere were no differences in the clinical effectiveness of the following antibiotic comparisons in adults with cellulitis:\n\n\n\noral cefalexin or oral clindamycin compared with IV cefazolin or IV clindamycin (Aboltins et al. 2015)\n\nIV benzylpenicillin compared with intramuscular benzylpenicillin (Kilburn et al. 2010).\n\n\n\nBased on 1\xa0systematic review (Kilburn et al. 2010) and 1\xa0RCT (Aboltins et al. 2015).\n\nNo systematic reviews or randomised controlled trials in children met the inclusion criteria.\n\n## Committee discussion on antibiotic dose frequency, course length and route of administration\n\nThe committee acknowledged that there was very limited evidence identified for antibiotic dose frequency.\n\nThe committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of side effects.\n\nBased on limited evidence and their experience, the committee agreed that a shorter course of antibiotics was generally as effective as a longer course of antibiotics for cellulitis or erysipelas, and a 5- to 7‑day course was sufficient for most people. However, the committee noted that only 1\xa0RCT (Brindle et al. 2017) used flucloxacillin for 5\xa0days and the authors expressed doubts about the quality of their data for dose and duration. Therefore, the committee discussed that the decision of whether a 5‑day or a 7‑day course was given would be based on clinical judgement of individual cases. The committee discussed that a longer course (up to 14\xa0days in total) may be needed for some people based on a clinical assessment of their symptoms and history. However, skin does take some time to return to normal, even after an effective course of antibiotics, and a full resolution of symptoms at 5\xa0to 7\xa0days would not be expected.\n\nBased on limited evidence, the committee agreed that oral antibiotics were as effective as intravenous antibiotics for treating cellulitis and erysipelas.\n\nIn line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that oral antibiotics should be used in preference to intravenous antibiotics where possible. Intravenous antibiotics should only be used for people who are severely ill, unable to tolerate oral treatment, or where oral treatment would not provide adequate coverage or tissue penetration.\n\nThe use of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible, for a total of 5\xa0to 7\xa0days. Again, a longer course (up to 14\xa0days in total) may be needed for some people based on clinical assessment.\n\n# Antibiotic prophylaxis for the prevention of recurrent cellulitis and erysipelas\n\nAntibiotic prophylaxis (with an intramuscular or oral penicillin, or oral erythromycin) significantly lowered the risk of recurrence of cellulitis or erysipelas compared with no treatment or placebo in a meta-analysis of 5\xa0RCTs in adults (approximately 46\xa0to 70\xa0years) with 1\xa0or 2\xa0previous episodes of cellulitis or erysipelas in the past 3\xa0months to 3\xa0years depending on the RCT.\n\nAntibiotic prophylaxis significantly lowered the incidence rate (episodes per person month) compared with no treatment or placebo in a meta-analysis of 4\xa0RCTs in adults with 1\xa0or 2\xa0previous episodes of cellulitis or erysipelas.\n\nAntibiotic prophylaxis significantly lowered the risk of an episode (time to next episode) of cellulitis or erysipelas compared with no treatment or placebo in a meta-analysis of 3\xa0RCTs in adults with 1\xa0or 2\xa0previous episodes of cellulitis or erysipelas.\n\nAntibiotic prophylaxis was not significantly different to no treatment or placebo for mortality or risk of hospitalisation in adults with 1\xa0or 2\xa0previous episodes of cellulitis or erysipelas.\n\nThere were no differences in the adverse events of antibiotic prophylaxis compared with no treatment or placebo in adults with cellulitis or erysipelas.\n\nBased on 1\xa0systematic review (Dalal et al. 2017).\n\nNo systematic reviews or randomised controlled trials in children met the inclusion criteria.\n\n## Committee discussion on antibiotic prophylaxis of recurrent cellulitis or erysipelas\n\nThe committee noted that recurrence is not uncommon in people who have had cellulitis or erysipelas. The committee also noted the limitations of the evidence for antibiotic prophylaxis, which was in adults only and mainly related to lower limb cellulitis. There was variation in the populations in the included studies for the number of previous episodes (1\xa0or\xa02) and the time periods over which recurrence was defined (up to 3\xa0years).\n\nThe committee discussed the evidence for prophylactic antibiotics in adults. Overall, antibiotics reduced the risk of cellulitis or erysipelas recurring but did not reduce the risk of hospitalisation or mortality, and the long-term effects on antibiotic resistance are unknown.\n\nThe committee agreed based on evidence and experience that antibiotic prophylaxis should not be routinely offered to prevent recurrent cellulitis or erysipelas because of the balance of risks and benefits in the overall population.\n\nHowever, they agreed based on evidence and experience that a trial of antibiotic prophylaxis could be considered for a higher-risk population, which the committee defined as adults who have had at least 2\xa0separate episodes of cellulitis or erysipelas in the previous 12\xa0months, which were managed in hospital, or where the care was under specialist advice. The populations in the antibiotic prophylaxis trials were more varied (having 1\xa0or 2\xa0previous episodes over up to 3\xa0years), but the committee wanted to ensure that prophylaxis would only be considered for those at highest risk.\n\nThe committee agreed that prophylaxis should only be considered following a discussion between a specialist and the person to ensure shared decision making, and should be reviewed every 6\xa0months. Prophylaxis may be appropriate in this higher-risk population because the benefits of prophylaxis may outweigh the risks. However, it is important to ensure that the previous episodes of cellulitis and erysipelas have been correctly diagnosed, any underlying condition (such as oedema, diabetes or venous insufficiency) is being managed optimally, and prophylaxis is reviewed at least every 6\xa0months.\n\nThe choice of antibiotic was low-dose phenoxymethylpenicillin, which was used in most of the trials in the systematic review, or low-dose erythromycin in penicillin allergy, which was used in 1\xa0trial in the systematic review. The committee discussed that alternative antibiotics may be appropriate with specialist advice, and that choice should be based on recent microbiological results where possible. Based on their experience and resistance data, the committee agreed that using the same antibiotic for treatment and prophylaxis should be avoided.\n\nThe committee recognised the importance of reviewing antibiotic prophylaxis, and considered that up to every 6\xa0months was reasonable based on possible adverse effects of antibiotics, the risk of resistance with long-term antibiotics, the possible need for any further investigations if recurrence of cellulitis or erysipelas, and to allow time to assess treatment success. People should also know to seek medical help if cellulitis or erysipelas recurs despite taking prophylaxis.\n\nTo reduce the risk of antimicrobial resistance, the committee agreed that each review should include a discussion around the success of prophylaxis and whether antibiotics should be continued, stopped or changed, taking into account the person's preferences for antibiotic use and the potential risk of antimicrobial resistance with long-term use of antibiotics. If treatment failure occurs and cellulitis or erysipelas recurs, the committee agreed that antibiotic prophylaxis should be stopped or changed to an alternative prophylactic antibiotic once the acute infection has been treated.\n\nNo recommendation for antibiotic prophylaxis in children was made because there was no evidence in this population.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).\n\n# Resource implications\n\nRecommended antibiotics are available as generic formulations. See Drug Tariff or BNF for costs.\n\nSee the evidence review for more information.'}
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https://www.nice.org.uk/guidance/ng141
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This guideline sets out an antimicrobial prescribing strategy for adults, young people, children and babies aged 72 hours and over with cellulitis and erysipelas. It aims to optimise antibiotic use and reduce antibiotic resistance.
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59f8648ee1965d6a897bfe3c672831815c1827bc
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nice
|
High-intensity focused ultrasound for glaucoma
|
High-intensity focused ultrasound for glaucoma
Evidence-based recommendations on high-intensity focused ultrasound for glaucoma in adults. This involves using high-intensity ultrasound to destroy a small amount of the tissue that makes fluid in the eye. This reduces the amount of fluid in the eyeball and reduces pressure, preventing more damage to vision.
# Recommendations
Evidence on the safety and efficacy of high-intensity focused ultrasound for glaucoma is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Research should ideally take the form of randomised controlled trials comparing this procedure with standard therapies and should report safety events and long-term outcomes.
NICE may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Glaucoma is usually a chronic condition associated with elevated intraocular pressure. The most common type of glaucoma in the UK is primary open-angle glaucoma, also known as chronic open-angle glaucoma. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness.
# Current treatments
NICE's guideline on glaucoma describes its diagnosis and management. Treatment is usually eye drops containing drugs that either reduce the production of aqueous humor (fluid) or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used.
# The procedure
This procedure uses high-intensity focused ultrasound (HIFU) to partially destroy the ciliary body to reduce the production of aqueous humor and thereby decrease the intraocular pressure.
The procedure can be done under regional, general or topical anaesthesia. One device available for this procedure consists of a compact operator console and a disposable probe (which includes a coupling cone and a therapy probe that generates the ultrasound beams). The coupling cone is placed directly on the centre of the patient's cornea and held in place by a low-vacuum suction ring. A ring-shaped therapy probe (connected to the console) that generates ultrasound beams is inserted into the cone. The space between the eye, cone and the probe is filled with saline solution to ensure dissemination of ultrasound energy. By pressing the foot switch, miniature transducers in the ring-shaped probe are sequentially activated to deliver HIFU beams directly into the ciliary body. These beams pass through the scleral tissue without disruption of ocular tissue to reach the ciliary body. The ultrasound heats and inactivates tissue within the ciliary body to decrease the production of aqueous humor.
|
{'Recommendations': 'Evidence on the safety and efficacy of high-intensity focused ultrasound for glaucoma is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nResearch should ideally take the form of randomised controlled trials comparing this procedure with standard therapies and should report safety events and long-term outcomes.\n\nNICE may update the guidance on publication of further evidence.', 'The condition, current treatments and procedure': "# The condition\n\nGlaucoma is usually a chronic condition associated with elevated intraocular pressure. The most common type of glaucoma in the UK is primary open-angle glaucoma, also known as chronic open-angle glaucoma. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness.\n\n# Current treatments\n\nNICE's guideline on glaucoma describes its diagnosis and management. Treatment is usually eye drops containing drugs that either reduce the production of aqueous humor (fluid) or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used.\n\n# The procedure\n\nThis procedure uses high-intensity focused ultrasound (HIFU) to partially destroy the ciliary body to reduce the production of aqueous humor and thereby decrease the intraocular pressure.\n\nThe procedure can be done under regional, general or topical anaesthesia. One device available for this procedure consists of a compact operator console and a disposable probe (which includes a coupling cone and a therapy probe that generates the ultrasound beams). The coupling cone is placed directly on the centre of the patient's cornea and held in place by a low-vacuum suction ring. A ring-shaped therapy probe (connected to the console) that generates ultrasound beams is inserted into the cone. The space between the eye, cone and the probe is filled with saline solution to ensure dissemination of ultrasound energy. By pressing the foot switch, miniature transducers in the ring-shaped probe are sequentially activated to deliver HIFU beams directly into the ciliary body. These beams pass through the scleral tissue without disruption of ocular tissue to reach the ciliary body. The ultrasound heats and inactivates tissue within the ciliary body to decrease the production of aqueous humor."}
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https://www.nice.org.uk/guidance/ipg661
|
Evidence-based recommendations on high-intensity focused ultrasound for glaucoma in adults. This involves using high-intensity ultrasound to destroy a small amount of the tissue that makes fluid in the eye. This reduces the amount of fluid in the eyeball and reduces pressure, preventing more damage to vision.
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3b998224028625cd0517b346f793d58c1ce96bf9
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nice
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Bioprosthetic plug insertion for anal fistula
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Bioprosthetic plug insertion for anal fistula
Evidence-based recommendations on bioprosthetic plug insertion for anal fistula in adults. This involves putting a plug into the fistula and stitching it in place. The plug is made from animal tissue (bioprosthetic). The aim is to block the fistula.
# Recommendations
Current evidence on the safety and efficacy of bioprosthetic plug insertion for anal fistula is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
The procedure should only be done by a surgeon experienced in managing anal fistulas.# The condition, current treatments and procedure
# The condition
An anal fistula is an abnormal tract between the anal canal and the skin around the anus. It usually results from previous anal abscesses (cryptoglandular) and can be associated with other conditions such as inflammatory bowel disease and cancer. It may cause symptoms such as pain or discomfort in the anal area, and leakage of blood or pus. Anal fistulas can be classified according to their anatomical relationship with the external sphincter. Intersphincteric fistulas are the most common type and cross only the internal sphincter. Trans-sphincteric fistulas pass through the internal and external sphincter.
# Current treatments
Treatment of anal fistulas commonly involves surgery. The type of surgery depends on the location and complexity of the fistula. For intersphincteric and low trans-sphincteric anal fistulas, the most common treatment is a fistulotomy or laying open of the fistula tract. For deeper fistulas that involve more muscle, and for recurrent fistulas, a seton (a piece of suture material or rubber sling) may be used, either alone or with fistulotomy. Setons can be loose (designed to drain the sepsis but not for cure), or snug or tight (designed to cut through the muscles in a slow controlled fashion). Fistulas that cross the external sphincter at a high level are sometimes treated with a mucosal advancement flap or other procedures to close the internal opening. Other options for treating anal fistulas are to fill the tract with glue or paste.
# The procedure
Bioprosthetic plug insertion for anal fistula aims to leave the sphincter muscles intact, allowing the use of subsequent treatments if needed.
The procedure is usually done using general anaesthesia. The fistula tract is identified using a probe or by imaging techniques, and it may be irrigated. A conical plug, usually made of porcine intestinal submucosa, is pulled into the tract until it blocks the internal opening. It is sutured in place at the internal opening. The external opening is not completely sealed so that drainage of the fistula can continue. The plug acts as a scaffold into which new tissue can grow.
|
{'Recommendations': 'Current evidence on the safety and efficacy of bioprosthetic plug insertion for anal fistula is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nThe procedure should only be done by a surgeon experienced in managing anal fistulas.', 'The condition, current treatments and procedure': '# The condition\n\nAn anal fistula is an abnormal tract between the anal canal and the skin around the anus. It usually results from previous anal abscesses (cryptoglandular) and can be associated with other conditions such as inflammatory bowel disease and cancer. It may cause symptoms such as pain or discomfort in the anal area, and leakage of blood or pus. Anal fistulas can be classified according to their anatomical relationship with the external sphincter. Intersphincteric fistulas are the most common type and cross only the internal sphincter. Trans-sphincteric fistulas pass through the internal and external sphincter.\n\n# Current treatments\n\nTreatment of anal fistulas commonly involves surgery. The type of surgery depends on the location and complexity of the fistula. For intersphincteric and low trans-sphincteric anal fistulas, the most common treatment is a fistulotomy or laying open of the fistula tract. For deeper fistulas that involve more muscle, and for recurrent fistulas, a seton (a piece of suture material or rubber sling) may be used, either alone or with fistulotomy. Setons can be loose (designed to drain the sepsis but not for cure), or snug or tight (designed to cut through the muscles in a slow controlled fashion). Fistulas that cross the external sphincter at a high level are sometimes treated with a mucosal advancement flap or other procedures to close the internal opening. Other options for treating anal fistulas are to fill the tract with glue or paste.\n\n# The procedure\n\nBioprosthetic plug insertion for anal fistula aims to leave the sphincter muscles intact, allowing the use of subsequent treatments if needed.\n\nThe procedure is usually done using general anaesthesia. The fistula tract is identified using a probe or by imaging techniques, and it may be irrigated. A conical plug, usually made of porcine intestinal submucosa, is pulled into the tract until it blocks the internal opening. It is sutured in place at the internal opening. The external opening is not completely sealed so that drainage of the fistula can continue. The plug acts as a scaffold into which new tissue can grow.'}
|
https://www.nice.org.uk/guidance/ipg662
|
Evidence-based recommendations on bioprosthetic plug insertion for anal fistula in adults. This involves putting a plug into the fistula and stitching it in place. The plug is made from animal tissue (bioprosthetic). The aim is to block the fistula.
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d4d7cfb6c3c3af8aedab5ecca8b484290da0c9ac
|
nice
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Abortion care
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Abortion care
This guideline covers care for women of any age (including girls and young women under 18) who request an abortion. It aims to improve the organisation of services and make them easier for women to access. Detailed recommendations on conducting abortions at different gestational stages are also included, to ensure that women get the safest and most effective care possible.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Note that mifepristone and misoprostol do not have UK marketing authorisations for most of the uses recommended in this guideline. When an unlicensed use is recommended, this is highlighted with a footnote in the recommendation.
Abortion Act 1967
Abortion in England, Scotland and Wales is primarily regulated by the Abortion Act 1967 (as amended by the Human Fertilisation and Embryology Act 1990) and regulations made under that Act – currently the Abortion Regulations 1991 (SI 1991/499). The Abortion Act regulates when and where abortions can take place lawfully.
In May 2014, the Department of Health and Social Care issued guidance in relation to requirements of the Abortion Act 1967. This guidance is intended for those responsible for commissioning, providing and managing the provision of abortion services to help them comply with the Abortion Act. Also in May 2014, the Department of Health and Social Care published procedures for the approval of independent sector places for the termination of pregnancy. Further government guidance has recently been issued in the form of letters from the Chief Medical Officer.
Providers of abortion services must comply with the Health and Social Care Act 2008 and regulations made under that Act. In particular, providers must register with the Care Quality Commission (CQC). This is because under section 10 of the Health and Social Care Act 2008, it is an offence to carry out a regulated activity without being registered with the CQC, and abortion is a 'regulated activity' under Regulation 3 and Schedule 1 (paragraph 11) of the Health and Social Care Act 2008 (Regulated Activities) Regulations 2014 (SI 2014/2936). The CQC imposes specific requirements on providers that are not English NHS bodies (see regulation 20 of the Care Quality Commission (Registration) Regulations 2009).
Additional relevant guidance:
the views of the British Medical Association on the laws and ethics of abortion
the termination of pregnancy nursing framework from the Royal College of Nursing
guidance from the Royal College of Obstetricians and Gynaecologists on the care of women requesting induced abortion.
This NICE guideline makes evidence-based recommendations on how to organise services and on how to conduct abortions within the legal framework set out by the Abortion Act 1967. It does not repeat things already covered by the legislation, Department of Health and Social Care guidance or other statutory regulations, and practitioners should therefore ensure they are adhering to all other applicable requirements when using this guideline.
Consent and Montgomery
Healthcare professionals should ensure that women have the information they need to make decisions and to give consent in line with General Medical Council guidance and the 2015 Montgomery ruling.
Gender
This guideline makes recommendations for women and people who are pregnant. For simplicity of language the guideline uses the term women throughout, but this should be taken to also include people who do not identify as women but who are pregnant.
# Service organisation
## Making it easier to access services
Commissioners and providers should work together to:
make information about abortion services (including how to access them) widely available
ensure that women are promptly referred onwards if a service cannot provide an abortion after a specific gestational age or by the woman's preferred method
avoid the need for women to repeat key steps (such as returning to their GP for referral, or repeated assessments or investigations).
Commissioners and providers should allow women to self-refer to abortion services.
Healthcare professionals should not allow their personal beliefs to delay access to abortion services.
Commissioners should consider upfront funding for travel and accommodation for women who:
are eligible for the NHS Healthcare Travel Costs Scheme and/or
need to travel to a service that is not available locally.Commissioners should make information available about any upfront funding to access services.
## Waiting times
Commissioners should work with providers to ensure abortion services have the capacity and resources to deliver the range of services needed with minimal delay.
Ensure minimal delay in the abortion process, and ideally:
provide the assessment within 1 week of the request
provide the abortion within 1 week of the assessment.
For women who would prefer to wait longer for an abortion, help them to make an informed decision by explaining the implications, including:
the legal limit for abortions, as stated in the Abortion Act
that delaying the abortion will increase the risk of complications, although the overall risk is low.
Do not require women to have compulsory counselling or compulsory time for reflection before the abortion. Provide or refer women for support to make a decision if they request this.
## Location of services
Consider providing abortion assessments by phone or video call, for women who prefer this.
Consider providing abortion services in a range of settings (including in the community and in hospitals), to meet the needs of the local population.
## Workforce and training
Abortion providers should maximise the role of nurses and midwives in providing care.
Trainee healthcare professionals and students who may care for women who request an abortion (for example nurses, midwives, and GPs) should have the chance to gain experience in abortion services during their training.
For specialties that include training in abortion as part of the core curriculum:
ensure all trainees have the training, unless they opt out due to a conscientious objection
include practical experience of abortion services and procedures in the curriculum.
If a trainee's placement service does not provide abortions, the trainee should gain experience with whoever is providing this service (either in the NHS or in the independent sector).
## Complex comorbidities
Specialist centres should be available as locally as possible, to reduce delays and travel times for women with complex needs or significant comorbidities.
Providers should develop pathways for women with complex needs or significant comorbidities to:
refer them to specialist centres if needed
minimise delays in accessing care.
## Avoiding stigma
When caring for women who are having an abortion, be aware of:
the anxiety they may have about perceived negative and judgemental attitudes from healthcare professionals
the impact that verbal and non-verbal communication may have on them.
Services should be sensitive to the concerns women have about their privacy and confidentiality, including their concerns that information about the abortion might be shared with healthcare professionals not directly involved in their care.
To find out why the committee made the recommendations and how they might affect services, see the rationale and impact section on service organisations .
Full details of the evidence and the committee's discussion are in evidence review A: accessibility and sustainability of abortion services and evidence review B: information needs of women undergoing an abortion.
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# Providing information
Reassure women that having an abortion is not associated with increased risk of infertility, breast cancer or mental health issues.
Provide information about the differences between medical and surgical abortion (including the benefits and risks), taking account of the woman's needs and preferences. Do this without being directive, so that women can make their own choice. See the NICE patient decision aids to help support these decisions.
As early as possible, provide women with detailed information to help them prepare for the abortion. Cover:
what it involves and what happens afterwards
how much pain and bleeding to expect.
Provide information in a range of formats, for example video or written information. Include information based on the experiences of women who have had an abortion.
For more guidance on providing information and helping women to make decisions about their care, see the NICE guideline on patient experience in adult NHS services.
Ask women if they want information on contraception, and if so provide information about the options available to them (see improving access to contraception).
For women who are having a medical abortion, explain:
that they may see the products of pregnancy as they are passed
what the products of pregnancy will look like and whether there may be any movement.
For women who are having a medical abortion at home, explain how to be sure that the pregnancy has ended (see follow-up after medical abortion up to and including 10+0 weeks).
Provide women with information on signs and symptoms that indicate they need medical help after an abortion, and who to contact if they do.
Provide women with information about the different options for management and disposal of pregnancy remains.
## Information for women who are having an abortion because of fetal anomaly
If a woman who is having an abortion for fetal anomaly cannot have her preferred method of abortion in the maternity service, establish a clear referral pathway with ongoing communication between services so that she can:
easily transfer to the abortion service
receive ongoing support from the maternity service
get more information about the anomaly.
Explain to women that there may not be any physical signs of a fetal anomaly.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on providing information .
Full details of the evidence and the committee's discussion are in evidence review B: information needs of women undergoing an abortion.
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# Anti-D prophylaxis
Offer anti-D prophylaxis to women who are rhesus D negative and are having an abortion after 10+0 weeks' gestation.
Do not offer anti-D prophylaxis to women who are having a medical abortion up to and including 10+0 weeks' gestation.
Consider anti-D prophylaxis for women who are rhesus D negative and are having a surgical abortion up to and including 10+0 weeks' gestation.
Providers should ensure that:
rhesus status testing and anti-D prophylaxis supply does not cause any delays to women having an abortion
anti-D prophylaxis is available at the time of the abortion.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on anti-D prophylaxis .
Full details of the evidence and the committee's discussion are in evidence review C: anti-D prophylaxis for women up to 13+6 weeks' gestation.
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# Preventing infection
For guidance on testing for sexually transmitted infections for women who are having an abortion, see the NICE guideline on preventing sexually transmitted infections and under-18 conceptions.
Do not routinely offer antibiotic prophylaxis to women who are having a medical abortion.
Offer antibiotic prophylaxis to women who are having surgical abortion.
When using doxycycline for antibiotic prophylaxis in medical or surgical abortion, consider oral doxycycline 100 mg twice a day for 3 days.
When using metronidazole for antibiotic prophylaxis in medical or surgical abortion, do not routinely offer it in combination with another broad-spectrum antibiotic such as doxycycline.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on preventing infection .
Full details of the evidence and the committee's discussion are in evidence review D: antibiotic prophylaxis for medical and surgical abortion.
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# Venous thromboembolism prophylaxis
For women who need pharmacological thromboprophylaxis, consider low‑molecular‑weight heparin for at least 7 days after the abortion.
For women who are at high risk of thrombosis, consider starting low‑molecular‑weight heparin before the abortion and giving it for longer afterwards.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on venous thromboembolism prophylaxis .
Full details of the evidence and the committee's discussion are in evidence review E: venous thromboembolism prophylaxis for women having abortion.
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# Choice of procedure for abortion
Offer a choice between medical or surgical abortion up to and including 23+6 weeks' gestation (surgical abortion can be performed shortly after 23+6 weeks' gestation only if feticide is given at or before 23+6 weeks' gestation, according to the 2019 clarification of the time limits in the Abortion Act). If any methods would not be clinically appropriate, explain why.
To help women decide between medical and surgical abortion, see the NICE patient decision aids on choosing medical or surgical abortion.
To find out why the committee made the recommendations, see the rationale and impact section on the choice of procedure for abortion .
Full details of the evidence and the committee's discussion are in evidence review B: information needs of women undergoing an abortion and evidence review K: medical versus surgical abortion between 13+0 and 24+0 weeks' gestation.
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# Abortion before definitive ultrasound evidence of an intrauterine pregnancy
Consider abortion before there is definitive ultrasound evidence of an intrauterine pregnancy (a yolk sac) for women who do not have signs or symptoms of an ectopic pregnancy.
For women who are having an abortion before there is definitive ultrasound evidence of an intrauterine pregnancy (a yolk sac):
explain that there is a small chance of an ectopic pregnancy
explain that they may need to have follow-up appointments to ensure the pregnancy has been terminated and to monitor for ectopic pregnancy
provide 24‑hour emergency contact details, and advise them to get in contact immediately if they develop symptoms that could indicate an ectopic pregnancy (see symptoms and signs of ectopic pregnancy and initial assessment in the NICE guideline on ectopic pregnancy and miscarriage).
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on abortion before definitive ultrasound evidence of an intrauterine pregnancy .
Full details of the evidence and the committee's discussion are in evidence review F: abortion before ultrasound evidence.
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# Expulsion at home for medical abortion up to and including 10+0 weeks
## Up to and including 9+6 weeks' gestation
For women who are having a medical abortion and will be taking the mifepristone up to and including 9+6 weeks' gestation, offer the option of expulsion at home. Mifepristone and misoprostol can be taken at home or in the clinic or hospital.This recommendation is based on the evidence for the safety of home expulsion. The legal limit for the gestational age at which mifepristone and misoprostol can be taken at home is specified in the Abortion Act 1967.
## At 10+0 weeks' gestation
For women who are having a medical abortion and will be taking the mifepristone at 10+0 weeks' gestation, offer the option of expulsion at home after they have taken the misoprostol. Misoprostol can be taken in the clinic or hospital.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on expulsion at home for medical abortion up to and including 10+0 weeks .
Full details of the evidence and the committee's discussion are in evidence review G: expulsion at home for early medical abortion.
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# Medical abortion up to and including 10+0 weeks
In September 2019, mifepristone for abortion only has a UK marketing authorisation for:
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 400 micrograms misoprostol orally or 1 mg gemeprost vaginally, up to and including 49 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 1 mg gemeprost vaginally, between 50 days and 63 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 1 mg gemeprost vaginally, between 50 days and 63 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 800 micrograms misoprostol vaginally, up to and including 63 days of amenorrhoea
mg orally for medical abortion for medical reasons, followed 36 to 48 hours later by prostaglandin administration, beyond the first trimester
mg orally for cervical priming, 36 to 48 hours before first trimester surgical abortion.
All other uses of mifepristone are off label. See NICE's information on prescribing medicines.
In September 2019, misoprostol for medical abortion only has a UK marketing authorisation for:
micrograms orally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48 hours after 600 mg mifepristone orally, up to and including 49 days of amenorrhoea
micrograms vaginally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48 hours after 200 mg mifepristone orally, up to and including 63 days of amenorrhoea.
All other uses of misoprostol (including for cervical priming and for abortion at later gestations) are off label. See NICE's information on prescribing medicines.
Offer interval treatment (usually 24 to 48 hours) with mifepristone and misoprostol to women who are having a medical abortion up to and including 10+0 weeks' gestation.
For women who are having a medical abortion up to and including 9+0 weeks' gestation, give them the choice of having mifepristone and vaginal misoprostol at the same time, but explain that:
the risk of ongoing pregnancy may be higher, and it may increase with gestation
it may take longer for the bleeding and pain to start
it is important for them to complete the same follow-up programme that is recommended for all medical abortions up to and including 10+0 weeks (recommendations 1.14.1 and 1.14.2).
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on the interval between mifepristone and misoprostol for medical abortion up to and including 10+0 weeks .
Full details of the evidence and the committee's discussion are in evidence review H: medical abortion up to 10+0 weeks' gestation.
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# Medical abortion between 10+1 and 23+6 weeks
In September 2019, mifepristone for abortion only has a UK marketing authorisation for:
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 400 micrograms misoprostol orally or 1 mg gemeprost vaginally, up to and including 49 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 1 mg gemeprost vaginally, between 50 days and 63 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 1 mg gemeprost vaginally, between 50 days and 63 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 800 micrograms misoprostol vaginally, up to and including 63 days of amenorrhoea
mg orally for medical abortion for medical reasons, followed 36 to 48 hours later by prostaglandin administration, beyond the first trimester
mg orally for cervical priming, 36 to 48 hours before first trimester surgical abortion.
All other uses of mifepristone are off label. See NICE's information on prescribing medicines.
In September 2019, misoprostol for medical abortion only has a UK marketing authorisation for:
micrograms orally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48 hours after 600 mg mifepristone orally, up to and including 49 days of amenorrhoea
micrograms vaginally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48 hours after 200 mg mifepristone orally, up to and including 63 days of amenorrhoea.
All other uses of misoprostol (including for cervical priming and for abortion at later gestations) are off label. See NICE's information on prescribing medicines.
For women who are having a medical abortion between 10+1 and 23+6 weeks' gestation and who have taken 200 mg mifepristone, offer an initial dose (36 to 48 hours after the mifepristone) of:
micrograms misoprostol, given vaginally, or
micrograms of misoprostol, given sublingually, for women who decline vaginal misoprostol.Follow the initial dose with 400 microgram doses of misoprostol (vaginal, sublingual or buccal), given every 3 hours until expulsion.
Use a shorter interval between mifepristone and misoprostol if the woman prefers this, but explain that it may take a longer time from taking the first misoprostol dose to complete the abortion.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on medical abortion between 10+1 and 23+6 weeks .
Full details of the evidence and the committee's discussion are in evidence review J: medical abortion between 10+1 and 24+0 weeks' gestation.
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# Medical abortion after 23+6 weeks
In September 2019, mifepristone for abortion only has a UK marketing authorisation for:
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 400 micrograms misoprostol orally or 1 mg gemeprost vaginally, up to and including 49 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 1 mg gemeprost vaginally, between 50 days and 63 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 1 mg gemeprost vaginally, between 50 days and 63 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 800 micrograms misoprostol vaginally, up to and including 63 days of amenorrhoea
mg orally for medical abortion for medical reasons, followed 36 to 48 hours later by prostaglandin administration, beyond the first trimester
mg orally for cervical priming, 36 to 48 hours before first trimester surgical abortion.
All other uses of mifepristone are off label. See NICE's information on prescribing medicines.
In September 2019, misoprostol for medical abortion only has a UK marketing authorisation for:
micrograms orally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48 hours after 600 mg mifepristone orally, up to and including 49 days of amenorrhoea
micrograms vaginally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48 hours after 200 mg mifepristone orally, up to and including 63 days of amenorrhoea.
All other uses of misoprostol (including for cervical priming and for abortion at later gestations) are off label. See NICE's information on prescribing medicines.
For women who are having a medical abortion between 24+0 and 25+0 weeks' gestation, consider 200 mg oral mifepristone, followed by 400 micrograms misoprostol (vaginal, buccal or sublingual) every 3 hours until delivery.
For women who are having a medical abortion between 25+1 and 28+0 weeks' gestation, consider 200 mg oral mifepristone, followed by 200 micrograms misoprostol (vaginal, buccal or sublingual) every 4 hours until delivery.
For women who are having a medical abortion after 28+0 weeks' gestation, consider 200 mg oral mifepristone, followed by 100 micrograms misoprostol (vaginal, buccal or sublingual) every 6 hours until delivery.
Be aware that:
the uterus is more sensitive to misoprostol as pregnancy advances
risk factors for uterine rupture include a pre-existing uterine scar, increased gestational age and multiparity.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on medical abortion after 23+6 weeks .
Full details of the evidence and the committee's discussion are in evidence review L: medical abortion after 24 weeks' gestation.
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# Cervical priming before surgical abortion
In September 2019, mifepristone for abortion only has a UK marketing authorisation for:
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 400 micrograms misoprostol orally or 1 mg gemeprost vaginally, up to and including 49 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 1 mg gemeprost vaginally, between 50 days and 63 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 1 mg gemeprost vaginally, between 50 days and 63 days of amenorrhoea
mg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 800 micrograms misoprostol vaginally, up to and including 63 days of amenorrhoea
mg orally for medical abortion for medical reasons, followed 36 to 48 hours later by prostaglandin administration, beyond the first trimester
mg orally for cervical priming, 36 to 48 hours before first trimester surgical abortion.
All other uses of mifepristone are off label. See NICE's information on prescribing medicines.
In September 2019, misoprostol for medical abortion only has a UK marketing authorisation for:
micrograms orally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48 hours after 600 mg mifepristone orally, up to and including 49 days of amenorrhoea
micrograms vaginally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48 hours after 200 mg mifepristone orally, up to and including 63 days of amenorrhoea.
All other uses of misoprostol (including for cervical priming and for abortion at later gestations) are off label. See NICE's information on prescribing medicines.
## Up to and including 13+6 weeks
For women who are having a surgical abortion up to and including 13+6 weeks' gestation, offer cervical priming with:
micrograms sublingual misoprostol, given 1 hour before the abortion or
micrograms vaginal misoprostol, given 3 hours before the abortion.If misoprostol cannot be used, consider cervical priming with 200 mg oral mifepristone, given 24 to 48 hours before the abortion.
Explain to women that cervical priming:
reduces the risk of incomplete abortion for women who are parous
makes dilation easier for women who are parous or nulliparous
may cause bleeding and pain before the procedure.
## Between 14+0 and 23+6 weeks
For women who are having a surgical abortion between 14+0 and 23+6 weeks' gestation, offer cervical priming.
For women who are having a surgical abortion between 14+0 and 16+0 weeks' gestation, consider:
-smotic dilators or
buccal, vaginal or sublingual misoprostol or
mg oral mifepristone, given the day before the abortion.
For women who are having a surgical abortion between 16+1 and 19+0 weeks' gestation, consider:
-smotic dilators or
buccal, vaginal or sublingual misoprostol.
For women who are having a surgical abortion between 19+1 and 23+6 weeks' gestation, offer osmotic dilators. In addition, consider:
mg oral mifepristone the day before the abortion and
inserting osmotic dilators at the same time as the mifepristone.
For women who are having a surgical abortion between 14+0 and 23+6 weeks' gestation and are having cervical priming with osmotic dilators, consider inserting the osmotic dilators the day before the abortion.
Do not offer misoprostol for cervical priming if the woman has had an osmotic dilator inserted the day before the abortion.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on cervical priming before surgical abortion .
Full details of the evidence and the committee's discussion are in evidence review M: cervical priming before surgical abortion.
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# Anaesthesia and sedation for surgical abortion
For women who are having surgical abortion, consider local anaesthesia alone, conscious sedation with local anaesthesia, deep sedation or general anaesthesia. To help women make an informed choice, discuss the options with them and explain that:
having local anaesthesia alone means they will be able to spend less time in hospital
intravenous sedation plus local anaesthesia will help if they are anxious about the procedure
with deep sedation or general anaesthesia they will not usually be aware during the procedure.
When using conscious sedation for a surgical abortion, use intravenous rather than oral sedation.
When using general anaesthesia for a surgical abortion, consider intravenous propofol and a short‑acting opioid (such as fentanyl) rather than inhalational anaesthesia.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and sedation for surgical abortion .
Full details of the evidence and the committee's discussion are in evidence review M: cervical priming before surgical abortion.
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# Follow-up and support after an abortion
## Follow-up after medical abortion up to and including 10+0 weeks
For women who have had a medical abortion up to and including 10+0 weeks' gestation with expulsion at home, offer the choice of self-assessment, including remote assessment (for example telephone or text messaging), as an alternative to clinic follow-up.
Provide women with a low-sensitivity or multi-level urine pregnancy test to exclude an ongoing pregnancy.
## Support after an abortion
Explain to women:
what aftercare and follow-up to expect
what to do if they have any problems after the abortion, including how to get help out of hours
that it is common to feel a range of emotions after the abortion.
Advise women to seek support if they need it, and how to access it (if relevant). This could include:
support from family and friends or pastoral support
peer support, or support groups for women who have had an abortion
counselling or psychological interventions.
Providers should be able to provide emotional support after abortions. They should tell women this support is available if they need it.
Providers should provide or refer women for counselling if requested.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on follow-up and support after an abortion .
Full details of the evidence and the committee's discussion are in evidence review I: follow-up after medical abortion up to 10+0 weeks and evidence review O: support after abortion.
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# Improving access to contraception
Commissioners and providers should ensure that the full range of reversible contraceptive options (depot medroxyprogesterone acetate , contraceptive implant, intrauterine methods, oral contraceptives, contraceptive patches, vaginal rings or barrier contraception) is available for women on the same day as their surgical or medical abortion.
Providers should ensure that healthcare professionals have the knowledge and skills to provide all contraceptive options.
Providers should ensure they can provide the contraceptive implant, and that women who choose this method are offered it on:
the day of the surgical abortion or
the day they take mifepristone (for medical abortions).
Providers should ensure they can provide intrauterine methods of contraception, and that women who choose this method are offered this:
at the same time as the surgical abortion or
as soon as possible after expulsion of the pregnancy (for medical abortions).
For women who are having a medical abortion and who choose DMPA intramuscular injection for contraception:
consider providing it at the same appointment when they take the mifepristone
explain that having the injection at this stage may increase the risk of ongoing pregnancy, although overall the risk is low.
To find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on contraception after abortion .
Full details of the evidence and the committee's discussion are in evidence review P: contraception after abortion.
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# Terms used in this guideline
## Fetal anomaly
Defined as pregnancies falling within section 1(1)(d) of the 1967 Abortion Act. This covers pregnancies where 2 medical practitioners are of the opinion that 'there is a substantial risk that if the child were born it would suffer from such physical or mental abnormalities as to be seriously handicapped'. This is referred to as ground E in the HSA1 form.
## Feticide
Feticide is the injection of digoxin or potassium chloride into the fetus, or an injection of digoxin into the amniotic cavity, to stop the fetal heart before an abortion.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Antibiotic prophylaxis for surgical abortion
What is the optimal antibiotic prophylaxis regimen for women who are having a surgical abortion?
To find out why the committee made the recommendation for research, see the rationale section on preventing infection .
Full details of the evidence and the committee's discussion are in evidence review D: antibiotic prophylaxis for medical and surgical abortion.
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## Cervical priming before surgical abortion
What are the most effective and acceptable methods of cervical priming before dilatation and evacuation after 16+0 weeks' gestation?
To find out why the committee made the recommendation for research, see the rationale section on cervical priming before surgical abortion .
Full details of the evidence and the committee's discussion are in evidence review M: cervical priming before surgical abortion.
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## Anti-D prophylaxis for surgical abortion
Should women having a surgical abortion up to and including 10+0 weeks' gestation have anti-D prophylaxis if they are RhD (or D) negative?
To find out why the committee made the recommendation for research, see the rationale section on anti-D prophylaxis for surgical abortion .
Full details of the evidence and the committee's discussion are in evidence review C: anti-D prophylaxis for women up to 13+6 weeks' gestation.
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## Expulsion at home for medical abortion
For women who are having medical abortion between 10+1 and 12+0 weeks, what is the efficacy and acceptability of expulsion at home compared with expulsion in a clinical setting?
To find out why the committee made the recommendation for research, see the rationale section on expulsion at home for medical abortion between 10+1 and 12+0 weeks .
Full details of the evidence and the committee's discussion are in evidence review G: expulsion at home for early medical abortion.
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## Anaesthesia and sedation for surgical abortion
What local anaesthetic techniques are most effective for women having surgical abortion?
To find out why the committee made the recommendations and how they might affect services, see the rationale section on anaesthesia and sedation for surgical abortion .
Full details of the evidence and the committee's discussion are in evidence review M: cervical priming before surgical abortion.
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# Other recommendations for research
## Medical abortion after 23+6 weeks
What is the effectiveness and safety of regimens using mifepristone and misoprostol for women who are having medical abortion after 23+6 weeks' gestation, particularly for those who have had a previous caesarean section or uterine surgery?
## Anaesthesia and sedation for surgical abortion
What is the optimal regimen for general anaesthesia for women having surgical abortion?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Service organisation
## Why the committee made the recommendations
Recommendations 1.1.1 to 1.1.4
Evidence showed that obtaining an abortion can be complicated for women and that the information available on how to do this is often inconsistent. There was also evidence that integrating and streamlining services would improve access.
There was evidence that women wanted a choice of abortion procedure. The committee agreed that it is not practical for all services to offer all abortion options. To ensure women still have a choice if local services do not provide the full range of options, the committee made a recommendation covering onward referral.
Evidence also showed that:
it can be difficult to get a prompt GP appointment
women may face negative attitudes from healthcare professionals, and that this makes it harder to get referrals for abortion.
With this in mind, the committee recommended that services enable women to self-refer. This will improve women's experiences and could also help them avoid stigma and negative attitudes when requesting an abortion. There was no evidence on the best way to enable self-referral (for example through dedicated booking systems, centralised referral, drop-in services, or online booking), so the committee could not make a more specific recommendation.
Although women can self-refer, some will still choose to see a healthcare professional. So that these women can also easily access abortion services, the committee made a recommendation for healthcare professionals on ensuring that they do not delay access because of their personal beliefs. This is in line with professional guidance on conscientious objection (for example from the General Medical Council), which protects the right to opt out of performing abortions but not the right to opt out of providing access to abortion services.
There was evidence that travel costs can be a significant barrier to accessing services. This may be a particular problem for women with low incomes and women who need to travel for a service that is not available locally. Women having an abortion often have to travel at very short notice and may have difficulty arranging funds before the appointment. The committee recognised that it will not always be possible to provide care locally, but they agreed that interventions such as upfront funding of women's travel and accommodation costs could improve access.
Recommendations 1.1.5 to 1.1.8
While abortion is very safe overall, there was evidence that morbidity and mortality increases for every additional week of gestation, so earlier abortions are safer. There was also evidence of long waiting times and delays for women trying to access abortion services. Reducing waiting times can ensure women have more options available, decrease adverse events, and improve women's experience.
In addition, there was strong evidence that substantial cost savings can be achieved if women present earlier for abortion. Most of this saving comes from women having a medical rather than a surgical abortion. With this in mind, the committee felt that it was important to make recommendations on minimising delays for assessment and abortion. Note that while recommendation 1.1.6 gives separate time frames for assessment and abortion, this is not intended to stop services that provide these on the same day from doing so.
In some countries there are local policies such as compulsory counselling and imposed time for reflection before women are allowed to have an abortion. The evidence showed that these can cause delays in accessing abortion services. Neither counselling nor enforced waiting periods are a legal requirement in the UK. The committee agreed, based on their experience, that these policies can cause distress and that many women do not want counselling. Therefore, the committee agreed that these policies should not be used. However, the committee did not want to discourage services from providing or referring women for support to help make a decision if requested, so they covered this in the recommendation.
The committee recognised that it is not possible for all services to offer abortions every day of the week. This can lead to a choice between travelling further to have an abortion sooner, or waiting longer to have an abortion closer to home. Further, while most women are certain of their decision to have an abortion at the time of the assessment, some women might want more time to consider their decision after this. It is important that women understand the implications of waiting, so the committee made a recommendation to address this.
Recommendations 1.1.9 to 1.1.10
Community services and telemedicine appointments are recommended because the evidence showed they improve access to abortion services. There was also limited evidence that patient satisfaction is the same with abortions provided by community or by hospital services, and with appointments provided via telemedicine or at the hospital.
The committee were aware that it can be distressing for women who are having an abortion to attend appointments alongside women who are continuing with their pregnancies. The committee agreed that it was important to minimise distress and protect dignity, but did not make a recommendation on separating these groups because:
the evidence on how effective this would be at reducing distress was not reviewed by the committee
there are resource issues and safety concerns with making this a requirement for all services
separating women who are having an abortion may stigmatise them and make them easy to identify (which is a concern for many women).
Recommendations 1.1.11 to 1.1.14
There was evidence that women prefer care led by nurses or midwives. Although there are legal restrictions that prevent nurses and midwives from providing certain parts of abortion services, the committee agreed that there are ways their role could still be expanded and that this would improve care.
The committee made recommendations on training because evidence showed that a shortage of trained staff with the necessary skills is making it harder to provide some abortion procedures. There was evidence that NHS hospital-based providers are losing clinical skills because abortion is currently mainly carried out in the independent sector. Ensuring all trainees have the training is important because otherwise healthcare professionals may see this training as optional, rather than as essential training for a common healthcare procedure.
Recommendations 1.1.15 to 1.1.16
There was no evidence on how to improve access for women with comorbid conditions. Based on their knowledge and experience, the committee recommended that services develop pathways for women having an abortion. This will reduce delays and improve access, particularly for women who need care at specialist centres.
Recommendations 1.1.17 to 1.1.18
There was evidence that women present later if they have had a negative experience from a previous abortion. However, no evidence was available on specific interventions to reduce stigma or improve privacy, so the committee made a general recommendation highlighting that the way professionals communicate with women can negatively impact on the woman's experience.
In addition, evidence shows that women are also concerned about privacy and confidentiality and are worried about reactions from other people. Further, the committee agreed, based on their experience, that women are often concerned that information about their abortion may be shared unnecessarily with other healthcare professionals. Therefore, the committee made a recommendation about being sensitive to those concerns.
## How the recommendations might affect current practice
Improving access to abortion services is likely to result in substantial cost savings. Most of this saving comes from women having a medical rather than a surgical abortion. Earlier abortions also have lower rates of complications. Recommendations on location of services, ease of access and complex comorbidities could reduce inequalities for:
women living in remote areas
women with low income
women with comorbid physical and/or mental health problems
vulnerable women
girls and younger women.
Funding for travel is already available for women with low income under the NHS Healthcare Travel Costs Scheme, but this policy requires that women pay upfront and claim back costs after the abortion. Setting up processes for upfront funding will involve some initial costs, but otherwise the recommendation for women with a low income will only affect the timing of the payment and not the absolute cost. There will be some costs involved with providing funding for women who do not have a low income but who are travelling for a service that is not available locally. The new costs involved with funding travel and accommodation may be regained through women having earlier abortions.
Even small reductions in waiting times would result in large cost savings. A reduction of 1 day in the average waiting time would save the NHS £1.6 million per year on procedure costs and treating adverse events. Because of this, even relatively expensive interventions would be cost saving if they decrease waiting times. To reduce waiting times, services will need to consider ways to enable more rapid referral and develop pathways for self-referral. Some abortion services may need to reconfigure so that they are available on a greater number of days per week. More collaboration between NHS services and the independent sector may also be needed. However, recommendations on expulsion at home and remote follow-up will minimise the number of appointments needed, again leading to cost savings.
Establishing dedicated phone and online booking systems, or centralised booking services, will have upfront costs. However, they are likely to lead to substantial savings through reduced waiting times.
Many services already have videoconferencing facilities. Videoconferencing software is not expensive, so services that don't have these facilities in place will not face significant upfront costs.
There has been an increase in community-based services in recent years, so additional costs associated with providing services in the community will be minimal. Women having an abortion in the community may need to make fewer arrangements regarding time off work, childcare and travel. This may enable them to present earlier for an abortion, which would result in cost savings for the NHS.
Women prefer care led by nurses or midwives. Expanding the role of these professionals should increase the number of appointments available and enable women to present earlier. Any upfront costs associated with providing training for nurses and midwives will likely be offset by cost savings from earlier abortions and reduced doctor hours.
Commissioners will need to work with national organisations such as Health Education England to agree changes to training curriculums.
Full details of the evidence and the committee's discussion are in evidence review A: accessibility and sustainability of abortion services and evidence review B: information needs of women undergoing an abortion.
Return to recommendations
# Providing information
Recommendations 1.2.1 to 1.2.10
## Why the committee made the recommendations
The recommendations are based on evidence showing what women want to know about abortion, and what formats they want information in. Some evidence came from women who were having abortions for specific reasons, such as fetal anomaly (under the Abortion Act). However, the committee agreed that improving information provision would benefit all women who are having an abortion, so made recommendations that could apply to everyone.
The committee also made some recommendations based on their knowledge and experience covering:
medical abortions at home
what to expect when viewing a fetus after abortion.
The committee were aware of systematic reviews and guidance from the Academy of Medical Royal Colleges (2011), American College of Obstetricians and Gynecologists (2009) and Royal College of Obstetricians and Gynaecologists (2011; 2015) that indicate there is no evidence that an abortion increases the risk of infertility, breast cancer or mental health issues. As there was evidence that women looked on the internet for information about abortion, and the committee were concerned that some of this information may be inaccurate, they made a recommendation about these risks to inform women.
The committee were aware that women wanted information on the options for management and disposal of pregnancy remains (including burial) after an abortion. However, the committee did not make a detailed recommendation in this area as this is covered by 2015 guidance from the Human Tissue Authority that outlines:
the options (including the right to take remains home)
the information that should be provided to the woman and how this should be communicated
the importance of meeting religious and cultural needs where possible.
Recommendations 1.2.11 to 1.2.12
For women having an abortion because of fetal anomaly, there was evidence that they wanted more information on the nature of the anomaly. The committee agreed that this would be better addressed by the maternity service that diagnosed the fetal anomaly, so included communication between services in their recommendation on service organisation.
There was evidence that women wanted information about how to tell other people (for example friends and family members) about the end of their pregnancy, but there was not enough evidence to make a recommendation.
## How the recommendations might affect current practice
Services already provide women with information about their abortion. These recommendations may mean services need to change what information they are providing, but the cost of giving women more information is minimal and will result in women being better informed about their options and the process for abortion.
Full details of the evidence and the committee's discussion are in evidence review B: information needs of women undergoing an abortion.
Return to recommendations
# Anti-D prophylaxis
Recommendations 1.3.1 to 1.3.4
## Why the committee made the recommendations
There was no evidence on anti-D prophylaxis for women having an abortion up to and including 13+6 weeks' gestation. There is also no international consensus on this, with significant variation between different international and national guidelines.
Current practice in the NHS is to give anti-D to all women who are having an abortion and are rhesus D negative. However, testing for rhesus status and then administering anti-D can result in significant delays for women. They may need to visit the service more than once to receive anti-D, and this can be a particular problem for women who are travelling a long way or who find it difficult to afford travel. The cost of testing for rhesus status and giving anti-D also needs to be considered.
With these points in mind, the committee made recommendations based on their knowledge and experience. They agreed that, for women up to and including 10+0 weeks' gestation, the volume of fetal blood cells transmitted to the mother is unlikely to cause maternal sensitisation. The impact of delays to the abortion, travel problems, and costs to services are likely to outweigh any benefit prophylaxis provides. The NICE guideline on ectopic pregnancy and miscarriage recommends against anti-D prophylaxis for women having medical management for these conditions. The committee agreed that the risks and benefits of anti-D prophylaxis would be similar for women having a medical abortion. Therefore, the committee made a recommendation in line with the NICE guideline on ectopic pregnancy and miscarriage.
Although there is no evidence to distinguish surgical and medical abortion on this topic, the committee agreed there may be risk of more fetal blood cell transmission during a surgical abortion. Because of this, anti-D prophylaxis may be beneficial for women having a surgical abortion up to and including 10+0 weeks' gestation.
In the independent sector, point-of-care testing is used and anti-D is provided immediately. In contrast, NHS transfusion laboratories usually follow the same processes for managing anti-D as they do for managing whole transfusion systems. This is unnecessary and introduces delays, and means that women must choose between not having testing and prophylaxis or returning to the service after the abortion. To help reduce delays, the committee made a recommendation in line with current practice in the independent sector.
In the absence of evidence, the precise benefits and risks of anti-D prophylaxis are unclear. The uncertainty is highest for women having a surgical abortion up to and including 10+0 weeks' gestation, so the committee made a research recommendation covering this group.
## How the recommendations might affect practice
Restricting anti-D prophylaxis to women who are most likely to benefit from it could potentially produce cost savings of over £1 million annually across the NHS. Staff will be freed up to focus on more important and beneficial areas of the abortion service.
NHS Trusts and transfusion laboratories may need to amend their systems and processes to ensure they can provide rhesus status testing and anti-D prophylaxis without introducing delays to the abortion process.
Full details of the evidence and the committee's discussion are in evidence review C: anti-D prophylaxis for women up to 13+6 weeks' gestation.
Return to recommendations
# Preventing infection
## Why the committee made the recommendations
Recommendations 1.4.1 to 1.4.5
The evidence on antibiotic prophylaxis for women who are having medical abortion showed lower rates of severe infection with antibiotic prophylaxis compared with no antibiotic prophylaxis. However, the committee had concerns with the quality of the evidence, and the absolute risk of severe infection was very low. In addition:
routinely prescribing antibiotics after medical abortion may increase the risk of antibiotic resistance
adherence is likely to be low
if using routine antibiotics the potential reduction in the risk of post-abortion infection is uncertain.
With these points in mind, the committee did not recommend routine antibiotic prophylaxis for women who are having a medical abortion. The committee believed that prophylaxis may be appropriate for women who are at high risk of infection, or who would find it difficult to access treatment at a later date if they screened positive for a sexually transmitted infection. However, there was no evidence to support recommending prophylaxis for a specific group.
Antibiotic prophylaxis is part of current clinical practice for women having a surgical abortion. The committee wanted to encourage this, so they made a recommendation in support.
The evidence reviewed did not identify which specific antibiotic regimen is most effective. Because of this, the committee agreed that further research would be beneficial and made a research recommendation. However, the committee were aware of a Cochrane review which showed the effectiveness of nitroimidazoles (such as metronidazole), tetracyclines (such as doxycycline) and beta lactams (such as amoxicillin).
A 7-day course of doxycycline is currently used in practice. There was no evidence comparing doxycycline with other antibiotics; however, there was some limited evidence on duration of doxycycline. The evidence was unclear on whether or not there were clinically important differences between 3‑day and 7‑day courses of doxycycline in the rates of pelvic inflammatory disease after abortion, patient adherence, vomiting, or diarrhoea. The committee recommended a 3‑day course because this may be as effective and adherence is likely to be better with a shorter course.
Metronidazole in combination with another broad-spectrum antibiotic is not routinely recommended because:
compared with doxycycline alone for surgical abortion, it was unclear if it made a clinically important difference to the rate of pelvic inflammatory disease after abortion in women who had elevated vaginal pH and amines in vaginal discharge, or a positive gram stain for bacterial vaginosis
although there was no evidence on the gastrointestinal side effects when compared with doxycycline alone, the committee agreed that in clinical practice metronidazole may be poorly tolerated with significant side effects.
However, the committee agreed that metronidazole is effective for anaerobic infections, so there may be situations where it is clinically indicated.
The evidence for the recommendations on doxycycline and metronidazole was based on antibiotic prophylaxis for surgical abortion. However, the committee agreed that the recommendations would also be appropriate if there is a need to use antibiotic prophylaxis for medical abortion as the causes of infection would be similar for both procedures, although the level of risk may differ.
The committee could not make recommendations about screening for sexually transmitted infections, because they did not review the evidence this. A cross-reference has been included to the NICE guideline on preventing sexually transmitted infections and under-18 conceptions.
## How the recommendation might affect practice
Despite the shortage of evidence, it is current clinical practice to offer antibiotic prophylaxis to women who are having medical abortion. Because of this, the recommendations will reduce the number of women having antibiotic prophylaxis for medical abortion. This has the potential to be cost saving and to reduce the risk of antibiotic resistance. The recommendation may also increase the number of women who accept screening for sexually transmitted infections. This is because women are more likely to accept screening if they are not given prophylactic antibiotics (which could make them believe screening and treatment for sexually transmitted infections, if present, was not needed).
The recommendation for surgical abortion supports routine antibiotic prophylaxis, which is current practice.
The 7‑day course of doxycycline is currently used in practice. Metronidazole is also currently used in combination with other broad-spectrum antibiotics. Switching to shorter courses of doxycycline and not using metronidazole in combination with other broad-spectrum antibiotics may lead to cost savings.
Full details of the evidence and the committee's discussion are in evidence review D: antibiotic prophylaxis for medical and surgical abortion.
Return to recommendations
# Venous thromboembolism prophylaxis
Recommendations 1.5.1 to 1.5.2
## Why the committee made the recommendations
There was no evidence on the optimal timing and duration of venous thromboembolism (VTE) prophylaxis for women having an abortion who need pharmacological thromboprophylaxis. In the absence of evidence, the committee made a recommendation based on the recommendations for women who have had a termination in the last 6 weeks in the NICE guideline on reducing the risk of venous thromboembolism.
The recommendation for women at high risk is based on the committee's knowledge and experience. They agreed that it may be safer to start prophylaxis earlier and provide it for longer in this group. However, the lack of evidence meant they were unable to be more specific. The recommendation is in line with antenatal and postnatal risk assessment tools from the Royal College of Obstetricians and Gynaecologists.
## How the recommendations might affect practice
These recommendations are in line with the NICE guideline on reducing the risk in venous thromboembolism. Unlike that guideline, the recommendations here cover all women at risk, rather than just those admitted to hospital. This means there may be an increase in the number of women receiving prophylaxis.
There will be increased costs from the increased use of low-molecular-weight heparin and the training needed to administer it. The size of this increase will depend on current local practice and the number of women who are at risk of thrombosis. These costs will be partially offset by a reduction in the incidence of VTE, but the savings associated with this may be small as VTE is rare in this context.
Full details of the evidence and the committee's discussion are in evidence review E: venous thromboembolism prophylaxis for women having abortion.
Return to recommendations
# Choice of procedure for abortion
Recommendations 1.6.1 to 1.6.2
## Why the committee made the recommendation
The evidence showed that women having an abortion for fetal anomaly preferred a choice between medical or surgical abortion, and in the committee's experience women having an abortion for other reasons also valued having a choice of procedure.
Comparing medical and surgical abortion in women between 13+0 and 23+6 weeks' gestation, the evidence showed that it was unclear whether or not there was a clinically important difference in:
haemorrhage that needed transfusion, or blood loss of 500 ml or more
abortion completed by the chosen method
uterine injury
infection within 1 month of the abortion.
It was also unclear from the evidence whether or not there was a clinically important difference in cervical injury between medical and surgical abortion. However, the committee agreed that the risk of cervical injury with medical abortion would be extremely low as no instruments or dilators are inserted into the cervix. There was a higher clinically important rate of incomplete abortion needing surgical intervention for women who had medical abortion. There was also some evidence that women prefer surgical abortion. However, the evidence in this area was limited, and the committee did not feel confident in making a recommendation in favour of one method. This guideline did not review evidence comparing medical and surgical abortion for women up to and including 12+6 weeks' gestation, because it is well established that both methods are highly safe at this gestational age and that they have similar effectiveness. In addition, evidence for abortions after 23+6 weeks was not reviewed because all abortions in England and Wales after this gestational age are medical procedures, with the exception of surgical abortions when feticide has been given at or before 23+6 weeks.
Given the evidence that women preferred a choice of procedure, and the lack of evidence that either procedure is superior, the committee recommended offering women up to and including 23+6 weeks a choice (as long as it is clinically appropriate).
## How the recommendation might affect current practice
This recommendation will lead to a change in practice because abortion services for women vary widely nationally. Many services only offer either surgical or medical abortion. There are also relatively few doctors trained to provide surgical abortion in the second trimester in the NHS, and most independent sector services are not set up to provide inpatient medical abortion.
To address these issues, greater collaboration may be needed between and across sectors to provide women with a choice of methods. Theatre teams in the NHS may also need support if they are going to introduce a new service offering surgical abortion by dilatation and evacuation. Modern dilatation and evacuation practice uses ultrasound scanning during surgery, so scan machines need to be in theatre and staff need to be able to undertake intraoperative scanning when needed.
Before services can start offering medical abortion, they need to ensure they have beds available and nursing staff who are trained to care for women having medical abortion in the second trimester.
Full details of the evidence and the committee's discussion are in evidence review B: information needs of women undergoing an abortion and evidence review K: medical versus surgical abortion between 13+0 and 24+0 weeks' gestation.
Return to recommendation
# Abortion before definitive ultrasound evidence of an intrauterine pregnancy
Recommendations 1.7.1 to 1.7.2
## Why the committee made the recommendations
Only limited evidence was available for this area. However, it suggested that abortion (medical or surgical) works just as well before there is definitive ultrasound evidence of an intrauterine pregnancy (that is, a yolk sac) as it does afterwards. There was no clinically important difference in the rates of complete abortion, whereas it was unclear whether or not there was a clinically important difference in the rates of missed ectopic pregnancy and ongoing pregnancy.
These findings matched the clinical experience of the committee for medical abortion at this stage for women who do not have signs or symptoms of an ectopic pregnancy. In addition, evidence from other areas of the guideline showed that women prefer to have the abortion as soon as possible.
As the evidence was limited, the committee felt that it was important to make women aware of the potential risk of not identifying an ectopic pregnancy, and what they should do if there is a problem.
## How the recommendations might affect current practice
Some services do not currently provide abortion before there is definitive ultrasound evidence of pregnancy. As a result, the recommendation will make abortion available earlier than it is currently provided. This will make it easier for women to access services and reduce waiting times. There may be a larger impact on providers of surgical abortion, as this is not always offered as early as medical abortion.
Services providing surgical abortion before ultrasound evidence will need to have systems to confirm that the pregnancy has been aspirated. For example, they will need to have staff trained to inspect the products of conception for the presence of chorionic villi and a gestational sac, and provide the necessary equipment to do this (typically a light box and a clear receiver) or immediate access to ultrasound. Services offering surgical or medical abortion before ultrasound evidence of pregnancy will also need to be able to assess serum human chorionic gonadotrophin (hCG), and have staff trained in interpreting test results. If an ectopic pregnancy is suspected, services will need to have processes in place to refer the woman promptly to an early pregnancy assessment unit.
Full details of the evidence and the committee's discussion are in evidence review F: abortion before ultrasound evidence.
Return to recommendations
# Expulsion at home for medical abortion up to and including 10+0 weeks
Recommendations 1.8.1 to 1.8.2
## Why the committee made the recommendation
These recommendations are based on the evidence on the safety of home expulsion. Separate recommendations were made for women up to and including 9+6 weeks gestation and women at 10+0 weeks gestation due to the legal limit at which misoprostol can be taken at home.
Comparing women up to and including 9+0 weeks' gestation at the time they take mifepristone with women who take it between 9+1 and 10+0 weeks, the evidence on home expulsion showed no difference in:
the risk of serious complications, such as the need for emergency care or hospitalisation, haemorrhage needing transfusion, or 500 ml or more blood loss
the rate of adverse events such as pain, vomiting and diarrhoea.
It was unclear whether or not there was a difference in rates of completed abortion without the need for surgical intervention in women who were up to and including 9+0 weeks when home expulsion was performed or between 9+1 and 10+0 weeks. Evidence on patient satisfaction showed it was the same in both groups.
The committee noted that the evidence on women having home expulsion up to and including 12+0 weeks was from a single low-quality study from settings outside the UK. They agreed that further research on home expulsion up to and including 12+0 weeks in the UK would be beneficial to inform future practice and made a research recommendation.
## How the recommendation might affect current practice
Currently, medical abortion with expulsion at home is offered for women who are up to and including 10+0 weeks gestation at the time they take mifepristone in some areas, but only up to and including 9+0 weeks in others. As well as standardising practice, the recommendations are likely to result in more women being able to have an early medical abortion at home. In current practice women need to be admitted to hospital and have to wait for bed availability. Expanding home expulsion would reduce the number of women admitted to hospital, reducing waiting times.
Full details of the evidence and the committee's discussion are in evidence review G: expulsion at home for early medical abortion.
Return to recommendation
# Medical abortion up to and including 10+0 weeks
Recommendations 1.9.1 to 1.9.2
## Why the committee made the recommendations
There was limited evidence comparing simultaneous mifepristone and misoprostol with interval treatment (misoprostol given 23 to 48 hours after mifepristone) for abortion in women who were up to and including 9+0 weeks' gestation. The evidence that was available showed no difference in:
-ngoing pregnancy rate
rates of haemorrhage that needed transfusion, or blood loss of 500 ml or more
patient satisfaction
the need for repeat misoprostol
incomplete abortion needing surgery.
However, for all of these outcomes apart from patient satisfaction, it was unclear whether or not there was a clinically important difference. In addition, the committee were concerned that the findings from this review were inconsistent with their experience. There is also another study (Lohr 2018) with different results to the studies that were covered in the evidence review. This study was not included in the review because it was not a randomised controlled trial. However, it was a much larger study (nearly 29,000 participants compared with 1,100 in the largest randomised controlled trial) and had a similar population to the studies in the evidence review. This study showed that:
the success rates of simultaneous administration were inversely proportional to the gestational age
as gestational age increases simultaneous administration becomes increasingly inferior to interval administration
for ongoing pregnancy, while the risk was low in both groups, the absolute risk was 1.5% higher after simultaneous treatment (2.4%) than after interval treatment (0.9%).
Given the size and relevance of this study, the committee believed it was important to take these findings into account when making recommendations.
There was evidence that bleeding and pain started later with simultaneous mifepristone and misoprostol. This may be an advantage for women who are taking both of the drugs in hospital or clinic before travelling home to complete the abortion. In addition, the total time from start to completion of abortion is shorter, and women may prefer simultaneous mifepristone and misoprostol because of this.
The committee specified vaginal misoprostol for simultaneous treatment because that was the only route of administration used in the evidence. The committee did not recommend simultaneous treatment as an option for women between 9+1 and 10+0 weeks' gestation because there was no evidence for women with a longer gestation period. Interval treatment was recommended for these women because it is standard clinical practice.
## How the recommendations might affect current practice
Simultaneous administration of mifepristone and misoprostol is not routinely offered, so these recommendations could result in changes to practice.
Full details of the evidence and the committee's discussion are in evidence review H: medical abortion up to 10+0 weeks' gestation.
Return to recommendations
# Medical abortion between 10+1 and 23+6 weeks
Recommendations 1.10.1 to 1.10.2
## Why the committee made the recommendations
Most studies included a vaginal loading dose of 800 micrograms misoprostol in their regimen. The dose for vaginal misoprostol is the same dose used for abortion up to and including 10+0 weeks' gestation, so this will be simpler for services to provide for women between 10+1 and 23+6 weeks' gestation. The evidence showed no significant difference between an initial dose of vaginal misoprostol compared with sublingual misoprostol on time to expulsion or rate of completed abortion. Some women will prefer not to have vaginal misoprostol, so giving the option of sublingual administration takes account of patient preference. The sublingual dose was taken from the study comparing the vaginal and sublingual doses. The evidence showed that oral misoprostol had more side effects than sublingual or vaginal regimens and also had a longer interval between induction and abortion. There was no evidence available regarding effectiveness of oral misoprostol administered as a loading dose. Because of this, no recommendation was made on oral misoprostol.
For follow-up doses, most of the studies reviewed used 400 micrograms misoprostol given vaginally, orally, sublingually or buccally. In addition, there was limited evidence that this dose had a shorter time to expulsion than the 200 microgram dose.
There was evidence that time to expulsion was shorter when there was a longer interval between mifepristone and misoprostol administration. In comparisons of different intervals:
a 36- to 38‑hour interval gave a shorter time to expulsion than simultaneous administration
a 48‑hour interval gave higher rates of completed abortion and shorter time to expulsion than a 24‑hour interval.
The committee noted that some women would prefer not to wait 36 to 48 hours between taking mifepristone and taking misoprostol, because of factors such as travel difficulties. To take account of patient preference, they recommended giving women the option of a shorter interval.
The committee were aware of guidelines from the Royal College of Obstetricians and Gynaecologists that recommend feticide for abortion after 21+6 weeks' gestation. However, the committee did not review the evidence on feticide, so they could not make recommendations on this.
## How the recommendations might affect current practice
These recommendations will reduce variations in practice in the use of misoprostol for abortion between 10+1 and 23+6 weeks. The recommendations will also reduce the use of oral misoprostol, which is used currently.
Full details of the evidence and the committee's discussion are in evidence review J: medical abortion between 10+1 and 24+0 weeks' gestation.
Return to recommendations
# Medical abortion after 23+6 weeks
Recommendations 1.11.1 to 1.11.4
## Why the committee made the recommendations
Abortion after 23+6 weeks' gestation is rare. In 2017, these abortions accounted for 0.1% of the total. The statutory grounds for abortion at this stage are for fetal anomaly or, in an emergency, either:
when continuing the pregnancy would involve risk to the life of the pregnant woman, greater than if the pregnancy were terminated or
to prevent grave permanent injury to her physical or mental health.
There was no evidence on which regimen is optimal for medical abortion after 23+6 weeks. In the absence of evidence, the committee based the recommendation for women between 24+0 and 25+0 weeks' gestation on the dose regimens for women having an abortion up to and including 23+6 weeks. Considering the increased sensitivity of the uterus to misoprostol as gestational age increases, the initial high loading dose of misoprostol was not included in the regimen for this group.
For women between 25+1 and 28+0 weeks' gestation, the recommendation is based on the committee's knowledge and experience. They noted that the uterus becomes more sensitive as gestational age increases and so the dose of misoprostol should be reduced. The recommendation is also in line with the International Federation of Gynecology and Obstetrics (FIGO) guidance on misoprostol for women at this gestation.
For women after 28+0 weeks' gestation, the committee recommended the regimen based on their expertise and on the guidance from FIGO.
Because the uterus becomes more sensitive to misoprostol later in gestation, women who have had a previous caesarean section or uterine surgery may be at higher risk of uterine rupture with increased doses of misoprostol. In the absence of evidence to recommend a different regimen for this group, the committee agreed that clinicians should be made aware of this risk. Given this risk and the lack of evidence in this area, the committee made a research recommendation on drug regimens for medical abortion after 23+6 weeks, particularly for women who have had a previous caesarean section or uterine surgery.
The committee were aware of guidelines from the Royal College of Obstetricians and Gynaecologists that recommend feticide for abortion after 21+6 weeks' gestation. However, the committee did not review the evidence on feticide, so they could not make recommendations on this.
## How the recommendations might affect current practice
There is currently no guidance on what regimen to use for medical abortion after 23+6 weeks. Current practice varies as a result, and some services use lower doses of misoprostol that may not be as clinically effective as higher doses. These recommendations will help to standardise practice.
Full details of the evidence and the committee's discussion are in evidence review L: medical abortion after 24 weeks' gestation.
Return to recommendations
# Cervical priming before surgical abortion
## Why the committee made the recommendations
Recommendations 1.12.1 to 1.12.2
There was good evidence that vaginal and sublingual misoprostol reduce the risk of an incomplete abortion and reduce the force needed to dilate the cervix, compared with no cervical priming.
The timings given were chosen to minimise the amount of time spent with preoperative pain and bleeding while still ensuring adequate priming. More force was needed to dilate the cervix when vaginal misoprostol was given 1 hour before the procedure, so this regimen needs to be given earlier than sublingual misoprostol. This means women will spend more time with preoperative pain and bleeding if they have vaginal misoprostol. However, based on the committee's experience, sublingual misoprostol causes more gastrointestinal side effects than vaginal misoprostol. It may therefore be less acceptable to women, and managing the side effects can place additional demands on the service. Because of these advantages and disadvantages, the committee recommended both so that women can choose which is best for them, and so that providers can be flexible (for example with appointment times) based on what works best for each woman.
The dose of 400 micrograms was chosen for both routes of misoprostol administration because there was more evidence for this than for 200 micrograms, and because it was unclear whether or not there were clinically important differences in side effects between the two.
There was very little evidence for mifepristone. However, the evidence that was available suggested that mifepristone may be as effective as misoprostol. Because of this, the committee recommended mifepristone when misoprostol cannot be used, so that women in this situation have another option. The dose is based on the evidence reviewed and on standard clinical practice. The timings are based on the evidence available, but a range is recommended because there was limited evidence comparing mifepristone given 48 hours before the procedure with mifepristone given 24 hours before the procedure.
While cervical priming makes the procedure safer, women may be put off by the possibility of preoperative pain and bleeding associated with its use. Women are more likely to choose cervical priming if the benefits and harms are fully explained to them, so the committee made a recommendation to ensure this happens.
Recommendations 1.12.3 to 1.12.8
Cervical priming is standard clinical practice for women having a surgical abortion between 14+0 and 23+6 weeks.
There was good evidence that cervical priming regimens using same day or overnight osmotic dilators either increase cervical dilation, make procedures easier to carry out, or both, compared with cervical priming without dilators. However, there was evidence that osmotic dilators are less acceptable to women than mifepristone or misoprostol. In addition, the evidence comparing single priming agents against each other was unclear on whether or not there are differences between dilators and mifepristone in a number of important outcomes, such as cervical trauma, uterine perforation and preoperative expulsion. It was also unclear whether misoprostol alone and osmotic dilators alone gave equivalent baseline cervical dilation, or whether there are clinically important differences. Therefore, the committee recommended all 3 options.
Mifepristone and misoprostol are only recommended between 14+0 and 16+0 weeks and between 14+0 and 19+0 weeks respectively because there was no evidence for them beyond these stages. There was evidence for the 200 mg oral dose of mifepristone given the day before the abortion, but not enough evidence to recommend a specific dose or timing for misoprostol.
There was no evidence for alternatives to osmotic dilators after 19+0 weeks. There was good evidence that mifepristone combined with osmotic dilators reduces procedural difficulty compared with osmotic dilators alone. However, it was unclear if there were differences in safety outcomes such as uterine perforation or cervical trauma. The committee recommended this regimen for women who were between 19+1 and 23+6 weeks' gestation, because later gestational age is associated with increased procedural difficulty.
The committee agreed that further research on whether pharmacological priming is an effective and acceptable alternative to osmotic dilators would be useful, so made a research recommendation.
Limited evidence showed that inserting osmotic dilators the day before the abortion will also make the procedure easier, compared with inserting them on the same day. However, this would involve an additional visit to the clinic, and this may not always be possible. The evidence on inserting osmotic dilators the day before the procedure only covered women having an abortion up to and including 17+6 weeks' gestation. Despite this, the committee agreed that women at later gestations may have the greatest benefit from inserting osmotic dilators the day before, as abortion becomes more complicated at later gestational ages. The committee agreed that further research comparing the timing of osmotic dilator insertion would be beneficial to inform future practice, so made a research recommendation.
Misoprostol does not provide any benefit when used in combination with osmotic dilators, and it may have additional side effects. Further, it was unclear from the evidence whether or not there was an increased risk of preoperative expulsion when the combination was used compared with dilators alone. It is feasible that this risk may increase with additional cervical priming. Therefore, the committee recommended that the combination is not used.
## How the recommendations might affect practice
These recommendations will reduce variations in practice in the use of cervical priming. The recommendations will also reduce the use of oral misoprostol, which is currently used but which has worse side effects than sublingual or vaginal regimens. The option to have misoprostol one hour before the procedure may make it easier and more convenient for women to have cervical priming, particularly if they live in remote areas with longer journey times.
The recommendations will likely increase the use of cervical priming, which may increase costs. The cost to individual services will depend on their current practice. However, this increased cost may be offset by savings from fewer additional operations for incomplete abortions.
These recommendations may lead to greater use of osmotic dilators, and may increase the number that are inserted the day before, requiring more women to attend an appointment for cervical priming the day before the abortion. This additional appointment will result in increased costs and burden on the woman and may not be possible for some women. There may be further costs for services that provide accommodation for women who have travelled for their abortion, but this will depend on local policies.
Overall, few women have a surgical abortion during the second trimester, so the absolute cost impact is likely to be small, although the impact on the woman and her family may be considerable.
Full details of the evidence and the committee's discussion are in evidence review M: cervical priming before surgical abortion.
Return to recommendations
# Anaesthesia and sedation for surgical abortion
Recommendations 1.13.1 to 1.13.3
## Why the committee made the recommendations
There was only limited evidence comparing different types of sedation or anaesthesia for surgical abortion. The evidence that was available did not show that any particular method was more effective. The committee are aware that women have different preferences on anaesthesia. For example:
some women need to minimise their recovery time (if they are driving home, or if they care for dependents)
some women are anxious about the procedure and would prefer not to be conscious during it.
With this in mind, the committee recommended discussing all the anaesthesia options and explaining the differences to the woman.
There was not enough evidence to recommend a specific method for administering local anaesthesia. The committee agreed that further research on local anaesthesia methods (including intrauterine anaesthesia) would be beneficial, so made a research recommendation.
There was good evidence that women who had intravenous conscious sedation experienced less pain and nausea than women who had oral conscious sedation. Women who had intravenous sedation were also more likely to say they would choose it again.
Inhalational anaesthetics cause dose-dependent uterine relaxation. This may cause more bleeding compared with other medications used for general anaesthesia, such as propofol. The evidence comparing propofol and sevoflurane did not show any difference in haemorrhage requiring transfusion or blood loss greater than 500 ml. However, this is a rare event and the evidence was from a single study, so the committee recommended more research.
## How the recommendations might affect practice
These recommendations will increase awareness of the options available for sedation or anaesthesia for surgical abortion, reduce variations in practice, and increase the choice available to women.
The recommendations will also reduce the use of oral conscious sedation, which is currently used but is not as effective as intravenous conscious sedation. Intravenous conscious sedation takes effect quicker than oral conscious sedation and has a shorter recovery time, so resource use should be reduced and scheduling flexibility may be improved as women spend less time in hospital. The recommendations may lead to a rise in the number of women opting for intravenous conscious sedation, causing an increased need for staff trained in administering it. Although conscious sedation is not currently used in all abortion services in the NHS, its use is widespread in other areas (such as endoscopy and assisted conception). As there are staff experienced in administering conscious sedation for other procedures, the resource impact in terms of staff training is not likely to be large.
Full details of the evidence and the committee's discussion are in evidence review M: cervical priming before surgical abortion.
Return to recommendations
# Follow-up and support after an abortion
## Why the committee made the recommendations
Recommendations 1.14.1 to 1.14.2
Limited evidence was available showing no clinically important difference between remote and clinic follow-up for rates of adherence to follow-up. It was unclear whether or not there was a clinically important difference between remote and clinic follow-up in rates of:
missed ongoing pregnancy
unscheduled phone calls or visits
surgical intervention.
There was only very limited indirect evidence on patient satisfaction, suggesting a preference for remote over clinic follow-up. No randomised controlled trial evidence was available for self-assessment, but the committee included this in the recommendation because it is offered in current practice, and it gives women an additional option.
Evidence on pregnancy tests was also limited, showing that it was unclear whether or not there was a clinically important difference in rates of missed ongoing pregnancy or surgical intervention with multi-level urine pregnancy tests (these have several thresholds of human chorionic gonadotrophin , such as 25, 100, 500, 2,000 and 10,000 international units ), compared with high-sensitivity urine pregnancy tests (with a typical detection threshold of 10 to 25 IU hCG). Rates of patient satisfaction also appeared to be the same with both types of test. However, the committee did not recommend high-sensitivity tests because these can lead to higher clinically important rates of unscheduled clinic visits due to high rates of false-positive results in the month following the abortion. Instead, the committee recommended either multi-level or low-sensitivity tests (detection limit 1,000 IU hCG), which are reliable 2 weeks after the abortion. Low-sensitivity tests are already widely used in the UK and the rest of Europe, and are approved for home use.
The evidence only included women having abortion up to and including 9+0 weeks' gestation. However, the committee agreed that the recommendations were appropriate for women having an abortion up to and including 10+0 weeks' gestation because:
this is current standard clinical practice and
the range of hCG remains above the detection limit (1,000 IU) into the second trimester.
Recommendations 1.14.3 to 1.14.6
The recommendations are based on evidence showing that some women sought support for a number of reasons after an abortion. The evidence showed that they sought support from various different sources and they valued support that was specific to their circumstances. However, it also suggested that women sometimes found it difficult to get the support they need.
While most of the evidence came from women having an abortion for fetal anomaly, the committee agreed that all women would benefit from information about what to expect and how to access support following an abortion, should they wish this. The committee also made a recommendation covering aftercare, based on their knowledge and experience.
## How the recommendations might affect practice
The use of low-sensitivity or multi-level pregnancy tests instead of a routine clinic visit for ultrasound will reduce the number of clinic visits needed for women and be associated with cost savings for services. The recommendations should also reduce variation in practice by reducing the use of high-sensitivity pregnancy tests. These tests are associated with more clinic visits and a longer time period before the outcome of the abortion can be confirmed.
These recommendations should make it easier for women to get support after an abortion, and reduce the variation in what support is offered.
The impact for providers will vary according to what support they currently offer but many providers already offer emotional support and have arrangements in place for referring women to counselling services.
Full details of the evidence and the committee's discussion are in evidence review I: follow-up after medical abortion up to 10+0 weeks and evidence review O: support after abortion.
Return to recommendations
# Improving access to contraception
Recommendations 1.15.1 to 1.15.5
## Why the committee made the recommendations
There was evidence that providing contraception immediately after a surgical abortion improved uptake and continued contraception use, compared with providing contraception later. There was some variation in these outcomes after medical abortion, but providing contraception immediately (or as soon as possible) after abortion still reduced rates of subsequent abortions. There were also higher rates of patient satisfaction when contraception was provided immediately.
There was limited evidence that:
more women received long-acting reversible contraception when providers had staff who were skilled in providing all types of contraception
having the full range of contraceptive methods available increased uptake and continued contraception use, and reduced the rate of subsequent abortions.
Skilled healthcare professionals are needed to administer a number of long-acting methods of contraception and ensure that the full range of contraceptive methods are available. Without them, it may not be possible for women to receive their preferred choice of contraception immediately. Therefore, although the evidence was limited, the committee made a recommendation that providers ensure they have the full range of contraceptive methods available, and staff with the skills to provide them.
When compared with delayed insertion, immediate implant insertion provides a clinically important reduction in the rates of subsequent unintended pregnancy, and higher rates of patient acceptability and satisfaction. The evidence also showed that it was uncertain whether or not there were clinically important differences in the rates of:
continuing pregnancy
incomplete abortion with the need for surgical intervention
complete abortion without the need for surgical intervention
subsequent unintended pregnancy at 3 months.
The evidence showed that, compared with delayed intrauterine insertion, early or immediate insertion of intrauterine devices provides either higher rates or no clinically important difference in rates of levonorgestrel intrauterine system (LNG-IUS) or copper intrauterine device (IUD) uptake and continued use. There was also evidence covering all gestational periods for LNG-IUS and covering gestations up to and including 9+0 weeks for IUD looking at:
uterine perforation
infection within 1 month
subsequent pregnancy within 1 year.
However, the evidence was unclear on whether or not there were clinically important differences in any of these outcomes. For uterine perforation, the absolute risk was very small. For infection, the evidence did not distinguish between infections caused by intrauterine device insertion and those caused by the abortion in the women who received the device early or immediately.
Immediate depot medroxyprogesterone acetate (DMPA) intramuscular injection provides a clinically significant improvement in patient satisfaction, compared with delayed injection. In addition, the evidence showed that it was unclear whether or not there were clinically significant differences between the 2 interventions in the rates of:
incomplete abortion with the need for surgical intervention
complete abortion without the need for surgical intervention
subsequent unintended pregnancy.
There was a potentially higher rate of ongoing pregnancy with immediate DMPA intramuscular injection compared with the delayed injection. However, there was uncertainty around this estimate, the absolute risk was small, and it was only seen in one study reviewed. Because of this, the committee agreed that immediate injection can be recommended as long as women are advised of the potential risk. There was no evidence to recommend a specific timing for DMPA administered subcutaneously.
## How the recommendations might affect practice
Currently, some providers do not offer DMPA intramuscular injection immediately, due to concerns that this might affect the efficacy of the abortion. Therefore, these recommendations will reduce variations in practice. There may be an initial cost associated with providing training for staff in abortion services to administer long-acting reversible contraception. However, this will be offset by not needing an additional appointment to administer contraception, and increased access leading to fewer subsequent unintended pregnancies and abortions.
There is unlikely to be a significant change in practice resulting from these recommendations as intrauterine contraception is currently already offered to women after a medical abortion; all that is likely to change is the timing.
These recommendations will reduce variation in practice on contraception provision after abortion. They will also increase the choices available to women. The impact on individual services will depend on current practice. In the independent sector, most services are commissioned to provide all forms of contraception whereas, in the NHS, some trusts have difficulty getting funding for certain contraceptive methods.
Overall, these recommendations should not increase costs or resource use, as the range of contraceptive methods covered is already available to women. However, there may be a change in who is funding contraception, with greater funding from clinical commissioning groups compared with local authorities. This will mean changes in the way services are organised, and commissioners will need to develop services to enable the recommendations.
Full details of the evidence and the committee's discussion are in evidence review P: contraception after abortion.
Return to recommendations# Context
Abortion is a common procedure. In 2018, 200,608 women in England and Wales had an abortion. Almost all of these abortions were funded by the NHS, but 72% were performed by the independent sector.
Most abortions are carried out because the pregnancy was unintended, and the majority of procedures (80% of abortions in England and Wales in 2018) are conducted in the first 10 weeks of pregnancy. Abortion is a safe procedure, and can be carried out medically (taking mifepristone followed by misoprostol) or surgically.
The trend in England and Wales over the past decade has been towards increasing use of medical abortion. In 2018, 71% of all abortions in England and Wales were medical, and this rises to 83% of abortions in the first 10 weeks of pregnancy.
In recent years, there have been changes in how and where abortion services are delivered. This has resulted in variation in the type and choice of procedures available across the NHS, for example, in the offer of local anaesthesia and sedation for a surgical procedure. In addition, the procedure used for medical abortion has been refined and women in the first 10 weeks (up to 9 weeks and 6 days) may now self‑administer misoprostol at home in England and Wales. Furthermore, methods for checking whether a medical abortion has been successful have also been simplified. Some of these developments could significantly reduce costs to the NHS and be more acceptable to women.
Abortion services also provide other important sexual and reproductive health services to women, including contraceptive services. However, there is marked variation across the country, involving different types of providers and, increasingly, organisations outside the NHS. In addition, accessing abortion services may be difficult for women who live in remote areas, who are in the second trimester of pregnancy, or who have complex pre-existing conditions or difficult social circumstances. In particular, abortion care is challenging for women living in Northern Ireland who currently have to travel to other parts of the UK in order to access services.
This guideline will help ensure that abortion procedures are carried out based on the best available evidence, and that a choice of services is easily accessible to all women who request an abortion.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Note that mifepristone and misoprostol do not have UK marketing authorisations for most of the uses recommended in this guideline. When an unlicensed use is recommended, this is highlighted with a footnote in the recommendation.\n\nAbortion Act 1967\n\nAbortion in England, Scotland and Wales is primarily regulated by the Abortion Act 1967 (as amended by the Human Fertilisation and Embryology Act 1990) and regulations made under that Act – currently the Abortion Regulations 1991 (SI\xa01991/499). The Abortion Act regulates when and where abortions can take place lawfully.\n\nIn May 2014, the Department of Health and Social Care issued guidance in relation to requirements of the Abortion Act 1967. This guidance is intended for those responsible for commissioning, providing and managing the provision of abortion services to help them comply with the Abortion Act. Also in May 2014, the Department of Health and Social Care published procedures for the approval of independent sector places for the termination of pregnancy. Further government guidance has recently been issued in the form of letters from the Chief Medical Officer.\n\nProviders of abortion services must comply with the Health and Social Care Act 2008 and regulations made under that Act. In particular, providers must register with the Care Quality Commission (CQC). This is because under section 10 of the Health and Social Care Act 2008, it is an offence to carry out a regulated activity without being registered with the CQC, and abortion is a 'regulated activity' under Regulation 3 and Schedule 1 (paragraph 11) of the Health and Social Care Act 2008 (Regulated Activities) Regulations 2014 (SI\xa02014/2936). The CQC imposes specific requirements on providers that are not English NHS bodies (see regulation 20 of the Care Quality Commission (Registration) Regulations 2009).\n\nAdditional relevant guidance:\n\nthe views of the British Medical Association on the laws and ethics of abortion\n\nthe termination of pregnancy nursing framework from the Royal College of Nursing\n\nguidance from the Royal College of Obstetricians and Gynaecologists on the care of women requesting induced abortion.\n\nThis NICE guideline makes evidence-based recommendations on how to organise services and on how to conduct abortions within the legal framework set out by the Abortion Act 1967. It does not repeat things already covered by the legislation, Department of Health and Social Care guidance or other statutory regulations, and practitioners should therefore ensure they are adhering to all other applicable requirements when using this guideline.\n\nConsent and Montgomery\n\nHealthcare professionals should ensure that women have the information they need to make decisions and to give consent in line with General Medical Council guidance and the 2015 Montgomery ruling.\n\nGender\n\nThis guideline makes recommendations for women and people who are pregnant. For simplicity of language the guideline uses the term women throughout, but this should be taken to also include people who do not identify as women but who are pregnant.\n\n# Service organisation\n\n## Making it easier to access services\n\nCommissioners and providers should work together to:\n\nmake information about abortion services (including how to access them) widely available\n\nensure that women are promptly referred onwards if a service cannot provide an abortion after a specific gestational age or by the woman's preferred method\n\navoid the need for women to repeat key steps (such as returning to their GP for referral, or repeated assessments or investigations).\n\nCommissioners and providers should allow women to self-refer to abortion services.\n\nHealthcare professionals should not allow their personal beliefs to delay access to abortion services.\n\nCommissioners should consider upfront funding for travel and accommodation for women who:\n\nare eligible for the NHS Healthcare Travel Costs Scheme and/or\n\nneed to travel to a service that is not available locally.Commissioners should make information available about any upfront funding to access services.\n\n## Waiting times\n\nCommissioners should work with providers to ensure abortion services have the capacity and resources to deliver the range of services needed with minimal delay.\n\nEnsure minimal delay in the abortion process, and ideally:\n\nprovide the assessment within 1\xa0week of the request\n\nprovide the abortion within 1\xa0week of the assessment.\n\nFor women who would prefer to wait longer for an abortion, help them to make an informed decision by explaining the implications, including:\n\nthe legal limit for abortions, as stated in the Abortion Act\n\nthat delaying the abortion will increase the risk of complications, although the overall risk is low.\n\nDo not require women to have compulsory counselling or compulsory time for reflection before the abortion. Provide or refer women for support to make a decision if they request this.\n\n## Location of services\n\nConsider providing abortion assessments by phone or video call, for women who prefer this.\n\nConsider providing abortion services in a range of settings (including in the community and in hospitals), to meet the needs of the local population.\n\n## Workforce and training\n\nAbortion providers should maximise the role of nurses and midwives in providing care.\n\nTrainee healthcare professionals and students who may care for women who request an abortion (for example nurses, midwives, and GPs) should have the chance to gain experience in abortion services during their training.\n\nFor specialties that include training in abortion as part of the core curriculum:\n\nensure all trainees have the training, unless they opt out due to a conscientious objection\n\ninclude practical experience of abortion services and procedures in the curriculum.\n\nIf a trainee's placement service does not provide abortions, the trainee should gain experience with whoever is providing this service (either in the NHS or in the independent sector).\n\n## Complex comorbidities\n\nSpecialist centres should be available as locally as possible, to reduce delays and travel times for women with complex needs or significant comorbidities.\n\nProviders should develop pathways for women with complex needs or significant comorbidities to:\n\nrefer them to specialist centres if needed\n\nminimise delays in accessing care.\n\n## Avoiding stigma\n\nWhen caring for women who are having an abortion, be aware of:\n\nthe anxiety they may have about perceived negative and judgemental attitudes from healthcare professionals\n\nthe impact that verbal and non-verbal communication may have on them.\n\nServices should be sensitive to the concerns women have about their privacy and confidentiality, including their concerns that information about the abortion might be shared with healthcare professionals not directly involved in their care.\n\nTo find out why the committee made the recommendations and how they might affect services, see the rationale and impact section on service organisations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: accessibility and sustainability of abortion services and evidence review\xa0B: information needs of women undergoing an abortion.\n\nLoading. Please wait.\n\n# Providing information\n\nReassure women that having an abortion is not associated with increased risk of infertility, breast cancer or mental health issues.\n\nProvide information about the differences between medical and surgical abortion (including the benefits and risks), taking account of the woman's needs and preferences. Do this without being directive, so that women can make their own choice. See the NICE patient decision aids to help support these decisions.\n\nAs early as possible, provide women with detailed information to help them prepare for the abortion. Cover:\n\nwhat it involves and what happens afterwards\n\nhow much pain and bleeding to expect.\n\nProvide information in a range of formats, for example video or written information. Include information based on the experiences of women who have had an abortion.\n\nFor more guidance on providing information and helping women to make decisions about their care, see the NICE guideline on patient experience in adult NHS services.\n\nAsk women if they want information on contraception, and if so provide information about the options available to them (see improving access to contraception).\n\nFor women who are having a medical abortion, explain:\n\nthat they may see the products of pregnancy as they are passed\n\nwhat the products of pregnancy will look like and whether there may be any movement.\n\nFor women who are having a medical abortion at home, explain how to be sure that the pregnancy has ended (see follow-up after medical abortion up to and including 10+0 weeks).\n\nProvide women with information on signs and symptoms that indicate they need medical help after an abortion, and who to contact if they do.\n\nProvide women with information about the different options for management and disposal of pregnancy remains.\n\n## Information for women who are having an abortion because of fetal anomaly\n\nIf a woman who is having an abortion for fetal anomaly cannot have her preferred method of abortion in the maternity service, establish a clear referral pathway with ongoing communication between services so that she can:\n\neasily transfer to the abortion service\n\nreceive ongoing support from the maternity service\n\nget more information about the anomaly.\n\nExplain to women that there may not be any physical signs of a fetal anomaly.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on providing information\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: information needs of women undergoing an abortion.\n\nLoading. Please wait.\n\n# Anti-D prophylaxis\n\nOffer anti-D prophylaxis to women who are rhesus D negative and are having an abortion after 10+0\xa0weeks' gestation.\n\nDo not offer anti-D prophylaxis to women who are having a medical abortion up to and including 10+0 weeks' gestation.\n\nConsider anti-D prophylaxis for women who are rhesus D negative and are having a surgical abortion up to and including 10+0 weeks' gestation.\n\nProviders should ensure that:\n\nrhesus status testing and anti-D prophylaxis supply does not cause any delays to women having an abortion\n\nanti-D prophylaxis is available at the time of the abortion.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on anti-D prophylaxis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: anti-D prophylaxis for women up to 13+6 weeks' gestation.\n\nLoading. Please wait.\n\n# Preventing infection\n\nFor guidance on testing for sexually transmitted infections for women who are having an abortion, see the NICE guideline on preventing sexually transmitted infections and under-18 conceptions.\n\nDo not routinely offer antibiotic prophylaxis to women who are having a medical abortion.\n\nOffer antibiotic prophylaxis to women who are having surgical abortion.\n\nWhen using doxycycline for antibiotic prophylaxis in medical or surgical abortion, consider oral doxycycline 100\xa0mg twice a day for 3 days.\n\nWhen using metronidazole for antibiotic prophylaxis in medical or surgical abortion, do not routinely offer it in combination with another broad-spectrum antibiotic such as doxycycline.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on preventing infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: antibiotic prophylaxis for medical and surgical abortion.\n\nLoading. Please wait.\n\n# Venous thromboembolism prophylaxis\n\nFor women who need pharmacological thromboprophylaxis, consider low‑molecular‑weight heparin for at least 7\xa0days after the abortion.\n\nFor women who are at high risk of thrombosis, consider starting low‑molecular‑weight heparin before the abortion and giving it for longer afterwards.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on venous thromboembolism prophylaxis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: venous thromboembolism prophylaxis for women having abortion.\n\nLoading. Please wait.\n\n# Choice of procedure for abortion\n\nOffer a choice between medical or surgical abortion up to and including 23+6\xa0weeks' gestation (surgical abortion can be performed shortly after 23+6\xa0weeks' gestation only if feticide is given at or before 23+6\xa0weeks' gestation, according to the 2019 clarification of the time limits in the Abortion Act). If any methods would not be clinically appropriate, explain why.\n\nTo help women decide between medical and surgical abortion, see the NICE patient decision aids on choosing medical or surgical abortion.\n\nTo find out why the committee made the recommendations, see the rationale and impact section on the choice of procedure for abortion\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: information needs of women undergoing an abortion and evidence review\xa0K: medical versus surgical abortion between 13+0 and 24+0 weeks' gestation.\n\nLoading. Please wait.\n\n# Abortion before definitive ultrasound evidence of an intrauterine pregnancy\n\nConsider abortion before there is definitive ultrasound evidence of an intrauterine pregnancy (a yolk sac) for women who do not have signs or symptoms of an ectopic pregnancy.\n\nFor women who are having an abortion before there is definitive ultrasound evidence of an intrauterine pregnancy (a yolk sac):\n\nexplain that there is a small chance of an ectopic pregnancy\n\nexplain that they may need to have follow-up appointments to ensure the pregnancy has been terminated and to monitor for ectopic pregnancy\n\nprovide 24‑hour emergency contact details, and advise them to get in contact immediately if they develop symptoms that could indicate an ectopic pregnancy (see symptoms and signs of ectopic pregnancy and initial assessment in the NICE guideline on ectopic pregnancy and miscarriage).\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on abortion before definitive ultrasound evidence of an intrauterine pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: abortion before ultrasound evidence.\n\nLoading. Please wait.\n\n# Expulsion at home for medical abortion up to and including 10+0 weeks\n\n## Up to and including 9+6 weeks' gestation\n\nFor women who are having a medical abortion and will be taking the mifepristone up to and including 9+6 weeks' gestation, offer the option of expulsion at home. Mifepristone and misoprostol can be taken at home or in the clinic or hospital.This recommendation is based on the evidence for the safety of home expulsion. The legal limit for the gestational age at which mifepristone and misoprostol can be taken at home is specified in the Abortion Act 1967.\n\n## At 10+0 weeks' gestation\n\nFor women who are having a medical abortion and will be taking the mifepristone at 10+0 weeks' gestation, offer the option of expulsion at home after they have taken the misoprostol. Misoprostol can be taken in the clinic or hospital.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on expulsion at home for medical abortion up to and including 10+0 weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: expulsion at home for early medical abortion.\n\nLoading. Please wait.\n\n# Medical abortion up to and including 10+0 weeks\n\nIn September 2019, mifepristone for abortion only has a UK marketing authorisation for:\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 400\xa0micrograms misoprostol orally or 1\xa0mg gemeprost vaginally, up to and including 49\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 1\xa0mg gemeprost vaginally, between 50 days and 63\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 1\xa0mg gemeprost vaginally, between 50\xa0days and 63\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 800\xa0micrograms misoprostol vaginally, up to and including 63\xa0days of amenorrhoea\n\nmg orally for medical abortion for medical reasons, followed 36 to 48\xa0hours later by prostaglandin administration, beyond the first trimester\n\nmg orally for cervical priming, 36 to 48\xa0hours before first trimester surgical abortion.\n\nAll other uses of mifepristone are off label. See NICE's information on prescribing medicines.\n\nIn September 2019, misoprostol for medical abortion only has a UK marketing authorisation for:\n\nmicrograms orally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48\xa0hours after 600\xa0mg mifepristone orally, up to and including 49\xa0days of amenorrhoea\n\nmicrograms vaginally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48\xa0hours after 200\xa0mg mifepristone orally, up to and including 63\xa0days of amenorrhoea.\n\nAll other uses of misoprostol (including for cervical priming and for abortion at later gestations) are off label. See NICE's information on prescribing medicines.\n\nOffer interval treatment (usually 24 to 48\xa0hours) with mifepristone and misoprostol to women who are having a medical abortion up to and including 10+0 weeks' gestation.\n\nFor women who are having a medical abortion up to and including 9+0\xa0weeks' gestation, give them the choice of having mifepristone and vaginal misoprostol at the same time, but explain that:\n\nthe risk of ongoing pregnancy may be higher, and it may increase with gestation\n\nit may take longer for the bleeding and pain to start\n\nit is important for them to complete the same follow-up programme that is recommended for all medical abortions up to and including 10+0 weeks (recommendations 1.14.1 and 1.14.2).\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on the interval between mifepristone and misoprostol for medical abortion up to and including 10+0 weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: medical abortion up to 10+0 weeks' gestation.\n\nLoading. Please wait.\n\n# Medical abortion between 10+1 and 23+6 weeks\n\nIn September 2019, mifepristone for abortion only has a UK marketing authorisation for:\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48 hours later by 400\xa0micrograms misoprostol orally or 1\xa0mg gemeprost vaginally, up to and including 49\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 1\xa0mg gemeprost vaginally, between 50\xa0days and 63\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 1\xa0mg gemeprost vaginally, between 50\xa0days and 63\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 800\xa0micrograms misoprostol vaginally, up to and including 63\xa0days of amenorrhoea\n\nmg orally for medical abortion for medical reasons, followed 36 to 48\xa0hours later by prostaglandin administration, beyond the first trimester\n\nmg orally for cervical priming, 36 to 48\xa0hours before first trimester surgical abortion.\n\nAll other uses of mifepristone are off label. See NICE's information on prescribing medicines.\n\nIn September 2019, misoprostol for medical abortion only has a UK marketing authorisation for:\n\nmicrograms orally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48\xa0hours after 600\xa0mg mifepristone orally, up to and including 49\xa0days of amenorrhoea\n\nmicrograms vaginally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48\xa0hours after 200\xa0mg mifepristone orally, up to and including 63\xa0days of amenorrhoea.\n\nAll other uses of misoprostol (including for cervical priming and for abortion at later gestations) are off label. See NICE's information on prescribing medicines.\n\nFor women who are having a medical abortion between 10+1 and 23+6\xa0weeks' gestation and who have taken 200\xa0mg mifepristone, offer an initial dose (36 to 48\xa0hours after the mifepristone) of:\n\nmicrograms misoprostol, given vaginally, or\n\nmicrograms of misoprostol, given sublingually, for women who decline vaginal misoprostol.Follow the initial dose with 400\xa0microgram doses of misoprostol (vaginal, sublingual or buccal), given every 3 hours until expulsion.\n\nUse a shorter interval between mifepristone and misoprostol if the woman prefers this, but explain that it may take a longer time from taking the first misoprostol dose to complete the abortion.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on medical abortion between 10+1 and 23+6 weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: medical abortion between 10+1 and 24+0 weeks' gestation.\n\nLoading. Please wait.\n\n# Medical abortion after 23+6 weeks\n\nIn September 2019, mifepristone for abortion only has a UK marketing authorisation for:\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 400\xa0micrograms misoprostol orally or 1\xa0mg gemeprost vaginally, up to and including 49\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 1\xa0mg gemeprost vaginally, between 50\xa0days and 63\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 1\xa0mg gemeprost vaginally, between 50\xa0days and 63\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 800\xa0micrograms misoprostol vaginally, up to and including 63\xa0days of amenorrhoea\n\nmg orally for medical abortion for medical reasons, followed 36 to 48\xa0hours later by prostaglandin administration, beyond the first trimester\n\nmg orally for cervical priming, 36 to 48\xa0hours before first trimester surgical abortion.\n\nAll other uses of mifepristone are off label. See NICE's information on prescribing medicines.\n\nIn September 2019, misoprostol for medical abortion only has a UK marketing authorisation for:\n\nmicrograms orally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48\xa0hours after 600 mg mifepristone orally, up to and including 49\xa0days of amenorrhoea\n\nmicrograms vaginally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48\xa0hours after 200\xa0mg mifepristone orally, up to and including 63\xa0days of amenorrhoea.\n\nAll other uses of misoprostol (including for cervical priming and for abortion at later gestations) are off label. See NICE's information on prescribing medicines.\n\nFor women who are having a medical abortion between 24+0 and 25+0\xa0weeks' gestation, consider 200\xa0mg oral mifepristone, followed by 400\xa0micrograms misoprostol (vaginal, buccal or sublingual) every 3\xa0hours until delivery.\n\nFor women who are having a medical abortion between 25+1 and 28+0\xa0weeks' gestation, consider 200\xa0mg oral mifepristone, followed by 200\xa0micrograms misoprostol (vaginal, buccal or sublingual) every 4\xa0hours until delivery.\n\nFor women who are having a medical abortion after 28+0\xa0weeks' gestation, consider 200\xa0mg oral mifepristone, followed by 100\xa0micrograms misoprostol (vaginal, buccal or sublingual) every 6\xa0hours until delivery.\n\nBe aware that:\n\nthe uterus is more sensitive to misoprostol as pregnancy advances\n\nrisk factors for uterine rupture include a pre-existing uterine scar, increased gestational age and multiparity.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on medical abortion after 23+6 weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: medical abortion after 24 weeks' gestation.\n\nLoading. Please wait.\n\n# Cervical priming before surgical abortion\n\nIn September 2019, mifepristone for abortion only has a UK marketing authorisation for:\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 400\xa0micrograms misoprostol orally or 1\xa0mg gemeprost vaginally, up to and including 49\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 1\xa0mg gemeprost vaginally, between 50\xa0days and 63\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 1\xa0mg gemeprost vaginally, between 50\xa0days and 63\xa0days of amenorrhoea\n\nmg orally for medical abortion of developing intrauterine pregnancy, followed 36 to 48\xa0hours later by 800\xa0micrograms misoprostol vaginally, up to and including 63\xa0days of amenorrhoea\n\nmg orally for medical abortion for medical reasons, followed 36 to 48\xa0hours later by prostaglandin administration, beyond the first trimester\n\nmg orally for cervical priming, 36 to 48 hours before first trimester surgical abortion.\n\nAll other uses of mifepristone are off label. See NICE's information on prescribing medicines.\n\nIn September 2019, misoprostol for medical abortion only has a UK marketing authorisation for:\n\nmicrograms orally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48\xa0hours after 600\xa0mg mifepristone orally, up to and including 49\xa0days of amenorrhoea\n\nmicrograms vaginally as an initial dose for medical abortion of developing intrauterine pregnancy, 36 to 48\xa0hours after 200\xa0mg mifepristone orally, up to and including 63\xa0days of amenorrhoea.\n\nAll other uses of misoprostol (including for cervical priming and for abortion at later gestations) are off label. See NICE's information on prescribing medicines.\n\n## Up to and including 13+6 weeks\n\nFor women who are having a surgical abortion up to and including 13+6\xa0weeks' gestation, offer cervical priming with:\n\nmicrograms sublingual misoprostol, given 1\xa0hour before the abortion or\n\nmicrograms vaginal misoprostol, given 3\xa0hours before the abortion.If misoprostol cannot be used, consider cervical priming with 200\xa0mg oral mifepristone, given 24 to 48\xa0hours before the abortion.\n\nExplain to women that cervical priming:\n\nreduces the risk of incomplete abortion for women who are parous\n\nmakes dilation easier for women who are parous or nulliparous\n\nmay cause bleeding and pain before the procedure.\n\n## Between 14+0 and 23+6 weeks\n\nFor women who are having a surgical abortion between 14+0 and 23+6\xa0weeks' gestation, offer cervical priming.\n\nFor women who are having a surgical abortion between 14+0 and 16+0 weeks' gestation, consider:\n\nosmotic dilators or\n\nbuccal, vaginal or sublingual misoprostol or\n\nmg oral mifepristone, given the day before the abortion.\n\nFor women who are having a surgical abortion between 16+1 and 19+0 weeks' gestation, consider:\n\nosmotic dilators or\n\nbuccal, vaginal or sublingual misoprostol.\n\nFor women who are having a surgical abortion between 19+1 and 23+6\xa0weeks' gestation, offer osmotic dilators. In addition, consider:\n\nmg oral mifepristone the day before the abortion and\n\ninserting osmotic dilators at the same time as the mifepristone.\n\nFor women who are having a surgical abortion between 14+0 and 23+6\xa0weeks' gestation and are having cervical priming with osmotic dilators, consider inserting the osmotic dilators the day before the abortion.\n\nDo not offer misoprostol for cervical priming if the woman has had an osmotic dilator inserted the day before the abortion.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on cervical priming before surgical abortion\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: cervical priming before surgical abortion.\n\nLoading. Please wait.\n\n# Anaesthesia and sedation for surgical abortion\n\nFor women who are having surgical abortion, consider local anaesthesia alone, conscious sedation with local anaesthesia, deep sedation or general anaesthesia. To help women make an informed choice, discuss the options with them and explain that:\n\nhaving local anaesthesia alone means they will be able to spend less time in hospital\n\nintravenous sedation plus local anaesthesia will help if they are anxious about the procedure\n\nwith deep sedation or general anaesthesia they will not usually be aware during the procedure.\n\nWhen using conscious sedation for a surgical abortion, use intravenous rather than oral sedation.\n\nWhen using general anaesthesia for a surgical abortion, consider intravenous propofol and a short‑acting opioid (such as fentanyl) rather than inhalational anaesthesia.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and sedation for surgical abortion\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: cervical priming before surgical abortion.\n\nLoading. Please wait.\n\n# Follow-up and support after an abortion\n\n## Follow-up after medical abortion up to and including 10+0 weeks\n\nFor women who have had a medical abortion up to and including 10+0\xa0weeks' gestation with expulsion at home, offer the choice of self-assessment, including remote assessment (for example telephone or text messaging), as an alternative to clinic follow-up.\n\nProvide women with a low-sensitivity or multi-level urine pregnancy test to exclude an ongoing pregnancy.\n\n## Support after an abortion\n\nExplain to women:\n\nwhat aftercare and follow-up to expect\n\nwhat to do if they have any problems after the abortion, including how to get help out of hours\n\nthat it is common to feel a range of emotions after the abortion.\n\nAdvise women to seek support if they need it, and how to access it (if relevant). This could include:\n\nsupport from family and friends or pastoral support\n\npeer support, or support groups for women who have had an abortion\n\ncounselling or psychological interventions.\n\nProviders should be able to provide emotional support after abortions. They should tell women this support is available if they need it.\n\nProviders should provide or refer women for counselling if requested.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on follow-up and support after an abortion\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: follow-up after medical abortion up to 10+0 weeks and evidence review\xa0O: support after abortion.\n\nLoading. Please wait.\n\n# Improving access to contraception\n\nCommissioners and providers should ensure that the full range of reversible contraceptive options (depot medroxyprogesterone acetate [DMPA], contraceptive implant, intrauterine methods, oral contraceptives, contraceptive patches, vaginal rings or barrier contraception) is available for women on the same day as their surgical or medical abortion.\n\nProviders should ensure that healthcare professionals have the knowledge and skills to provide all contraceptive options.\n\nProviders should ensure they can provide the contraceptive implant, and that women who choose this method are offered it on:\n\nthe day of the surgical abortion or\n\nthe day they take mifepristone (for medical abortions).\n\nProviders should ensure they can provide intrauterine methods of contraception, and that women who choose this method are offered this:\n\nat the same time as the surgical abortion or\n\nas soon as possible after expulsion of the pregnancy (for medical abortions).\n\nFor women who are having a medical abortion and who choose DMPA intramuscular injection for contraception:\n\nconsider providing it at the same appointment when they take the mifepristone\n\nexplain that having the injection at this stage may increase the risk of ongoing pregnancy, although overall the risk is low.\n\nTo find out why the committee made the recommendations and how they might affect practice, see the rationale and impact section on contraception after abortion\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0P: contraception after abortion.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Fetal anomaly\n\nDefined as pregnancies falling within section 1(1)(d) of the 1967 Abortion Act. This covers pregnancies where 2 medical practitioners are of the opinion that 'there is a substantial risk that if the child were born it would suffer from such physical or mental abnormalities as to be seriously handicapped'. This is referred to as ground E in the HSA1 form.\n\n## Feticide\n\nFeticide is the injection of digoxin or potassium chloride into the fetus, or an injection of digoxin into the amniotic cavity, to stop the fetal heart before an abortion.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Antibiotic prophylaxis for surgical abortion\n\nWhat is the optimal antibiotic prophylaxis regimen for women who are having a surgical abortion?\n\nTo find out why the committee made the recommendation for research, see the rationale section on preventing infection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: antibiotic prophylaxis for medical and surgical abortion.\n\nLoading. Please wait.\n\n## Cervical priming before surgical abortion\n\nWhat are the most effective and acceptable methods of cervical priming before dilatation and evacuation after 16+0\xa0weeks' gestation?\n\nTo find out why the committee made the recommendation for research, see the rationale section on cervical priming before surgical abortion\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: cervical priming before surgical abortion.\n\nLoading. Please wait.\n\n## Anti-D prophylaxis for surgical abortion\n\nShould women having a surgical abortion up to and including 10+0\xa0weeks' gestation have anti-D prophylaxis if they are RhD (or D) negative?\n\nTo find out why the committee made the recommendation for research, see the rationale section on anti-D prophylaxis for surgical abortion\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: anti-D prophylaxis for women up to 13+6 weeks' gestation.\n\nLoading. Please wait.\n\n## Expulsion at home for medical abortion\n\nFor women who are having medical abortion between 10+1 and 12+0\xa0weeks, what is the efficacy and acceptability of expulsion at home compared with expulsion in a clinical setting?\n\nTo find out why the committee made the recommendation for research, see the rationale section on expulsion at home for medical abortion between 10+1 and 12+0 weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: expulsion at home for early medical abortion.\n\nLoading. Please wait.\n\n## Anaesthesia and sedation for surgical abortion\n\nWhat local anaesthetic techniques are most effective for women having surgical abortion?\n\nTo find out why the committee made the recommendations and how they might affect services, see the rationale section on anaesthesia and sedation for surgical abortion\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: cervical priming before surgical abortion.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Medical abortion after 23+6 weeks\n\nWhat is the effectiveness and safety of regimens using mifepristone and misoprostol for women who are having medical abortion after 23+6\xa0weeks' gestation, particularly for those who have had a previous caesarean section or uterine surgery?\n\n## Anaesthesia and sedation for surgical abortion\n\nWhat is the optimal regimen for general anaesthesia for women having surgical abortion?", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Service organisation\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.1 to 1.1.4\n\nEvidence showed that obtaining an abortion can be complicated for women and that the information available on how to do this is often inconsistent. There was also evidence that integrating and streamlining services would improve access.\n\nThere was evidence that women wanted a choice of abortion procedure. The committee agreed that it is not practical for all services to offer all abortion options. To ensure women still have a choice if local services do not provide the full range of options, the committee made a recommendation covering onward referral.\n\nEvidence also showed that:\n\nit can be difficult to get a prompt GP appointment\n\nwomen may face negative attitudes from healthcare professionals, and that this makes it harder to get referrals for abortion.\n\nWith this in mind, the committee recommended that services enable women to self-refer. This will improve women's experiences and could also help them avoid stigma and negative attitudes when requesting an abortion. There was no evidence on the best way to enable self-referral (for example through dedicated booking systems, centralised referral, drop-in services, or online booking), so the committee could not make a more specific recommendation.\n\nAlthough women can self-refer, some will still choose to see a healthcare professional. So that these women can also easily access abortion services, the committee made a recommendation for healthcare professionals on ensuring that they do not delay access because of their personal beliefs. This is in line with professional guidance on conscientious objection (for example from the General Medical Council), which protects the right to opt out of performing abortions but not the right to opt out of providing access to abortion services.\n\nThere was evidence that travel costs can be a significant barrier to accessing services. This may be a particular problem for women with low incomes and women who need to travel for a service that is not available locally. Women having an abortion often have to travel at very short notice and may have difficulty arranging funds before the appointment. The committee recognised that it will not always be possible to provide care locally, but they agreed that interventions such as upfront funding of women's travel and accommodation costs could improve access.\n\nRecommendations 1.1.5 to 1.1.8\n\nWhile abortion is very safe overall, there was evidence that morbidity and mortality increases for every additional week of gestation, so earlier abortions are safer. There was also evidence of long waiting times and delays for women trying to access abortion services. Reducing waiting times can ensure women have more options available, decrease adverse events, and improve women's experience.\n\nIn addition, there was strong evidence that substantial cost savings can be achieved if women present earlier for abortion. Most of this saving comes from women having a medical rather than a surgical abortion. With this in mind, the committee felt that it was important to make recommendations on minimising delays for assessment and abortion. Note that while recommendation 1.1.6 gives separate time frames for assessment and abortion, this is not intended to stop services that provide these on the same day from doing so.\n\nIn some countries there are local policies such as compulsory counselling and imposed time for reflection before women are allowed to have an abortion. The evidence showed that these can cause delays in accessing abortion services. Neither counselling nor enforced waiting periods are a legal requirement in the UK. The committee agreed, based on their experience, that these policies can cause distress and that many women do not want counselling. Therefore, the committee agreed that these policies should not be used. However, the committee did not want to discourage services from providing or referring women for support to help make a decision if requested, so they covered this in the recommendation.\n\nThe committee recognised that it is not possible for all services to offer abortions every day of the week. This can lead to a choice between travelling further to have an abortion sooner, or waiting longer to have an abortion closer to home. Further, while most women are certain of their decision to have an abortion at the time of the assessment, some women might want more time to consider their decision after this. It is important that women understand the implications of waiting, so the committee made a recommendation to address this.\n\nRecommendations 1.1.9 to 1.1.10\n\nCommunity services and telemedicine appointments are recommended because the evidence showed they improve access to abortion services. There was also limited evidence that patient satisfaction is the same with abortions provided by community or by hospital services, and with appointments provided via telemedicine or at the hospital.\n\nThe committee were aware that it can be distressing for women who are having an abortion to attend appointments alongside women who are continuing with their pregnancies. The committee agreed that it was important to minimise distress and protect dignity, but did not make a recommendation on separating these groups because:\n\nthe evidence on how effective this would be at reducing distress was not reviewed by the committee\n\nthere are resource issues and safety concerns with making this a requirement for all services\n\nseparating women who are having an abortion may stigmatise them and make them easy to identify (which is a concern for many women).\n\nRecommendations 1.1.11 to 1.1.14\n\nThere was evidence that women prefer care led by nurses or midwives. Although there are legal restrictions that prevent nurses and midwives from providing certain parts of abortion services, the committee agreed that there are ways their role could still be expanded and that this would improve care.\n\nThe committee made recommendations on training because evidence showed that a shortage of trained staff with the necessary skills is making it harder to provide some abortion procedures. There was evidence that NHS hospital-based providers are losing clinical skills because abortion is currently mainly carried out in the independent sector. Ensuring all trainees have the training is important because otherwise healthcare professionals may see this training as optional, rather than as essential training for a common healthcare procedure.\n\nRecommendations 1.1.15 to 1.1.16\n\nThere was no evidence on how to improve access for women with comorbid conditions. Based on their knowledge and experience, the committee recommended that services develop pathways for women having an abortion. This will reduce delays and improve access, particularly for women who need care at specialist centres.\n\nRecommendations 1.1.17 to 1.1.18\n\nThere was evidence that women present later if they have had a negative experience from a previous abortion. However, no evidence was available on specific interventions to reduce stigma or improve privacy, so the committee made a general recommendation highlighting that the way professionals communicate with women can negatively impact on the woman's experience.\n\nIn addition, evidence shows that women are also concerned about privacy and confidentiality and are worried about reactions from other people. Further, the committee agreed, based on their experience, that women are often concerned that information about their abortion may be shared unnecessarily with other healthcare professionals. Therefore, the committee made a recommendation about being sensitive to those concerns.\n\n## How the recommendations might affect current practice\n\nImproving access to abortion services is likely to result in substantial cost savings. Most of this saving comes from women having a medical rather than a surgical abortion. Earlier abortions also have lower rates of complications. Recommendations on location of services, ease of access and complex comorbidities could reduce inequalities for:\n\nwomen living in remote areas\n\nwomen with low income\n\nwomen with comorbid physical and/or mental health problems\n\nvulnerable women\n\ngirls and younger women.\n\nFunding for travel is already available for women with low income under the NHS Healthcare Travel Costs Scheme, but this policy requires that women pay upfront and claim back costs after the abortion. Setting up processes for upfront funding will involve some initial costs, but otherwise the recommendation for women with a low income will only affect the timing of the payment and not the absolute cost. There will be some costs involved with providing funding for women who do not have a low income but who are travelling for a service that is not available locally. The new costs involved with funding travel and accommodation may be regained through women having earlier abortions.\n\nEven small reductions in waiting times would result in large cost savings. A reduction of 1\xa0day in the average waiting time would save the NHS £1.6\xa0million per year on procedure costs and treating adverse events. Because of this, even relatively expensive interventions would be cost saving if they decrease waiting times. To reduce waiting times, services will need to consider ways to enable more rapid referral and develop pathways for self-referral. Some abortion services may need to reconfigure so that they are available on a greater number of days per week. More collaboration between NHS services and the independent sector may also be needed. However, recommendations on expulsion at home and remote follow-up will minimise the number of appointments needed, again leading to cost savings.\n\nEstablishing dedicated phone and online booking systems, or centralised booking services, will have upfront costs. However, they are likely to lead to substantial savings through reduced waiting times.\n\nMany services already have videoconferencing facilities. Videoconferencing software is not expensive, so services that don't have these facilities in place will not face significant upfront costs.\n\nThere has been an increase in community-based services in recent years, so additional costs associated with providing services in the community will be minimal. Women having an abortion in the community may need to make fewer arrangements regarding time off work, childcare and travel. This may enable them to present earlier for an abortion, which would result in cost savings for the NHS.\n\nWomen prefer care led by nurses or midwives. Expanding the role of these professionals should increase the number of appointments available and enable women to present earlier. Any upfront costs associated with providing training for nurses and midwives will likely be offset by cost savings from earlier abortions and reduced doctor hours.\n\nCommissioners will need to work with national organisations such as Health Education England to agree changes to training curriculums.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: accessibility and sustainability of abortion services and evidence review\xa0B: information needs of women undergoing an abortion.\n\nReturn to recommendations\n\n# Providing information\n\nRecommendations 1.2.1 to 1.2.10\n\n## Why the committee made the recommendations\n\nThe recommendations are based on evidence showing what women want to know about abortion, and what formats they want information in. Some evidence came from women who were having abortions for specific reasons, such as fetal anomaly (under the Abortion Act). However, the committee agreed that improving information provision would benefit all women who are having an abortion, so made recommendations that could apply to everyone.\n\nThe committee also made some recommendations based on their knowledge and experience covering:\n\nmedical abortions at home\n\nwhat to expect when viewing a fetus after abortion.\n\nThe committee were aware of systematic reviews and guidance from the Academy of Medical Royal Colleges (2011), American College of Obstetricians and Gynecologists (2009) and Royal College of Obstetricians and Gynaecologists (2011; 2015) that indicate there is no evidence that an abortion increases the risk of infertility, breast cancer or mental health issues. As there was evidence that women looked on the internet for information about abortion, and the committee were concerned that some of this information may be inaccurate, they made a recommendation about these risks to inform women.\n\nThe committee were aware that women wanted information on the options for management and disposal of pregnancy remains (including burial) after an abortion. However, the committee did not make a detailed recommendation in this area as this is covered by 2015 guidance from the Human Tissue Authority that outlines:\n\nthe options (including the right to take remains home)\n\nthe information that should be provided to the woman and how this should be communicated\n\nthe importance of meeting religious and cultural needs where possible.\n\nRecommendations 1.2.11 to 1.2.12\n\nFor women having an abortion because of fetal anomaly, there was evidence that they wanted more information on the nature of the anomaly. The committee agreed that this would be better addressed by the maternity service that diagnosed the fetal anomaly, so included communication between services in their recommendation on service organisation.\n\nThere was evidence that women wanted information about how to tell other people (for example friends and family members) about the end of their pregnancy, but there was not enough evidence to make a recommendation.\n\n## How the recommendations might affect current practice\n\nServices already provide women with information about their abortion. These recommendations may mean services need to change what information they are providing, but the cost of giving women more information is minimal and will result in women being better informed about their options and the process for abortion.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: information needs of women undergoing an abortion.\n\nReturn to recommendations\n\n# Anti-D prophylaxis\n\nRecommendations 1.3.1 to 1.3.4\n\n## Why the committee made the recommendations\n\nThere was no evidence on anti-D prophylaxis for women having an abortion up to and including 13+6\xa0weeks' gestation. There is also no international consensus on this, with significant variation between different international and national guidelines.\n\nCurrent practice in the NHS is to give anti-D to all women who are having an abortion and are rhesus D negative. However, testing for rhesus status and then administering anti-D can result in significant delays for women. They may need to visit the service more than once to receive anti-D, and this can be a particular problem for women who are travelling a long way or who find it difficult to afford travel. The cost of testing for rhesus status and giving anti-D also needs to be considered.\n\nWith these points in mind, the committee made recommendations based on their knowledge and experience. They agreed that, for women up to and including 10+0\xa0weeks' gestation, the volume of fetal blood cells transmitted to the mother is unlikely to cause maternal sensitisation. The impact of delays to the abortion, travel problems, and costs to services are likely to outweigh any benefit prophylaxis provides. The NICE guideline on ectopic pregnancy and miscarriage recommends against anti-D prophylaxis for women having medical management for these conditions. The committee agreed that the risks and benefits of anti-D prophylaxis would be similar for women having a medical abortion. Therefore, the committee made a recommendation in line with the NICE guideline on ectopic pregnancy and miscarriage.\n\nAlthough there is no evidence to distinguish surgical and medical abortion on this topic, the committee agreed there may be risk of more fetal blood cell transmission during a surgical abortion. Because of this, anti-D prophylaxis may be beneficial for women having a surgical abortion up to and including 10+0 weeks' gestation.\n\nIn the independent sector, point-of-care testing is used and anti-D is provided immediately. In contrast, NHS transfusion laboratories usually follow the same processes for managing anti-D as they do for managing whole transfusion systems. This is unnecessary and introduces delays, and means that women must choose between not having testing and prophylaxis or returning to the service after the abortion. To help reduce delays, the committee made a recommendation in line with current practice in the independent sector.\n\nIn the absence of evidence, the precise benefits and risks of anti-D prophylaxis are unclear. The uncertainty is highest for women having a surgical abortion up to and including 10+0\xa0weeks' gestation, so the committee made a research recommendation covering this group.\n\n## How the recommendations might affect practice\n\nRestricting anti-D prophylaxis to women who are most likely to benefit from it could potentially produce cost savings of over £1\xa0million annually across the NHS. Staff will be freed up to focus on more important and beneficial areas of the abortion service.\n\nNHS Trusts and transfusion laboratories may need to amend their systems and processes to ensure they can provide rhesus status testing and anti-D prophylaxis without introducing delays to the abortion process.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: anti-D prophylaxis for women up to 13+6 weeks' gestation.\n\nReturn to recommendations\n\n# Preventing infection\n\n## Why the committee made the recommendations\n\nRecommendations 1.4.1 to 1.4.5\n\nThe evidence on antibiotic prophylaxis for women who are having medical abortion showed lower rates of severe infection with antibiotic prophylaxis compared with no antibiotic prophylaxis. However, the committee had concerns with the quality of the evidence, and the absolute risk of severe infection was very low. In addition:\n\nroutinely prescribing antibiotics after medical abortion may increase the risk of antibiotic resistance\n\nadherence is likely to be low\n\nif using routine antibiotics the potential reduction in the risk of post-abortion infection is uncertain.\n\nWith these points in mind, the committee did not recommend routine antibiotic prophylaxis for women who are having a medical abortion. The committee believed that prophylaxis may be appropriate for women who are at high risk of infection, or who would find it difficult to access treatment at a later date if they screened positive for a sexually transmitted infection. However, there was no evidence to support recommending prophylaxis for a specific group.\n\nAntibiotic prophylaxis is part of current clinical practice for women having a surgical abortion. The committee wanted to encourage this, so they made a recommendation in support.\n\nThe evidence reviewed did not identify which specific antibiotic regimen is most effective. Because of this, the committee agreed that further research would be beneficial and made a research recommendation. However, the committee were aware of a Cochrane review which showed the effectiveness of nitroimidazoles (such as metronidazole), tetracyclines (such as doxycycline) and beta lactams (such as amoxicillin).\n\nA 7-day course of doxycycline is currently used in practice. There was no evidence comparing doxycycline with other antibiotics; however, there was some limited evidence on duration of doxycycline. The evidence was unclear on whether or not there were clinically important differences between 3‑day and 7‑day courses of doxycycline in the rates of pelvic inflammatory disease after abortion, patient adherence, vomiting, or diarrhoea. The committee recommended a 3‑day course because this may be as effective and adherence is likely to be better with a shorter course.\n\nMetronidazole in combination with another broad-spectrum antibiotic is not routinely recommended because:\n\ncompared with doxycycline alone for surgical abortion, it was unclear if it made a clinically important difference to the rate of pelvic inflammatory disease after abortion in women who had elevated vaginal pH and amines in vaginal discharge, or a positive gram stain for bacterial vaginosis\n\nalthough there was no evidence on the gastrointestinal side effects when compared with doxycycline alone, the committee agreed that in clinical practice metronidazole may be poorly tolerated with significant side effects.\n\nHowever, the committee agreed that metronidazole is effective for anaerobic infections, so there may be situations where it is clinically indicated.\n\nThe evidence for the recommendations on doxycycline and metronidazole was based on antibiotic prophylaxis for surgical abortion. However, the committee agreed that the recommendations would also be appropriate if there is a need to use antibiotic prophylaxis for medical abortion as the causes of infection would be similar for both procedures, although the level of risk may differ.\n\nThe committee could not make recommendations about screening for sexually transmitted infections, because they did not review the evidence this. A cross-reference has been included to the NICE guideline on preventing sexually transmitted infections and under-18 conceptions.\n\n## How the recommendation might affect practice\n\nDespite the shortage of evidence, it is current clinical practice to offer antibiotic prophylaxis to women who are having medical abortion. Because of this, the recommendations will reduce the number of women having antibiotic prophylaxis for medical abortion. This has the potential to be cost saving and to reduce the risk of antibiotic resistance. The recommendation may also increase the number of women who accept screening for sexually transmitted infections. This is because women are more likely to accept screening if they are not given prophylactic antibiotics (which could make them believe screening and treatment for sexually transmitted infections, if present, was not needed).\n\nThe recommendation for surgical abortion supports routine antibiotic prophylaxis, which is current practice.\n\nThe 7‑day course of doxycycline is currently used in practice. Metronidazole is also currently used in combination with other broad-spectrum antibiotics. Switching to shorter courses of doxycycline and not using metronidazole in combination with other broad-spectrum antibiotics may lead to cost savings.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: antibiotic prophylaxis for medical and surgical abortion.\n\nReturn to recommendations\n\n# Venous thromboembolism prophylaxis\n\nRecommendations 1.5.1 to 1.5.2\n\n## Why the committee made the recommendations\n\nThere was no evidence on the optimal timing and duration of venous thromboembolism (VTE) prophylaxis for women having an abortion who need pharmacological thromboprophylaxis. In the absence of evidence, the committee made a recommendation based on the recommendations for women who have had a termination in the last 6 weeks in the NICE guideline on reducing the risk of venous thromboembolism.\n\nThe recommendation for women at high risk is based on the committee's knowledge and experience. They agreed that it may be safer to start prophylaxis earlier and provide it for longer in this group. However, the lack of evidence meant they were unable to be more specific. The recommendation is in line with antenatal and postnatal risk assessment tools from the Royal College of Obstetricians and Gynaecologists.\n\n## How the recommendations might affect practice\n\nThese recommendations are in line with the NICE guideline on reducing the risk in venous thromboembolism. Unlike that guideline, the recommendations here cover all women at risk, rather than just those admitted to hospital. This means there may be an increase in the number of women receiving prophylaxis.\n\nThere will be increased costs from the increased use of low-molecular-weight heparin and the training needed to administer it. The size of this increase will depend on current local practice and the number of women who are at risk of thrombosis. These costs will be partially offset by a reduction in the incidence of VTE, but the savings associated with this may be small as VTE is rare in this context.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: venous thromboembolism prophylaxis for women having abortion.\n\nReturn to recommendations\n\n# Choice of procedure for abortion\n\nRecommendations 1.6.1 to 1.6.2\n\n## Why the committee made the recommendation\n\nThe evidence showed that women having an abortion for fetal anomaly preferred a choice between medical or surgical abortion, and in the committee's experience women having an abortion for other reasons also valued having a choice of procedure.\n\nComparing medical and surgical abortion in women between 13+0 and 23+6\xa0weeks' gestation, the evidence showed that it was unclear whether or not there was a clinically important difference in:\n\nhaemorrhage that needed transfusion, or blood loss of 500\xa0ml or more\n\nabortion completed by the chosen method\n\nuterine injury\n\ninfection within 1\xa0month of the abortion.\n\nIt was also unclear from the evidence whether or not there was a clinically important difference in cervical injury between medical and surgical abortion. However, the committee agreed that the risk of cervical injury with medical abortion would be extremely low as no instruments or dilators are inserted into the cervix. There was a higher clinically important rate of incomplete abortion needing surgical intervention for women who had medical abortion. There was also some evidence that women prefer surgical abortion. However, the evidence in this area was limited, and the committee did not feel confident in making a recommendation in favour of one\xa0method. This guideline did not review evidence comparing medical and surgical abortion for women up to and including 12+6\xa0weeks' gestation, because it is well established that both methods are highly safe at this gestational age and that they have similar effectiveness. In addition, evidence for abortions after 23+6\xa0weeks was not reviewed because all abortions in England and Wales after this gestational age are medical procedures, with the exception of surgical abortions when feticide has been given at or before 23+6 weeks.\n\nGiven the evidence that women preferred a choice of procedure, and the lack of evidence that either procedure is superior, the committee recommended offering women up to and including 23+6\xa0weeks a choice (as long as it is clinically appropriate).\n\n## How the recommendation might affect current practice\n\nThis recommendation will lead to a change in practice because abortion services for women vary widely nationally. Many services only offer either surgical or medical abortion. There are also relatively few doctors trained to provide surgical abortion in the second trimester in the NHS, and most independent sector services are not set up to provide inpatient medical abortion.\n\nTo address these issues, greater collaboration may be needed between and across sectors to provide women with a choice of methods. Theatre teams in the NHS may also need support if they are going to introduce a new service offering surgical abortion by dilatation and evacuation. Modern dilatation and evacuation practice uses ultrasound scanning during surgery, so scan machines need to be in theatre and staff need to be able to undertake intraoperative scanning when needed.\n\nBefore services can start offering medical abortion, they need to ensure they have beds available and nursing staff who are trained to care for women having medical abortion in the second trimester.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: information needs of women undergoing an abortion and evidence review\xa0K: medical versus surgical abortion between 13+0 and 24+0 weeks' gestation.\n\nReturn to recommendation\n\n# Abortion before definitive ultrasound evidence of an intrauterine pregnancy\n\nRecommendations 1.7.1 to 1.7.2\n\n## Why the committee made the recommendations\n\nOnly limited evidence was available for this area. However, it suggested that abortion (medical or surgical) works just as well before there is definitive ultrasound evidence of an intrauterine pregnancy (that is, a yolk sac) as it does afterwards. There was no clinically important difference in the rates of complete abortion, whereas it was unclear whether or not there was a clinically important difference in the rates of missed ectopic pregnancy and ongoing pregnancy.\n\nThese findings matched the clinical experience of the committee for medical abortion at this stage for women who do not have signs or symptoms of an ectopic pregnancy. In addition, evidence from other areas of the guideline showed that women prefer to have the abortion as soon as possible.\n\nAs the evidence was limited, the committee felt that it was important to make women aware of the potential risk of not identifying an ectopic pregnancy, and what they should do if there is a problem.\n\n## How the recommendations might affect current practice\n\nSome services do not currently provide abortion before there is definitive ultrasound evidence of pregnancy. As a result, the recommendation will make abortion available earlier than it is currently provided. This will make it easier for women to access services and reduce waiting times. There may be a larger impact on providers of surgical abortion, as this is not always offered as early as medical abortion.\n\nServices providing surgical abortion before ultrasound evidence will need to have systems to confirm that the pregnancy has been aspirated. For example, they will need to have staff trained to inspect the products of conception for the presence of chorionic villi and a gestational sac, and provide the necessary equipment to do this (typically a light box and a clear receiver) or immediate access to ultrasound. Services offering surgical or medical abortion before ultrasound evidence of pregnancy will also need to be able to assess serum human chorionic gonadotrophin (hCG), and have staff trained in interpreting test results. If an ectopic pregnancy is suspected, services will need to have processes in place to refer the woman promptly to an early pregnancy assessment unit.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: abortion before ultrasound evidence.\n\nReturn to recommendations\n\n# Expulsion at home for medical abortion up to and including 10+0 weeks\n\nRecommendations 1.8.1 to 1.8.2\n\n## Why the committee made the recommendation\n\nThese recommendations are based on the evidence on the safety of home expulsion. Separate recommendations were made for women up to and including 9+6 weeks gestation and women at 10+0 weeks gestation due to the legal limit at which misoprostol can be taken at home.\n\nComparing women up to and including 9+0 weeks' gestation at the time they take mifepristone with women who take it between 9+1 and 10+0\xa0weeks, the evidence on home expulsion showed no difference in:\n\nthe risk of serious complications, such as the need for emergency care or hospitalisation, haemorrhage needing transfusion, or 500\xa0ml or more blood loss\n\nthe rate of adverse events such as pain, vomiting and diarrhoea.\n\nIt was unclear whether or not there was a difference in rates of completed abortion without the need for surgical intervention in women who were up to and including 9+0 weeks when home expulsion was performed or between 9+1 and 10+0\xa0weeks. Evidence on patient satisfaction showed it was the same in both groups.\n\nThe committee noted that the evidence on women having home expulsion up to and including 12+0\xa0weeks was from a single low-quality study from settings outside the UK. They agreed that further research on home expulsion up to and including 12+0\xa0weeks in the UK would be beneficial to inform future practice and made a research recommendation.\n\n## How the recommendation might affect current practice\n\nCurrently, medical abortion with expulsion at home is offered for women who are up to and including 10+0 weeks gestation at the time they take mifepristone in some areas, but only up to and including 9+0\xa0weeks in others. As well as standardising practice, the recommendations are likely to result in more women being able to have an early medical abortion at home. In current practice women need to be admitted to hospital and have to wait for bed availability. Expanding home expulsion would reduce the number of women admitted to hospital, reducing waiting times.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: expulsion at home for early medical abortion.\n\nReturn to recommendation\n\n# Medical abortion up to and including 10+0 weeks\n\nRecommendations 1.9.1 to 1.9.2\n\n## Why the committee made the recommendations\n\nThere was limited evidence comparing simultaneous mifepristone and misoprostol with interval treatment (misoprostol given 23 to 48\xa0hours after mifepristone) for abortion in women who were up to and including 9+0\xa0weeks' gestation. The evidence that was available showed no difference in:\n\nongoing pregnancy rate\n\nrates of haemorrhage that needed transfusion, or blood loss of 500\xa0ml or more\n\npatient satisfaction\n\nthe need for repeat misoprostol\n\nincomplete abortion needing surgery.\n\nHowever, for all of these outcomes apart from patient satisfaction, it was unclear whether or not there was a clinically important difference. In addition, the committee were concerned that the findings from this review were inconsistent with their experience. There is also another study (Lohr 2018) with different results to the studies that were covered in the evidence review. This study was not included in the review because it was not a randomised controlled trial. However, it was a much larger study (nearly 29,000\xa0participants compared with 1,100 in the largest randomised controlled trial) and had a similar population to the studies in the evidence review. This study showed that:\n\nthe success rates of simultaneous administration were inversely proportional to the gestational age\n\nas gestational age increases simultaneous administration becomes increasingly inferior to interval administration\n\nfor ongoing pregnancy, while the risk was low in both groups, the absolute risk was 1.5% higher after simultaneous treatment (2.4%) than after interval treatment (0.9%).\n\nGiven the size and relevance of this study, the committee believed it was important to take these findings into account when making recommendations.\n\nThere was evidence that bleeding and pain started later with simultaneous mifepristone and misoprostol. This may be an advantage for women who are taking both of the drugs in hospital or clinic before travelling home to complete the abortion. In addition, the total time from start to completion of abortion is shorter, and women may prefer simultaneous mifepristone and misoprostol because of this.\n\nThe committee specified vaginal misoprostol for simultaneous treatment because that was the only route of administration used in the evidence. The committee did not recommend simultaneous treatment as an option for women between 9+1 and 10+0\xa0weeks' gestation because there was no evidence for women with a longer gestation period. Interval treatment was recommended for these women because it is standard clinical practice.\n\n## How the recommendations might affect current practice\n\nSimultaneous administration of mifepristone and misoprostol is not routinely offered, so these recommendations could result in changes to practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: medical abortion up to 10+0 weeks' gestation.\n\nReturn to recommendations\n\n# Medical abortion between 10+1 and 23+6 weeks\n\nRecommendations 1.10.1 to 1.10.2\n\n## Why the committee made the recommendations\n\nMost studies included a vaginal loading dose of 800\xa0micrograms misoprostol in their regimen. The dose for vaginal misoprostol is the same dose used for abortion up to and including 10+0\xa0weeks' gestation, so this will be simpler for services to provide for women between 10+1 and 23+6\xa0weeks' gestation. The evidence showed no significant difference between an initial dose of vaginal misoprostol compared with sublingual misoprostol on time to expulsion or rate of completed abortion. Some women will prefer not to have vaginal misoprostol, so giving the option of sublingual administration takes account of patient preference. The sublingual dose was taken from the study comparing the vaginal and sublingual doses. The evidence showed that oral misoprostol had more side effects than sublingual or vaginal regimens and also had a longer interval between induction and abortion. There was no evidence available regarding effectiveness of oral misoprostol administered as a loading dose. Because of this, no recommendation was made on oral misoprostol.\n\nFor follow-up doses, most of the studies reviewed used 400\xa0micrograms misoprostol given vaginally, orally, sublingually or buccally. In addition, there was limited evidence that this dose had a shorter time to expulsion than the 200\xa0microgram dose.\n\nThere was evidence that time to expulsion was shorter when there was a longer interval between mifepristone and misoprostol administration. In comparisons of different intervals:\n\na 36- to 38‑hour interval gave a shorter time to expulsion than simultaneous administration\n\na 48‑hour interval gave higher rates of completed abortion and shorter time to expulsion than a 24‑hour interval.\n\nThe committee noted that some women would prefer not to wait 36 to 48\xa0hours between taking mifepristone and taking misoprostol, because of factors such as travel difficulties. To take account of patient preference, they recommended giving women the option of a shorter interval.\n\nThe committee were aware of guidelines from the Royal College of Obstetricians and Gynaecologists that recommend feticide for abortion after 21+6 weeks' gestation. However, the committee did not review the evidence on feticide, so they could not make recommendations on this.\n\n## How the recommendations might affect current practice\n\nThese recommendations will reduce variations in practice in the use of misoprostol for abortion between 10+1 and 23+6 weeks. The recommendations will also reduce the use of oral misoprostol, which is used currently.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: medical abortion between 10+1 and 24+0 weeks' gestation.\n\nReturn to recommendations\n\n# Medical abortion after 23+6 weeks\n\nRecommendations 1.11.1 to 1.11.4\n\n## Why the committee made the recommendations\n\nAbortion after 23+6\xa0weeks' gestation is rare. In 2017, these abortions accounted for 0.1% of the total. The statutory grounds for abortion at this stage are for fetal anomaly or, in an emergency, either:\n\nwhen continuing the pregnancy would involve risk to the life of the pregnant woman, greater than if the pregnancy were terminated or\n\nto prevent grave permanent injury to her physical or mental health.\n\nThere was no evidence on which regimen is optimal for medical abortion after 23+6\xa0weeks. In the absence of evidence, the committee based the recommendation for women between 24+0 and 25+0\xa0weeks' gestation on the dose regimens for women having an abortion up to and including 23+6\xa0weeks. Considering the increased sensitivity of the uterus to misoprostol as gestational age increases, the initial high loading dose of misoprostol was not included in the regimen for this group.\n\nFor women between 25+1 and 28+0\xa0weeks' gestation, the recommendation is based on the committee's knowledge and experience. They noted that the uterus becomes more sensitive as gestational age increases and so the dose of misoprostol should be reduced. The recommendation is also in line with the International Federation of Gynecology and Obstetrics (FIGO) guidance on misoprostol for women at this gestation.\n\nFor women after 28+0\xa0weeks' gestation, the committee recommended the regimen based on their expertise and on the guidance from FIGO.\n\nBecause the uterus becomes more sensitive to misoprostol later in gestation, women who have had a previous caesarean section or uterine surgery may be at higher risk of uterine rupture with increased doses of misoprostol. In the absence of evidence to recommend a different regimen for this group, the committee agreed that clinicians should be made aware of this risk. Given this risk and the lack of evidence in this area, the committee made a research recommendation on drug regimens for medical abortion after 23+6\xa0weeks, particularly for women who have had a previous caesarean section or uterine surgery.\n\nThe committee were aware of guidelines from the Royal College of Obstetricians and Gynaecologists that recommend feticide for abortion after 21+6 weeks' gestation. However, the committee did not review the evidence on feticide, so they could not make recommendations on this.\n\n## How the recommendations might affect current practice\n\nThere is currently no guidance on what regimen to use for medical abortion after 23+6\xa0weeks. Current practice varies as a result, and some services use lower doses of misoprostol that may not be as clinically effective as higher doses. These recommendations will help to standardise practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: medical abortion after 24 weeks' gestation.\n\nReturn to recommendations\n\n# Cervical priming before surgical abortion\n\n## Why the committee made the recommendations\n\nRecommendations 1.12.1 to 1.12.2\n\nThere was good evidence that vaginal and sublingual misoprostol reduce the risk of an incomplete abortion and reduce the force needed to dilate the cervix, compared with no cervical priming.\n\nThe timings given were chosen to minimise the amount of time spent with preoperative pain and bleeding while still ensuring adequate priming. More force was needed to dilate the cervix when vaginal misoprostol was given 1\xa0hour before the procedure, so this regimen needs to be given earlier than sublingual misoprostol. This means women will spend more time with preoperative pain and bleeding if they have vaginal misoprostol. However, based on the committee's experience, sublingual misoprostol causes more gastrointestinal side effects than vaginal misoprostol. It may therefore be less acceptable to women, and managing the side effects can place additional demands on the service. Because of these advantages and disadvantages, the committee recommended both so that women can choose which is best for them, and so that providers can be flexible (for example with appointment times) based on what works best for each woman.\n\nThe dose of 400\xa0micrograms was chosen for both routes of misoprostol administration because there was more evidence for this than for 200\xa0micrograms, and because it was unclear whether or not there were clinically important differences in side effects between the two.\n\nThere was very little evidence for mifepristone. However, the evidence that was available suggested that mifepristone may be as effective as misoprostol. Because of this, the committee recommended mifepristone when misoprostol cannot be used, so that women in this situation have another option. The dose is based on the evidence reviewed and on standard clinical practice. The timings are based on the evidence available, but a range is recommended because there was limited evidence comparing mifepristone given 48\xa0hours before the procedure with mifepristone given 24\xa0hours before the procedure.\n\nWhile cervical priming makes the procedure safer, women may be put off by the possibility of preoperative pain and bleeding associated with its use. Women are more likely to choose cervical priming if the benefits and harms are fully explained to them, so the committee made a recommendation to ensure this happens.\n\nRecommendations 1.12.3 to 1.12.8\n\nCervical priming is standard clinical practice for women having a surgical abortion between 14+0 and 23+6 weeks.\n\nThere was good evidence that cervical priming regimens using same day or overnight osmotic dilators either increase cervical dilation, make procedures easier to carry out, or both, compared with cervical priming without dilators. However, there was evidence that osmotic dilators are less acceptable to women than mifepristone or misoprostol. In addition, the evidence comparing single priming agents against each other was unclear on whether or not there are differences between dilators and mifepristone in a number of important outcomes, such as cervical trauma, uterine perforation and preoperative expulsion. It was also unclear whether misoprostol alone and osmotic dilators alone gave equivalent baseline cervical dilation, or whether there are clinically important differences. Therefore, the committee recommended all 3 options.\n\nMifepristone and misoprostol are only recommended between 14+0\xa0and 16+0\xa0weeks and between 14+0 and 19+0\xa0weeks respectively because there was no evidence for them beyond these stages. There was evidence for the 200\xa0mg oral dose of mifepristone given the day before the abortion, but not enough evidence to recommend a specific dose or timing for misoprostol.\n\nThere was no evidence for alternatives to osmotic dilators after 19+0 weeks. There was good evidence that mifepristone combined with osmotic dilators reduces procedural difficulty compared with osmotic dilators alone. However, it was unclear if there were differences in safety outcomes such as uterine perforation or cervical trauma. The committee recommended this regimen for women who were between 19+1\xa0and 23+6\xa0weeks' gestation, because later gestational age is associated with increased procedural difficulty.\n\nThe committee agreed that further research on whether pharmacological priming is an effective and acceptable alternative to osmotic dilators would be useful, so made a research recommendation.\n\nLimited evidence showed that inserting osmotic dilators the day before the abortion will also make the procedure easier, compared with inserting them on the same day. However, this would involve an additional visit to the clinic, and this may not always be possible. The evidence on inserting osmotic dilators the day before the procedure only covered women having an abortion up to and including 17+6 weeks' gestation. Despite this, the committee agreed that women at later gestations may have the greatest benefit from inserting osmotic dilators the day before, as abortion becomes more complicated at later gestational ages. The committee agreed that further research comparing the timing of osmotic dilator insertion would be beneficial to inform future practice, so made a research recommendation.\n\nMisoprostol does not provide any benefit when used in combination with osmotic dilators, and it may have additional side effects. Further, it was unclear from the evidence whether or not there was an increased risk of preoperative expulsion when the combination was used compared with dilators alone. It is feasible that this risk may increase with additional cervical priming. Therefore, the committee recommended that the combination is not used.\n\n## How the recommendations might affect practice\n\nThese recommendations will reduce variations in practice in the use of cervical priming. The recommendations will also reduce the use of oral misoprostol, which is currently used but which has worse side effects than sublingual or vaginal regimens. The option to have misoprostol one\xa0hour before the procedure may make it easier and more convenient for women to have cervical priming, particularly if they live in remote areas with longer journey times.\n\nThe recommendations will likely increase the use of cervical priming, which may increase costs. The cost to individual services will depend on their current practice. However, this increased cost may be offset by savings from fewer additional operations for incomplete abortions.\n\nThese recommendations may lead to greater use of osmotic dilators, and may increase the number that are inserted the day before, requiring more women to attend an appointment for cervical priming the day before the abortion. This additional appointment will result in increased costs and burden on the woman and may not be possible for some women. There may be further costs for services that provide accommodation for women who have travelled for their abortion, but this will depend on local policies.\n\nOverall, few women have a surgical abortion during the second trimester, so the absolute cost impact is likely to be small, although the impact on the woman and her family may be considerable.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: cervical priming before surgical abortion.\n\nReturn to recommendations\n\n# Anaesthesia and sedation for surgical abortion\n\nRecommendations 1.13.1 to 1.13.3\n\n## Why the committee made the recommendations\n\nThere was only limited evidence comparing different types of sedation or anaesthesia for surgical abortion. The evidence that was available did not show that any particular method was more effective. The committee are aware that women have different preferences on anaesthesia. For example:\n\nsome women need to minimise their recovery time (if they are driving home, or if they care for dependents)\n\nsome women are anxious about the procedure and would prefer not to be conscious during it.\n\nWith this in mind, the committee recommended discussing all the anaesthesia options and explaining the differences to the woman.\n\nThere was not enough evidence to recommend a specific method for administering local anaesthesia. The committee agreed that further research on local anaesthesia methods (including intrauterine anaesthesia) would be beneficial, so made a research recommendation.\n\nThere was good evidence that women who had intravenous conscious sedation experienced less pain and nausea than women who had oral conscious sedation. Women who had intravenous sedation were also more likely to say they would choose it again.\n\nInhalational anaesthetics cause dose-dependent uterine relaxation. This may cause more bleeding compared with other medications used for general anaesthesia, such as propofol. The evidence comparing propofol and sevoflurane did not show any difference in haemorrhage requiring transfusion or blood loss greater than 500\xa0ml. However, this is a rare event and the evidence was from a single study, so the committee recommended more research.\n\n## How the recommendations might affect practice\n\nThese recommendations will increase awareness of the options available for sedation or anaesthesia for surgical abortion, reduce variations in practice, and increase the choice available to women.\n\nThe recommendations will also reduce the use of oral conscious sedation, which is currently used but is not as effective as intravenous conscious sedation. Intravenous conscious sedation takes effect quicker than oral conscious sedation and has a shorter recovery time, so resource use should be reduced and scheduling flexibility may be improved as women spend less time in hospital. The recommendations may lead to a rise in the number of women opting for intravenous conscious sedation, causing an increased need for staff trained in administering it. Although conscious sedation is not currently used in all abortion services in the NHS, its use is widespread in other areas (such as endoscopy and assisted conception). As there are staff experienced in administering conscious sedation for other procedures, the resource impact in terms of staff training is not likely to be large.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: cervical priming before surgical abortion.\n\nReturn to recommendations\n\n# Follow-up and support after an abortion\n\n## Why the committee made the recommendations\n\nRecommendations 1.14.1 to 1.14.2\n\nLimited evidence was available showing no clinically important difference between remote and clinic follow-up for rates of adherence to follow-up. It was unclear whether or not there was a clinically important difference between remote and clinic follow-up in rates of:\n\nmissed ongoing pregnancy\n\nunscheduled phone calls or visits\n\nsurgical intervention.\n\nThere was only very limited indirect evidence on patient satisfaction, suggesting a preference for remote over clinic follow-up. No randomised controlled trial evidence was available for self-assessment, but the committee included this in the recommendation because it is offered in current practice, and it gives women an additional option.\n\nEvidence on pregnancy tests was also limited, showing that it was unclear whether or not there was a clinically important difference in rates of missed ongoing pregnancy or surgical intervention with multi-level urine pregnancy tests (these have several thresholds of human chorionic gonadotrophin [hCG], such as 25, 100, 500, 2,000 and 10,000\xa0international units [IU]), compared with high-sensitivity urine pregnancy tests (with a typical detection threshold of 10\xa0to 25\xa0IU hCG). Rates of patient satisfaction also appeared to be the same with both types of test. However, the committee did not recommend high-sensitivity tests because these can lead to higher clinically important rates of unscheduled clinic visits due to high rates of false-positive results in the month following the abortion. Instead, the committee recommended either multi-level or low-sensitivity tests (detection limit 1,000\xa0IU hCG), which are reliable 2\xa0weeks after the abortion. Low-sensitivity tests are already widely used in the UK and the rest of Europe, and are approved for home use.\n\nThe evidence only included women having abortion up to and including 9+0\xa0weeks' gestation. However, the committee agreed that the recommendations were appropriate for women having an abortion up to and including 10+0\xa0weeks' gestation because:\n\nthis is current standard clinical practice and\n\nthe range of hCG remains above the detection limit (1,000\xa0IU) into the second trimester.\n\nRecommendations 1.14.3 to 1.14.6\n\nThe recommendations are based on evidence showing that some women sought support for a number of reasons after an abortion. The evidence showed that they sought support from various different sources and they valued support that was specific to their circumstances. However, it also suggested that women sometimes found it difficult to get the support they need.\n\nWhile most of the evidence came from women having an abortion for fetal anomaly, the committee agreed that all women would benefit from information about what to expect and how to access support following an abortion, should they wish this. The committee also made a recommendation covering aftercare, based on their knowledge and experience.\n\n## How the recommendations might affect practice\n\nThe use of low-sensitivity or multi-level pregnancy tests instead of a routine clinic visit for ultrasound will reduce the number of clinic visits needed for women and be associated with cost savings for services. The recommendations should also reduce variation in practice by reducing the use of high-sensitivity pregnancy tests. These tests are associated with more clinic visits and a longer time period before the outcome of the abortion can be confirmed.\n\nThese recommendations should make it easier for women to get support after an abortion, and reduce the variation in what support is offered.\n\nThe impact for providers will vary according to what support they currently offer but many providers already offer emotional support and have arrangements in place for referring women to counselling services.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: follow-up after medical abortion up to 10+0 weeks and evidence review\xa0O: support after abortion.\n\nReturn to recommendations\n\n# Improving access to contraception\n\nRecommendations 1.15.1 to 1.15.5\n\n## Why the committee made the recommendations\n\nThere was evidence that providing contraception immediately after a surgical abortion improved uptake and continued contraception use, compared with providing contraception later. There was some variation in these outcomes after medical abortion, but providing contraception immediately (or as soon as possible) after abortion still reduced rates of subsequent abortions. There were also higher rates of patient satisfaction when contraception was provided immediately.\n\nThere was limited evidence that:\n\nmore women received long-acting reversible contraception when providers had staff who were skilled in providing all types of contraception\n\nhaving the full range of contraceptive methods available increased uptake and continued contraception use, and reduced the rate of subsequent abortions.\n\nSkilled healthcare professionals are needed to administer a number of long-acting methods of contraception and ensure that the full range of contraceptive methods are available. Without them, it may not be possible for women to receive their preferred choice of contraception immediately. Therefore, although the evidence was limited, the committee made a recommendation that providers ensure they have the full range of contraceptive methods available, and staff with the skills to provide them.\n\nWhen compared with delayed insertion, immediate implant insertion provides a clinically important reduction in the rates of subsequent unintended pregnancy, and higher rates of patient acceptability and satisfaction. The evidence also showed that it was uncertain whether or not there were clinically important differences in the rates of:\n\ncontinuing pregnancy\n\nincomplete abortion with the need for surgical intervention\n\ncomplete abortion without the need for surgical intervention\n\nsubsequent unintended pregnancy at 3\xa0months.\n\nThe evidence showed that, compared with delayed intrauterine insertion, early or immediate insertion of intrauterine devices provides either higher rates or no clinically important difference in rates of levonorgestrel intrauterine system (LNG-IUS) or copper intrauterine device (IUD) uptake and continued use. There was also evidence covering all gestational periods for LNG-IUS and covering gestations up to and including 9+0\xa0weeks for IUD looking at:\n\nuterine perforation\n\ninfection within 1\xa0month\n\nsubsequent pregnancy within 1\xa0year.\n\nHowever, the evidence was unclear on whether or not there were clinically important differences in any of these outcomes. For uterine perforation, the absolute risk was very small. For infection, the evidence did not distinguish between infections caused by intrauterine device insertion and those caused by the abortion in the women who received the device early or immediately.\n\nImmediate depot medroxyprogesterone acetate (DMPA) intramuscular injection provides a clinically significant improvement in patient satisfaction, compared with delayed injection. In addition, the evidence showed that it was unclear whether or not there were clinically significant differences between the 2 interventions in the rates of:\n\nincomplete abortion with the need for surgical intervention\n\ncomplete abortion without the need for surgical intervention\n\nsubsequent unintended pregnancy.\n\nThere was a potentially higher rate of ongoing pregnancy with immediate DMPA intramuscular injection compared with the delayed injection. However, there was uncertainty around this estimate, the absolute risk was small, and it was only seen in one\xa0study reviewed. Because of this, the committee agreed that immediate injection can be recommended as long as women are advised of the potential risk. There was no evidence to recommend a specific timing for DMPA administered subcutaneously.\n\n## How the recommendations might affect practice\n\nCurrently, some providers do not offer DMPA intramuscular injection immediately, due to concerns that this might affect the efficacy of the abortion. Therefore, these recommendations will reduce variations in practice. There may be an initial cost associated with providing training for staff in abortion services to administer long-acting reversible contraception. However, this will be offset by not needing an additional appointment to administer contraception, and increased access leading to fewer subsequent unintended pregnancies and abortions.\n\nThere is unlikely to be a significant change in practice resulting from these recommendations as intrauterine contraception is currently already offered to women after a medical abortion; all that is likely to change is the timing.\n\nThese recommendations will reduce variation in practice on contraception provision after abortion. They will also increase the choices available to women. The impact on individual services will depend on current practice. In the independent sector, most services are commissioned to provide all forms of contraception whereas, in the NHS, some trusts have difficulty getting funding for certain contraceptive methods.\n\nOverall, these recommendations should not increase costs or resource use, as the range of contraceptive methods covered is already available to women. However, there may be a change in who is funding contraception, with greater funding from clinical commissioning groups compared with local authorities. This will mean changes in the way services are organised, and commissioners will need to develop services to enable the recommendations.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0P: contraception after abortion.\n\nReturn to recommendations", 'Context': 'Abortion is a common procedure. In 2018, 200,608\xa0women in England and Wales had an abortion. Almost all of these abortions were funded by the NHS, but 72% were performed by the independent sector.\n\nMost abortions are carried out because the pregnancy was unintended, and the majority of procedures (80% of abortions in England and Wales in 2018) are conducted in the first 10\xa0weeks of pregnancy. Abortion is a safe procedure, and can be carried out medically (taking mifepristone followed by misoprostol) or surgically.\n\nThe trend in England and Wales over the past decade has been towards increasing use of medical abortion. In 2018, 71% of all abortions in England and Wales were medical, and this rises to 83% of abortions in the first 10 weeks of pregnancy.\n\nIn recent years, there have been changes in how and where abortion services are delivered. This has resulted in variation in the type and choice of procedures available across the NHS, for example, in the offer of local anaesthesia and sedation for a surgical procedure. In addition, the procedure used for medical abortion has been refined and women in the first 10\xa0weeks (up to 9\xa0weeks and 6\xa0days) may now self‑administer misoprostol at home in England and Wales. Furthermore, methods for checking whether a medical abortion has been successful have also been simplified. Some of these developments could significantly reduce costs to the NHS and be more acceptable to women.\n\nAbortion services also provide other important sexual and reproductive health services to women, including contraceptive services. However, there is marked variation across the country, involving different types of providers and, increasingly, organisations outside the NHS. In addition, accessing abortion services may be difficult for women who live in remote areas, who are in the second trimester of pregnancy, or who have complex pre-existing conditions or difficult social circumstances. In particular, abortion care is challenging for women living in Northern Ireland who currently have to travel to other parts of the UK in order to access services.\n\nThis guideline will help ensure that abortion procedures are carried out based on the best available evidence, and that a choice of services is easily accessible to all women who request an abortion.'}
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https://www.nice.org.uk/guidance/ng140
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This guideline covers care for women of any age (including girls and young women under 18) who request an abortion. It aims to improve the organisation of services and make them easier for women to access. Detailed recommendations on conducting abortions at different gestational stages are also included, to ensure that women get the safest and most effective care possible.
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89883ed181da79d59dddd7329047ccf2e9ccb468
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nice
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Tegaderm CHG securement dressing for vascular access sites in critically ill adults
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Tegaderm CHG securement dressing for vascular access sites in critically ill adults
Evidence-based recommendations on The 3M Tegaderm CHG IV securement dressing for central venous and arterial catheter insertion sites.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by companies. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.
The case for adopting the 3M Tegaderm CHG IV securement dressing for central venous and arterial catheter insertion sites is supported by the evidence. This technology allows observation, and provides antiseptic coverage, of the catheter insertion site. It reduces catheter‑related bloodstream infections and local site infections compared with semipermeable transparent (standard) dressings. It can be used with existing care bundles.
The 3M Tegaderm CHG IV securement dressing should be considered for use in critically ill adults who need a central venous or arterial catheter in intensive care or high dependency units.
The estimated cost saving from using a 3M Tegaderm CHG IV securement dressing (Tegaderm CHG) instead of a standard transparent semipermeable dressing is £93 per patient. This estimate is based on a baseline catheter‑related bloodstream infection rate of 1.48 per 1,000 catheter days. Tegaderm CHG is estimated to be cost neutral when the baseline catheter‑related bloodstream infection rate is 0.18 per 1,000 catheter days, and cost incurring when the baseline rate falls below that figure. # The technology
# Description of the technology
The 3M Tegaderm CHG IV securement dressing (Tegaderm CHG) is a sterile transparent semipermeable polyurethane adhesive dressing with an integrated gel pad containing a 2% concentration by weight of chlorhexidine gluconate (CHG).
Tegaderm CHG is used to secure percutaneous devices and to cover and protect central venous and arterial catheter insertion sites. It aims to provide an effective barrier against external contamination. The dressing and the integrated gel pad are transparent to allow observation of the catheter insertion site. The integrated gel pad is designed to reduce skin and catheter colonisation in order to suppress regrowth of microorganisms commonly related to catheter‑related bloodstream infections (CRBSI). The dressing is available in 4 different sizes but the most commonly‑used size, accounting for 85% of sales, measures 8.5 cm×11.5 cm.
Tegaderm CHG was CE‑marked as a class III device in April 2009 to cover and protect catheter sites and to secure devices to the skin. There was a modification to the dressing design in 2011 to include a breathable film.
The cost of Tegaderm CHG stated in the company's submission was £6.21. This cost was based on the list price of the Tegaderm CHG 1657R (8.5 cm×11.5 cm) dressing; the cost includes VAT. The cost has been updated in the 2019 revision to £6.09 per dressing.
The claimed benefits of Tegaderm CHG presented by the company are:
A 60% reduction in the incidence of CRBSI in adult critical care patients with intravascular catheters.
Reduced risk of mortality due to catheter‑related infections.
Reduced incidence of skin and catheter colonisation during treatment with central venous catheters or arterial catheters.
Reduced length of stay in critical care or high dependency units.
Reduced costs for diagnosis of CRBSI.
Reduced material and staff costs for treatment of catheter‑related infection.
# Current management
NICE's guideline on healthcare-associated infections provides guidance on using dressings in adults and children with vascular access devices (central venous catheters or peripherally‑inserted central catheters) in primary and community care settings. The guideline recommends that the skin at the central venous catheter insertion site, and the surrounding skin during dressing changes, should be decontaminated with CHG in 70% alcohol and allowed to air dry. If the company's recommendations prohibit the use of alcohol with their catheters, an aqueous solution of CHG should be considered. The guideline further recommends using a sterile, transparent semipermeable membrane dressing to cover the vascular access device insertion site, and changing the dressing every 7 days or sooner if it is no longer intact or if moisture collects under it. A sterile gauze dressing, covered with a sterile transparent semipermeable dressing, should be considered only if the patient has profuse perspiration, or if the vascular access device insertion site is bleeding or oozing. The guideline states that systemic antimicrobial prophylaxis should not be used routinely to prevent catheter colonisation or CRBSI, either before insertion or during the use of a central venous catheter. It makes no specific recommendations about using CHG‑impregnated dressings, although the full guideline notes that they may be cost effective compared with sterile transparent semipermeable membrane dressings based on limited evidence from 1 study, Crawford et al. (2004).
The Department of Health commissioned the epic3 guideline on preventing healthcare‑associated infections in NHS hospitals in England. The guideline recommends using a sterile transparent semipermeable dressing to cover the intravascular insertion point as best practice in both adults and children. The guideline recommends, based on high‑quality evidence, a single application of 2% CHG in 70% isopropyl alcohol (or povidone‑iodine alcohol for patients with sensitivity to CHG) to clean the central catheter insertion site during dressing changes, and allowing it to air dry. The guideline also recommends, based largely on randomised controlled trial evidence, that hospitals consider using a CHG‑impregnated sponge dressing in adults with a central venous catheter, as a strategy to reduce CRBSI.
NICE carried out a 2‑year surveillance review of its infection guideline in September 2014 and decided not to update it. It noted that further research is needed to establish the efficacy of CHG dressings applied to CHG‑prepared skin to prevent CRBSI in patients with venous access devices.
Care bundles are a structured way of improving the processes of care and patient outcomes. They consist of a set of simple to implement evidence‑based practices, that when performed collectively and reliably, have been proven to improve patient outcomes. Central venous catheter care is an example of a care bundle produced by the Department of Health in 2010.# Clinical evidence
# Summary of clinical evidence
The key clinical outcomes for the 3M Tegaderm CHG IV securement dressing (Tegaderm CHG) presented in the decision problem were:
catheter‑related bloodstream infections (CRBSI)
skin and catheter colonisation
length of stay in critical care or high dependency unit
mortality caused by catheter‑related infections
dermatitis
local site infection
quality of life
device‑related adverse events.
The company identified 5 studies that met their inclusion criteria. There were 3 studies (Maryniak et al. 2009; Olson et al. 2008 and Rupp et al. 2008) that reported nursing satisfaction scores on various aspects of dressing design and performance; these were excluded from the clinical evidence review (see section 3.11). An unpublished study by Scoppettuolo et al. (2012) was also excluded because the results from intensive care unit and non‑intensive care unit patients were not reported separately. The company presented the remaining study by Timsit et al. (2012).
The External Assessment Centre agreed with including Timsit et al. (2012) and excluding the 4 remaining studies identified.
The External Assessment Centre carried out a further literature search to identify all prospective comparative studies including at least 2 of the 3 dressing types in the scope: Tegaderm CHG, a semipermeable transparent (standard) dressing and a chlorhexidine gluconate (CHG)‑impregnated dressing. This search returned 1,755 records of which 4 were considered relevant. Of the 4 studies identified, 2 involved Tegaderm. One of the 2 studies involving Tegaderm was presented by the company (Timsit et al. 2012); the other was identified by the company as an ongoing study (Karpanen et al. 2014) with interim results published after the company's submission of evidence. The External Assessment Centre considered the Timsit et al. (2012) study to be relevant to the decision problem despite the fact that both the intervention and control groups were not swabbed with 2% CHG in alcohol as specified in the decision problem. The other 2 studies (Timsit et al. 2009 and Roberts et al. 1998) compared a CHG‑impregnated sponge dressing (Biopatch, Johnson and Johnson) against standard dressings, and were included by the External Assessment Centre to provide an indirect comparison between Tegaderm CHG and a CHG‑impregnated dressing.
Timsit et al. (2012) reported a large multicentre randomised controlled trial, based in 12 intensive care units in France, involving 1,879 patients and 4,163 intravascular catheters (2,201 arterial and 1,962 central venous catheters). Patients needing intravascular access were randomised to 1 of 3 groups: Tegaderm CHG (938 patients), standard dressing (Tegaderm transparent film dressing; 476 patients) or highly‑adhesive dressing (Tegaderm HP transparent film dressing; 465 patients). Assessors were blinded to dressing type. Patients had their skin prepared with povidone‑iodine in alcohol or 0.5% chlorhexidine in alcohol. Dressings were replaced after 24 hours and then every 3 to 7 days depending on the centre, or as needed if there was leaking or soiling. The study follow‑up period was 48 hours after discharge from the intensive care unit.
Outcomes were reported on an intention‑to‑treat basis. These were reported for each group, and comparative statistical analyses were done between the Tegaderm CHG group and the 2 non‑CHG‑dressing groups combined (the standard and highly‑adhesive dressing groups), and between the standard dressing group and the highly‑adhesive dressing group. Results showed that CRBSI rates were significantly lower in the Tegaderm CHG group, at 0.5 per 1,000 catheter days compared with 1.3 for the highly‑adhesive dressing and standard dressing groups combined (hazard ratio for CHG compared with non‑CHG dressings 0.402; 95% confidence interval 0.186 to 0.868, p=0.02). Catheter and skin colonisation were significantly lower in the Tegaderm CHG group at 4.3 per 1,000 catheter days compared with 9.6 for the standard dressing group, 12.5 for the highly‑adhesive dressing group, and 10.9 for the 2 non‑CHG dressing groups combined (HR for CHG compared with non‑CHG dressings 0.412; 95% CI 0.306 to 0.556, p<0.0001). Major catheter‑related infections (defined as catheter‑related sepsis with or without CRBSI), were also significantly lower in the Tegaderm CHG group, at 0.7 per 1,000 catheter days compared with 2.3 for the standard dressing group and 1.9 for the highly‑adhesive dressing group (HR for CHG compared with non‑CHG dressings 0.328; 95% CI 0.174 to 0.619, p=0.0006). Patients with a Tegaderm CHG dressing had a significantly higher rate of severe contact dermatitis needing removal of the dressing; 1.1% compared with 0.1% for the standard dressing and 0.5% for the highly‑adhesive dressing, p<0.0001. Also, abnormal International Contact Dermatitis Research Group (ICDRG) scores, measured at each dressing change and at catheter removal, were significantly higher for Tegaderm CHG at 2.3%, compared with 1% for the non‑CHG dressings (0.7% for the standard dressing and 1.4% for the highly‑adhesive dressing, p<0.0001). No systemic adverse events related to any of the dressings were reported. The authors concluded that Tegaderm CHG was associated with a lower rate of major catheter‑related infections than either of the non‑CHG dressings.
Karpanen et al. (2014) reported interim results, in the form of a poster presentation, of a non‑randomised prospective comparative observational study of 273 intensive care unit patients at University Hospitals Birmingham NHS Foundation Trust. Patients had Tegaderm CHG or a standard dressing (Tegaderm IV dressing). Patients in both groups had standard catheter care, including skin preparation with 2% CHG in 70% alcohol. Based on interim results in the 273 patients, there were 10 instances (7.4%) of colonisation of the intradermal section of the central venous catheter in the Tegaderm CHG group compared with 22 (14.6%) in the standard dressing group (p=0.037). There were 10 instances (7.4%) of tip colonisation of the central venous catheter reported in the Tegaderm CHG group compared with 20 instances (16.1%) in the standard dressing group (p=0.08). Adverse events were not reported. The authors concluded that adopting Tegaderm CHG reduced bacterial numbers on the skin and reduced the bacterial load at the central venous catheter insertion site compared with the standard dressing.
## Studies on the comparator technologies
Timsit et al. (2009) reported on a multicentre, 2×2 factorial randomised controlled trial involving 1,636 patients in 7 intensive care units in France. The study had 2 aims: to assess the superiority of a CHG‑impregnated sponge compared with a standard dressing on rates of major catheter‑related infection; and to determine the effect on outcomes of a 3- or 7‑day dressing change. Patients were randomised to 1 of 4 groups by both dressing type (CHG‑impregnated sponge plus a standard dressing or a standard dressing alone) and frequency of dressing change (every 3 or 7 days). In all patients an antiseptic solution of 5% povidone‑iodine in 70% ethanol was applied and all dressings were changed 24 hours after catheter insertion and then every 3 or 7 days. The follow‑up period was 48 hours after discharge from the intensive care unit, and all outcomes were based on intention‑to‑treat analyses.
CRBSI rates were significantly lower in the CHG‑impregnated sponge group at 0.4 per 1,000 catheter days compared with 1.3 for the standard dressing group (HR 0.24; 95% CI 0.09 to 0.65, p=0.005). Catheter and skin colonisation rates were significantly lower in the CHG‑impregnated sponge group, 0.6 per 1,000 catheter days compared with 1.4 for the standard dressing group (HR 0.36; 95% CI 0.28 to 0.46, p<0.001). Major catheter‑related infection rates were significantly lower in the CHG‑impregnated sponge group, 0.6 per 1,000 catheter days compared with 1.4 for the standard dressing group (HR 0.39; 95% CI 0.16 to 0.93, p=0.03). There was no statistically significant difference in these outcomes between the 3- or 7‑day dressing change groups.
The rate of severe contact dermatitis, needing removal of the dressing, was 0.53% for the CHG‑impregnated sponge group and 0% for the standard dressing group (no statistical analyses reported). Abnormal ICDRG scores, measured at each dressing change and at catheter removal, were significantly higher for the CHG‑impregnated sponge group at 1.49% compared with 1.02% for the standard dressing group, p=0.02. No systemic adverse events related to the dressings were reported. The authors concluded that the CHG‑impregnated sponge dressing was associated with a reduction in the risk of infection, even with low background infection rates, compared with the standard dressing.
Roberts et al. (1998) carried out a single‑centre randomised controlled trial involving 32 patients with 40 catheters in an Australian intensive care unit. Patients were randomised to have a CHG‑impregnated sponge (Biopatch) plus a standard dressing or a standard dressing alone (Opsite IV 3000, Smith and Nephew). Skin was prepared with 0.5% CHG in alcohol and dressings were changed every 3 days. There was 1 CRBSI in the CHG-impregnated sponge group, and none in the standard dressing group (p value not reported). There were 2 instances of catheter colonisation on the central venous catheter tip, and 4 at the exit site in the CHG‑impregnated sponge group compared with 1 case and 3 cases respectively for the standard dressing group; neither difference was statistically significant. Adverse events were not reported. The authors stated that the data were insufficient to draw conclusions from this study.
The External Assessment Centre critically appraised the methodology of each study. It judged that the studies by Timsit et al. (2009 and 2012) were the most relevant and best conducted. The study by Roberts et al. (1998) was underpowered to determine the statistical significance of outcomes; provided few details on the methodology used; included no details on how randomisation was achieved; and only provided information on age and gender of the study population at baseline. The poster presentation by Karpanen et al. (2014) contained insufficient detail for the External Assessment Centre to fully appraise its methodology and accurately judge its relevance to the decision problem.
The External Assessment Centre considered the company's submission to be consistent with the scope. However, it noted that the company's submission did not compare Tegaderm CHG with other CHG‑impregnated dressings because no direct comparative evidence was found in the literature review. The Timsit et al. (2012) study included by the company used internationally‑recognised definitions for catheter colonisation and CRBSI. Mortality caused by catheter‑related infections, local site infection, and quality of life were not addressed in the company's submission. However, given the evidence for a link between CRBSI and mortality, the External Assessment Centre considered it plausible that if Tegaderm CHG reduced CRBSI, it would have a positive effect on CRBSI‑related mortality in practice. The External Assessment Centre noted that the CRBSI rate of 1.3 per 1,000 catheter days reported in Timsit et al. (2012) was similar to that reported for the NHS in England in the Matching Michigan study of 1.48 per 1,000 catheter days, making its results generalisable to the NHS. However, it also noted that the mortality of 31% for the intensive care units in France in the Timsit studies was substantially higher than the 9.1% mortality reported for adult critical care units in the NHS. This suggests that whereas their demographics were similar, the intensive care units in France probably had more severely ill patients than the UK intensive care units. The skin preparation protocols followed by the intensive care units in France differed from those recommended for the NHS, which were specified in the decision problem.
## Adverse events
The company searched the Medicines and Healthcare Products Regulatory Agency (MHRA), Food and Drug Administration (FDA) and Manufacturer and User Facility Device Experience (MAUDE) systems to identify surveillance reports relating to Tegaderm CHG, between 7 January 2000 and 29 July 2013. This revealed 1 result from the MHRA and 109 results from MAUDE. The company also searched its post‑marketing surveillance data for reported skin reactions. This identified a marked reduction in reports, both in numbers and relative to increasing sales, after a modification to the dressing design in 2011 to incorporate a breathable film.
The External Assessment Centre found that the company's search of the MAUDE and MHRA systems accurately reported, in detail, the adverse events for Tegaderm CHG. Overall, it considered the company's search for adverse events to be robust.
The External Assessment Centre extended the company's search to 28 November 2014 and identified a further 17 results. These results generally described local skin reactions within 48 hours of dressing application, and many were self‑limiting. There were 2 deaths reported in MAUDE, but these were not directly linked to Tegaderm CHG.
The company also did a search of the MHRA and MAUDE systems to identify post‑marketing surveillance reports for the Biopatch (CHG‑impregnated sponge) and Opsite IV 3000 (standard) dressings, but it did not report the search terms and dates used. The External Assessment Centre did its own searches of these systems between 1 January 2012 and 30 November 2014. These searches identified 73 records for Biopatch, which were similar in nature to the 29 records for Tegaderm CHG over the same period. However, the External Assessment Centre emphasised that these figures allow no comparison of event rates because no data were available on the numbers of dressings used over this period. One record reported a death; however this was not directly linked to Biopatch. Only 1 minor, self‑correcting adverse reaction was found for the Opsite IV 3000 dressing over this period.
## Committee considerations
The Committee considered that the evidence showed that Tegaderm CHG was effective in reducing CRBSI compared with standard semipermeable transparent dressings. It considered that the Tegaderm CHG and CHG‑impregnated sponge dressings were clinically equivalent in terms of reducing CRBSI. However, it noted that Tegaderm CHG offers the additional benefit of being able to see the catheter insertion site. The Committee was advised by clinical experts that being able to see the catheter insertion site allows the care bundle checks that are needed to minimise infection rates. It was also advised that nurses find Tegaderm CHG easier to apply than CHG‑impregnated sponge dressings.
The Committee noted that the study evidence was largely from intensive care units in France that followed different skin preparation guidelines and that may have had more severely ill patients than those generally found in the UK. The Committee considered that this evidence was nevertheless generalisable to the UK, based on advice from experts and the External Assessment Centre and on the knowledge of its members.
The Committee heard from clinical experts that different definitions and measurement methods are used to diagnose CRBSI, making comparison of infection rates difficult. It was advised that a diagnosis of CRBSI should involve tests to confirm that the catheter was the source of the bloodstream infection (typically culture of the catheter tip). It discussed using less rigorous definitions; specifically central line associated bloodstream infection (CLABSI), which is used in hospitals where cultures of the tip, or peripheral blood, are not systematically done. The Committee was advised that using CLABSI risked overestimating the rate of CRBSI and therefore overestimating any potential cost savings from using Tegaderm CHG.
The Committee was advised by clinical experts that introducing care bundles into intensive care units had significantly reduced rates of CRBSI, but that it is not possible to identify which specific components of a care bundle have led to the reductions in infection rates. It was advised that Tegaderm CHG could be used with existing care bundles as an additional method for minimising rates of CRBSI, but it would not replace the need to use care bundles. The Committee noted that in some hospitals existing infection control procedures may have reduced baseline CRBSI rates to such low levels that they may not be able to realise the benefits of introducing Tegaderm CHG (see section 5.19).# NHS considerations
# System impact
The company proposed that using the 3M Tegaderm CHG IV securement dressing (Tegaderm CHG) would not result in changes to the current care pathway or need additional resources. The External Assessment Centre agreed with these assumptions.
Using Tegaderm CHG instead of a standard dressing does not need any special additional training. At the topic selection phase, the Committee received expert advice that confirmed that minimal additional training would be needed.
The company provided Hospital Episodes Statistics data showing that there were 237,710 adult critical care episodes, 92,710 of which involved stays of over 48 hours, in 2012/13. Based on expert opinion the company estimated that 95% of these patients would need a central venous and/or arterial catheter, providing an estimate of the population for Tegaderm CHG each year of between 88,074 and 225,824. The company estimated that Tegaderm CHG currently accounts for 15% of the dressings used in the population described in the scope. Were the use of Tegaderm CHG to become standard practice, it was assumed that this figure would rise to 80%.
## Qualitative evidence on ease of use and performance
The company provided supplementary information from 3 randomised controlled trials (Maryniak et al. 2009; Olson et al. 2008 and Rupp et al. 2008) on the performance of Tegaderm CHG compared with a standard dressing (either Tegaderm IV or Opsite IV 3000, Smith and Nephew). These studies were not included in the company's main submission because they were not limited to critically ill patients and used non‑validated methods in their nurse‑reported dressing satisfaction and performance outcome measures.
The External Assessment Centre agreed with the company's decision to exclude these studies from the clinical evidence. The External Assessment Centre collated information on the ease of use and performance of Tegaderm CHG using advice from experts, evidence from the company and from its own searches.
Maryniak et al. (2009) reported a prospective observational study involving 217 inpatients and outpatients (107 patients had Tegaderm CHG and 110 patients had an unspecified standard dressing). Olson et al. (2008) carried out a randomised controlled trial with 63 hospitalised patients (33 patients had Tegaderm CHG and 30 patients had a standard dressing – Tegaderm IV), some of whom were in intensive care units. Rupp et al. (2008) completed a randomised controlled trial with 60 hospitalised patients (30 patients had Tegaderm CHG and 30 patients had a standard dressing – Opsite IV 3000). All studies were done in the USA, none of them specifically considered critically ill patients and satisfaction with the dressings was judged by the clinical staff. The results showed that the nurses were significantly more satisfied with Tegaderm CHG than with standard dressings in all 3 studies (p<0.05). Tegaderm CHG was reported to provide a more satisfactory dressing securement, was easier to apply and had improved adherence. There were mixed results, and largely insignificant differences, in terms of nurse satisfaction with ease of correct application, transparency (site visibility), ease of dressing removal, and reported patient discomfort levels during dressing wear.
The External Assessment Centre identified a number of studies comparing the ease of use of Tegaderm CHG against a chlorhexidine gluconate (CHG)‑impregnated sponge. Eyberg et al. (2008) reported a randomised controlled trial comparing Tegaderm CHG against a CHG‑impregnated sponge (Biopatch) in which 12 clinicians were randomly allocated to apply and remove 1 of the dressings on the left or right side of the neck in 12 healthy volunteers. Outcome measures included overall performance, ease of correct application, ease of removal, ability to see the intravenous site, ease of training and intuitive application. Clinicians found that Tegaderm CHG was significantly better than the CHG‑impregnated sponge across all outcome measures (p<0.05). There were 2 poster presentations (Zehrer et al. 2009; Deschneau et al. 2008) that reported on questionnaires completed by nurses after using the dressings. In both studies Tegaderm CHG performed significantly better overall than the CHG‑impregnated sponge.
Advice provided during evaluation from 3 experts with experience of using both Tegaderm CHG and standard dressings was that, in general, clinician experience of applying and removing Tegaderm CHG was similar to standard dressings. There was 1 expert who stated that it takes longer to remove Tegaderm CHG and that there may be a few incorrect applications at first. The remaining 2 experts stated that the time taken to apply or remove the dressing is the same or similar for both Tegaderm CHG and standard dressings.
There were 2 experts who had experience of using both Tegaderm CHG and CHG‑impregnated sponge dressings. They reported minimal differences between the ease of use of the 2 types of dressings. One expert suggested that applying and removing Tegaderm CHG is quicker than for the CHG‑impregnated sponge. The other reported that some nurses had placed the CHG‑impregnated sponge upside down and therefore had to use a replacement.
## Committee considerations
Based on evidence from the company, the External Assessment Centre and expert advice, the Committee was satisfied that Tegaderm CHG would not involve significant changes to current care pathways and the use of existing care bundles.
The Committee was advised by clinical experts that care bundles are of great importance in minimising infection rates. It was advised that care bundles include many components and that it is difficult to identify any specific components that are driving the improvement in infection rates. The Committee concluded that Tegaderm CHG could contribute to preventing catheter-related bloodstream infections (CRBSI) but it would not replace the need for existing infection control practices.
The Committee was advised by specialists that being able to see the catheter insertion site is useful, allowing early recognition of any dermatitis or infection. Redness at the catheter insertion site can be an early sign of infection, which may be considered with other clinical signs to raise suspicion of CRBSI. The Committee noted that not all CRBSI is associated with visible changes at the insertion site.
The Committee noted that the cost savings associated with adopting Tegaderm CHG instead of a standard dressing depend on baseline CRBSI rates (see section 5.24). The Committee considered that it was important for intensive care and high dependency units to review their local CRBSI rates when considering whether to adopt Tegaderm CHG.# Cost considerations
# Cost evidence
The company did a literature search and identified 5 studies that met their selection criteria. All studies used cost–benefit analyses. Of these, 3 studies were done in the USA (Veenstra et al. 1999; Crawford et al. 2004 and Ye et al. 2011), 1 study was done in the UK (Hockenhull et al. 2008) and 1 study was done in France (Schwebel et al. 2012). In 2 of the studies, the comparison was between an antiseptic‑impregnated catheter and a standard catheter (Veenstra et al. 1999 and Hockenhull et al. 2008). In the remaining 3 studies (Crawford et al. 2004; Schwebel et al. 2012 and Ye et al. 2011), the intervention was a chlorhexidine gluconate (CHG)‑impregnated dressing and the comparator was a standard dressing. None of the included studies involved the 3M Tegaderm CHG IV securement dressing (Tegaderm CHG).
The External Assessment Centre considered none of the company's identified studies to be relevant because they did not compare Tegaderm CHG with either of the comparators. It did additional searches and identified 4 economic studies; all used cost–benefit analyses and compared Tegaderm CHG with a standard dressing (Maunoury et al. 2013, 2014 and Palka‑Santini et al. 2014a, 2014b). All were published as conference abstracts after the company's searches. All the studies were carried out from the perspective of the health service in France, were written by the same authors, and used data from Timsit et al. (2012). Each study used different model structures or reported different results, all involved a non‑homogeneous Markov model, and were concerned with various measures of infection. No statistically significant differences in costs were reported between the dressings. The External Assessment Centre was unable to assess the relevance of these data to the NHS given the limited information provided.
# Economic model
The company presented a cost analysis comparing Tegaderm CHG against a standard dressing (Tegaderm IV 1635). The costs of another commonly used, but more expensive, standard dressing (Opsite IV 3000, Smith and Nephew) were also quoted, but not used in the model. The company did not include the CHG‑impregnated sponge dressing in the model because of the lack of direct comparative clinical evidence. The economic model presented by the company was a decision tree with a short time horizon that included the catheterisation period and any additional length of stay associated with catheter‑related bloodstream infections (CRBSI). The model used an NHS perspective. The decision tree simulated intensive care unit patients who had an absolute risk of getting CRBSI, local site infection or dermatitis. Each outcome was a separate health state and the model captured the number of patients in each state and the cost of being in that state (dressings and management costs).
Each time the model was run, Monte Carlo simulation was used to select values at random from the pre‑specified distributions associated with each of the input parameters, apart from the unit cost of the dressings. This approach allowed the effects of the joint uncertainty across the parameters of the model to be considered. The company's base‑case results were probabilistic, based on 1,000 iterations of the model.
The External Assessment Centre considered that the structure of the model was appropriate, capturing the main differences in reported clinical outcomes and cost differences between Tegaderm CHG and standard dressings. However, it noted that the model diagram did not include in its end states patients who had no complications, and amended the model diagram to include this state. The company did not report any structural assumptions in the model. However, the External Assessment Centre identified the following:
There was no difference in outcomes beyond the short time horizon of the study.
The length of time a patient has a catheter was not influenced by whether or not they had an infection (CRBSI or local).
The risk of having any of the study outcomes was mutually exclusive and independent.
The dressings only affected actual outcomes and not suspected outcomes, which would also incur costs of investigation.
Infection rates were assumed to be linear regardless of catheter dwell time.
There were no practical differences in dressing management between the dressings such as time to apply and remove, wastage and training.
The External Assessment Centre judged that these simplifying assumptions were unlikely to influence the results of the company's model significantly.
The company used data from Timsit et al. (2012) to populate the parameters for all the clinical end points in the model. The model's time horizon of 10 days was based on the mean duration of catheterisation for critically ill patients reported in the study by Ye et al. (2012). Patients who had a CRBSI incurred an additional length of stay of 3 days in an intensive care unit and 7 days in a ward, with resource use costs based on figures reported in the Hockenhull et al. (2008) study. Baseline rates or risks for the clinical end points were obtained from a number of sources. The rate for CRBSI (1.48 per 1,000 catheter days) was taken from Bion et al. (2012), based on 2010 final quarter figures from the Matching Michigan study; for local site infection (0.1 per patient) from Ye et al. (2011); and risk for dermatitis (0.0026 per catheter) from Schwebel et al. (2012).
The costs for the Tegaderm CHG and the standard dressing (Tegaderm IV 1635) used in the company's model were based on the cost of the most commonly‑used size of dressing, and were £6.21 and £1.34 respectively. These figures were provided by the company.
The cost for a CRBSI of £9,900 was based on the figure reported in the health technology assessment paper by Hockenhull et al. (2010), inflated to 2012/13 prices. This value was used in NICE's guideline on healthcare-associated infections. The company produced its own cost estimate for CRBSI based on resource use identified through expert advice, which agreed with this £9,900 figure. The cost of dermatitis of £150 used in the company's model was based on the cost of 4 standard dressings, removing the existing catheter, and replacing it with a new catheter. Local site infections were given a cost of £250 based on the US $400 figure reported in the study by Saint et al. (2000).
The company's base‑case results reported an average cost of £99.63 per patient for the Tegaderm CHG dressing compared with £176.89 per patient for the standard dressing. This would give an average saving of £77.26 per patient if Tegaderm CHG were adopted. The probability of Tegaderm CHG being cost saving over standard dressings was calculated at 98.5%. The key driver of this cost saving was avoiding CRBSI through using Tegaderm CHG.
The company presented univariate deterministic analysis on both the cost of CRBSI and its baseline rate to explore how robust the estimated cost savings of Tegaderm CHG compared with standard dressings were to changes in these key variables. If a low estimate of CRBSI rate of 0.5 per 1,000 catheter days was used the cost savings with Tegaderm CHG were £23 per patient; if a high estimate of 5.5 per 1,000 catheter days was used the savings with Tegaderm CHG increased to £135 per patient. Based on a low estimate of £5,000 for treating a CRBSI and a high estimate of £15,000, Tegaderm CHG generated cost savings per patient of £36 and £119 respectively.
# Parameter revisions by the External Assessment Centre
The External Assessment Centre reviewed the parameters and costs used in the company's model. It contacted clinical experts who validated the company's estimated resource use associated with CRBSI.
The External Assessment Centre revised the company's value for baseline local site infection rate to 0.14 per 1,000 catheter days based on 2013 audited rates for NHS Wales published by the Welsh Healthcare Associated Infection Programme (2014).
The External Assessment Centre judged it more appropriate to use the probability of 1 case of dermatitis per 476 patients reported in the Timsit et al. (2012) study. The External Assessment Centre revised the relative risk of dermatitis to 1, based on commercial‑in‑confidence global event data provided by the company on the reduced rate of dermatitis after design improvements in the breathability of the Tegaderm CHG dressing.
The External Assessment Centre calculated a weighted average cost for the dressings, taken from the NHS Supply Chain costs. For Tegaderm CHG the cost was based on the proportionate sales figures for the 4 dressing sizes and was estimated as £6.26 per dressing. The cost of the standard dressing was based on the proportionate sales figures of 2 commonly‑used standard dressings, Tegaderm IV and Opsite IV 3000, and was estimated as £1.54 per dressing. The External Assessment Centre estimated the cost of a CHG‑impregnated dressing to be £8.13.
The External Assessment Centre was advised by experts that it was not usual procedure to remove the catheter if a patient developed dermatitis. It therefore considered that the company's costs of the consequences of dermatitis overestimated the true cost. The External Assessment Centre therefore estimated a lower value, which involved the costs of dressings only, but assumed, as did the company, that patients with dermatitis would need more frequent dressing changes. It assumed the use of 1 additional dressing. Therefore the cost of dermatitis was revised to £6.
The study by Saint et al. (2000), which provided the cost for local site infection used in the company's model, provided no details on how that cost was generated. The External Assessment Centre therefore sought expert advice to derive its own cost estimate, £100, which was lower than that used in the company's model.
The External Assessment Centre also sought expert advice on the number of dressings used. This agreed with the company's estimate of 3 dressings over a 10‑day catheterisation period.
The External Assessment Centre identified 2 main weaknesses in the company's economic analysis. First, there was no rationale for the choice of distributions and coefficients used in the probabilistic sensitivity analysis done by the company. However, the External Assessment Centre noted that this was not needed as part of the submission template. Second, the company did not attempt to make any judgement on the comparative cost effectiveness of Tegaderm CHG and a CHG‑impregnated sponge dressing. The External Assessment Centre addressed both these concerns in the assessment report.
The External Assessment Centre re‑ran the company's model with their revisions to the parameter values and distributions. It also ran an additional scenario in which the baseline CRBSI rate for England was substituted with that reported for Scotland in 2013 of 0.3 per 1,000 catheter days. Both deterministic and probabilistic sensitivity analyses were done. The External Assessment Centre's deterministic base‑case results using CRBSI data from England produced an average per patient cost of £77.75 for Tegaderm CHG and £151.29 for a standard dressing, a cost saving of £73.54. When CRBSI data from Scotland were used, Tegaderm CHG had an average per patient cost of £30.79 and a standard dressing cost of £34.47; a cost saving of £3.68 per patient. The External Assessment Centre varied the baseline CRBSI rate and identified the threshold at which Tegaderm CHG was cost neutral as 0.24 per 1,000 catheter days.
The External Assessment Centre ran both univariate and multivariate probabilistic sensitivity analyses, varying the model parameters using their ranges and distributions. In the probabilistic sensitivity analysis varying all the model parameters, Tegaderm CHG had a 97.8% probability of being cost saving using the baseline CRBSI rate for England, but this fell to 57.9% when the figure for Scotland was used.
The External Assessment Centre also presented an exploratory cost analysis of Tegaderm CHG compared with CHG‑impregnated sponge dressings. There were no comparative data and from the limited evidence available (including similar data on adverse events), the External Assessment Centre concluded that it was plausible to assume that the 2 dressings had similar safety and efficacy. Without hard data on outcomes this exploratory work relied on observational studies and expert opinion. This suggested that resource use was similar between the 2 dressings, with any cost differences relying on acquisition cost. Based on NHS Supply Chain costs for Biopatch and the cheapest standard dressing (Tegaderm IV) the cost for a CHG‑impregnated sponge dressing was calculated at £8.13, compared with £6.26 for Tegaderm CHG. No sales data were available through the NHS Supply Chain. Expert opinion indicated that NHS trusts would probably purchase through other sources at a lower price than the NHS Supply Chain listed price. Therefore the External Assessment Centre calculated additional costings using the price provided by 3M for Biopatch, of £5.16 per dressing. This resulted in a total price of £6.49, slightly more expensive than Tegaderm CHG.
# Committee considerations
The Committee noted the cost modelling presented by the company and the adjustments made by the External Assessment Centre. It considered that the revisions made by the External Assessment Centre were plausible. The Committee considered that the External Assessment Centre's sensitivity analyses addressed the uncertainties in the economic model. It concluded that the estimated cost savings for Tegaderm CHG compared with standard semipermeable transparent dressings were likely to be realised in practice, with actual savings dependent on the baseline CRBSI rate.
The Committee considered that the baseline CRBSI rate was a key driver of the savings in the cost model. It noted that Tegaderm CHG was cost neutral when the baseline CRBSI rate was 0.24 per 1,000 catheter days and became cost incurring when the baseline rate fell below that figure. The Committee heard expert opinion that CRBSI rates in England have been falling in recent years. It heard from both the External Assessment Centre and the experts that there are differences in the definition and measurement of CRBSI between different countries and different hospitals, which makes comparison of infection rates difficult. The Committee concluded that Tegaderm CHG is likely to be cost saving in hospitals where the baseline CRBSI rate is above about 0.24 per 1,000 catheter days. It also concluded that Tegaderm CHG could potentially provide a useful way of reducing infection rates further in those hospitals that have not managed to do this by other means.
# guidance review
For the guidance review, the External Assessment Centre revised the model to reflect 2019 costs. The main parameter changes were (original guidance values given in brackets):
baseline incidence rate of CRBSI for Scottish intensive care units: 0.28 per 1000 catheter days (0.3 per 1,000 catheter days)
baseline incidence rate of local site infection: 0.4 per 1,000 catheter days (0.14 per 1,000 catheter days)
baseline incidence rate of dermatitis: 0.3 per 1,000 catheter days (0.002 1‑year probability)
the effectiveness of Tegaderm CHG for preventing CRBSI: 0.402 hazard ratio (0.45 relative risk)
length of stay with catheterisation: 13 days (10 days).The cost of Tegaderm CHG was also updated to reflect the 2% decrease in the cost of the dressing (from £6.21 to £6.09). The External Assessment Centre assumed this reduction was implemented in all sizes of Tegaderm CHG and estimated an updated weighted average of £6.14 (£6.26), using the sales proportions from the original cost model. Other costs from the original model were adjusted for inflation. Deterministic base‑case results for the 2019 revised model produced an average per patient cost of £106.62 (£77.75) for Tegaderm CHG and £199.69 (£151.29) for a standard dressing, a cost saving of £93.07 (£73.54) when considering a baseline CRBSI rate of 1.48 per 1,000 catheter days. When CRBSI data from Scotland were used, Tegaderm CHG had an average per patient cost of £35.80 (£30.79) and a standard dressing cost of £43.30 (£34.47): a cost saving of £7.50 (£3.68) per patient. In the probabilistic sensitivity analysis, Tegaderm CHG had a 98.9% (97.8%) probability of being cost saving using the baseline CRBSI rate for England, but this fell to 50.3% (57.9%) when the figure for Scotland was used. The External Assessment Centre varied the baseline CRBSI rate and identified the threshold at which Tegaderm CHG was cost neutral as 0.18 (0.24) per 1,000 catheter days. Further details of the 2019 revised model are in the cost model update report. # Conclusions
The Committee concluded that the evidence showed that the 3M Tegaderm CHG IV securement dressing (Tegaderm CHG) offers better protection against catheter‑related bloodstream infection (CRBSI) than sterile semipermeable transparent dressings. Based on indirect evidence, the Committee considered that Tegaderm CHG also offers equivalent protection against CRBSI to chlorhexidine gluconate (CHG)‑impregnated sponge dressings, but has other advantages, specifically being able to see the catheter insertion site.
The Committee accepted the External Assessment Centre's revised model and sensitivity analysis which estimated costs in relation to the baseline CRBSI rate. It concluded that Tegaderm CHG could generate cost savings of £73 per patient when the baseline CRBSI rate was 1.48 per 1,000 catheter days, as cited in the Matching Michigan study for intensive care units in England (based on April 2009 to April 2011 data). However, the Committee was aware of advice that baseline CRBSI rates have fallen in recent years and acknowledged the importance of the External Assessment Centre's estimate that Tegaderm CHG is likely to be cost neutral when the baseline CRBSI rate is 0.24 per 1,000 catheter days, and to incur costs when it falls below that level. It therefore concluded that hospitals should take their baseline CRBSI rate into account when making decisions about whether to adopt Tegaderm CHG. Andrew DillonChief ExecutiveJuly 2015
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{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified to NICE by companies. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.\n\nThe case for adopting the 3M Tegaderm\xa0CHG\xa0IV securement dressing for central venous and arterial catheter insertion sites is supported by the evidence. This technology allows observation, and provides antiseptic coverage, of the catheter insertion site. It reduces catheter‑related bloodstream infections and local site infections compared with semipermeable transparent (standard) dressings. It can be used with existing care bundles.\n\nThe 3M Tegaderm\xa0CHG\xa0IV securement dressing should be considered for use in critically ill adults who need a central venous or arterial catheter in intensive care or high dependency units.\n\nThe estimated cost saving from using a 3M Tegaderm\xa0CHG\xa0IV securement dressing (Tegaderm\xa0CHG) instead of a standard transparent semipermeable dressing is £93 per patient. This estimate is based on a baseline catheter‑related bloodstream infection rate of 1.48 per 1,000\xa0catheter days. Tegaderm\xa0CHG is estimated to be cost neutral when the baseline catheter‑related bloodstream infection rate is 0.18 per 1,000\xa0catheter days, and cost incurring when the baseline rate falls below that figure. [2019 – see section\xa05.25]", 'The technology': "# Description of the technology\n\nThe 3M Tegaderm\xa0CHG\xa0IV securement dressing (Tegaderm\xa0CHG) is a sterile transparent semipermeable polyurethane adhesive dressing with an integrated gel pad containing a 2% concentration by weight of chlorhexidine gluconate (CHG).\n\nTegaderm\xa0CHG is used to secure percutaneous devices and to cover and protect central venous and arterial catheter insertion sites. It aims to provide an effective barrier against external contamination. The dressing and the integrated gel pad are transparent to allow observation of the catheter insertion site. The integrated gel pad is designed to reduce skin and catheter colonisation in order to suppress regrowth of microorganisms commonly related to catheter‑related bloodstream infections (CRBSI). The dressing is available in 4\xa0different sizes but the most commonly‑used size, accounting for 85% of sales, measures 8.5\xa0cm×11.5\xa0cm.\n\nTegaderm\xa0CHG was CE‑marked as a class\xa0III device in April 2009 to cover and protect catheter sites and to secure devices to the skin. There was a modification to the dressing design in 2011 to include a breathable film.\n\nThe cost of Tegaderm\xa0CHG stated in the company's submission was £6.21. This cost was based on the list price of the Tegaderm\xa0CHG 1657R (8.5\xa0cm×11.5\xa0cm) dressing; the cost includes VAT. The cost has been updated in the 2019 revision to £6.09 per dressing. [2019 – see section\xa05.25]\n\nThe claimed benefits of Tegaderm\xa0CHG presented by the company are:\n\nA 60% reduction in the incidence of CRBSI in adult critical care patients with intravascular catheters.\n\nReduced risk of mortality due to catheter‑related infections.\n\nReduced incidence of skin and catheter colonisation during treatment with central venous catheters or arterial catheters.\n\nReduced length of stay in critical care or high dependency units.\n\nReduced costs for diagnosis of CRBSI.\n\nReduced material and staff costs for treatment of catheter‑related infection.\n\n# Current management\n\nNICE's guideline on healthcare-associated infections provides guidance on using dressings in adults and children with vascular access devices (central venous catheters or peripherally‑inserted central catheters) in primary and community care settings. The guideline recommends that the skin at the central venous catheter insertion site, and the surrounding skin during dressing changes, should be decontaminated with CHG in 70% alcohol and allowed to air dry. If the company's recommendations prohibit the use of alcohol with their catheters, an aqueous solution of CHG should be considered. The guideline further recommends using a sterile, transparent semipermeable membrane dressing to cover the vascular access device insertion site, and changing the dressing every 7\xa0days or sooner if it is no longer intact or if moisture collects under it. A sterile gauze dressing, covered with a sterile transparent semipermeable dressing, should be considered only if the patient has profuse perspiration, or if the vascular access device insertion site is bleeding or oozing. The guideline states that systemic antimicrobial prophylaxis should not be used routinely to prevent catheter colonisation or CRBSI, either before insertion or during the use of a central venous catheter. It makes no specific recommendations about using CHG‑impregnated dressings, although the full guideline notes that they may be cost effective compared with sterile transparent semipermeable membrane dressings based on limited evidence from 1\xa0study, Crawford et al. (2004).\n\nThe Department of Health commissioned the epic3 guideline on preventing healthcare‑associated infections in NHS hospitals in England. The guideline recommends using a sterile transparent semipermeable dressing to cover the intravascular insertion point as best practice in both adults and children. The guideline recommends, based on high‑quality evidence, a single application of 2% CHG in 70% isopropyl alcohol (or povidone‑iodine alcohol for patients with sensitivity to CHG) to clean the central catheter insertion site during dressing changes, and allowing it to air dry. The guideline also recommends, based largely on randomised controlled trial evidence, that hospitals consider using a CHG‑impregnated sponge dressing in adults with a central venous catheter, as a strategy to reduce CRBSI.\n\nNICE carried out a 2‑year surveillance review of its infection guideline in September 2014 and decided not to update it. It noted that further research is needed to establish the efficacy of CHG dressings applied to CHG‑prepared skin to prevent CRBSI in patients with venous access devices.\n\nCare bundles are a structured way of improving the processes of care and patient outcomes. They consist of a set of simple to implement evidence‑based practices, that when performed collectively and reliably, have been proven to improve patient outcomes. Central venous catheter care is an example of a care bundle produced by the Department of Health in 2010.", 'Clinical evidence': "# Summary of clinical evidence\n\nThe key clinical outcomes for the 3M Tegaderm\xa0CHG\xa0IV securement dressing (Tegaderm\xa0CHG) presented in the decision problem were:\n\ncatheter‑related bloodstream infections (CRBSI)\n\nskin and catheter colonisation\n\nlength of stay in critical care or high dependency unit\n\nmortality caused by catheter‑related infections\n\ndermatitis\n\nlocal site infection\n\nquality of life\n\ndevice‑related adverse events.\n\nThe company identified 5\xa0studies that met their inclusion criteria. There were 3\xa0studies (Maryniak et al. 2009; Olson et al. 2008 and Rupp et al. 2008) that reported nursing satisfaction scores on various aspects of dressing design and performance; these were excluded from the clinical evidence review (see section\xa03.11). An unpublished study by Scoppettuolo et al. (2012) was also excluded because the results from intensive care unit and non‑intensive care unit patients were not reported separately. The company presented the remaining study by Timsit et al. (2012).\n\nThe External Assessment Centre agreed with including Timsit et al. (2012) and excluding the 4 remaining studies identified.\n\nThe External Assessment Centre carried out a further literature search to identify all prospective comparative studies including at least 2 of the 3\xa0dressing types in the scope: Tegaderm\xa0CHG, a semipermeable transparent (standard) dressing and a chlorhexidine gluconate (CHG)‑impregnated dressing. This search returned 1,755\xa0records of which 4 were considered relevant. Of the 4\xa0studies identified, 2\xa0involved Tegaderm. One of the 2\xa0studies involving Tegaderm was presented by the company (Timsit et al. 2012); the other was identified by the company as an ongoing study (Karpanen et al. 2014) with interim results published after the company's submission of evidence. The External Assessment Centre considered the Timsit et al. (2012) study to be relevant to the decision problem despite the fact that both the intervention and control groups were not swabbed with 2% CHG in alcohol as specified in the decision problem. The other 2\xa0studies (Timsit et al. 2009 and Roberts et al. 1998) compared a CHG‑impregnated sponge dressing (Biopatch, Johnson and Johnson) against standard dressings, and were included by the External Assessment Centre to provide an indirect comparison between Tegaderm\xa0CHG and a CHG‑impregnated dressing.\n\nTimsit et al. (2012) reported a large multicentre randomised controlled trial, based in 12\xa0intensive care units in France, involving 1,879\xa0patients and 4,163\xa0intravascular catheters (2,201\xa0arterial and 1,962\xa0central venous catheters). Patients needing intravascular access were randomised to 1 of 3\xa0groups: Tegaderm\xa0CHG (938\xa0patients), standard dressing (Tegaderm transparent film dressing; 476\xa0patients) or highly‑adhesive dressing (Tegaderm HP transparent film dressing; 465\xa0patients). Assessors were blinded to dressing type. Patients had their skin prepared with povidone‑iodine in alcohol or 0.5% chlorhexidine in alcohol. Dressings were replaced after 24\xa0hours and then every 3 to 7\xa0days depending on the centre, or as needed if there was leaking or soiling. The study follow‑up period was 48\xa0hours after discharge from the intensive care unit.\n\nOutcomes were reported on an intention‑to‑treat basis. These were reported for each group, and comparative statistical analyses were done between the Tegaderm\xa0CHG group and the 2\xa0non‑CHG‑dressing groups combined (the standard and highly‑adhesive dressing groups), and between the standard dressing group and the highly‑adhesive dressing group. Results showed that CRBSI rates were significantly lower in the Tegaderm\xa0CHG group, at 0.5\xa0per 1,000\xa0catheter days compared with 1.3 for the highly‑adhesive dressing and standard dressing groups combined (hazard ratio [HR] for CHG compared with non‑CHG dressings 0.402; 95% confidence interval [CI]\xa00.186\xa0to\xa00.868, p=0.02). Catheter and skin colonisation were significantly lower in the Tegaderm\xa0CHG group at 4.3 per 1,000\xa0catheter days compared with 9.6 for the standard dressing group, 12.5 for the highly‑adhesive dressing group, and 10.9 for the 2\xa0non‑CHG dressing groups combined (HR for CHG compared with non‑CHG dressings 0.412; 95%\xa0CI 0.306\xa0to\xa00.556, p<0.0001). Major catheter‑related infections (defined as catheter‑related sepsis with or without CRBSI), were also significantly lower in the Tegaderm\xa0CHG group, at 0.7 per 1,000\xa0catheter days compared with 2.3 for the standard dressing group and 1.9 for the highly‑adhesive dressing group (HR for CHG compared with non‑CHG dressings 0.328; 95%\xa0CI 0.174\xa0to\xa00.619, p=0.0006). Patients with a Tegaderm\xa0CHG dressing had a significantly higher rate of severe contact dermatitis needing removal of the dressing; 1.1% compared with 0.1% for the standard dressing and 0.5% for the highly‑adhesive dressing, p<0.0001. Also, abnormal International Contact Dermatitis Research Group (ICDRG) scores, measured at each dressing change and at catheter removal, were significantly higher for Tegaderm\xa0CHG at 2.3%, compared with 1% for the non‑CHG dressings (0.7% for the standard dressing and 1.4% for the highly‑adhesive dressing, p<0.0001). No systemic adverse events related to any of the dressings were reported. The authors concluded that Tegaderm\xa0CHG was associated with a lower rate of major catheter‑related infections than either of the non‑CHG dressings.\n\nKarpanen et al. (2014) reported interim results, in the form of a poster presentation, of a non‑randomised prospective comparative observational study of 273\xa0intensive care unit patients at University Hospitals Birmingham NHS Foundation Trust. Patients had Tegaderm\xa0CHG or a standard dressing (Tegaderm\xa0IV dressing). Patients in both groups had standard catheter care, including skin preparation with 2% CHG in 70% alcohol. Based on interim results in the 273\xa0patients, there were 10\xa0instances (7.4%) of colonisation of the intradermal section of the central venous catheter in the Tegaderm\xa0CHG group compared with 22 (14.6%) in the standard dressing group (p=0.037). There were 10\xa0instances (7.4%) of tip colonisation of the central venous catheter reported in the Tegaderm\xa0CHG group compared with 20\xa0instances (16.1%) in the standard dressing group (p=0.08). Adverse events were not reported. The authors concluded that adopting Tegaderm\xa0CHG reduced bacterial numbers on the skin and reduced the bacterial load at the central venous catheter insertion site compared with the standard dressing.\n\n## Studies on the comparator technologies\n\nTimsit et al. (2009) reported on a multicentre, 2×2 factorial randomised controlled trial involving 1,636\xa0patients in 7\xa0intensive care units in France. The study had 2\xa0aims: to assess the superiority of a CHG‑impregnated sponge compared with a standard dressing on rates of major catheter‑related infection; and to determine the effect on outcomes of a 3- or 7‑day dressing change. Patients were randomised to 1 of 4\xa0groups by both dressing type (CHG‑impregnated sponge [Biopatch] plus a standard dressing [Tegaderm] or a standard dressing alone) and frequency of dressing change (every 3 or 7\xa0days). In all patients an antiseptic solution of 5% povidone‑iodine in 70% ethanol was applied and all dressings were changed 24\xa0hours after catheter insertion and then every 3 or 7\xa0days. The follow‑up period was 48\xa0hours after discharge from the intensive care unit, and all outcomes were based on intention‑to‑treat analyses.\n\nCRBSI rates were significantly lower in the CHG‑impregnated sponge group at 0.4 per 1,000\xa0catheter days compared with 1.3 for the standard dressing group (HR 0.24; 95%\xa0CI 0.09\xa0to\xa00.65, p=0.005). Catheter and skin colonisation rates were significantly lower in the CHG‑impregnated sponge group, 0.6\xa0per 1,000\xa0catheter days compared with 1.4 for the standard dressing group (HR 0.36; 95%\xa0CI 0.28\xa0to\xa00.46, p<0.001). Major catheter‑related infection rates were significantly lower in the CHG‑impregnated sponge group, 0.6 per 1,000\xa0catheter days compared with 1.4 for the standard dressing group (HR 0.39; 95%\xa0CI 0.16\xa0to\xa00.93, p=0.03). There was no statistically significant difference in these outcomes between the 3- or 7‑day dressing change groups.\n\nThe rate of severe contact dermatitis, needing removal of the dressing, was 0.53% for the CHG‑impregnated sponge group and 0% for the standard dressing group (no statistical analyses reported). Abnormal ICDRG scores, measured at each dressing change and at catheter removal, were significantly higher for the CHG‑impregnated sponge group at 1.49% compared with 1.02% for the standard dressing group, p=0.02. No systemic adverse events related to the dressings were reported. The authors concluded that the CHG‑impregnated sponge dressing was associated with a reduction in the risk of infection, even with low background infection rates, compared with the standard dressing.\n\nRoberts et al. (1998) carried out a single‑centre randomised controlled trial involving 32\xa0patients with 40\xa0catheters in an Australian intensive care unit. Patients were randomised to have a CHG‑impregnated sponge (Biopatch) plus a standard dressing or a standard dressing alone (Opsite\xa0IV\xa03000, Smith and Nephew). Skin was prepared with 0.5% CHG in alcohol and dressings were changed every 3\xa0days. There was 1\xa0CRBSI in the CHG-impregnated sponge group, and none in the standard dressing group (p\xa0value not reported). There were 2\xa0instances of catheter colonisation on the central venous catheter tip, and 4 at the exit site in the CHG‑impregnated sponge group compared with 1\xa0case and 3\xa0cases respectively for the standard dressing group; neither difference was statistically significant. Adverse events were not reported. The authors stated that the data were insufficient to draw conclusions from this study.\n\nThe External Assessment Centre critically appraised the methodology of each study. It judged that the studies by Timsit et al. (2009 and 2012) were the most relevant and best conducted. The study by Roberts et al. (1998) was underpowered to determine the statistical significance of outcomes; provided few details on the methodology used; included no details on how randomisation was achieved; and only provided information on age and gender of the study population at baseline. The poster presentation by Karpanen et al. (2014) contained insufficient detail for the External Assessment Centre to fully appraise its methodology and accurately judge its relevance to the decision problem.\n\nThe External Assessment Centre considered the company's submission to be consistent with the scope. However, it noted that the company's submission did not compare Tegaderm CHG with other CHG‑impregnated dressings because no direct comparative evidence was found in the literature review. The Timsit et al. (2012) study included by the company used internationally‑recognised definitions for catheter colonisation and CRBSI. Mortality caused by catheter‑related infections, local site infection, and quality of life were not addressed in the company's submission. However, given the evidence for a link between CRBSI and mortality, the External Assessment Centre considered it plausible that if Tegaderm\xa0CHG reduced CRBSI, it would have a positive effect on CRBSI‑related mortality in practice. The External Assessment Centre noted that the CRBSI rate of 1.3 per 1,000\xa0catheter days reported in Timsit et al. (2012) was similar to that reported for the NHS in England in the Matching Michigan study of 1.48 per 1,000\xa0catheter days, making its results generalisable to the NHS. However, it also noted that the mortality of 31% for the intensive care units in France in the Timsit studies was substantially higher than the 9.1% mortality reported for adult critical care units in the NHS. This suggests that whereas their demographics were similar, the intensive care units in France probably had more severely ill patients than the UK intensive care units. The skin preparation protocols followed by the intensive care units in France differed from those recommended for the NHS, which were specified in the decision problem.\n\n## Adverse events\n\nThe company searched the Medicines and Healthcare Products Regulatory Agency (MHRA), Food and Drug Administration (FDA) and Manufacturer and User Facility Device Experience (MAUDE) systems to identify surveillance reports relating to Tegaderm\xa0CHG, between 7 January 2000 and 29 July 2013. This revealed 1\xa0result from the MHRA and 109\xa0results from MAUDE. The company also searched its post‑marketing surveillance data for reported skin reactions. This identified a marked reduction in reports, both in numbers and relative to increasing sales, after a modification to the dressing design in 2011 to incorporate a breathable film.\n\nThe External Assessment Centre found that the company's search of the MAUDE and MHRA systems accurately reported, in detail, the adverse events for Tegaderm\xa0CHG. Overall, it considered the company's search for adverse events to be robust.\n\nThe External Assessment Centre extended the company's search to 28 November 2014 and identified a further 17\xa0results. These results generally described local skin reactions within 48\xa0hours of dressing application, and many were self‑limiting. There were 2\xa0deaths reported in MAUDE, but these were not directly linked to Tegaderm\xa0CHG.\n\nThe company also did a search of the MHRA and MAUDE systems to identify post‑marketing surveillance reports for the Biopatch (CHG‑impregnated sponge) and Opsite\xa0IV\xa03000 (standard) dressings, but it did not report the search terms and dates used. The External Assessment Centre did its own searches of these systems between 1 January 2012 and 30 November 2014. These searches identified 73\xa0records for Biopatch, which were similar in nature to the 29\xa0records for Tegaderm\xa0CHG over the same period. However, the External Assessment Centre emphasised that these figures allow no comparison of event rates because no data were available on the numbers of dressings used over this period. One record reported a death; however this was not directly linked to Biopatch. Only 1\xa0minor, self‑correcting adverse reaction was found for the Opsite\xa0IV\xa03000 dressing over this period.\n\n## Committee considerations\n\nThe Committee considered that the evidence showed that Tegaderm\xa0CHG was effective in reducing CRBSI compared with standard semipermeable transparent dressings. It considered that the Tegaderm\xa0CHG and CHG‑impregnated sponge dressings were clinically equivalent in terms of reducing CRBSI. However, it noted that Tegaderm\xa0CHG offers the additional benefit of being able to see the catheter insertion site. The Committee was advised by clinical experts that being able to see the catheter insertion site allows the care bundle checks that are needed to minimise infection rates. It was also advised that nurses find Tegaderm\xa0CHG easier to apply than CHG‑impregnated sponge dressings.\n\nThe Committee noted that the study evidence was largely from intensive care units in France that followed different skin preparation guidelines and that may have had more severely ill patients than those generally found in the UK. The Committee considered that this evidence was nevertheless generalisable to the UK, based on advice from experts and the External Assessment Centre and on the knowledge of its members.\n\nThe Committee heard from clinical experts that different definitions and measurement methods are used to diagnose CRBSI, making comparison of infection rates difficult. It was advised that a diagnosis of CRBSI should involve tests to confirm that the catheter was the source of the bloodstream infection (typically culture of the catheter tip). It discussed using less rigorous definitions; specifically central line associated bloodstream infection (CLABSI), which is used in hospitals where cultures of the tip, or peripheral blood, are not systematically done. The Committee was advised that using CLABSI risked overestimating the rate of CRBSI and therefore overestimating any potential cost savings from using Tegaderm CHG.\n\nThe Committee was advised by clinical experts that introducing care bundles into intensive care units had significantly reduced rates of CRBSI, but that it is not possible to identify which specific components of a care bundle have led to the reductions in infection rates. It was advised that Tegaderm\xa0CHG could be used with existing care bundles as an additional method for minimising rates of CRBSI, but it would not replace the need to use care bundles. The Committee noted that in some hospitals existing infection control procedures may have reduced baseline CRBSI rates to such low levels that they may not be able to realise the benefits of introducing Tegaderm\xa0CHG (see section\xa05.19).", 'NHS considerations': "# System impact\n\nThe company proposed that using the 3M Tegaderm\xa0CHG\xa0IV securement dressing (Tegaderm\xa0CHG) would not result in changes to the current care pathway or need additional resources. The External Assessment Centre agreed with these assumptions.\n\nUsing Tegaderm\xa0CHG instead of a standard dressing does not need any special additional training. At the topic selection phase, the Committee received expert advice that confirmed that minimal additional training would be needed.\n\nThe company provided Hospital Episodes Statistics data showing that there were 237,710\xa0adult critical care episodes, 92,710 of which involved stays of over 48\xa0hours, in 2012/13. Based on expert opinion the company estimated that 95% of these patients would need a central venous and/or arterial catheter, providing an estimate of the population for Tegaderm\xa0CHG each year of between 88,074 and 225,824. The company estimated that Tegaderm\xa0CHG currently accounts for 15% of the dressings used in the population described in the scope. Were the use of Tegaderm\xa0CHG to become standard practice, it was assumed that this figure would rise to 80%.\n\n## Qualitative evidence on ease of use and performance\n\nThe company provided supplementary information from 3\xa0randomised controlled trials (Maryniak et al. 2009; Olson et al. 2008 and Rupp et al. 2008) on the performance of Tegaderm\xa0CHG compared with a standard dressing (either Tegaderm\xa0IV or Opsite\xa0IV\xa03000, Smith and Nephew). These studies were not included in the company's main submission because they were not limited to critically ill patients and used non‑validated methods in their nurse‑reported dressing satisfaction and performance outcome measures.\n\nThe External Assessment Centre agreed with the company's decision to exclude these studies from the clinical evidence. The External Assessment Centre collated information on the ease of use and performance of Tegaderm\xa0CHG using advice from experts, evidence from the company and from its own searches.\n\nMaryniak et al. (2009) reported a prospective observational study involving 217\xa0inpatients and outpatients (107\xa0patients had Tegaderm\xa0CHG and 110\xa0patients had an unspecified standard dressing). Olson et al. (2008) carried out a randomised controlled trial with 63\xa0hospitalised patients (33\xa0patients had Tegaderm\xa0CHG and 30\xa0patients had a standard dressing – Tegaderm IV), some of whom were in intensive care units. Rupp et al. (2008) completed a randomised controlled trial with 60\xa0hospitalised patients (30\xa0patients had Tegaderm\xa0CHG and 30\xa0patients had a standard dressing – Opsite\xa0IV\xa03000). All studies were done in the USA, none of them specifically considered critically ill patients and satisfaction with the dressings was judged by the clinical staff. The results showed that the nurses were significantly more satisfied with Tegaderm\xa0CHG than with standard dressings in all 3\xa0studies (p<0.05). Tegaderm\xa0CHG was reported to provide a more satisfactory dressing securement, was easier to apply and had improved adherence. There were mixed results, and largely insignificant differences, in terms of nurse satisfaction with ease of correct application, transparency (site visibility), ease of dressing removal, and reported patient discomfort levels during dressing wear.\n\nThe External Assessment Centre identified a number of studies comparing the ease of use of Tegaderm\xa0CHG against a chlorhexidine gluconate (CHG)‑impregnated sponge. Eyberg et al. (2008) reported a randomised controlled trial comparing Tegaderm\xa0CHG against a CHG‑impregnated sponge (Biopatch) in which 12\xa0clinicians were randomly allocated to apply and remove 1\xa0of the dressings on the left or right side of the neck in 12\xa0healthy volunteers. Outcome measures included overall performance, ease of correct application, ease of removal, ability to see the intravenous site, ease of training and intuitive application. Clinicians found that Tegaderm\xa0CHG was significantly better than the CHG‑impregnated sponge across all outcome measures (p<0.05). There were 2\xa0poster presentations (Zehrer et al. 2009; Deschneau et al. 2008) that reported on questionnaires completed by nurses after using the dressings. In both studies Tegaderm\xa0CHG performed significantly better overall than the CHG‑impregnated sponge.\n\nAdvice provided during evaluation from 3\xa0experts with experience of using both Tegaderm\xa0CHG and standard dressings was that, in general, clinician experience of applying and removing Tegaderm\xa0CHG was similar to standard dressings. There was 1\xa0expert who stated that it takes longer to remove Tegaderm\xa0CHG and that there may be a few incorrect applications at first. The remaining 2\xa0experts stated that the time taken to apply or remove the dressing is the same or similar for both Tegaderm\xa0CHG and standard dressings.\n\nThere were 2\xa0experts who had experience of using both Tegaderm\xa0CHG and CHG‑impregnated sponge dressings. They reported minimal differences between the ease of use of the 2\xa0types of dressings. One expert suggested that applying and removing Tegaderm\xa0CHG is quicker than for the CHG‑impregnated sponge. The other reported that some nurses had placed the CHG‑impregnated sponge upside down and therefore had to use a replacement.\n\n## Committee considerations\n\nBased on evidence from the company, the External Assessment Centre and expert advice, the Committee was satisfied that Tegaderm\xa0CHG would not involve significant changes to current care pathways and the use of existing care bundles.\n\nThe Committee was advised by clinical experts that care bundles are of great importance in minimising infection rates. It was advised that care bundles include many components and that it is difficult to identify any specific components that are driving the improvement in infection rates. The Committee concluded that Tegaderm\xa0CHG could contribute to preventing catheter-related bloodstream infections (CRBSI) but it would not replace the need for existing infection control practices.\n\nThe Committee was advised by specialists that being able to see the catheter insertion site is useful, allowing early recognition of any dermatitis or infection. Redness at the catheter insertion site can be an early sign of infection, which may be considered with other clinical signs to raise suspicion of CRBSI. The Committee noted that not all CRBSI is associated with visible changes at the insertion site.\n\nThe Committee noted that the cost savings associated with adopting Tegaderm\xa0CHG instead of a standard dressing depend on baseline CRBSI rates (see section\xa05.24). The Committee considered that it was important for intensive care and high dependency units to review their local CRBSI rates when considering whether to adopt Tegaderm\xa0CHG.", 'Cost considerations': "# Cost evidence\n\nThe company did a literature search and identified 5\xa0studies that met their selection criteria. All studies used cost–benefit analyses. Of these, 3\xa0studies were done in the USA (Veenstra et al. 1999; Crawford et al. 2004 and Ye et al. 2011), 1\xa0study was done in the UK (Hockenhull et al. 2008) and 1\xa0study was done in France (Schwebel et al. 2012). In 2 of the studies, the comparison was between an antiseptic‑impregnated catheter and a standard catheter (Veenstra et al. 1999 and Hockenhull et al. 2008). In the remaining 3\xa0studies (Crawford et al. 2004; Schwebel et al. 2012 and Ye et al. 2011), the intervention was a chlorhexidine gluconate (CHG)‑impregnated dressing and the comparator was a standard dressing. None of the included studies involved the 3M Tegaderm\xa0CHG\xa0IV securement dressing (Tegaderm\xa0CHG).\n\nThe External Assessment Centre considered none of the company's identified studies to be relevant because they did not compare Tegaderm\xa0CHG with either of the comparators. It did additional searches and identified 4\xa0economic studies; all used cost–benefit analyses and compared Tegaderm\xa0CHG with a standard dressing (Maunoury et al. 2013, 2014 and Palka‑Santini et al. 2014a, 2014b). All were published as conference abstracts after the company's searches. All the studies were carried out from the perspective of the health service in France, were written by the same authors, and used data from Timsit et al. (2012). Each study used different model structures or reported different results, all involved a non‑homogeneous Markov model, and were concerned with various measures of infection. No statistically significant differences in costs were reported between the dressings. The External Assessment Centre was unable to assess the relevance of these data to the NHS given the limited information provided.\n\n# Economic model\n\nThe company presented a cost analysis comparing Tegaderm\xa0CHG against a standard dressing (Tegaderm\xa0IV\xa01635). The costs of another commonly used, but more expensive, standard dressing (Opsite\xa0IV\xa03000, Smith and Nephew) were also quoted, but not used in the model. The company did not include the CHG‑impregnated sponge dressing in the model because of the lack of direct comparative clinical evidence. The economic model presented by the company was a decision tree with a short time horizon that included the catheterisation period and any additional length of stay associated with catheter‑related bloodstream infections (CRBSI). The model used an NHS perspective. The decision tree simulated intensive care unit patients who had an absolute risk of getting CRBSI, local site infection or dermatitis. Each outcome was a separate health state and the model captured the number of patients in each state and the cost of being in that state (dressings and management costs).\n\nEach time the model was run, Monte Carlo simulation was used to select values at random from the pre‑specified distributions associated with each of the input parameters, apart from the unit cost of the dressings. This approach allowed the effects of the joint uncertainty across the parameters of the model to be considered. The company's base‑case results were probabilistic, based on 1,000\xa0iterations of the model.\n\nThe External Assessment Centre considered that the structure of the model was appropriate, capturing the main differences in reported clinical outcomes and cost differences between Tegaderm\xa0CHG and standard dressings. However, it noted that the model diagram did not include in its end states patients who had no complications, and amended the model diagram to include this state. The company did not report any structural assumptions in the model. However, the External Assessment Centre identified the following:\n\nThere was no difference in outcomes beyond the short time horizon of the study.\n\nThe length of time a patient has a catheter was not influenced by whether or not they had an infection (CRBSI or local).\n\nThe risk of having any of the study outcomes was mutually exclusive and independent.\n\nThe dressings only affected actual outcomes and not suspected outcomes, which would also incur costs of investigation.\n\nInfection rates were assumed to be linear regardless of catheter dwell time.\n\nThere were no practical differences in dressing management between the dressings such as time to apply and remove, wastage and training.\n\nThe External Assessment Centre judged that these simplifying assumptions were unlikely to influence the results of the company's model significantly.\n\nThe company used data from Timsit et al. (2012) to populate the parameters for all the clinical end points in the model. The model's time horizon of 10\xa0days was based on the mean duration of catheterisation for critically ill patients reported in the study by Ye et al. (2012). Patients who had a CRBSI incurred an additional length of stay of 3\xa0days in an intensive care unit and 7\xa0days in a ward, with resource use costs based on figures reported in the Hockenhull et al. (2008) study. Baseline rates or risks for the clinical end points were obtained from a number of sources. The rate for CRBSI (1.48 per 1,000\xa0catheter days) was taken from Bion et al. (2012), based on 2010 final quarter figures from the Matching Michigan study; for local site infection (0.1\xa0per patient) from Ye et al. (2011); and risk for dermatitis (0.0026\xa0per catheter) from Schwebel et al. (2012).\n\nThe costs for the Tegaderm\xa0CHG and the standard dressing (Tegaderm\xa0IV\xa01635) used in the company's model were based on the cost of the most commonly‑used size of dressing, and were £6.21 and £1.34 respectively. These figures were provided by the company.\n\nThe cost for a CRBSI of £9,900 was based on the figure reported in the health technology assessment paper by Hockenhull et al. (2010), inflated to 2012/13 prices. This value was used in NICE's guideline on healthcare-associated infections. The company produced its own cost estimate for CRBSI based on resource use identified through expert advice, which agreed with this £9,900 figure. The cost of dermatitis of £150 used in the company's model was based on the cost of 4\xa0standard dressings, removing the existing catheter, and replacing it with a new catheter. Local site infections were given a cost of £250 based on the US\xa0$400 figure reported in the study by Saint et al. (2000).\n\nThe company's base‑case results reported an average cost of £99.63 per patient for the Tegaderm\xa0CHG dressing compared with £176.89 per patient for the standard dressing. This would give an average saving of £77.26 per patient if Tegaderm\xa0CHG were adopted. The probability of Tegaderm\xa0CHG being cost saving over standard dressings was calculated at 98.5%. The key driver of this cost saving was avoiding CRBSI through using Tegaderm\xa0CHG.\n\nThe company presented univariate deterministic analysis on both the cost of CRBSI and its baseline rate to explore how robust the estimated cost savings of Tegaderm\xa0CHG compared with standard dressings were to changes in these key variables. If a low estimate of CRBSI rate of 0.5 per 1,000\xa0catheter days was used the cost savings with Tegaderm\xa0CHG were £23 per patient; if a high estimate of 5.5 per 1,000\xa0catheter days was used the savings with Tegaderm\xa0CHG increased to £135 per patient. Based on a low estimate of £5,000 for treating a CRBSI and a high estimate of £15,000, Tegaderm\xa0CHG generated cost savings per patient of £36 and £119 respectively.\n\n# Parameter revisions by the External Assessment Centre\n\nThe External Assessment Centre reviewed the parameters and costs used in the company's model. It contacted clinical experts who validated the company's estimated resource use associated with CRBSI.\n\nThe External Assessment Centre revised the company's value for baseline local site infection rate to 0.14 per 1,000\xa0catheter days based on 2013 audited rates for NHS Wales published by the Welsh Healthcare Associated Infection Programme (2014).\n\nThe External Assessment Centre judged it more appropriate to use the probability of 1\xa0case of dermatitis per 476\xa0patients reported in the Timsit et al. (2012) study. The External Assessment Centre revised the relative risk of dermatitis to\xa01, based on commercial‑in‑confidence global event data provided by the company on the reduced rate of dermatitis after design improvements in the breathability of the Tegaderm\xa0CHG dressing.\n\nThe External Assessment Centre calculated a weighted average cost for the dressings, taken from the NHS Supply Chain costs. For Tegaderm\xa0CHG the cost was based on the proportionate sales figures for the 4\xa0dressing sizes and was estimated as £6.26 per dressing. The cost of the standard dressing was based on the proportionate sales figures of 2\xa0commonly‑used standard dressings, Tegaderm\xa0IV and Opsite\xa0IV\xa03000, and was estimated as £1.54 per dressing. The External Assessment Centre estimated the cost of a CHG‑impregnated dressing to be £8.13.\n\nThe External Assessment Centre was advised by experts that it was not usual procedure to remove the catheter if a patient developed dermatitis. It therefore considered that the company's costs of the consequences of dermatitis overestimated the true cost. The External Assessment Centre therefore estimated a lower value, which involved the costs of dressings only, but assumed, as did the company, that patients with dermatitis would need more frequent dressing changes. It assumed the use of 1\xa0additional dressing. Therefore the cost of dermatitis was revised to £6.\n\nThe study by Saint et al. (2000), which provided the cost for local site infection used in the company's model, provided no details on how that cost was generated. The External Assessment Centre therefore sought expert advice to derive its own cost estimate, £100, which was lower than that used in the company's model.\n\nThe External Assessment Centre also sought expert advice on the number of dressings used. This agreed with the company's estimate of 3\xa0dressings over a 10‑day catheterisation period.\n\nThe External Assessment Centre identified 2\xa0main weaknesses in the company's economic analysis. First, there was no rationale for the choice of distributions and coefficients used in the probabilistic sensitivity analysis done by the company. However, the External Assessment Centre noted that this was not needed as part of the submission template. Second, the company did not attempt to make any judgement on the comparative cost effectiveness of Tegaderm\xa0CHG and a CHG‑impregnated sponge dressing. The External Assessment Centre addressed both these concerns in the assessment report.\n\nThe External Assessment Centre re‑ran the company's model with their revisions to the parameter values and distributions. It also ran an additional scenario in which the baseline CRBSI rate for England was substituted with that reported for Scotland in 2013 of 0.3 per 1,000\xa0catheter days. Both deterministic and probabilistic sensitivity analyses were done. The External Assessment Centre's deterministic base‑case results using CRBSI data from England produced an average per patient cost of £77.75 for Tegaderm\xa0CHG and £151.29 for a standard dressing, a cost saving of £73.54. When CRBSI data from Scotland were used, Tegaderm\xa0CHG had an average per patient cost of £30.79 and a standard dressing cost of £34.47; a cost saving of £3.68 per patient. The External Assessment Centre varied the baseline CRBSI rate and identified the threshold at which Tegaderm\xa0CHG was cost neutral as 0.24 per 1,000\xa0catheter days.\n\nThe External Assessment Centre ran both univariate and multivariate probabilistic sensitivity analyses, varying the model parameters using their ranges and distributions. In the probabilistic sensitivity analysis varying all the model parameters, Tegaderm\xa0CHG had a 97.8% probability of being cost saving using the baseline CRBSI rate for England, but this fell to 57.9% when the figure for Scotland was used.\n\nThe External Assessment Centre also presented an exploratory cost analysis of Tegaderm\xa0CHG compared with CHG‑impregnated sponge dressings. There were no comparative data and from the limited evidence available (including similar data on adverse events), the External Assessment Centre concluded that it was plausible to assume that the 2\xa0dressings had similar safety and efficacy. Without hard data on outcomes this exploratory work relied on observational studies and expert opinion. This suggested that resource use was similar between the 2\xa0dressings, with any cost differences relying on acquisition cost. Based on NHS Supply Chain costs for Biopatch and the cheapest standard dressing (Tegaderm\xa0IV) the cost for a CHG‑impregnated sponge dressing was calculated at £8.13, compared with £6.26 for Tegaderm\xa0CHG. No sales data were available through the NHS Supply Chain. Expert opinion indicated that NHS trusts would probably purchase through other sources at a lower price than the NHS Supply Chain listed price. Therefore the External Assessment Centre calculated additional costings using the price provided by 3M for Biopatch, of £5.16 per dressing. This resulted in a total price of £6.49, slightly more expensive than Tegaderm\xa0CHG.\n\n# Committee considerations\n\nThe Committee noted the cost modelling presented by the company and the adjustments made by the External Assessment Centre. It considered that the revisions made by the External Assessment Centre were plausible. The Committee considered that the External Assessment Centre's sensitivity analyses addressed the uncertainties in the economic model. It concluded that the estimated cost savings for Tegaderm\xa0CHG compared with standard semipermeable transparent dressings were likely to be realised in practice, with actual savings dependent on the baseline CRBSI rate.\n\nThe Committee considered that the baseline CRBSI rate was a key driver of the savings in the cost model. It noted that Tegaderm\xa0CHG was cost neutral when the baseline CRBSI rate was 0.24 per 1,000 catheter days and became cost incurring when the baseline rate fell below that figure. The Committee heard expert opinion that CRBSI rates in England have been falling in recent years. It heard from both the External Assessment Centre and the experts that there are differences in the definition and measurement of CRBSI between different countries and different hospitals, which makes comparison of infection rates difficult. The Committee concluded that Tegaderm\xa0CHG is likely to be cost saving in hospitals where the baseline CRBSI rate is above about 0.24 per 1,000\xa0catheter days. It also concluded that Tegaderm\xa0CHG could potentially provide a useful way of reducing infection rates further in those hospitals that have not managed to do this by other means.\n\n# guidance review\n\nFor the guidance review, the External Assessment Centre revised the model to reflect 2019 costs. The main parameter changes were (original guidance values given in brackets):\n\nbaseline incidence rate of CRBSI for Scottish intensive care units: 0.28 per 1000\xa0catheter days (0.3\xa0per 1,000\xa0catheter days)\n\nbaseline incidence rate of local site infection: 0.4 per 1,000\xa0catheter days (0.14 per 1,000\xa0catheter days)\n\nbaseline incidence rate of dermatitis: 0.3 per 1,000\xa0catheter days (0.002 1‑year probability)\n\nthe effectiveness of Tegaderm\xa0CHG for preventing CRBSI: 0.402\xa0hazard ratio (0.45\xa0relative risk)\n\nlength of stay with catheterisation: 13\xa0days (10\xa0days).The cost of Tegaderm\xa0CHG was also updated to reflect the 2% decrease in the cost of the dressing (from £6.21 to £6.09). The External Assessment Centre assumed this reduction was implemented in all sizes of Tegaderm\xa0CHG and estimated an updated weighted average of £6.14 (£6.26), using the sales proportions from the original cost model. Other costs from the original model were adjusted for inflation. Deterministic base‑case results for the 2019 revised model produced an average per patient cost of £106.62 (£77.75) for Tegaderm\xa0CHG and £199.69 (£151.29) for a standard dressing, a cost saving of £93.07 (£73.54) when considering a baseline CRBSI rate of 1.48\xa0per 1,000\xa0catheter days. When CRBSI data from Scotland were used, Tegaderm\xa0CHG had an average per patient cost of £35.80 (£30.79) and a standard dressing cost of £43.30 (£34.47): a cost saving of £7.50 (£3.68) per patient. In the probabilistic sensitivity analysis, Tegaderm\xa0CHG had a 98.9% (97.8%) probability of being cost saving using the baseline CRBSI rate for England, but this fell to 50.3% (57.9%) when the figure for Scotland was used. The External Assessment Centre varied the baseline CRBSI rate and identified the threshold at which Tegaderm\xa0CHG was cost neutral as 0.18 (0.24) per 1,000\xa0catheter days. Further details of the 2019 revised model are in the cost model update report. ", 'Conclusions': "The Committee concluded that the evidence showed that the 3M Tegaderm\xa0CHG\xa0IV securement dressing (Tegaderm\xa0CHG) offers better protection against catheter‑related bloodstream infection (CRBSI) than sterile semipermeable transparent dressings. Based on indirect evidence, the Committee considered that Tegaderm\xa0CHG also offers equivalent protection against CRBSI to chlorhexidine gluconate (CHG)‑impregnated sponge dressings, but has other advantages, specifically being able to see the catheter insertion site.\n\nThe Committee accepted the External Assessment Centre's revised model and sensitivity analysis which estimated costs in relation to the baseline CRBSI rate. It concluded that Tegaderm\xa0CHG could generate cost savings of £73 per patient when the baseline CRBSI rate was 1.48 per 1,000 catheter days, as cited in the Matching Michigan study for intensive care units in England (based on April 2009 to April 2011 data). However, the Committee was aware of advice that baseline CRBSI rates have fallen in recent years and acknowledged the importance of the External Assessment Centre's estimate that Tegaderm\xa0CHG is likely to be cost neutral when the baseline CRBSI rate is 0.24 per 1,000\xa0catheter days, and to incur costs when it falls below that level. It therefore concluded that hospitals should take their baseline CRBSI rate into account when making decisions about whether to adopt Tegaderm\xa0CHG. Andrew DillonChief ExecutiveJuly 2015"}
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https://www.nice.org.uk/guidance/mtg25
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Evidence-based recommendations on The 3M Tegaderm CHG IV securement dressing for central venous and arterial catheter insertion sites.
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7dadfdb21e0a51a2b5e077b17f986e3af3f0321c
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nice
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Pneumonia (community-acquired): antimicrobial prescribing
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Pneumonia (community-acquired): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for community-acquired pneumonia. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing community-acquired pneumonia
## Treatment for adults, young people and children
Offer an antibiotic(s) for adults, young people and children with community-acquired pneumonia. When choosing an antibiotic (see the recommendations on choice of antibiotic), take account of:
the severity assessment for adults, as set out in table 1
the severity of symptoms or signs for children and young people, based on clinical judgement
the risk of developing complications, for example, if the person has relevant comorbidity such as severe lung disease or immunosuppression
local antimicrobial resistance and surveillance data (such as flu and Mycoplasma pneumoniae infection rates)
recent antibiotic use
recent microbiological results, including colonisation with multidrug-resistant bacteria.At the time of publication (September 2019), no validated severity assessment tools are available for children and young people with community-acquired pneumonia, and severity of symptoms or signs should be based on clinical judgement.
Start antibiotic treatment as soon as possible after establishing a diagnosis of community-acquired pneumonia, and certainly within 4 hours (within 1 hour if the person has suspected sepsis and meets any of the high risk criteria for this – see the NICE guideline on sepsis).
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
If intravenous antibiotics are given, review by 48 hours and consider switching to oral antibiotics if possible.
This recommendation has been removed.
For children and young people in hospital with community-acquired pneumonia, and severe symptoms or signs or a comorbidity, consider sending a sample (for example, sputum sample) for microbiological testing.
## Advice
Give advice to adults, young people and children with community-acquired pneumonia about:
possible adverse effects of the antibiotic(s)
how long symptoms are likely to last
seeking medical help (if the person is receiving treatment in the community) if:
symptoms worsen rapidly or significantly or
symptoms do not start to improve within 3 days or
the person becomes systemically very unwell.
## Reassessment
Reassess adults, young people and children with community-acquired pneumonia if symptoms or signs do not improve as expected or worsen rapidly or significantly.
When reassessing adults, young people and children with community-acquired pneumonia, be aware of possible non-bacterial causes, such as flu.
If a sample has been sent for microbiological testing:
review the choice of antibiotic(s) when results are available and
consider changing the antibiotic(s) according to results, using a narrower-spectrum antibiotic, if appropriate.
Send a sample (for example, a sputum sample) for microbiological testing if symptoms or signs have not improved following antibiotic treatment, and this has not been done already.
## Referral and seeking specialist advice
Refer adults with community-acquired pneumonia to hospital if they have:
any symptoms or signs suggesting a more serious illness or condition (for example, cardiorespiratory failure or sepsis) or
symptoms that are not improving as expected with antibiotics.
Consider referring adults with community-acquired pneumonia to hospital, or seek specialist advice, if they:
have bacteria that are resistant to oral antibiotics or
cannot take oral medicines (exploring locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, if this is appropriate).
Consider referring children and young people with community-acquired pneumonia to hospital, or seek specialist paediatric advice on further investigation and management.
See the evidence and committee discussion on antibiotic prescribing strategies and choice of antibiotics.
# Choice of antibiotic
When prescribing an antibiotic(s) for community-acquired pneumonia:
follow table 1 for adults aged 18 years and over
follow table 2 for children and young people under 18 years.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotic if low severity (based on clinical judgement and guided by a CRB65 score 0 or a CURB65 score 0 or 1 when these scores can be calculated)
Amoxicillin:
mg three times a day (higher doses can be used; see the BNF) for 5 days
Alternative oral antibiotics if low severity, for penicillin allergy or if amoxicillin unsuitable (for example, if atypical pathogens suspected)
Doxycycline:
mg on first day, then 100 mg once a day for 4 days (5‑day course in total)
Clarithromycin:
mg twice a day for 5 days
Erythromycin (in pregnancy):
mg four times a day for 5 days
First-choice oral antibiotics if moderate severity (based on clinical judgement and guided by a CRB65 score 1 or 2, or a CURB65 score 2 when these scores can be calculated; guided by microbiological results when available)
Amoxicillin:
mg three times a day (higher doses can be used; see the BNF) for 5 days
With (if atypical pathogens suspected)
Clarithromycin:
mg twice a day for 5 days
Or
Erythromycin (in pregnancy):
mg four times a day for 5 days
Alternative oral antibiotics if moderate severity, for penicillin allergy (guided by microbiological results when available)
Doxycycline:
mg on first day, then 100 mg once a day for 4 days (5‑day course in total)
Clarithromycin:
mg twice a day for 5 days
First-choice antibiotics if high severity (based on clinical judgement and guided by a CRB65 score 3 or 4, or a CURB65 score 3 to 5 when these scores can be calculated; guided by microbiological results when available)
Co‑amoxiclav:
/125 mg three times a day orally or 1.2 g three times a day intravenously for 5 days
With
Clarithromycin:
mg twice a day orally or intravenously for 5 days
Or
Erythromycin (in pregnancy):
mg four times a day orally for 5 days
Alternative antibiotic if high severity, for penicillin allergy (guided by microbiological results when available; consult a local microbiologist if fluoroquinolone not appropriate)
Levofloxacin (consider safety issues):
mg twice a day orally or intravenously for 5 days
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics if possible.
Stop antibiotic treatment after 5 days unless microbiological results suggest a longer course is needed or the person is not clinically stable, for example, if they have had a fever in the past 48 hours or have more than 1 sign of clinical instability (systolic blood pressure less than 90 mmHg, heart rate more than 100/minute, respiratory rate more than 24/minute, arterial oxygen saturation less than 90% or partial pressure of oxygen of more than 60 mmHg in room air).
For fluoroquinolone antibiotics, see Medicines and Healthcare products Regulatory Agency (MHRA) advice for restrictions and precautions because of very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution for people over 60 years and avoiding coadministration with a corticosteroid (March 2019).
Consider adding a macrolide to amoxicillin if atypical pathogens are suspected, and review when microbiological results are available. Mycoplasma pneumoniae infection occurs in outbreaks approximately every 4 years.
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
CRB65: confusion, respiratory rate 30/minute or more, blood pressure (systolic less than 90 mmHg or diastolic 60 mmHg or less), age 65 or more
CURB65: confusion, urea more than 7 mmol/litre, respiratory rate 30/minute or more, blood pressure (systolic less than 90 mmHg or diastolic 60 mmHg or less), age 65 or more
Treatment
Antibiotic, dosage and course length
Children under 1 month
Refer to paediatric specialist
First-choice oral antibiotic for children 1 month and over if non-severe symptoms or signs (based on clinical judgement)
Amoxicillin:
month to 11 months, 125 mg three times a day for 5 days
year to 4 years, 250 mg three times a day for 5 days
years to 17 years, 500 mg three times a day for 5 days (higher doses can be used for all ages; see BNF for children)
Alternative oral antibiotics if non-severe symptoms or signs (based on clinical judgement), for penicillin allergy or if amoxicillin unsuitable (for example, atypical pathogens suspected)
Clarithromycin:
month to 11 years:
Under 8 kg, 7.5 mg/kg twice a day for 5 days
kg to 11 kg, 62.5 mg twice a day for 5 days
kg to 19 kg, 125 mg twice a day for 5 days
kg to 29 kg, 187.5 mg twice a day for 5 days
kg to 40 kg, 250 mg twice a day for 5 days
years to 17 years:
mg to 500 mg twice a day for 5 days
Erythromycin (in pregnancy):
years to 17 years, 250 mg to 500 mg four times a day for 5 days
Doxycycline:
years to 17 years, 200 mg on first day, then 100 mg once a day for 4 days (5‑day course in total)
(see BNF for children for use of doxycycline in children under 12)
First-choice antibiotic(s) if
severe symptoms
or signs (based on clinical judgement; guided by microbiological results when available)
Co‑amoxiclav:
Oral doses:
month to 11 months, 0.5 ml/kg of 125/31 suspension three times a day for 5 days
years to 5 years, 10 ml of 125/31 suspension three times a day or 0.5 ml/kg of 125/31 suspension three times a day for 5 days (or 5 ml of 250/62 suspension)
years to 11 years, 10 ml of 250/62 suspension three times a day or 0.3 ml/kg of 250/62 suspension three times a day for 5 days
years to 17 years, 500/125 mg three times a day for 5 days
Intravenous doses:
month to 2 months, 30 mg/kg twice a day
months to 17 years, 30 mg/kg three times a day (maximum 1.2 g per dose three times a day)
With (if atypical pathogen suspected)
Clarithromycin:
Oral doses:
month to 11 years:
Under 8 kg, 7.5 mg/kg twice a day for 5 days
kg to 11 kg, 62.5 mg twice a day for 5 days
kg to 19 kg, 125 mg twice a day for 5 days
kg to 29 kg, 187.5 mg twice a day for 5 days
kg to 40 kg, 250 mg twice a day for 5 days
years to 17 years:
mg to 500 mg twice a day for 5 days
Intravenous doses:
month to 11 years, 7.5 mg/kg twice a day (maximum 500 mg per dose)
years to 17 years, 500 mg twice a day
Or
Erythromycin (in pregnancy):
years to 17 years, 250 mg to 500 mg four times a day orally for 5 days
Alternative antibiotics if
severe symptoms or signs(based on clinical judgement), for penicillin allergy (guided by microbiological results when available)
Consult local microbiologist
See the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics if possible.
Stop antibiotic treatment after 5 days unless microbiological results suggest a longer course is needed or the person is not clinically stable (fever in past 48 hours or more than 1 sign of clinical instability ).
Mycoplasma pneumoniae infection occurs in outbreaks approximately every 4 years and is more common in school-aged children.
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
See the committee discussions on choice of antibiotics and antibiotic course length.
# Terms used in the guideline
## Severe community-acquired pneumonia in children and young people
Features of severe community-acquired pneumonia in children and young people include difficulty breathing, oxygen saturation less than 90%, raised heart rate, grunting, very severe chest indrawing, inability to breastfeed or drink, lethargy and a reduced level of consciousness.
## CRB65
CRB65 is used in primary care to assess 30‑day mortality risk in adults with pneumonia. The score is calculated by giving 1 point for each of the following prognostic features: confusion, respiratory rate 30/minute or more, low systolic or diastolic blood pressure, age 65 or more). Risk of death is stratified as follows:
: low risk (less than 1% mortality risk)
-r 2: intermediate risk (1% to 10% mortality risk)
-r 4: high risk (more than 10% mortality risk).
## CURB65
CURB65 is used in hospital to assess 30‑day mortality risk in adults with pneumonia. The score is calculated by giving 1 point for each of the following prognostic features: (confusion, urea more than 7 mmol/litre, respiratory rate 30/minute or more, low systolic or diastolic blood pressure, age 65 or more). Risk of death is stratified as follows:
-r 1: low risk (less than 3% mortality risk)
: intermediate risk (3% to 15% mortality risk)
to 5: high risk (more than 15% mortality risk).
Adults with score of 1 and particularly 2 are at increased risk of death (should be considered for hospital referral) and people with a score of 3 or more are at high risk of death (require urgent hospital admission).# Summary of the evidence
This is a summary of the evidence. For full details, see the evidence review.
Community‑acquired pneumonia is a lower respiratory tract infection that is most commonly caused by bacterial infection (British Thoracic Society guideline on community-acquired pneumonia in adults, 2009).
The main bacterial pathogen is Streptococcus pneumoniae (NICE clinical knowledge summaries on chest infections in adults, 2015), however Mycoplasma pneumoniae occurs in outbreaks approximately every 4 years in the UK and is much more common in school-aged children (BTS 2009).
Although bacterial infection is the most common cause of community-acquired pneumonia, viral infection causes approximately 13% of cases in adults (BTS 2009) and approximately 66% of cases in children and young people (Jain et al. 2015).
Low-severity, community-acquired pneumonia in adults includes people with pneumonia severity index (PSI) score of I or II, CRB65 score 0 or CURB65 score 0 or 1. Moderate- to high-severity, community-acquired pneumonia in adults includes people with PSI score of III to V, CRB65 score 1 to 4 or CURB65 score 2 to 5.
The severity of infection was not always clearly defined in the studies, and was often based on clinical judgement. The management setting (community or hospital) was used to indicate the severity of symptoms when this was not described in the studies (through either severity assessment scores or clinical judgement).
# Antibiotic prescribing strategies
In adults with moderate‑ to high-severity community-acquired pneumonia, an antibiotic prescribing strategy guided by results of pneumococcal and Legionella pneumophila urine antigen tests was not significantly different from a strategy that used broad-spectrum antibiotics without antigen testing for the outcomes of mortality, clinical relapse and hospital admissions (1 randomised controlled trial , Falguera et al. 2009).
In adults with mixed severity community-acquired pneumonia, a strategy of stopping antibiotics based on guidelines was not different to physician-guided stopping for a range of outcomes, including mortality, symptoms, recurrence, length of hospital stay and adverse events. Stopping antibiotics based on guidelines was associated with a longer total antibiotic course length (including intravenous and oral antibiotics) but with a shorter time taking intravenous antibiotics (2 RCTs, Uranga et al. 2016 and Aliberti et al. 2017).
In children aged 1 month to 5 years with severe community-acquired pneumonia, a strategy of intravenous antibiotics then switching to oral antibiotics (based on a specified drop in body temperature and stable clinical signs) reduced hospital stay by about 1 day, compared with standard care (intravenous then switching to oral antibiotics at least 48 hours after dissipation of fever). There was no difference in readmissions (1 non-inferiority RCT, In-iw et al. 2015).
Committee discussions on antibiotic prescribing strategies
The committee discussed that the study designs were not appropriate for determining which antibiotic prescribing strategies were most effective, because the antibiotics used in the studies on prescribing strategies had very broad antibacterial cover.
The committee discussed that although community-acquired pneumonia can be caused by a viral infection, it is difficult to distinguish this from a bacterial infection. Based on the high mortality rate, the committee agreed that all people with community-acquired pneumonia should be offered an antibiotic.
The committee was aware that the NICE guideline on pneumonia in adults (2014) recommended antibiotic treatment as soon as possible, and within 4 hours for people admitted to hospital with community-acquired pneumonia. The committee agreed that this was also applicable to people receiving treatment in the community. The committee also agreed that people with suspected sepsis and high risk criteria (as described in the NICE guideline on sepsis) would need more urgent treatment.
Because there were no major differences between stopping antibiotics based on guidelines and stopping antibiotics based on clinical judgement, the committee agreed that clinical judgement should be used when deciding when to stop antibiotic treatment. This should usually be after 5 days.
The committee agreed that the criteria (fever in the past 48 hours, blood pressure, heart rate, respiratory rate and oxygen saturations) used in the study by Uranga et al. (2016) should be considered during decision making (see the committee discussion on antibiotic course length).
The committee discussed the evidence in children suggesting a reduced length of hospital stay with switching from intravenous to oral antibiotics when clinical signs were stable compared with switching following 48 hours of dissipation of fever. However, because other important clinical outcomes were not reported (such as mortality or cure), and no evidence was available in adults for this prescribing strategy, the committee agreed that if applicable, the decision for switching from intravenous to oral antibiotics in adults, young people and children should be based on clinical judgement (see the evidence summary and committee discussion section on route of administration).
In children and young people with severe symptoms or signs, the committee agreed that a broad-spectrum antibiotic would be needed initially to cover the range of possible pathogens, including the addition of a macrolide if atypical pneumonia was suspected (see the committee discussion on choice of antibiotics).
The committee was concerned about the risk of antimicrobial resistance from using broad-spectrum antibiotics for longer than necessary. Therefore, the committee agreed that in children and young people in hospital, with severe symptoms or signs or a comorbidity (who were more likely to be on broad-spectrum antibiotics), sending a sample for microbiological testing should be considered. They recognised that obtaining a sample for testing is not always possible, especially in young children.
The committee agreed that when microbiological results are available, the antibiotic should be reviewed and changed accordingly (for example, if bacteria are found to be resistant or atypical pathogens are not isolated) if symptoms are not already improving, using a narrower-spectrum antibiotic if appropriate.
The committee agreed that first-line antibiotics would be effective in most children and young people with non‑severe symptoms or signs, and therefore microbiological testing would not be needed routinely to guide antibiotic choice.
# Choice of antibiotics
## Efficacy of antibiotics
Low-severity community-acquired pneumonia in adults
There were no differences in the clinical effectiveness of the following antibiotic comparisons (course length varied but usually ranged from 7 to 14 days) in adults with low-severity community-acquired pneumonia:
clarithromycin compared with amoxicillin (Pakhale et al. 2014)
clarithromycin compared with erythromycin (Pakhale et al. 2014)
azithromycin compared with clarithromycin (Pakhale et al. 2014)
azithromycin compared with co‑amoxiclav (Paris et al. 2008)
azithromycin compared with levofloxacin (Pakhale et al. 2014)
a cephalosporin (cefuroxime or cefditoren) compared with co‑amoxiclav (Maimon et al. 2008)
levofloxacin compared with ceftriaxone plus azithromycin (Raz-Pasteur et al. 2015).
Some differences were seen for some efficacy outcomes for other antibiotic comparisons in adults with low-severity community-acquired pneumonia.
Amoxicillin improved clinical cure rates (in intention-to-treat analysis only) and complete resolution at 30 days, compared with phenoxymethylpenicillin (Llor et al. 2017).
Cefixime significantly reduced respiratory rate, radiological consolidations and bacterial isolates compared with ciprofloxacin, but there was no significant differences in temperature reduction or pulse rate (Ige et al. 2015).
Evidence for efficacy of antibiotics for low-severity community-acquired pneumonia in adults is based on 3 systematic reviews (Pakhale et al. 2014, Maimon et al. 2008 and Raz-Pasteur et al. 2015), 1 RCT (Ige et al. 2015) and 2 non‑inferiority RCTs (Llor et al. 2017 and Paris et al. 2008).
Moderate- to high-severity community-acquired pneumonia in adults
There were no differences in the clinical effectiveness of the following antibiotic comparisons (course length varied but usually ranged from 7 to 14 days) in adults with moderate‑ to high-severity community-acquired pneumonia:
a macrolide compared with antibiotics targeted at non-atypical pathogens (penicillins, beta-lactam plus beta-lactamase inhibitors, cephalosporins and carbapenems; Eliakim-Raz et al. 2012)
a fluoroquinolone compared with antibiotics targeted at non-atypical pathogens (penicillins, beta-lactam plus beta-lactamase inhibitors and cephalosporins; Eliakim-Raz et al. 2012)
levofloxacin compared with tigecycline (Nemeth et al. 2015)
levofloxacin compared with doxycycline (Nemeth et al. 2015)
-floxacin compared with erythromycin (Skalsky et al. 2013)
moxifloxacin compared with levofloxacin (Yuan et al. 2012)
ertapenem compared with ceftriaxone (Bai et al. 2014)
a macrolide compared with a beta-lactam antibiotic plus macrolide (Raz-Pasteur et al. 2015)
a fluoroquinolone compared with a beta-lactam antibiotic plus fluoroquinolone (Raz-Pasteur et al. 2015)
ceftriaxone plus azithromycin compared with ceftriaxone plus a macrolide (clarithromycin or erythromycin; Tamm et al. 2007)
ceftobiprole compared with ceftriaxone plus linezolid (in suspected methicillin-resistant Staphylococcus aureus infection (Nicholson et al. 2012).
For other antibiotic comparisons in adults with moderate‑ or high-severity community-acquired pneumonia, some differences were seen in some efficacy outcomes:
Antibiotics targeted at atypical pathogens (macrolides and fluoroquinolones) compared with antibiotics targeted at non-atypical pathogens (penicillins, beta‑lactam plus beta-lactamase inhibitors, cephalosporins and carbapenems): overall there were no significant differences in mortality or clinical failure, but there was significantly less bacteriological failure with antibiotics targeted at atypical pathogens. Some minor differences were seen in subgroup analyses, including significantly lower clinical failure with antibiotics targeted at atypical pathogens in adults with Legionella pneumophila infection (Eliakim-Raz et al. 2012).
Ceftriaxone compared with ceftaroline fosamil: there was no significant difference in mortality, but clinical cure was significantly increased with ceftriaxone (El Hajj et al. 2017).
A fluoroquinolone (levofloxacin or moxifloxacin) compared with a beta-lactam antibiotic plus macrolide: there were no significant differences in mortality or microbiological failure, but clinical failure was significantly reduced with a fluoroquinolone (result not significant in adults with pneumococcal pneumonia; Raz-Pasteur et al. 2015).
A beta-lactam antibiotic (co‑amoxiclav or cefuroxime) plus upfront clarithromycin (upfront dual therapy) compared with a beta-lactam antibiotic (co‑amoxiclav or cefuroxime) plus clarithromycin only when a positive Legionella pneumophila urine sample was confirmed (test-dependant dual therapy): there was no significant difference in mortality or clinical stability; in people with an atypical (but not non-atypical) infection, upfront dual therapy was significantly better for achieving clinical stability compared with test-dependant dual therapy; there were no significant differences in admission to intensive care, incidence of complicated pleural effusion, length of hospital stay or long-term readmission rates.
Evidence for efficacy of antibiotics for moderate-to high‑severity community-acquired pneumonia in adults is based on 7 systematic reviews (Eliakim-Raz et al. 2012, Nemeth et al. 2015, Skalsky et al. 2013, El Hajj et al. 2017, Yuan et al. 2012, Bai et al. 2014 and Raz-Pasteur et al. 2015) and 3 non-inferiority RCTs (Garin et al. 2014, Nicholson et al. 2012 and Tamm et al. 2007).
Non-severe community-acquired pneumonia in children and young people
Evidence (1 systematic review, Lodha et al. 2013) was identified on the following antibiotic comparisons (course length varied but usually ranged from 4 to 10 days) for treatment of non-severe community-acquired pneumonia, for which no significant differences were found for the efficacy outcomes reported:
azithromycin compared with erythromycin
azithromycin compared with co‑amoxiclav
clarithromycin compared with erythromycin
co-trimoxazole compared with amoxicillin
cefpodoxime compared with co‑amoxiclav
For other antibiotic comparisons in children and young people with non-severe community-acquired pneumonia, some differences were seen in the following efficacy outcomes:
Co-amoxiclav was significantly better than amoxicillin for improving cure rate (94% versus 60%) and improving poor or no response rate (2% versus 20%) in children aged 2 to 12 years.
Amoxicillin was significantly better than chloramphenicol for improving cure rate in children aged 2 to 59 months.
Severe community-acquired pneumonia in children and young people
Evidence (Lodha et al. 2013 unless otherwise stated) was identified on the following antibiotic comparisons for treatment (course length varied but usually ranged from 3 to 10 days) of severe or very severe community-acquired pneumonia in children and young people, for which no significant differences were found for the outcomes reported:
amoxicillin compared with an unspecified penicillin
amoxicillin compared with ampicillin
amoxicillin compared with cefuroxime
amoxicillin compared with clarithromycin
levofloxacin compared with beta‑lactam antibiotics (co‑amoxiclav or ceftriaxone)
cefuroxime compared with clarithromycin
co-trimoxazole compared with chloramphenicol
ceftaroline fosamil compared with ceftriaxone (Cannavino et al. 2016).
benzylpenicillin plus gentamicin compared with co‑amoxiclav
an unspecified penicillin plus chloramphenicol compared with ampicillin
benzylpenicillin plus chloramphenicol compared with chloramphenicol
an unspecified penicillin plus gentamicin compared with chloramphenicol
chloramphenicol plus an unspecified penicillin compared with ceftriaxone
ceftriaxone plus vancomycin compared with ceftaroline fosamil (Blumer et al. 2016).
For other antibiotic comparisons in children and young people with severe community-acquired pneumonia, some differences were seen in the following efficacy outcomes:
Ampicillin plus gentamicin was significantly better than chloramphenicol in children with very severe pneumonia, aged 2 to 59 months for clinical failure at all time points, but there was no significant difference in mortality. Significantly fewer children given ampicillin plus gentamicin needed to change antibiotics before day 21.
A penicillin (unspecified) plus gentamicin was not significantly different to chloramphenicol for mortality in children with severe community-acquired pneumonia, aged 1 to 59 months, but readmissions were significantly lower with a penicillin plus gentamicin.
Evidence for efficacy of antibiotics for severe community-acquired pneumonia in children and young people is based on 1 systematic review (Lodha et al. 2013) and 2 RCTs (Cannavino et al. 2016 and Blumer et al. 2016).
## Safety of antibiotics
Antibiotic-associated diarrhoea is estimated to occur in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE CKS on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, August 2019).
Macrolides should be used with caution in people with a predisposition to QT interval prolongation (BNF, August 2019).
Tetracyclines, including doxycycline, can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant or breastfeeding women, and use in children under 12 years is either contraindicated or cautioned for use in severe or life-threatening infections where there are no alternatives (BNF, August 2019).
Fluoroquinolones have restrictions and precautions around their use because of rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems (MHRA Drug Safety Update, March 2019). They may also be associated with a small increased risk of aortic aneurysm and dissection, particularly in older people (MHRA Drug Safety Update, November 2018).
Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, August 2019).
Overall, adverse effects of antibiotics were similar in the studies, although some differences were seen for the following antibiotic comparisons in people with community-acquired pneumonia:
Adverse events were significantly higher with azithromycin compared with levofloxacin (19.9% versus 12.3%) and erythromycin compared with clarithromycin (45.7% versus 21.4%; Pakhale et al. 2014), and abdominal pain was significantly worse with azithromycin compared with co‑amoxiclav (9.6% versus 1.5%; Paris et al. 2008), in adults with low-severity community-acquired pneumonia.
Adverse events, treatment discontinuations and diarrhoea were significantly lower with a fluoroquinolone compared with beta-lactam antibiotic plus a macrolide in adults with moderate- to high-severity community-acquired pneumonia (Raz-Pasteur et al. 2015).
Adverse events were significantly lower with a macrolide compared with a beta-lactam antibiotic plus macrolide in adults with moderate‑ to high-severity community-acquired pneumonia (Raz-Pasteur et al. 2015).
Adverse events were significantly higher with ceftobiprole compared with ceftriaxone plus linezolid in adults with suspected MRSA infection (Nicholson et al. 2012).
Adverse events were significantly lower with azithromycin compared with co‑amoxiclav in children with non-severe community-acquired pneumonia (Lodha et al. 2013).
Significantly more children with severe community-acquired pneumonia had 1 or more adverse events with ceftriaxone plus vancomycin compared with ceftaroline fosamil (Blumer et al. 2016).
See the summaries of product characteristics for information on contraindications, cautions, drug interactions and adverse effects of individual medicines.
Committee discussions on choice of antibiotics
The committee noted that using the care setting as a proxy for the severity of community-acquired pneumonia may not always be appropriate, and that some studies in outpatients may include people with moderate-severity community-acquired pneumonia, or a mixed severity population. They recognised that hospital admission criteria in other countries may differ from UK practice.
The committee discussed the pathogens which cause community-acquired pneumonia and noted that Streptococcus pneumoniae is the most common cause. Based on their experience, the committee noted that atypical pathogens are the causative organism in around 10% to 15% of moderate- to high-severity infections.
Adults with community-acquired pneumonia
The committee discussed the evidence on choice of antibiotics in adults with low-severity community-acquired pneumonia and in adults with moderate- to high-severity community-acquired pneumonia.
The committee was aware that the CRB65 (in primary care) and CURB65 (in hospital) mortality risk scores were recommended in the NICE guideline on pneumonia in adults for assessing the risk of mortality with community-acquired pneumonia. The committee discussed evidence which used the pneumonia severity index to assess severity; however, they agreed that, when they can be calculated, CRB65 and CURB65 scores should be used in conjunction with clinical judgement to assess severity in adults.
Based on limited evidence showing no major differences in clinical effectiveness between antibiotics or classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by their experience of which antibiotics have good activity against likely pathogens and cause the least harm, with as narrow spectrum as possible to minimise the risk of antimicrobial resistance. The committee considered the adverse effects associated with individual antibiotics, for example, increased risk of Clostridium difficile infection, along with the risk of harm from not adequately treating the infection.
Based on their experience, the first-choice antibiotic for adults with low-severity community-acquired pneumonia is amoxicillin (a penicillin), which has good activity against Streptococcus pneumoniae and is associated with fewer adverse effects and relatively low resistance rates. Amoxicillin is routinely used as first-line treatment and the committee agreed that there was no evidence to support changing current practice.
Alternative antibiotics are doxycycline (a tetracycline), clarithromycin (a macrolide) and erythromycin (an alternative macrolide in pregnancy), for people with low-severity community-acquired pneumonia and penicillin allergy, or when amoxicillin may not be appropriate, for example, if an atypical infection is suspected. These antibiotics have good activity against Streptococcus pneumoniae; however, because of their broader spectrum of activity (and because some of them also have additional safety warnings), the committee agreed that these antibiotics should be used only when there is a clinical reason not to use amoxicillin.
The committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
Although evidence for doxycycline was not identified in people with low-severity community-acquired pneumonia, the committee agreed that evidence identified in hospitalised adults could include a mixed severity population. From its experience, the committee agreed that doxycycline is an appropriate choice as an alternative to a macrolide.
The committee discussed the evidence of effectiveness for azithromycin. However, it agreed that because of its long half-life and therefore increased likelihood of resistance, it was a less suitable choice than other macrolides.
From its experience, the committee agreed that although the available evidence does not differentiate between people with moderate-severity disease and those with high-severity disease, there is a clinical distinction between these groups which require different treatment options. Therefore, separate recommendations on antibiotic choice were made for moderate-severity and high-severity community-acquired pneumonia.
The committee recognised that there was not clear evidence that the addition of a macrolide to amoxicillin was effective for treating moderate- to high-severity community-acquired pneumonia in adults, although this was current routine practice. However, the committee had concerns about the consistency and quality of the evidence identified.
Based on their experience, the first-choice antibiotic for adults with moderate-severity community-acquired pneumonia is amoxicillin (a penicillin), with the addition of a macrolide if an atypical pathogen is suspected. Choices of macrolides are clarithromycin or erythromycin (in pregnancy). The committee based this decision on its experience of current practice, and because dual therapy with amoxicillin plus a macrolide provides broader spectrum of activity which is more likely to target atypical pathogens. In this population when the causative pathogen is not known, the risk of adverse effects and increased antimicrobial resistance with dual therapy is likely to be outweighed by the clinical benefit.
Based on its experience, the committee agreed that if dual therapy with amoxicillin plus a macrolide is given to people with moderate-severity community-acquired pneumonia, this should be reviewed when microbiological results are available. Microbiological results may be useful to guide a decision to stop the macrolide, helping to reduce the risk of resistance and adverse effects with dual therapy.
Alternative antibiotics for adults with moderate-severity community-acquired pneumonia and penicillin allergy are doxycycline (a tetracycline) or clarithromycin (a macrolide) alone. This is based on the committee's experience that these antibiotics have good activity against Streptococcus pneumoniae, as well as atypical infections. The committee noted that there are no reasonable alternatives for dual therapy in adults who are unable to take a penicillin, for example, due to penicillin allergy.
The committee discussed evidence that fluoroquinolone monotherapy (levofloxacin or moxifloxacin) was as effective as beta-lactam plus macrolide dual therapy for people with moderate- to high-severity community-acquired pneumonia. However, they noted the safety concerns with fluoroquinolones, such as tendon damage and aortic aneurysm. The committee noted that the licence is restricted in community-acquired pneumonia, and agreed that fluroquinolones should only be used when other medicines cannot be prescribed or have been ineffective.
The committee agreed that if first and alternative antibiotic choices are not appropriate for adults with low- or moderate-severity community-acquired pneumonia, clinical judgement or seeking specialist advise from a local microbiologist is appropriate.
Based on its experience, the first-choice antibiotic for adults with high-severity community-acquired pneumonia is co‑amoxiclav (a penicillin with a beta-lactamase inhibitor) with clarithromycin or erythromycin (in pregnancy). This provides broad-spectrum gram-negative cover and cover for atypical pathogens. The high risk of mortality in this population outweighs the potential adverse effects and increased risk of antimicrobial resistance with broad-spectrum antibiotics.
The alternative antibiotic for adults with high-severity community-acquired pneumonia and penicillin allergy is levofloxacin. The committee discussed the evidence of effectiveness for levofloxacin and recognised that Legionella pneumophila infection is more common in this population. The committee agreed that the high risk of mortality without appropriate treatment in this population outweighs the safety concerns and therefore agreed that levofloxacin monotherapy is an appropriate alternative.
The committee discussed the evidence that doxycycline is as effective as levofloxacin for adults with moderate- to high-severity community-acquired pneumonia. However, the evidence for doxycycline comes from 1 small study with a 0% mortality rate, suggesting this is not a high-severity population. Therefore, the committee agreed that there is insufficient evidence to recommend doxycycline for this population.
The committee agreed that people with high-severity community-acquired pneumonia and penicillin allergy, in whom a fluoroquinolone is not appropriate, is likely to be a small population and specialist microbiological advice should be sought.
Children and young people with community-acquired pneumonia
The committee was not aware of any validated severity assessment tools for children and young people with community-acquired pneumonia. The committee agreed that features which suggest severe community-acquired pneumonia in children and young people include difficulty breathing, oxygen saturation less than 90%, raised heart rate, grunting, very severe chest indrawing, inability to breastfeed or drink, lethargy and reduced level of consciousness. The severity of symptoms and signs should be assessed by clinical judgement, taking into account these features.
Based on the evidence identified and its experience, the committee agreed that it was appropriate to make separate recommendations for non-severe and severe community-acquired pneumonia.
Given the specialist expertise needed for treatment of children under 1 month with community-acquired pneumonia, the committee agreed that these children should have their treatment managed by a paediatric specialist.
Overall, the committee agreed there was limited evidence relevant to UK practice, and that the evidence had major limitations.
Therefore, the committee agreed that the choice of antibiotics in children and young people should largely be driven by its experience of which antibiotics have good activity against likely pathogens and cause the least harm, with as narrow spectrum as possible to minimise the risk of antimicrobial resistance.
The committee discussed evidence that co‑amoxiclav was more effective than amoxicillin for children with non-severe community-acquired pneumonia. However, the committee noted that this was based on 1 small RCT within a systematic review, and a lower than expected response rate to amoxicillin was reported compared with other studies in children, which may have been due to sub‑therapeutic dosing.
Based on their experience, the first-choice antibiotic for children and young people with community-acquired pneumonia and non-severe symptoms or signs is amoxicillin, which is effective against the most common causative pathogens and is well tolerated. The committee also recognised the clinical experience of the effectiveness of amoxicillin in children and young people, and its common use in current practice.
Alternative antibiotics are clarithromycin, erythromycin (in pregnancy) and doxycycline (in young people aged 12 to 17 years only) for children and young people with non-severe symptoms or signs and penicillin allergy, or if amoxicillin is unsuitable (for example, if an atypical pathogen is suspected). These antibiotics have good activity against Streptococcus pneumoniae; however, because of their broader spectrum of activity, the committee agreed that these antibiotics should only be used when there is a clinical reason not to use amoxicillin.
The committee agreed that if first and alternative antibiotic choices are not appropriate for children and young people with non-severe community-acquired pneumonia, clinical judgement or seeking specialist advice from a local microbiologist is appropriate.
The committee highlighted that the evidence identified for children and young people with severe community-acquired pneumonia was conducted in low-income countries, where severe pneumonia may be more common. The committee was aware that children with severe community-acquired pneumonia in the UK will usually have underlying respiratory conditions. Therefore, the evidence identified may not be directly relevant to UK practice.
Based on its experience, the first-choice antibiotic for children and young people with severe community-acquired pneumonia is co‑amoxiclav, with the addition of clarithromycin or erythromycin (in pregnancy) if an atypical pathogen is suspected. The committee discussed that children and young people with severe symptoms or signs are likely to be at higher risk of treatment failure with amoxicillin, and therefore need broader-spectrum antibiotics to target a range of possible causative organisms. Antibiotics to cover atypical pathogens should also be available if atypical infection is suspected. In this population when the causative pathogen is not known, the risk of adverse effects and increased antimicrobial resistance with dual therapy is likely to be outweighed by the clinical benefit.
The committee agreed that children and young people with severe community-acquired pneumonia and penicillin allergy is likely to be a small population and specialist microbiological advice should be sought.
Safety netting for all people with community-acquired pneumonia
The committee recognised that community-acquired pneumonia is potentially a life‑threatening infection and that a person's condition may change rapidly.
The committee agreed that advice should be given to adults, young people and children about:
the possible adverse effects of the antibiotic and
how long symptoms are likely to last and
seeking medical help (if the person is receiving treatment in the community) if symptoms worsen rapidly or significantly, do not start to improve within 3 days, or they become systemically very unwell.
They agreed that adults, young people and children should be reassessed if symptoms or signs do not improve as expected or worsen rapidly or significantly. If symptoms or signs have not improved following antibiotic treatment, a microbiological sample should be sent for testing if this has not been done already to help guide further treatment. The committee was aware that obtaining a microbiological sample may not always be possible.
The committee was aware that community-acquired pneumonia can be caused by a viral infection and therefore agreed that during reassessment, non-bacterial causes of community-acquired pneumonia, such as infection with flu, should be taken into account.
The committee was aware of recommendations from NICE guidelines on pneumonia in adults and sepsis that cover when to refer people to hospital.
The committee agreed by consensus that adults with any symptoms or signs suggesting a more serious illness or condition or, with symptoms that are not improving as expected with antibiotics, should be referred to hospital if they are being treated in the community.
The committee recognised that not all children and young people need to have their treatment managed in hospital, and referral should be based on clinical judgement because no evidence was identified. They agreed that community-acquired pneumonia is less common in children and young people, and that referral to hospital should be considered, or specialist paediatric advice on further investigation and management should be sought.
The committee also agreed by consensus that referral or seeking specialist advice should be considered for adults with community-acquired pneumonia who have bacteria that are resistant to oral antibiotics, or who cannot take oral antibiotics (to explore locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, if this is appropriate).
# Antibiotic dosage
Low‑dose antibiotics were not significantly different from high‑dose antibiotics for any clinical or bacteriological outcomes reported, in adults with low-severity community-acquired pneumonia:
levofloxacin 500 mg once a day compared with levofloxacin 750 mg once a day; 1 non-inferiority RCT, Zhao et al. 2016).
co-amoxiclav 875/125 mg three times a day compared with co‑amoxiclav 2000/125 mg twice a day, including in a subgroup analysis of adults with atypical pathogens, S. pneumoniae or H. influenzae infection (1 non-inferiority RCT, Siquier et al. 2006).
Low‑dose amoxicillin (45 mg/kg/day divided into 3 doses) was not significantly different to high‑dose amoxicillin (90 mg/kg/day divided into 3 doses) for clinical improvement in young children (2 to 59 months) with non-severe community-acquired pneumonia (1 non-inferiority RCT, Hazir et al. 2007).
Amoxicillin given twice a day (total 50 mg/kg/day) was not significantly different to amoxicillin given three times a day at the same dose (total 50 mg/kg/day) for clinical failure rates in young children (2 to 59 months) with non-severe community-acquired pneumonia (1 non-inferiority RCT, Vilas-Boas et al. 2014).
Low‑dose benzylpenicillin (200,000 IU/kg/day divided into 4 doses) was not significantly different to high‑dose benzylpenicillin (400,000 IU/kg/day divided into 4 doses) for duration of hospital stay, duration of intravenous treatment or C‑reactive protein levels in young children (3 months to 15 years) with severe community-acquired pneumonia (1 RCT, Amarilyo et al. 2014).
No evidence from systematic reviews or RCTs was identified in adults with moderate- or high-severity community-acquired pneumonia.
Committee discussions on antibiotic dosage
Based on evidence showing no differences between low‑dose and high‑dose antibiotics, and its experience, the committee agreed that usual BNF doses for community-acquired pneumonia (or respiratory tract infections) should be used. However, they recognised the importance of consulting BNF, BNF for children and MHRA advice for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and for information on administering intravenous antibiotics.
The committee noted that no evidence was identified in adults with moderate- or high-severity community-acquired pneumonia, and only 1 small RCT in young children with severe community-acquired pneumonia was identified. Based on its experience and the higher risk of mortality in people with a severe infection, the committee agreed that where a range of doses are given, the higher dose is appropriate for these people.
Based on clinical experience and evidence in adults with low-severity community-acquired pneumonia that high‑dose erythromycin is associated with more adverse effects, the committee agreed that the usual BNF dose for erythromycin should be used when this is recommended as an option for women and young women aged 8 years and over who are pregnant.
# Antibiotic course length
Short‑course antibiotics (3 to 7 days) were not significantly different to long‑course antibiotics (10 to 14 days) for mortality or clinical failure in adults with low- to moderate-severity community-acquired pneumonia (1 systematic review, Li et al. 2007).
Short‑course amoxicillin (3 days) was not significantly different to long‑course amoxicillin (8 days) for clinical cure, bacteriological or radiological success, and length of hospital stay, in adults with low‑ to moderate-severity community-acquired pneumonia (1 RCT, El Moussaoui et al. 2006).
Short‑course antibiotics (amoxicillin or co-trimoxazole for 3 days) were not significantly different to a 5‑day course of the same antibiotic for clinical cure or relapse, in young children (2 to 59 months) with non-severe community-acquired pneumonia. The same results were seen when amoxicillin and co‑trimoxazole were analysed separately (1 systematic review, Haider et al. 2008).
Short‑course amoxicillin (3 days) was significantly worse than a 10‑day course of amoxicillin (at the same dose) for treatment failure (4/10 versus 0/56) in young children (6 to 59 months) with non-severe community-acquired pneumonia (1 RCT, Greenberg et al. 2014).
Short‑course amoxicillin (5 days) was not significantly different to a 10‑day course of amoxicillin (at the same dose) for treatment failure in young children (6 to 59 months) with non-severe community-acquired pneumonia. However, C‑reactive protein at day 5 to 7 was significantly worse with the 5‑day course (1 RCT, Greenberg et al. 2014).
No evidence from systematic reviews or RCTs was identified in adults or children with severe community-acquired pneumonia.
Committee discussions on antibiotic course length
The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects. However, an effective course length is important in community-acquired pneumonia because this can be a life-threatening infection.
The committee discussed evidence for antibiotic course length in adults, young people and children with community-acquired pneumonia. Overall, there did not appear to be major differences between short‑ and long‑course antibiotics, but they noted some inconsistency in the evidence for adults and children. It was also aware that no evidence was identified in children and young people with severe community-acquired pneumonia.
The committee agreed that there were several limitations which reduced the applicability of the evidence to UK practice (for example, evidence on antibiotic comparisons not recommended or available in the UK, or a lack of critical outcome reporting).
The committee noted the Uranga et al. (2016) study carried out in adults, which found that antibiotics given for a minimum of 5 days, with a strategy of stopping treatment if fever was absent for 48 hours, and there was no more than 1 associated sign of clinical instability, was not different to usual physician's practice. It also noted a similar study (Aliberti et al. 2017), also carried out in adults, which found that antibiotics given for a minimum for 5 days, with a strategy of stopping treatment if clinically stable for 48 hours, was not different to usual physician practice. (See the committee discussion on antibiotic prescribing strategies.)
Based on its experience and the risks of antimicrobial resistance with longer courses, the committee agreed by consensus that a 5‑day course of recommended antibiotics was appropriate to treat community-acquired pneumonia for adults, young people and children.
# Antibiotic route of administration
Intravenous antibiotics switching to oral antibiotics after 2 to 4 days if there was clinical improvement was not significantly different to continuous intravenous antibiotics for mortality, treatment success or recurrence of infection in adults with moderate‑ to high severity community-acquired pneumonia. However, there were significantly fewer days in hospital and adverse events with the switch to oral antibiotics (1 systematic review, Athanassa et al. 2008).
Oral antibiotics (amoxicillin or co‑trimoxazole) were not significantly different to intravenous or intermuscular penicillins for clinical failure rate in children and young people (1 month to 18 years) with non-severe community-acquired pneumonia (1 systematic review, Lodha et al. 2013).
Oral antibiotics (amoxicillin or co‑trimoxazole) were significantly better than intravenous or intramuscular penicillins for mortality (0.05% versus 0.56%), in children and young people (3 months to 18 years) with severe community-acquired pneumonia. However, there were no significant differences in the rates of cure, clinical failure, hospitalisation or relapse, including when oral amoxicillin was analysed separately (Lodha et al. 2013).
Committee discussions on antibiotic route of administration
The committee discussed evidence on route of administration, which found that oral antibiotics are as effective as injectable antibiotics for children and young people with non-severe community-acquired pneumonia and are more effective for children and young people with severe community-acquired pneumonia.
Based on the evidence and taking account of the principles of antimicrobial stewardship, the committee agreed that oral antibiotics should be given first line for most children and young people, unless they cannot take oral medicines (for example, if they are vomiting), or the severity of infection means that intravenous antibiotics are required.
Based on its experience, the principles of antimicrobial stewardship and supported by the evidence in children and young people, the committee agreed that oral antibiotics should also usually be given first line for adults.
For people with non‑severe symptoms or signs, intravenous antibiotics may be required if the person is unable to take oral medicines.
In line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that if intravenous antibiotics are used initially, this should be reviewed by 48 hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration. See the NICE guideline on medicines adherence.
# Resource implications
Recommended antibiotics are all available as generic formulations. See the Drug Tariff and the BNF for costs.
See the evidence review for more information.
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{'Recommendations': "# Managing community-acquired pneumonia\n\n## Treatment for adults, young people and children\n\nOffer an antibiotic(s) for adults, young people and children with community-acquired pneumonia. When choosing an antibiotic (see the recommendations on choice of antibiotic), take account of:\n\nthe severity assessment for adults, as set out in table\xa01 [amended 2021]\n\nthe severity of symptoms or signs for children and young people, based on clinical judgement\n\nthe risk of developing complications, for example, if the person has relevant comorbidity such as severe lung disease or immunosuppression\n\nlocal antimicrobial resistance and surveillance data (such as flu and Mycoplasma pneumoniae infection rates)\n\nrecent antibiotic use\n\nrecent microbiological results, including colonisation with multidrug-resistant bacteria.At the time of publication (September 2019), no validated severity assessment tools are available for children and young people with community-acquired pneumonia, and severity of symptoms or signs should be based on clinical judgement.\n\nStart antibiotic treatment as soon as possible after establishing a diagnosis of community-acquired pneumonia, and certainly within 4\xa0hours (within 1\xa0hour if the person has suspected sepsis and meets any of the high risk criteria for this – see the NICE guideline on sepsis).\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nIf intravenous antibiotics are given, review by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nThis recommendation has been removed.\n\nFor children and young people in hospital with community-acquired pneumonia, and severe symptoms or signs or a comorbidity, consider sending a sample (for example, sputum sample) for microbiological testing.\n\n## Advice\n\nGive advice to adults, young people and children with community-acquired pneumonia about:\n\npossible adverse effects of the antibiotic(s)\n\nhow long symptoms are likely to last\n\nseeking medical help (if the person is receiving treatment in the community) if:\n\n\n\nsymptoms worsen rapidly or significantly or\n\nsymptoms do not start to improve within 3\xa0days or\n\nthe person becomes systemically very unwell.\n\n\n\n## Reassessment\n\nReassess adults, young people and children with community-acquired pneumonia if symptoms or signs do not improve as expected or worsen rapidly or significantly.\n\nWhen reassessing adults, young people and children with community-acquired pneumonia, be aware of possible non-bacterial causes, such as flu.\n\nIf a sample has been sent for microbiological testing:\n\nreview the choice of antibiotic(s) when results are available and\n\nconsider changing the antibiotic(s) according to results, using a narrower-spectrum antibiotic, if appropriate.\n\nSend a sample (for example, a sputum sample) for microbiological testing if symptoms or signs have not improved following antibiotic treatment, and this has not been done already.\n\n## Referral and seeking specialist advice\n\nRefer adults with community-acquired pneumonia to hospital if they have:\n\nany symptoms or signs suggesting a more serious illness or condition (for example, cardiorespiratory failure or sepsis) or\n\nsymptoms that are not improving as expected with antibiotics. [amended 2021]\n\nConsider referring adults with community-acquired pneumonia to hospital, or seek specialist advice, if they:\n\nhave bacteria that are resistant to oral antibiotics or\n\ncannot take oral medicines (exploring locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, if this is appropriate).\n\nConsider referring children and young people with community-acquired pneumonia to hospital, or seek specialist paediatric advice on further investigation and management.\n\nSee the evidence and committee discussion on antibiotic prescribing strategies and choice of antibiotics.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic(s) for community-acquired pneumonia:\n\nfollow table\xa01 for adults aged 18\xa0years and over\n\nfollow table\xa02 for children and young people under 18\xa0years.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotic if low severity (based on clinical judgement and guided by a CRB65 score\xa00 or a CURB65 score\xa00 or\xa01 when these scores can be calculated)\n\nAmoxicillin:\n\nmg three times a day (higher doses can be used; see the BNF) for 5\xa0days\n\nAlternative oral antibiotics if low severity, for penicillin allergy or if amoxicillin unsuitable (for example, if atypical pathogens suspected)\n\nDoxycycline:\n\nmg on first day, then 100\xa0mg once a day for 4\xa0days (5‑day course in total)\n\n\n\nClarithromycin:\n\nmg twice a day for 5\xa0days\n\n\n\nErythromycin (in pregnancy):\n\nmg four times a day for 5\xa0days\n\nFirst-choice oral antibiotics if moderate severity (based on clinical judgement and guided by a CRB65 score\xa01 or\xa02, or a CURB65 score\xa02 when these scores can be calculated; guided by microbiological results when available)\n\nAmoxicillin:\n\nmg three times a day (higher doses can be used; see the BNF) for 5\xa0days\n\nWith (if atypical pathogens suspected)\n\nClarithromycin:\n\nmg twice a day for 5\xa0days\n\nOr\n\nErythromycin (in pregnancy):\n\nmg four times a day for 5\xa0days\n\nAlternative oral antibiotics if moderate severity, for penicillin allergy (guided by microbiological results when available)\n\nDoxycycline:\n\nmg on first day, then 100\xa0mg once a day for 4\xa0days (5‑day course in total)\n\n\n\nClarithromycin:\n\nmg twice a day for 5\xa0days\n\nFirst-choice antibiotics if high severity (based on clinical judgement and guided by a CRB65 score\xa03 or\xa04, or a CURB65 score\xa03 to\xa05 when these scores can be calculated; guided by microbiological results when available)\n\nCo‑amoxiclav:\n\n/125\xa0mg three times a day orally or 1.2\xa0g three times a day intravenously for 5\xa0days\n\nWith\n\nClarithromycin:\n\nmg twice a day orally or intravenously for 5\xa0days\n\nOr\n\nErythromycin (in pregnancy):\n\nmg four times a day orally for 5\xa0days\n\nAlternative antibiotic if high severity, for penicillin allergy (guided by microbiological results when available; consult a local microbiologist if fluoroquinolone not appropriate)\n\nLevofloxacin (consider safety issues):\n\nmg twice a day orally or intravenously for 5\xa0days\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nStop antibiotic treatment after 5\xa0days unless microbiological results suggest a longer course is needed or the person is not clinically stable, for example, if they have had a fever in the past 48\xa0hours or have more than 1\xa0sign of clinical instability (systolic blood pressure less than 90\xa0mmHg, heart rate more than 100/minute, respiratory rate more than 24/minute, arterial oxygen saturation less than 90% or partial pressure of oxygen of more than 60\xa0mmHg in room air).\n\nFor fluoroquinolone antibiotics, see Medicines and Healthcare products Regulatory Agency (MHRA) advice for restrictions and precautions because of very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution for people over 60\xa0years and avoiding coadministration with a corticosteroid (March\xa02019).\n\nConsider adding a macrolide to amoxicillin if atypical pathogens are suspected, and review when microbiological results are available. Mycoplasma pneumoniae infection occurs in outbreaks approximately every 4\xa0years.\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nCRB65: confusion, respiratory rate 30/minute or more, blood pressure (systolic less than 90\xa0mmHg or diastolic 60\xa0mmHg or less), age 65 or more\n\nCURB65: confusion, urea more than 7\xa0mmol/litre, respiratory rate 30/minute or more, blood pressure (systolic less than 90\xa0mmHg or diastolic 60\xa0mmHg or less), age 65 or more\n\nTreatment\n\nAntibiotic, dosage and course length\n\nChildren under 1\xa0month\n\nRefer to paediatric specialist\n\nFirst-choice oral antibiotic for children 1\xa0month and over if non-severe symptoms or signs (based on clinical judgement)\n\nAmoxicillin:\n\nmonth to 11\xa0months, 125\xa0mg three times a day for 5\xa0days\n\nyear to 4\xa0years, 250\xa0mg three times a day for 5\xa0days\n\nyears to 17\xa0years, 500\xa0mg three times a day for 5\xa0days (higher doses can be used for all ages; see BNF for children)\n\nAlternative oral antibiotics if non-severe symptoms or signs (based on clinical judgement), for penicillin allergy or if amoxicillin unsuitable (for example, atypical pathogens suspected)\n\nClarithromycin:\n\nmonth to 11\xa0years:\n\nUnder 8\xa0kg, 7.5\xa0mg/kg twice a day for 5\xa0days\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day for 5\xa0days\n\nkg to 19\xa0kg, 125\xa0mg twice a day for 5\xa0days\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day for 5\xa0days\n\nkg to 40\xa0kg, 250\xa0mg twice a day for 5\xa0days\n\nyears to 17\xa0years:\n\nmg to 500\xa0mg twice a day for 5\xa0days\n\n\n\nErythromycin (in pregnancy):\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg four times a day for 5\xa0days\n\n\n\nDoxycycline:\n\nyears to 17\xa0years, 200\xa0mg on first day, then 100\xa0mg once a day for 4\xa0days (5‑day course in total)\n\n(see BNF for children for use of doxycycline in children under\xa012)\n\nFirst-choice antibiotic(s) if \n severe symptoms\n or signs (based on clinical judgement; guided by microbiological results when available)\n\nCo‑amoxiclav:\n\nOral doses:\n\nmonth to 11\xa0months, 0.5\xa0ml/kg of 125/31 suspension three times a day for 5\xa0days\n\nyears to 5\xa0years, 10\xa0ml of 125/31 suspension three times a day or 0.5\xa0ml/kg of 125/31 suspension three times a day for 5\xa0days (or 5\xa0ml of 250/62 suspension)\n\nyears to 11\xa0years, 10\xa0ml of 250/62 suspension three times a day or 0.3\xa0ml/kg of 250/62 suspension three times a day for 5\xa0days\n\nyears to 17\xa0years, 500/125\xa0mg three times a day for 5\xa0days\n\nIntravenous doses:\n\nmonth to 2\xa0months, 30\xa0mg/kg twice a day\n\nmonths to 17\xa0years, 30\xa0mg/kg three times a day (maximum 1.2\xa0g per dose three times a day)\n\nWith (if atypical pathogen suspected)\n\nClarithromycin:\n\nOral doses:\n\nmonth to 11\xa0years:\n\nUnder 8\xa0kg, 7.5\xa0mg/kg twice a day for 5\xa0days\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day for 5\xa0days\n\nkg to 19\xa0kg, 125\xa0mg twice a day for 5\xa0days\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day for 5\xa0days\n\nkg to 40\xa0kg, 250\xa0mg twice a day for 5\xa0days\n\nyears to 17\xa0years:\n\nmg to 500\xa0mg twice a day for 5\xa0days\n\nIntravenous doses:\n\nmonth to 11\xa0years, 7.5\xa0mg/kg twice a day (maximum 500\xa0mg per dose)\n\nyears to 17\xa0years, 500\xa0mg twice a day\n\nOr\n\nErythromycin (in pregnancy):\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg four times a day orally for 5\xa0days\n\nAlternative antibiotics if \n severe symptoms or signs(based on clinical judgement), for penicillin allergy (guided by microbiological results when available)\n\nConsult local microbiologist\n\nSee the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nStop antibiotic treatment after 5\xa0days unless microbiological results suggest a longer course is needed or the person is not clinically stable (fever in past 48\xa0hours or more than 1\xa0sign of clinical instability [systolic blood pressure less than 90\xa0mmHg, heart rate more than 100/minute, respiratory rate less than 24/minute, arterial oxygen saturation less than 90% or PaO2\xa0under 60\xa0mmHg in room air]).\n\nMycoplasma pneumoniae infection occurs in outbreaks approximately every 4\xa0years and is more common in school-aged children.\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nSee the committee discussions on choice of antibiotics and antibiotic course length.\n\n# Terms used in the guideline\n\n## Severe community-acquired pneumonia in children and young people\n\nFeatures of severe community-acquired pneumonia in children and young people include difficulty breathing, oxygen saturation less than 90%, raised heart rate, grunting, very severe chest indrawing, inability to breastfeed or drink, lethargy and a reduced level of consciousness.\n\n## CRB65\n\nCRB65 is used in primary care to assess 30‑day mortality risk in adults with pneumonia. The score is calculated by giving 1\xa0point for each of the following prognostic features: confusion, respiratory rate 30/minute or more, low systolic [less than 90\xa0mmHg] or diastolic [60\xa0mmHg or less] blood pressure, age 65 or more). Risk of death is stratified as follows:\n\n: low risk (less than 1% mortality risk)\n\nor 2: intermediate risk (1% to 10% mortality risk)\n\nor 4: high risk (more than 10% mortality risk).\n\n## CURB65\n\nCURB65 is used in hospital to assess 30‑day mortality risk in adults with pneumonia. The score is calculated by giving 1\xa0point for each of the following prognostic features: (confusion, urea more than 7\xa0mmol/litre, respiratory rate 30/minute or more, low systolic [less than 90\xa0mmHg] or diastolic [60\xa0mmHg or less] blood pressure, age 65 or more). Risk of death is stratified as follows:\n\nor 1: low risk (less than 3% mortality risk)\n\n: intermediate risk (3% to 15% mortality risk)\n\nto 5: high risk (more than 15% mortality risk).\n\nAdults with score of\xa01 and particularly\xa02 are at increased risk of death (should be considered for hospital referral) and people with a score of 3\xa0or more are at high risk of death (require urgent hospital admission).", 'Summary of the evidence': "This is a summary of the evidence. For full details, see the evidence review.\n\nCommunity‑acquired pneumonia is a lower respiratory tract infection that is most commonly caused by bacterial infection (British Thoracic Society [BTS] guideline on community-acquired pneumonia in adults, 2009).\n\nThe main bacterial pathogen is Streptococcus pneumoniae (NICE clinical knowledge summaries [CKS] on chest infections in adults, 2015), however Mycoplasma pneumoniae occurs in outbreaks approximately every 4\xa0years in the UK and is much more common in school-aged children (BTS 2009).\n\nAlthough bacterial infection is the most common cause of community-acquired pneumonia, viral infection causes approximately 13% of cases in adults (BTS 2009) and approximately 66% of cases in children and young people (Jain et al.\xa02015).\n\nLow-severity, community-acquired pneumonia in adults includes people with pneumonia severity index (PSI) score of I\xa0or\xa0II, CRB65 score\xa00 or CURB65 score 0\xa0or\xa01. Moderate- to high-severity, community-acquired pneumonia in adults includes people with PSI score of III\xa0to\xa0V, CRB65 score 1\xa0to\xa04 or CURB65 score 2\xa0to\xa05.\n\nThe severity of infection was not always clearly defined in the studies, and was often based on clinical judgement. The management setting (community or hospital) was used to indicate the severity of symptoms when this was not described in the studies (through either severity assessment scores or clinical judgement).\n\n# Antibiotic prescribing strategies\n\nIn adults with moderate‑ to high-severity community-acquired pneumonia, an antibiotic prescribing strategy guided by results of pneumococcal and Legionella pneumophila urine antigen tests was not significantly different from a strategy that used broad-spectrum antibiotics without antigen testing for the outcomes of mortality, clinical relapse and hospital admissions (1\xa0randomised controlled trial [RCT], Falguera et al. 2009).\n\nIn adults with mixed severity community-acquired pneumonia, a strategy of stopping antibiotics based on guidelines was not different to physician-guided stopping for a range of outcomes, including mortality, symptoms, recurrence, length of hospital stay and adverse events. Stopping antibiotics based on guidelines was associated with a longer total antibiotic course length (including intravenous and oral antibiotics) but with a shorter time taking intravenous antibiotics (2\xa0RCTs, Uranga et al. 2016 and Aliberti et al. 2017).\n\nIn children aged 1\xa0month to 5\xa0years with severe community-acquired pneumonia, a strategy of intravenous antibiotics then switching to oral antibiotics (based on a specified drop in body temperature and stable clinical signs) reduced hospital stay by about 1\xa0day, compared with standard care (intravenous then switching to oral antibiotics at least 48\xa0hours after dissipation of fever). There was no difference in readmissions (1\xa0non-inferiority RCT, In-iw et al.\xa02015).\n\nCommittee discussions on antibiotic prescribing strategies\n\nThe committee discussed that the study designs were not appropriate for determining which antibiotic prescribing strategies were most effective, because the antibiotics used in the studies on prescribing strategies had very broad antibacterial cover.\n\nThe committee discussed that although community-acquired pneumonia can be caused by a viral infection, it is difficult to distinguish this from a bacterial infection. Based on the high mortality rate, the committee agreed that all people with community-acquired pneumonia should be offered an antibiotic.\n\nThe committee was aware that the NICE guideline on pneumonia in adults (2014) recommended antibiotic treatment as soon as possible, and within 4\xa0hours for people admitted to hospital with community-acquired pneumonia. The committee agreed that this was also applicable to people receiving treatment in the community. The committee also agreed that people with suspected sepsis and high risk criteria (as described in the NICE guideline on sepsis) would need more urgent treatment.\n\nBecause there were no major differences between stopping antibiotics based on guidelines and stopping antibiotics based on clinical judgement, the committee agreed that clinical judgement should be used when deciding when to stop antibiotic treatment. This should usually be after 5\xa0days.\n\nThe committee agreed that the criteria (fever in the past 48\xa0hours, blood pressure, heart rate, respiratory rate and oxygen saturations) used in the study by Uranga et\xa0al. (2016) should be considered during decision making (see the committee discussion on antibiotic course length).\n\nThe committee discussed the evidence in children suggesting a reduced length of hospital stay with switching from intravenous to oral antibiotics when clinical signs were stable compared with switching following 48\xa0hours of dissipation of fever. However, because other important clinical outcomes were not reported (such as mortality or cure), and no evidence was available in adults for this prescribing strategy, the committee agreed that if applicable, the decision for switching from intravenous to oral antibiotics in adults, young people and children should be based on clinical judgement (see the evidence summary and committee discussion section on route of administration).\n\nIn children and young people with severe symptoms or signs, the committee agreed that a broad-spectrum antibiotic would be needed initially to cover the range of possible pathogens, including the addition of a macrolide if atypical pneumonia was suspected (see the committee discussion on choice of antibiotics).\n\nThe committee was concerned about the risk of antimicrobial resistance from using broad-spectrum antibiotics for longer than necessary. Therefore, the committee agreed that in children and young people in hospital, with severe symptoms or signs or a comorbidity (who were more likely to be on broad-spectrum antibiotics), sending a sample for microbiological testing should be considered. They recognised that obtaining a sample for testing is not always possible, especially in young children.\n\nThe committee agreed that when microbiological results are available, the antibiotic should be reviewed and changed accordingly (for example, if bacteria are found to be resistant or atypical pathogens are not isolated) if symptoms are not already improving, using a narrower-spectrum antibiotic if appropriate.\n\nThe committee agreed that first-line antibiotics would be effective in most children and young people with non‑severe symptoms or signs, and therefore microbiological testing would not be needed routinely to guide antibiotic choice.\n\n# Choice of antibiotics\n\n## Efficacy of antibiotics\n\nLow-severity community-acquired pneumonia in adults\n\nThere were no differences in the clinical effectiveness of the following antibiotic comparisons (course length varied but usually ranged from 7\xa0to 14\xa0days) in adults with low-severity community-acquired pneumonia:\n\n\n\nclarithromycin compared with amoxicillin (Pakhale et al. 2014)\n\nclarithromycin compared with erythromycin (Pakhale et al. 2014)\n\nazithromycin compared with clarithromycin (Pakhale et al. 2014)\n\nazithromycin compared with co‑amoxiclav (Paris et al. 2008)\n\nazithromycin compared with levofloxacin (Pakhale et al. 2014)\n\na cephalosporin (cefuroxime or cefditoren) compared with co‑amoxiclav (Maimon et al. 2008)\n\nlevofloxacin compared with ceftriaxone plus azithromycin (Raz-Pasteur et al. 2015).\n\n\n\nSome differences were seen for some efficacy outcomes for other antibiotic comparisons in adults with low-severity community-acquired pneumonia.\n\n\n\nAmoxicillin improved clinical cure rates (in intention-to-treat analysis only) and complete resolution at 30\xa0days, compared with phenoxymethylpenicillin (Llor et al. 2017).\n\nCefixime significantly reduced respiratory rate, radiological consolidations and bacterial isolates compared with ciprofloxacin, but there was no significant differences in temperature reduction or pulse rate (Ige et al. 2015).\n\n\n\nEvidence for efficacy of antibiotics for low-severity community-acquired pneumonia in adults is based on 3\xa0systematic reviews (Pakhale et al. 2014, Maimon et al. 2008 and Raz-Pasteur et al. 2015), 1\xa0RCT (Ige et al. 2015) and 2\xa0non‑inferiority RCTs (Llor et al. 2017 and Paris et al. 2008).\n\nModerate- to high-severity community-acquired pneumonia in adults\n\nThere were no differences in the clinical effectiveness of the following antibiotic comparisons (course length varied but usually ranged from 7\xa0to 14\xa0days) in adults with moderate‑ to high-severity community-acquired pneumonia:\n\n\n\na macrolide compared with antibiotics targeted at non-atypical pathogens (penicillins, beta-lactam plus beta-lactamase inhibitors, cephalosporins and carbapenems; Eliakim-Raz et al. 2012)\n\na fluoroquinolone compared with antibiotics targeted at non-atypical pathogens (penicillins, beta-lactam plus beta-lactamase inhibitors and cephalosporins; Eliakim-Raz et al. 2012)\n\nlevofloxacin compared with tigecycline (Nemeth et al. 2015)\n\nlevofloxacin compared with doxycycline (Nemeth et al. 2015)\n\nofloxacin compared with erythromycin (Skalsky et al. 2013)\n\nmoxifloxacin compared with levofloxacin (Yuan et al. 2012)\n\nertapenem compared with ceftriaxone (Bai et al. 2014)\n\na macrolide compared with a beta-lactam antibiotic plus macrolide (Raz-Pasteur et al. 2015)\n\na fluoroquinolone compared with a beta-lactam antibiotic plus fluoroquinolone (Raz-Pasteur et al. 2015)\n\nceftriaxone plus azithromycin compared with ceftriaxone plus a macrolide (clarithromycin or erythromycin; Tamm et al. 2007)\n\nceftobiprole compared with ceftriaxone plus linezolid (in suspected methicillin-resistant Staphylococcus aureus [MRSA] infection (Nicholson et al. 2012).\n\n\n\nFor other antibiotic comparisons in adults with moderate‑ or high-severity community-acquired pneumonia, some differences were seen in some efficacy outcomes:\n\n\n\nAntibiotics targeted at atypical pathogens (macrolides and fluoroquinolones) compared with antibiotics targeted at non-atypical pathogens (penicillins, beta‑lactam plus beta-lactamase inhibitors, cephalosporins and carbapenems): overall there were no significant differences in mortality or clinical failure, but there was significantly less bacteriological failure with antibiotics targeted at atypical pathogens. Some minor differences were seen in subgroup analyses, including significantly lower clinical failure with antibiotics targeted at atypical pathogens in adults with Legionella pneumophila infection (Eliakim-Raz et al. 2012).\n\nCeftriaxone compared with ceftaroline fosamil: there was no significant difference in mortality, but clinical cure was significantly increased with ceftriaxone (El Hajj et al. 2017).\n\nA fluoroquinolone (levofloxacin or moxifloxacin) compared with a beta-lactam antibiotic plus macrolide: there were no significant differences in mortality or microbiological failure, but clinical failure was significantly reduced with a fluoroquinolone (result not significant in adults with pneumococcal pneumonia; Raz-Pasteur et al. 2015).\n\nA beta-lactam antibiotic (co‑amoxiclav or cefuroxime) plus upfront clarithromycin (upfront dual therapy) compared with a beta-lactam antibiotic (co‑amoxiclav or cefuroxime) plus clarithromycin only when a positive Legionella pneumophila urine sample was confirmed (test-dependant dual therapy): there was no significant difference in mortality or clinical stability; in people with an atypical (but not non-atypical) infection, upfront dual therapy was significantly better for achieving clinical stability compared with test-dependant dual therapy; there were no significant differences in admission to intensive care, incidence of complicated pleural effusion, length of hospital stay or long-term readmission rates.\n\n\n\nEvidence for efficacy of antibiotics for moderate-to high‑severity community-acquired pneumonia in adults is based on 7\xa0systematic reviews (Eliakim-Raz et al. 2012, Nemeth et al. 2015, Skalsky et al. 2013, El Hajj et al. 2017, Yuan et al. 2012, Bai et al. 2014 and Raz-Pasteur et al. 2015) and 3\xa0non-inferiority RCTs (Garin et al. 2014, Nicholson et al. 2012 and Tamm et al. 2007).\n\nNon-severe community-acquired pneumonia in children and young people\n\nEvidence (1\xa0systematic review, Lodha et al. 2013) was identified on the following antibiotic comparisons (course length varied but usually ranged from 4\xa0to 10\xa0days) for treatment of non-severe community-acquired pneumonia, for which no significant differences were found for the efficacy outcomes reported:\n\n\n\nazithromycin compared with erythromycin\n\nazithromycin compared with co‑amoxiclav\n\nclarithromycin compared with erythromycin\n\nco-trimoxazole compared with amoxicillin\n\ncefpodoxime compared with co‑amoxiclav\n\n\n\nFor other antibiotic comparisons in children and young people with non-severe community-acquired pneumonia, some differences were seen in the following efficacy outcomes:\n\n\n\nCo-amoxiclav was significantly better than amoxicillin for improving cure rate (94% versus 60%) and improving poor or no response rate (2% versus 20%) in children aged 2\xa0to\xa012\xa0years.\n\nAmoxicillin was significantly better than chloramphenicol for improving cure rate in children aged 2\xa0to\xa059\xa0months.\n\n\n\nSevere community-acquired pneumonia in children and young people\n\nEvidence (Lodha et al. 2013 unless otherwise stated) was identified on the following antibiotic comparisons for treatment (course length varied but usually ranged from 3\xa0to\xa010\xa0days) of severe or very severe community-acquired pneumonia in children and young people, for which no significant differences were found for the outcomes reported:\n\n\n\namoxicillin compared with an unspecified penicillin\n\namoxicillin compared with ampicillin\n\namoxicillin compared with cefuroxime\n\namoxicillin compared with clarithromycin\n\nlevofloxacin compared with beta‑lactam antibiotics (co‑amoxiclav or ceftriaxone)\n\ncefuroxime compared with clarithromycin\n\nco-trimoxazole compared with chloramphenicol\n\nceftaroline fosamil compared with ceftriaxone (Cannavino et al. 2016).\n\nbenzylpenicillin plus gentamicin compared with co‑amoxiclav\n\nan unspecified penicillin plus chloramphenicol compared with ampicillin\n\nbenzylpenicillin plus chloramphenicol compared with chloramphenicol\n\nan unspecified penicillin plus gentamicin compared with chloramphenicol\n\nchloramphenicol plus an unspecified penicillin compared with ceftriaxone\n\nceftriaxone plus vancomycin compared with ceftaroline fosamil (Blumer et al. 2016).\n\n\n\nFor other antibiotic comparisons in children and young people with severe community-acquired pneumonia, some differences were seen in the following efficacy outcomes:\n\n\n\nAmpicillin plus gentamicin was significantly better than chloramphenicol in children with very severe pneumonia, aged 2\xa0to\xa059\xa0months for clinical failure at all time points, but there was no significant difference in mortality. Significantly fewer children given ampicillin plus gentamicin needed to change antibiotics before day\xa021.\n\nA penicillin (unspecified) plus gentamicin was not significantly different to chloramphenicol for mortality in children with severe community-acquired pneumonia, aged 1\xa0to\xa059\xa0months, but readmissions were significantly lower with a penicillin plus gentamicin.\n\n\n\nEvidence for efficacy of antibiotics for severe community-acquired pneumonia in children and young people is based on 1\xa0systematic review (Lodha et al. 2013) and 2\xa0RCTs (Cannavino et al. 2016 and Blumer et al. 2016).\n\n## Safety of antibiotics\n\nAntibiotic-associated diarrhoea is estimated to occur in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE CKS on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, August 2019).\n\nMacrolides should be used with caution in people with a predisposition to QT interval prolongation (BNF, August 2019).\n\nTetracyclines, including doxycycline, can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant or breastfeeding women, and use in children under 12\xa0years is either contraindicated or cautioned for use in severe or life-threatening infections where there are no alternatives (BNF, August 2019).\n\nFluoroquinolones have restrictions and precautions around their use because of rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems (MHRA Drug Safety Update, March 2019). They may also be associated with a small increased risk of aortic aneurysm and dissection, particularly in older people (MHRA Drug Safety Update, November 2018).\n\nTendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, August 2019).\n\nOverall, adverse effects of antibiotics were similar in the studies, although some differences were seen for the following antibiotic comparisons in people with community-acquired pneumonia:\n\n\n\nAdverse events were significantly higher with azithromycin compared with levofloxacin (19.9% versus 12.3%) and erythromycin compared with clarithromycin (45.7% versus 21.4%; Pakhale et al. 2014), and abdominal pain was significantly worse with azithromycin compared with co‑amoxiclav (9.6% versus 1.5%; Paris et al. 2008), in adults with low-severity community-acquired pneumonia.\n\nAdverse events, treatment discontinuations and diarrhoea were significantly lower with a fluoroquinolone compared with beta-lactam antibiotic plus a macrolide in adults with moderate- to high-severity community-acquired pneumonia (Raz-Pasteur et al. 2015).\n\nAdverse events were significantly lower with a macrolide compared with a beta-lactam antibiotic plus macrolide in adults with moderate‑ to high-severity community-acquired pneumonia (Raz-Pasteur et al. 2015).\n\nAdverse events were significantly higher with ceftobiprole compared with ceftriaxone plus linezolid in adults with suspected MRSA infection (Nicholson et al. 2012).\n\nAdverse events were significantly lower with azithromycin compared with co‑amoxiclav in children with non-severe community-acquired pneumonia (Lodha et al. 2013).\n\nSignificantly more children with severe community-acquired pneumonia had 1\xa0or more adverse events with ceftriaxone plus vancomycin compared with ceftaroline fosamil (Blumer et al. 2016).\n\n\n\nSee the summaries of product characteristics for information on contraindications, cautions, drug interactions and adverse effects of individual medicines.\n\nCommittee discussions on choice of antibiotics\n\nThe committee noted that using the care setting as a proxy for the severity of community-acquired pneumonia may not always be appropriate, and that some studies in outpatients may include people with moderate-severity community-acquired pneumonia, or a mixed severity population. They recognised that hospital admission criteria in other countries may differ from UK practice.\n\nThe committee discussed the pathogens which cause community-acquired pneumonia and noted that Streptococcus pneumoniae is the most common cause. Based on their experience, the committee noted that atypical pathogens are the causative organism in around 10% to 15% of moderate- to high-severity infections.\n\nAdults with community-acquired pneumonia\n\nThe committee discussed the evidence on choice of antibiotics in adults with low-severity community-acquired pneumonia and in adults with moderate- to high-severity community-acquired pneumonia.\n\nThe committee was aware that the CRB65 (in primary care) and CURB65 (in hospital) mortality risk scores were recommended in the NICE guideline on pneumonia in adults for assessing the risk of mortality with community-acquired pneumonia. The committee discussed evidence which used the pneumonia severity index to assess severity; however, they agreed that, when they can be calculated, CRB65 and CURB65 scores should be used in conjunction with clinical judgement to assess severity in adults.\n\nBased on limited evidence showing no major differences in clinical effectiveness between antibiotics or classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by their experience of which antibiotics have good activity against likely pathogens and cause the least harm, with as narrow spectrum as possible to minimise the risk of antimicrobial resistance. The committee considered the adverse effects associated with individual antibiotics, for example, increased risk of Clostridium difficile infection, along with the risk of harm from not adequately treating the infection.\n\nBased on their experience, the first-choice antibiotic for adults with low-severity community-acquired pneumonia is amoxicillin (a penicillin), which has good activity against Streptococcus pneumoniae and is associated with fewer adverse effects and relatively low resistance rates. Amoxicillin is routinely used as first-line treatment and the committee agreed that there was no evidence to support changing current practice.\n\nAlternative antibiotics are doxycycline (a tetracycline), clarithromycin (a macrolide) and erythromycin (an alternative macrolide in pregnancy), for people with low-severity community-acquired pneumonia and penicillin allergy, or when amoxicillin may not be appropriate, for example, if an atypical infection is suspected. These antibiotics have good activity against Streptococcus pneumoniae; however, because of their broader spectrum of activity (and because some of them also have additional safety warnings), the committee agreed that these antibiotics should be used only when there is a clinical reason not to use amoxicillin.\n\nThe committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.\n\nAlthough evidence for doxycycline was not identified in people with low-severity community-acquired pneumonia, the committee agreed that evidence identified in hospitalised adults could include a mixed severity population. From its experience, the committee agreed that doxycycline is an appropriate choice as an alternative to a macrolide.\n\nThe committee discussed the evidence of effectiveness for azithromycin. However, it agreed that because of its long half-life and therefore increased likelihood of resistance, it was a less suitable choice than other macrolides.\n\nFrom its experience, the committee agreed that although the available evidence does not differentiate between people with moderate-severity disease and those with high-severity disease, there is a clinical distinction between these groups which require different treatment options. Therefore, separate recommendations on antibiotic choice were made for moderate-severity and high-severity community-acquired pneumonia.\n\nThe committee recognised that there was not clear evidence that the addition of a macrolide to amoxicillin was effective for treating moderate- to high-severity community-acquired pneumonia in adults, although this was current routine practice. However, the committee had concerns about the consistency and quality of the evidence identified.\n\nBased on their experience, the first-choice antibiotic for adults with moderate-severity community-acquired pneumonia is amoxicillin (a penicillin), with the addition of a macrolide if an atypical pathogen is suspected. Choices of macrolides are clarithromycin or erythromycin (in pregnancy). The committee based this decision on its experience of current practice, and because dual therapy with amoxicillin plus a macrolide provides broader spectrum of activity which is more likely to target atypical pathogens. In this population when the causative pathogen is not known, the risk of adverse effects and increased antimicrobial resistance with dual therapy is likely to be outweighed by the clinical benefit.\n\nBased on its experience, the committee agreed that if dual therapy with amoxicillin plus a macrolide is given to people with moderate-severity community-acquired pneumonia, this should be reviewed when microbiological results are available. Microbiological results may be useful to guide a decision to stop the macrolide, helping to reduce the risk of resistance and adverse effects with dual therapy.\n\nAlternative antibiotics for adults with moderate-severity community-acquired pneumonia and penicillin allergy are doxycycline (a tetracycline) or clarithromycin (a macrolide) alone. This is based on the committee's experience that these antibiotics have good activity against Streptococcus pneumoniae, as well as atypical infections. The committee noted that there are no reasonable alternatives for dual therapy in adults who are unable to take a penicillin, for example, due to penicillin allergy.\n\nThe committee discussed evidence that fluoroquinolone monotherapy (levofloxacin or moxifloxacin) was as effective as beta-lactam plus macrolide dual therapy for people with moderate- to high-severity community-acquired pneumonia. However, they noted the safety concerns with fluoroquinolones, such as tendon damage and aortic aneurysm. The committee noted that the licence is restricted in community-acquired pneumonia, and agreed that fluroquinolones should only be used when other medicines cannot be prescribed or have been ineffective.\n\nThe committee agreed that if first and alternative antibiotic choices are not appropriate for adults with low- or moderate-severity community-acquired pneumonia, clinical judgement or seeking specialist advise from a local microbiologist is appropriate.\n\nBased on its experience, the first-choice antibiotic for adults with high-severity community-acquired pneumonia is co‑amoxiclav (a penicillin with a beta-lactamase inhibitor) with clarithromycin or erythromycin (in pregnancy). This provides broad-spectrum gram-negative cover and cover for atypical pathogens. The high risk of mortality in this population outweighs the potential adverse effects and increased risk of antimicrobial resistance with broad-spectrum antibiotics.\n\nThe alternative antibiotic for adults with high-severity community-acquired pneumonia and penicillin allergy is levofloxacin. The committee discussed the evidence of effectiveness for levofloxacin and recognised that Legionella pneumophila infection is more common in this population. The committee agreed that the high risk of mortality without appropriate treatment in this population outweighs the safety concerns and therefore agreed that levofloxacin monotherapy is an appropriate alternative.\n\nThe committee discussed the evidence that doxycycline is as effective as levofloxacin for adults with moderate- to high-severity community-acquired pneumonia. However, the evidence for doxycycline comes from 1\xa0small study with a 0% mortality rate, suggesting this is not a high-severity population. Therefore, the committee agreed that there is insufficient evidence to recommend doxycycline for this population.\n\nThe committee agreed that people with high-severity community-acquired pneumonia and penicillin allergy, in whom a fluoroquinolone is not appropriate, is likely to be a small population and specialist microbiological advice should be sought.\n\nChildren and young people with community-acquired pneumonia\n\nThe committee was not aware of any validated severity assessment tools for children and young people with community-acquired pneumonia. The committee agreed that features which suggest severe community-acquired pneumonia in children and young people include difficulty breathing, oxygen saturation less than 90%, raised heart rate, grunting, very severe chest indrawing, inability to breastfeed or drink, lethargy and reduced level of consciousness. The severity of symptoms and signs should be assessed by clinical judgement, taking into account these features.\n\nBased on the evidence identified and its experience, the committee agreed that it was appropriate to make separate recommendations for non-severe and severe community-acquired pneumonia.\n\nGiven the specialist expertise needed for treatment of children under 1\xa0month with community-acquired pneumonia, the committee agreed that these children should have their treatment managed by a paediatric specialist.\n\nOverall, the committee agreed there was limited evidence relevant to UK practice, and that the evidence had major limitations.\n\nTherefore, the committee agreed that the choice of antibiotics in children and young people should largely be driven by its experience of which antibiotics have good activity against likely pathogens and cause the least harm, with as narrow spectrum as possible to minimise the risk of antimicrobial resistance.\n\nThe committee discussed evidence that co‑amoxiclav was more effective than amoxicillin for children with non-severe community-acquired pneumonia. However, the committee noted that this was based on 1\xa0small RCT within a systematic review, and a lower than expected response rate to amoxicillin was reported compared with other studies in children, which may have been due to sub‑therapeutic dosing.\n\nBased on their experience, the first-choice antibiotic for children and young people with community-acquired pneumonia and non-severe symptoms or signs is amoxicillin, which is effective against the most common causative pathogens and is well tolerated. The committee also recognised the clinical experience of the effectiveness of amoxicillin in children and young people, and its common use in current practice.\n\nAlternative antibiotics are clarithromycin, erythromycin (in pregnancy) and doxycycline (in young people aged 12 to 17 years only) for children and young people with non-severe symptoms or signs and penicillin allergy, or if amoxicillin is unsuitable (for example, if an atypical pathogen is suspected). These antibiotics have good activity against Streptococcus pneumoniae; however, because of their broader spectrum of activity, the committee agreed that these antibiotics should only be used when there is a clinical reason not to use amoxicillin.\n\nThe committee agreed that if first and alternative antibiotic choices are not appropriate for children and young people with non-severe community-acquired pneumonia, clinical judgement or seeking specialist advice from a local microbiologist is appropriate.\n\nThe committee highlighted that the evidence identified for children and young people with severe community-acquired pneumonia was conducted in low-income countries, where severe pneumonia may be more common. The committee was aware that children with severe community-acquired pneumonia in the UK will usually have underlying respiratory conditions. Therefore, the evidence identified may not be directly relevant to UK practice.\n\nBased on its experience, the first-choice antibiotic for children and young people with severe community-acquired pneumonia is co‑amoxiclav, with the addition of clarithromycin or erythromycin (in pregnancy) if an atypical pathogen is suspected. The committee discussed that children and young people with severe symptoms or signs are likely to be at higher risk of treatment failure with amoxicillin, and therefore need broader-spectrum antibiotics to target a range of possible causative organisms. Antibiotics to cover atypical pathogens should also be available if atypical infection is suspected. In this population when the causative pathogen is not known, the risk of adverse effects and increased antimicrobial resistance with dual therapy is likely to be outweighed by the clinical benefit.\n\nThe committee agreed that children and young people with severe community-acquired pneumonia and penicillin allergy is likely to be a small population and specialist microbiological advice should be sought.\n\nSafety netting for all people with community-acquired pneumonia\n\nThe committee recognised that community-acquired pneumonia is potentially a life‑threatening infection and that a person's condition may change rapidly.\n\nThe committee agreed that advice should be given to adults, young people and children about:\n\n\n\nthe possible adverse effects of the antibiotic and\n\nhow long symptoms are likely to last and\n\nseeking medical help (if the person is receiving treatment in the community) if symptoms worsen rapidly or significantly, do not start to improve within 3\xa0days, or they become systemically very unwell.\n\n\n\nThey agreed that adults, young people and children should be reassessed if symptoms or signs do not improve as expected or worsen rapidly or significantly. If symptoms or signs have not improved following antibiotic treatment, a microbiological sample should be sent for testing if this has not been done already to help guide further treatment. The committee was aware that obtaining a microbiological sample may not always be possible.\n\nThe committee was aware that community-acquired pneumonia can be caused by a viral infection and therefore agreed that during reassessment, non-bacterial causes of community-acquired pneumonia, such as infection with flu, should be taken into account.\n\nThe committee was aware of recommendations from NICE guidelines on pneumonia in adults and sepsis that cover when to refer people to hospital.\n\nThe committee agreed by consensus that adults with any symptoms or signs suggesting a more serious illness or condition or, with symptoms that are not improving as expected with antibiotics, should be referred to hospital if they are being treated in the community.\n\nThe committee recognised that not all children and young people need to have their treatment managed in hospital, and referral should be based on clinical judgement because no evidence was identified. They agreed that community-acquired pneumonia is less common in children and young people, and that referral to hospital should be considered, or specialist paediatric advice on further investigation and management should be sought.\n\nThe committee also agreed by consensus that referral or seeking specialist advice should be considered for adults with community-acquired pneumonia who have bacteria that are resistant to oral antibiotics, or who cannot take oral antibiotics (to explore locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, if this is appropriate).\n\n# Antibiotic dosage\n\nLow‑dose antibiotics were not significantly different from high‑dose antibiotics for any clinical or bacteriological outcomes reported, in adults with low-severity community-acquired pneumonia:\n\n\n\nlevofloxacin 500\xa0mg once a day compared with levofloxacin 750\xa0mg once a day; 1\xa0non-inferiority RCT, Zhao et al. 2016).\n\nco-amoxiclav 875/125\xa0mg three times a day compared with co‑amoxiclav 2000/125\xa0mg twice a day, including in a subgroup analysis of adults with atypical pathogens, S.\xa0pneumoniae or H.\xa0influenzae infection (1\xa0non-inferiority RCT, Siquier et al. 2006).\n\n\n\nLow‑dose amoxicillin (45\xa0mg/kg/day divided into 3\xa0doses) was not significantly different to high‑dose amoxicillin (90\xa0mg/kg/day divided into 3\xa0doses) for clinical improvement in young children (2\xa0to\xa059\xa0months) with non-severe community-acquired pneumonia (1\xa0non-inferiority RCT, Hazir et al. 2007).\n\nAmoxicillin given twice a day (total 50\xa0mg/kg/day) was not significantly different to amoxicillin given three times a day at the same dose (total 50\xa0mg/kg/day) for clinical failure rates in young children (2\xa0to\xa059\xa0months) with non-severe community-acquired pneumonia (1\xa0non-inferiority RCT, Vilas-Boas et al. 2014).\n\nLow‑dose benzylpenicillin (200,000\xa0IU/kg/day divided into 4\xa0doses) was not significantly different to high‑dose benzylpenicillin (400,000\xa0IU/kg/day divided into 4\xa0doses) for duration of hospital stay, duration of intravenous treatment or C‑reactive protein levels in young children (3\xa0months to 15\xa0years) with severe community-acquired pneumonia (1\xa0RCT, Amarilyo et al. 2014).\n\nNo evidence from systematic reviews or RCTs was identified in adults with moderate- or high-severity community-acquired pneumonia.\n\nCommittee discussions on antibiotic dosage\n\nBased on evidence showing no differences between low‑dose and high‑dose antibiotics, and its experience, the committee agreed that usual BNF doses for community-acquired pneumonia (or respiratory tract infections) should be used. However, they recognised the importance of consulting BNF, BNF for children and MHRA advice for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and for information on administering intravenous antibiotics.\n\nThe committee noted that no evidence was identified in adults with moderate- or high-severity community-acquired pneumonia, and only 1\xa0small RCT in young children with severe community-acquired pneumonia was identified. Based on its experience and the higher risk of mortality in people with a severe infection, the committee agreed that where a range of doses are given, the higher dose is appropriate for these people.\n\nBased on clinical experience and evidence in adults with low-severity community-acquired pneumonia that high‑dose erythromycin is associated with more adverse effects, the committee agreed that the usual BNF dose for erythromycin should be used when this is recommended as an option for women and young women aged 8\xa0years and over who are pregnant.\n\n# Antibiotic course length\n\nShort‑course antibiotics (3\xa0to\xa07\xa0days) were not significantly different to long‑course antibiotics (10\xa0to\xa014\xa0days) for mortality or clinical failure in adults with low- to moderate-severity community-acquired pneumonia (1\xa0systematic review, Li et al. 2007).\n\nShort‑course amoxicillin (3\xa0days) was not significantly different to long‑course amoxicillin (8\xa0days) for clinical cure, bacteriological or radiological success, and length of hospital stay, in adults with low‑ to moderate-severity community-acquired pneumonia (1\xa0RCT, El Moussaoui et al. 2006).\n\nShort‑course antibiotics (amoxicillin or co-trimoxazole for 3\xa0days) were not significantly different to a 5‑day course of the same antibiotic for clinical cure or relapse, in young children (2\xa0to\xa059\xa0months) with non-severe community-acquired pneumonia. The same results were seen when amoxicillin and co‑trimoxazole were analysed separately (1\xa0systematic review, Haider et al. 2008).\n\nShort‑course amoxicillin (3\xa0days) was significantly worse than a 10‑day course of amoxicillin (at the same dose) for treatment failure (4/10 versus 0/56) in young children (6\xa0to\xa059\xa0months) with non-severe community-acquired pneumonia (1\xa0RCT, Greenberg et al. 2014).\n\nShort‑course amoxicillin (5\xa0days) was not significantly different to a 10‑day course of amoxicillin (at the same dose) for treatment failure in young children (6\xa0to\xa059\xa0months) with non-severe community-acquired pneumonia. However, C‑reactive protein at day\xa05\xa0to\xa07 was significantly worse with the 5‑day course (1\xa0RCT, Greenberg et al. 2014).\n\nNo evidence from systematic reviews or RCTs was identified in adults or children with severe community-acquired pneumonia.\n\nCommittee discussions on antibiotic course length\n\nThe committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects. However, an effective course length is important in community-acquired pneumonia because this can be a life-threatening infection.\n\nThe committee discussed evidence for antibiotic course length in adults, young people and children with community-acquired pneumonia. Overall, there did not appear to be major differences between short‑ and long‑course antibiotics, but they noted some inconsistency in the evidence for adults and children. It was also aware that no evidence was identified in children and young people with severe community-acquired pneumonia.\n\nThe committee agreed that there were several limitations which reduced the applicability of the evidence to UK practice (for example, evidence on antibiotic comparisons not recommended or available in the UK, or a lack of critical outcome reporting).\n\nThe committee noted the Uranga et al. (2016) study carried out in adults, which found that antibiotics given for a minimum of 5\xa0days, with a strategy of stopping treatment if fever was absent for 48\xa0hours, and there was no more than 1\xa0associated sign of clinical instability, was not different to usual physician's practice. It also noted a similar study (Aliberti et al. 2017), also carried out in adults, which found that antibiotics given for a minimum for 5\xa0days, with a strategy of stopping treatment if clinically stable for 48\xa0hours, was not different to usual physician practice. (See the committee discussion on antibiotic prescribing strategies.)\n\nBased on its experience and the risks of antimicrobial resistance with longer courses, the committee agreed by consensus that a 5‑day course of recommended antibiotics was appropriate to treat community-acquired pneumonia for adults, young people and children.\n\n# Antibiotic route of administration\n\nIntravenous antibiotics switching to oral antibiotics after 2\xa0to\xa04\xa0days if there was clinical improvement was not significantly different to continuous intravenous antibiotics for mortality, treatment success or recurrence of infection in adults with moderate‑ to high severity community-acquired pneumonia. However, there were significantly fewer days in hospital and adverse events with the switch to oral antibiotics (1\xa0systematic review, Athanassa et al. 2008).\n\nOral antibiotics (amoxicillin or co‑trimoxazole) were not significantly different to intravenous or intermuscular penicillins for clinical failure rate in children and young people (1\xa0month to 18\xa0years) with non-severe community-acquired pneumonia (1\xa0systematic review, Lodha et al. 2013).\n\nOral antibiotics (amoxicillin or co‑trimoxazole) were significantly better than intravenous or intramuscular penicillins for mortality (0.05% versus 0.56%), in children and young people (3\xa0months to 18\xa0years) with severe community-acquired pneumonia. However, there were no significant differences in the rates of cure, clinical failure, hospitalisation or relapse, including when oral amoxicillin was analysed separately (Lodha et al.\xa02013).\n\nCommittee discussions on antibiotic route of administration\n\nThe committee discussed evidence on route of administration, which found that oral antibiotics are as effective as injectable antibiotics for children and young people with non-severe community-acquired pneumonia and are more effective for children and young people with severe community-acquired pneumonia.\n\nBased on the evidence and taking account of the principles of antimicrobial stewardship, the committee agreed that oral antibiotics should be given first line for most children and young people, unless they cannot take oral medicines (for example, if they are vomiting), or the severity of infection means that intravenous antibiotics are required.\n\nBased on its experience, the principles of antimicrobial stewardship and supported by the evidence in children and young people, the committee agreed that oral antibiotics should also usually be given first line for adults.\n\nFor people with non‑severe symptoms or signs, intravenous antibiotics may be required if the person is unable to take oral medicines.\n\nIn line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that if intravenous antibiotics are used initially, this should be reviewed by 48\xa0hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration. See the NICE guideline on medicines adherence.\n\n# Resource implications\n\nRecommended antibiotics are all available as generic formulations. See the Drug Tariff and the BNF for costs.\n\nSee the evidence review for more information.'}
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https://www.nice.org.uk/guidance/ng138
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This guideline sets out an antimicrobial prescribing strategy for community-acquired pneumonia. It aims to optimise antibiotic use and reduce antibiotic resistance.
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b2104d368adea3d6bb15f8783f12f388e28df2c2
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nice
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Pneumonia (hospital-acquired): antimicrobial prescribing
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Pneumonia (hospital-acquired): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for hospital‑acquired pneumonia. It does not cover ventilator‑associated pneumonia. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
For recommendations on identifying and treating hospital-acquired bacterial pneumonia secondary to COVID-19, see our rapid guideline on managing acute COVID-19.
# Managing hospital-acquired pneumonia
## Treatment for adults, young people and children
For adults, young people and children with symptoms or signs of pneumonia starting within 48 hours of hospital admission, follow the NICE guideline on community-acquired pneumonia.
Offer an antibiotic(s) for adults, young people and children with hospital-acquired pneumonia. When choosing an antibiotic(s) (see the recommendations on choice of antibiotic), take account of:
the severity of symptoms or signs (at the time of publication, in September 2019, no validated severity assessment tools are available for hospital-acquired pneumonia, and severity of symptoms or signs should be based on clinical judgement)
the number of days in hospital before onset of symptoms
the risk of developing complications, for example, if the person has a relevant comorbidity such as severe lung disease or immunosuppression
local hospital and ward-based antimicrobial resistance data
recent antibiotic use
recent microbiological results, including colonisation with multidrug-resistant bacteria
recent contact with a health or social care setting before current admission
the risk of adverse effects with broad-spectrum antibiotics, such as Clostridium difficile infection.
Start antibiotic treatment as soon as possible after establishing a diagnosis of hospital-acquired pneumonia, and certainly within 4 hours (within 1 hour if the person has suspected sepsis and meets any of the high risk criteria for this – see the NICE guideline on sepsis).
Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
If intravenous antibiotics are given, review by 48 hours and consider switching to oral antibiotics if possible.
Send a sample (for example, sputum sample, nasopharyngeal swab or tracheal aspirate) for microbiological testing.
## Reassessment and specialist advice
When microbiological results are available:
review the choice of antibiotic(s) and
change the antibiotic(s) according to results, using a narrower-spectrum antibiotic, if appropriate.
Reassess adults, young people and children with hospital-acquired pneumonia if symptoms do not improve as expected or worsen rapidly or significantly.
Seek specialist advice from a microbiologist for adults, young people and children with hospital-acquired pneumonia if they have:
symptoms that are not improving as expected with antibiotics or
multidrug-resistant bacteria.
Follow the NICE guideline on care of dying adults in the last days of life when caring for adults with hospital-acquired pneumonia who are approaching their end of life.
See the evidence and committee discussions on antibiotic prescribing strategies and choice of antibiotics.
# Choice of antibiotic
When prescribing an antibiotic(s) for hospital-acquired pneumonia:
follow table 1 for adults aged 18 years and over
follow table 2 for children and young people under 18 years.
Consider following the NICE guideline on community-acquired pneumonia for choice of antibiotic for adults, young people and children with symptoms or signs of pneumonia starting within days 3 to 5 of hospital admission who are not at higher risk of resistance. Higher risk of resistance includes relevant comorbidity (such as severe lung disease or immunosuppression), recent use of broad-spectrum antibiotics, colonisation with multidrug-resistant bacteria, and recent contact with health and social care settings before current admission.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotic if non‑severe symptoms or signs, and not at higher risk of resistance (guided by microbiological results when available)
Co-amoxiclav:
/125 mg three times a day for 5 days then review
Alternative oral antibiotics if non‑severe symptoms or signs, and not at higher risk of resistance, for penicillin allergy or if co‑amoxiclav unsuitable (based on specialist microbiological advice and local resistance data)
Options include:
Doxycycline:
mg on first day, then 100 mg once a day for 4 days (5‑day course) then review
Cefalexin (caution in penicillin allergy):
mg twice or three times a day (can be increased to 1 g to 1.5 g three or four times a day) for 5 days then review
Co‑trimoxazole (off-label use):
mg twice a day for 5 days then review
(see BNF for information on monitoring)
Levofloxacin (only if switching from intravenous levofloxacin with specialist advice; off-label use; consider safety issues):
mg once or twice a day for 5 days then review
First-choice intravenous antibiotics if severe symptoms or signs (for example, symptoms or signs of sepsis) or at higher risk of resistance (based on specialist microbiological advice and local resistance data)
Options include:
Piperacillin with tazobactam:
g three times a day (increased to 4.5 g four times a day if severe infection)
Ceftazidime:
g three times a day
Ceftriaxone:
g once a day
Cefuroxime:
mg three times a day (increased to 750 mg four times a day or 1.5 g three or four times a day if severe infection)
Meropenem:
g to 1 g three times a day
Ceftazidime with avibactam:
/0.5 g three times a day
Levofloxacin (off-label use; consider safety issues):
mg once or twice a day (use higher dosage if severe infection)
Antibiotics to be added if suspected or confirmed meticillin-resistant
Staphylococcus aureus
infection (dual therapy with a first-choice intravenous antibiotic)
Vancomycin:
mg/kg to 20 mg/kg two or three times a day intravenously, adjusted according to serum vancomycin concentration (a loading dose of 25 mg/kg to 30 mg/kg can be used in seriously ill people); maximum 2 g per dose
(see BNF for information on monitoring)
Teicoplanin:
Initially 6 mg/kg every 12 hours for 3 doses, then 6 mg/kg once a day intravenously
(see BNF for information on monitoring)
Linezolid (if vancomycin cannot be used; specialist advice only):
mg twice a day orally or intravenously
(see BNF for information on monitoring)
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.
Higher risk of resistance includes symptoms or signs starting more than 5 days after hospital admission, relevant comorbidity such as severe lung disease or immunosuppression, recent use of broad-spectrum antibiotics, colonisation with multidrug-resistant bacteria, and recent contact with a health or social care setting before current admission.
Review treatment after a total of 5 days of antibiotics and consider stopping antibiotics if clinically stable. Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics for a total of 5 days, then review.
For off-label use, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information.
See Medicines and Healthcare products Regulatory Agency (MHRA) advice for restrictions and precautions for using fluoroquinolone antibiotics because of very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution for people over 60 years and avoiding coadministration with a corticosteroid (March 2019).
Treatment
Antibiotic, dosage and course length
Choice for children under 1 month
Antibiotic choice based on local resistance data and specialist microbiological advice
First choice oral antibiotic for children aged 1 month and over if non-severe symptoms or signs and not at higher risk of resistance (guided by microbiological results when available)
Co‑amoxiclav:
month to 11 months, 0.5 ml/kg of 125/31 suspension three times a day for 5 days, then review
year to 5 years, 10 ml of 125/31 suspension (or 5 ml of 250/62 suspension) three times a day, or 0.5 ml/kg of 125/31 suspension three times a day for 5 days, then review
years to 11 years, 10 ml of 250/62 suspension three times a day or 0.3 ml/kg of 250/62 suspension three times a day for 5 days, then review
years to 17 years, 500/125 mg three times a day for 5 days, then review
Alternative oral antibiotic for children aged 1 month and over if non-severe symptoms or signs and not at higher risk of resistance, for penicillin allergy or if co‑amoxiclav unsuitable (other options may be suitable based on specialist microbiological advice and local resistance data)
Clarithromycin:
month to 11 years:
Under 8 kg, 7.5 mg/kg twice a day for 5 days, then review
kg to 11 kg, 62.5 mg twice a day for 5 days, then review
kg to 19 kg, 125 mg twice a day for 5 days, then review
kg to 29 kg, 187.5 mg twice a day for 5 days, then review
kg to 40 kg, 250 mg twice a day for 5 days, then review
years to 17 years, 500 mg twice a day for 5 days, then review
First-choice intravenous antibiotics if severe symptoms or signs (for example, symptoms or signs of sepsis), or at higher risk of resistance (antibiotic choice should be based on specialist microbiological advice and local resistance data)
Options include:
Piperacillin with tazobactam:
month to 11 years, 90 mg/kg three or four times a day (maximum 4.5 g per dose four times a day)
years to 17 years, 4.5 g three times a day (increased to 4.5 g four times a day if severe infection)
Ceftazidime:
month to 17 years, 25 mg/kg three times a day (50 mg/kg three times a day if severe infection; maximum 6 g per day)
Ceftriaxone:
month to 11 years (up to 50 kg), 50 mg/kg to 80 mg/kg once a day (use dose at higher end of range if severe infection; maximum 4 g per day)
years to 11 years (50 kg and above), 2 g once a day
years to 17 years, 2 g once a day
Antibiotics to be added if suspected or confirmed meticillin-resistant
Staphylococcus aureus
infection (dual therapy with a first-choice intravenous antibiotic)
Teicoplanin:
month, initially 16 mg/kg for 1 dose, then 8 mg/kg once daily, subsequent dose to be given 24 hours after initial dose (doses given by intravenous infusion)
months to 11 years, initially 10 mg/kg every 12 hours intravenously for 3 doses, then 6 mg/kg to 10 mg/kg once daily intravenously
years to 17 years, initially 6 mg/kg every 12 hours intravenously for 3 doses, then 6 mg/kg once daily intravenously
(see BNF for children for information on monitoring)
Vancomycin:
month to 11 years, 10 mg/kg to 15 mg/kg four times a day intravenously, adjusted according to serum-vancomycin concentration
years to 17 years, 15 mg/kg to 20 mg/kg two or three times a day intravenously, adjusted according to serum vancomycin concentration (a loading dose of 25 mg/kg to 30 mg/kg can be used in seriously ill people); maximum 2 g per dose
(see BNF for children for information on monitoring)
Linezolid (if vancomycin cannot be used; off-label use; specialist advice only):
months to 11 years, 10 mg/kg three times a day orally or intravenously (maximum 600 mg per dose)
years to 17 years, 600 mg twice a day orally or intravenously
(see BNF for children for information on monitoring)
See the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.
Higher risk of resistance includes symptoms or signs starting more than 5 days after hospital admission, relevant comorbidity such as severe lung disease or immunosuppression, recent use of broad-spectrum antibiotics, colonisation with multidrug-resistant bacteria, and recent contact with a health or social care setting before current admission.
Review treatment after a total of 5 days of antibiotics and consider stopping antibiotics if clinically stable. Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics for a total of 5 days, then review.
For off-label use, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information.
See the evidence and committee discussions on choice of antibiotic and antibiotic course length, dosage and route of administration.
# Terms used in the guideline
## Hospital-acquired pneumonia
Pneumonia that develops 48 hours or more after hospital admission and that was not incubating at hospital admission. When managed in hospital, the diagnosis is usually confirmed by chest X‑ray. For the purpose of this guideline, pneumonia that develops in hospital after intubation (ventilator-associated pneumonia) is excluded from this definition.# Summary of the evidence
This is a summary of the evidence. For full details, see the evidence review.
Hospital-acquired pneumonia is a lower respiratory tract infection that may be life threatening.
Early-onset hospital-acquired pneumonia (less than 5 days after admission to hospital) is usually caused by Streptococcus pneumoniae and late-onset (more than 5 days after admission to hospital) is usually caused by microorganisms that are acquired in hospital, most commonly methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and other non-pseudomonal gram-negative bacteria.
No evidence from systematic reviews or randomised controlled trials (RCTs) was identified in children or young people under 18 years.
# Antibiotic prescribing strategies
An antibiotic prescribing strategy (guided by results of immediate bronchoscopy with protected specimen brush sample culture) was not significantly different from immediate antibiotics for clinical cure and mortality up to 28 days in adults with hospital-acquired pneumonia (non-ventilated; Herer et al. 2009). Bronchoscopy was carried out within 24 hours of clinical diagnosis and gram-stain results (available 4 hours to 6 hours after bronchoscopy) were used to modify treatment.
The total costs (antibiotics and bronchoscopy) of each strategy were not significantly different overall.
An antibiotic prescribing strategy of using antibiotics with very broad antimicrobial cover (imipenem with cilastatin plus vancomycin) followed by de‑escalation to a broad-spectrum antibiotic based on culture results was significantly better than empirical antibiotics for achieving adequate initial antimicrobial cover. However, there were no significant differences in clinical outcomes, including mortality up to 28 days (Kim et al. 2012). This study included non-ventilated adults with hospital-acquired pneumonia and a small proportion of adults with ventilator-associated pneumonia (8.3%).
The overall incidence of multidrug-resistant bacteria was significantly higher with very broad antimicrobial cover followed by de‑escalation, compared with empirical antibiotics.
Evidence for antibiotic prescribing strategies is based on 2 RCTs (Herer et al. 2009 and Kim et al. 2012).
Committee discussion on antibiotic prescribing strategies
The committee noted that the bronchoscopy antibiotic prescribing strategy used by Herer et al. (2009) was not consistent with clinical practice in the UK; culture results are not usually available within 24 hours and sputum cultures are more common than gram staining of bronchoscopy samples.
The committee noted that overall there were no significant differences in clinical outcomes between the 2 prescribing strategies. Because of the lack of applicability to UK practice, and the small sample size, the committee agreed that there was insufficient evidence to show that the prescribing strategies were equivalent.
The committee discussed evidence from Kim et al. (2012) suggesting no difference in clinical outcomes between a prescribing strategy of very-broad-spectrum antibiotics with de‑escalation, compared with empirical antibiotics. However, the committee was concerned that the rate of emergence of multidrug-resistant bacteria was significantly higher with the very-broad-spectrum antibiotics followed by de‑escalation strategy.
The committee was concerned about the risk of antimicrobial resistance from using very-broad-spectrum antibiotics for longer than necessary, as well as the high rates of adverse effects in some of the included studies. Therefore, the committee concluded that a respiratory sample (for example, sputum sample, nasopharyngeal swab or tracheal aspirate) should be taken and sent for microbiological testing if possible. This reflects current practice.
The committee agreed that when microbiological results are available, the antibiotic should be reviewed and changed accordingly (for example, if bacteria are found to be resistant), using a narrower-spectrum antibiotic, if appropriate.
# Choice of antibiotics
## Efficacy of antibiotics
Overall, there were no differences in the clinical effectiveness (clinical cure or mortality) in a range of antibiotic comparisons in adults with hospital-acquired pneumonia:
penicillin with beta-lactamase inhibitor (piperacillin with tazobactam) compared with a carbapenem (imipenem with cilastatin; Schmitt et al. 2006)
cephalosporin with beta-lactamase inhibitor (ceftazidime with avibactam) compared with a carbapenem (meropenem; Torres et al. 2017)
tetracycline (tigecycline) compared with a carbapenem (imipenem with cilastatin; Freire et al. 2010 and Ramirez et al. 2013)
fluoroquinolone (moxifloxacin) compared with a cephalosporin (ceftriaxone followed by cefuroxime; Hoffken et al. 2007)
cephalosporin (ceftobiprole) compared with cephalosporin plus oxazolidinone (ceftazidime plus linezolid; Awad et al. 2014)
glycopeptide (telavancin) compared with glycopeptide (vancomycin; Rubinstein et al. 2011 reported in Rubinstein et al. 2014).
Evidence for efficacy of antibiotics is based on 6 RCTs (Schmitt et al. 2006, Torres et al. 2017, Freire et al. 2010, Ramirez et al. 2013, Hoffken et al. 2007 and Awad et al. 2014) and 1 post-hoc analysis of an RCT (Rubinstein et al. 2014).
## Safety of antibiotics
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, August 2019).
Macrolides (for example, clarithromycin) should be used with caution in people with a predisposition to QT interval prolongation (BNF, August 2019).
Tetracyclines (for example, doxycycline), can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant or breastfeeding women, and use in children under 12 years is either contraindicated or cautioned for use in severe or life-threatening infections where there are no alternatives (BNF, August 2019).
Co-trimoxazole is associated with rare but serious side effects including blood disorders and Stevens–Johnson syndrome. It is cautioned for use in older people because there is an increased risk of serious adverse effects, and in those with a predisposition to hyperkalaemia. Monitoring of blood counts is recommended with prolonged treatment (BNF, August 2019).
Fluoroquinolones have restrictions and precautions around their use because of rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems (MHRA Drug Safety Update, March 2019). They may also be associated with a small increased risk of aortic aneurysm and dissection, particularly in older people (MHRA Drug Safety Update, November 2018).
Glycopeptide (for example, vancomycin and teicoplanin) doses are based on body weight. Therapeutic drug monitoring and monitoring of various patient parameters including blood count, urinalysis, auditory function, hepatic function and renal function is recommended depending on the particular glycopeptide (BNF, August 2019).
Severe optic neuropathy can occur with linezolid, particularly if used for longer than 28 days. Blood disorders have also been reported and weekly full blood counts are recommended (BNF, August 2019).
Overall, there were no significant differences in adverse effects in the studies between antibiotics or classes of antibiotics in people with hospital-acquired pneumonia.
Treatment-related adverse events were significantly higher with moxifloxacin compared with a cephalosporin (intravenous ceftriaxone then oral cefuroxime; 30% versus 16%, number needed to harm 7 ).
Significantly more people stopped treatment because of adverse events with tigecycline than with imipenem with cilastatin (10.9% versus 6.6%, NNH 23 ).
See the summaries of product characteristics for information on contraindications, cautions, drug interactions and adverse effects of individual medicines.
Committee discussion on choice of antibiotics
The committee agreed that prompt antibiotic treatment should be offered to everyone with hospital-acquired pneumonia.
The committee discussed the definition of hospital-acquired pneumonia. Because it includes people with pneumonia that develops 48 hours or more after hospital admission and that was not incubating at hospital admission, the committee agreed that the NICE guideline on community-acquired pneumonia should be followed for people with symptoms or signs of pneumonia starting on days 1 or 2 after hospital admission.
The committee discussed the timing of antibiotic treatment and was aware of current practice to offer antibiotics within 4 hours. No systematic reviews or RCTs were identified, and the committee agreed that there was no reason to change current practice. However, they noted that the timing should be within 4 hours of an established diagnosis to avoid inappropriate use of broad-spectrum antibiotics.
The committee noted that evidence was identified in adults only, and for a limited number of head-to-head antibiotic comparisons. They agreed that recommendations for children and young people should be based on its experience and extrapolation of evidence in adults, taking account of any relevant medicines safety concerns.
Given the clinical expertise needed for assessing and managing hospital-acquired pneumonia in very young children (under 1 month), the committee agreed that the choice of antibiotic in these children should be based on local resistance data and specialist microbiological advice.
Overall, the limited evidence showed no differences in clinical effectiveness between different broad-spectrum antibiotics or classes of antibiotics, with some small differences in the rates of adverse effects. The committee noted the high rates of adverse events for many broad-spectrum antibiotics included in the studies.
The committee discussed the most common causes of hospital-acquired pneumonia. They agreed that cause is often uncertain because many people do not have a microbiological diagnosis.
They recognised that S. pneumoniae is the most common cause in people who develop hospital-acquired pneumonia within 5 days of hospital admission. The risk of having a multidrug-resistant infection with P. aeruginosa, MRSA or extended-spectrum beta-lactamases (ESBLs) increases in people who develop the infection after more than 5 days of being in hospital, although resistance rates vary locally.
Therefore, the committee agreed that for people with symptoms or signs of pneumonia starting on days 3 to 5 after hospital admission who are not at high risk of resistance, it may be appropriate to follow the NICE guideline on community-acquired pneumonia for recommendations on the choice of antibiotic, based on their clinical judgement. This would give the option to treat some people with amoxicillin, which is a narrower-spectrum antibiotic with activity against S. pneumoniae.
Based on experience, the committee agreed that there are several factors that need to be taken into account when choosing an antibiotic, including the severity of symptoms or signs. The committee did not know of any validated tools for assessing the severity of hospital-acquired pneumonia, and therefore agreed that this should be based on clinical judgement.
The committee also agreed that some people are at higher risk of developing complications, for example, people with a comorbidity such as severe lung disease or immunosuppression.
The committee recognised that, when available, local antimicrobial resistance data are an important consideration in hospital-acquired pneumonia, including at hospital and ward-based level (particularly in high-risk areas such as intensive care, high-dependency units, haematology or oncology).
The committee also agreed that recent use of broad-spectrum antibiotics and recent contact with healthcare services before the current hospital admission were also highly likely to increase the risk of resistant pathogens.
The committee agreed that taking account of these factors would optimise the appropriate use of broad-spectrum antibiotics and minimise the risk of antimicrobial resistance.
The committee agreed that an antibiotic should be started empirically, so as not to delay treatment for an infection with a high-mortality risk.
The committee agreed that the choice of antibiotic should be based on its experience of which antibiotics are effective against likely pathogens and cause the least harm, with the narrowest spectrum possible to minimise the risk of antimicrobial resistance and adverse effects. However, the committee discussed that people with severe symptoms or signs and those at higher risk of resistance will need broad-spectrum antibiotics with high activity against likely organisms.
Based on its experience, the committee recommended co‑amoxiclav as first-choice antibiotic for people with non‑severe symptoms or signs who are not at higher risk of resistance; co‑amoxiclav is a broad-spectrum antibiotic that combines a penicillin with a beta-lactamase inhibitor and has good activity against common pathogens, such as S. pneumoniae and Haemophilus influenzae. The committee also recognised the extensive clinical experience of its effectiveness in this population.
For adults with non‑severe symptoms or signs who are not at higher risk of resistance, with penicillin allergy or in whom co‑amoxiclav is unsuitable (for example, because of local resistance data), the committee agreed that the choice of an alternative antibiotic should be based on local resistance data and specialist microbiological advice only. They agreed that options include:
doxycycline (a tetracycline)
cefalexin (a cephalosporin; not suitable if there is a risk of penicillin-resistant pneumococci)
co‑trimoxazole (trimethoprim plus a sulfonamide)
levofloxacin (a fluoroquinolone; only to be used when switching from IV antibiotics, following specialist advice).
Co‑trimoxazole and levofloxacin are not licensed for hospital-acquired pneumonia, so use would be off-label.
In children and young people with penicillin allergy or in whom co‑amoxiclav is unsuitable, the alternative antibiotic is clarithromycin (a macrolide); this has good activity against common pathogens and is appropriate for use in children and young people. However, the committee recognised that other options may be suitable based on local resistance data and specialist microbiological advice.
The committee agreed that specialist advice should be sought for young women who are pregnant with penicillin allergy or in whom co‑amoxiclav is unsuitable, because they were not able to specify an alternative antibiotic for this population.
Based on its experience, the committee recognised that many broad-spectrum antibiotics would be appropriate as first-choice intravenous antibiotics for people with severe symptoms or signs, or who are at higher risk of resistance. It agreed that the choice should be based on local resistance data and following specialist microbiological advice. Options include:
piperacillin with tazobactam (an antipseudomonal penicillin with a beta-lactamase inhibitor)
ceftazidime (a third-generation cephalosporin)
ceftriaxone (a third-generation cephalosporin)
cefuroxime (a second-generation cephalosporin; in adults)
meropenem (a carbapenem; in adults)
ceftazidime with avibactam (a third-generation cephalosporin with a beta-lactamase inhibitor; in adults)
levofloxacin (in adults).
These antibiotics have good activity against common pathogens in this population, including multidrug-resistant P. aeruginosa, ESBLs and some carbapenemase-producing gram-negative bacteria.
The committee discussed that a small number of people with hospital-acquired pneumonia may have suspected or confirmed infection with MRSA. Therefore, based on their experience, the committee agreed that for these people, 1 of the following antibiotics with activity against MRSA should be added to the treatment regimen:
vancomycin (a glycopeptide)
teicoplanin (a glycopeptide)
linezolid (an oxazolidinone; if vancomycin cannot be used, following specialist advice only). Linezolid is not licensed in children and young people under 18 years, so use would be off-label.
Based on its experience, the committee recommended the same oral antibiotics (discussed above) for people with severe symptoms or signs or at higher risk of resistance who have initially received intravenous antibiotics, to complete the antibiotic course when intravenous antibiotics are no longer required.
The committee recognised that hospital-acquired pneumonia requires careful monitoring. It agreed by consensus that a person's condition should be reassessed if symptoms do not improve as expected or worsen rapidly or significantly at any time.
The committee agreed that for people with symptoms that are not improving as expected with antibiotics, or who are known to have multidrug-resistant bacteria, specialist advice from a microbiologist should be sought.
# Antibiotic course length, dosage and route of administration
No systematic reviews or RCTs were identified that compared antibiotic course lengths, dosage or route of administration.
Committee discussions on antibiotic course length, dosage and route of administration
The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and adverse effects from broad-spectrum antibiotics. However, hospital-acquired pneumonia is a serious infection with a high-mortality risk and needs effective treatment.
Based on its experience and extrapolation of evidence for people with community-acquired pneumonia (see the NICE guideline on community-acquired pneumonia), the committee agreed that a total course of 5 days of antibiotics was the minimum required.
The committee agreed that antibiotic treatment should be reviewed at 5 days. Stopping the antibiotic should be considered on an individual basis if the person is judged to be clinically stable.
Based on its experience, the committee agreed that usual BNF and BNF for children doses for hospital-acquired pneumonia, or severe susceptible infections should be used.
In line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, oral antibiotics should be given first line if the person can take them, and if the severity of their infection does not require intravenous antibiotics. The use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.
For people with severe symptoms or signs or at higher risk of resistance, the committee agreed that intravenous antibiotics should always be given initially.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).
# Resource implications
Recommended antibiotics (except ceftazidime with avibactam) are available as generic formulations. See the Drug Tariff and the BNF for costs.
See the evidence review for more information.
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{'Recommendations': "For recommendations on identifying and treating hospital-acquired bacterial pneumonia secondary to COVID-19, see our rapid guideline on managing acute COVID-19.\n\n# Managing hospital-acquired pneumonia\n\n## Treatment for adults, young people and children\n\nFor adults, young people and children with symptoms or signs of pneumonia starting within 48\xa0hours of hospital admission, follow the NICE guideline on community-acquired pneumonia.\n\nOffer an antibiotic(s) for adults, young people and children with hospital-acquired pneumonia. When choosing an antibiotic(s) (see the recommendations on choice of antibiotic), take account of:\n\nthe severity of symptoms or signs (at the time of publication, in September 2019, no validated severity assessment tools are available for hospital-acquired pneumonia, and severity of symptoms or signs should be based on clinical judgement)\n\nthe number of days in hospital before onset of symptoms\n\nthe risk of developing complications, for example, if the person has a relevant comorbidity such as severe lung disease or immunosuppression\n\nlocal hospital and ward-based antimicrobial resistance data\n\nrecent antibiotic use\n\nrecent microbiological results, including colonisation with multidrug-resistant bacteria\n\nrecent contact with a health or social care setting before current admission\n\nthe risk of adverse effects with broad-spectrum antibiotics, such as Clostridium difficile infection.\n\nStart antibiotic treatment as soon as possible after establishing a diagnosis of hospital-acquired pneumonia, and certainly within 4\xa0hours (within 1\xa0hour if the person has suspected sepsis and meets any of the high risk criteria for this – see the NICE guideline on sepsis).\n\nGive oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nIf intravenous antibiotics are given, review by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nSend a sample (for example, sputum sample, nasopharyngeal swab or tracheal aspirate) for microbiological testing.\n\n## Reassessment and specialist advice\n\nWhen microbiological results are available:\n\nreview the choice of antibiotic(s) and\n\nchange the antibiotic(s) according to results, using a narrower-spectrum antibiotic, if appropriate.\n\nReassess adults, young people and children with hospital-acquired pneumonia if symptoms do not improve as expected or worsen rapidly or significantly.\n\nSeek specialist advice from a microbiologist for adults, young people and children with hospital-acquired pneumonia if they have:\n\nsymptoms that are not improving as expected with antibiotics or\n\nmultidrug-resistant bacteria.\n\nFollow the NICE guideline on care of dying adults in the last days of life when caring for adults with hospital-acquired pneumonia who are approaching their end of life.\n\nSee the evidence and committee discussions on antibiotic prescribing strategies and choice of antibiotics.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic(s) for hospital-acquired pneumonia:\n\nfollow table\xa01 for adults aged 18\xa0years and over\n\nfollow table\xa02 for children and young people under 18\xa0years.\n\nConsider following the NICE guideline on community-acquired pneumonia for choice of antibiotic for adults, young people and children with symptoms or signs of pneumonia starting within days\xa03\xa0to\xa05 of hospital admission who are not at higher risk of resistance. Higher risk of resistance includes relevant comorbidity (such as severe lung disease or immunosuppression), recent use of broad-spectrum antibiotics, colonisation with multidrug-resistant bacteria, and recent contact with health and social care settings before current admission.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotic if non‑severe symptoms or signs, and not at higher risk of resistance (guided by microbiological results when available)\n\nCo-amoxiclav:\n\n/125\xa0mg three times a day for 5\xa0days then review\n\nAlternative oral antibiotics if non‑severe symptoms or signs, and not at higher risk of resistance, for penicillin allergy or if co‑amoxiclav unsuitable (based on specialist microbiological advice and local resistance data)\n\nOptions include:\n\nDoxycycline:\n\nmg on first day, then 100\xa0mg once a day for 4\xa0days (5‑day course) then review\n\n\n\nCefalexin (caution in penicillin allergy):\n\nmg twice or three times a day (can be increased to 1\xa0g to 1.5\xa0g three or four times a day) for 5\xa0days then review\n\n\n\nCo‑trimoxazole (off-label use):\n\nmg twice a day for 5\xa0days then review\n\n(see BNF for information on monitoring)\n\n\n\nLevofloxacin (only if switching from intravenous levofloxacin with specialist advice; off-label use; consider safety issues):\n\nmg once or twice a day for 5\xa0days then review\n\nFirst-choice intravenous antibiotics if severe symptoms or signs (for example, symptoms or signs of sepsis) or at higher risk of resistance (based on specialist microbiological advice and local resistance data)\n\nOptions include:\n\nPiperacillin with tazobactam:\n\ng three times a day (increased to 4.5\xa0g four times a day if severe infection)\n\n\n\nCeftazidime:\n\ng three times a day\n\n\n\nCeftriaxone:\n\ng once a day\n\n\n\nCefuroxime:\n\nmg three times a day (increased to 750\xa0mg four times a day or 1.5\xa0g three or four times a day if severe infection) [amended October 2020]\n\n\n\nMeropenem:\n\ng to 1\xa0g three times a day\n\n\n\nCeftazidime with avibactam:\n\n/0.5\xa0g three times a day\n\n\n\nLevofloxacin (off-label use; consider safety issues):\n\nmg once or twice a day (use higher dosage if severe infection)\n\nAntibiotics to be added if suspected or confirmed meticillin-resistant \n \n Staphylococcus aureus\n \n infection (dual therapy with a first-choice intravenous antibiotic)\n\nVancomycin:\n\nmg/kg to 20\xa0mg/kg two or three times a day intravenously, adjusted according to serum vancomycin concentration (a loading dose of 25\xa0mg/kg to 30\xa0mg/kg can be used in seriously ill people); maximum 2\xa0g per dose\n\n(see BNF for information on monitoring)\n\n\n\nTeicoplanin:\n\nInitially\xa06 mg/kg every 12\xa0hours for 3\xa0doses, then 6\xa0mg/kg once a day intravenously\n\n(see BNF for information on monitoring)\n\n\n\nLinezolid (if vancomycin cannot be used; specialist advice only):\n\nmg twice a day orally or intravenously\n\n(see BNF for information on monitoring)\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.\n\nHigher risk of resistance includes symptoms or signs starting more than 5\xa0days after hospital admission, relevant comorbidity such as severe lung disease or immunosuppression, recent use of broad-spectrum antibiotics, colonisation with multidrug-resistant bacteria, and recent contact with a health or social care setting before current admission.\n\nReview treatment after a total of 5\xa0days of antibiotics and consider stopping antibiotics if clinically stable. Review intravenous antibiotics by 48\xa0hours and consider switching to oral antibiotics for a total of 5\xa0days, then review.\n\nFor off-label use, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information.\n\nSee Medicines and Healthcare products Regulatory Agency (MHRA) advice for restrictions and precautions for using fluoroquinolone antibiotics because of very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution for people over 60\xa0years and avoiding coadministration with a corticosteroid (March\xa02019).\n\n\n\nTreatment\n\nAntibiotic, dosage and course length\n\nChoice for children under 1\xa0month\n\nAntibiotic choice based on local resistance data and specialist microbiological advice\n\nFirst choice oral antibiotic for children aged 1\xa0month and over if non-severe symptoms or signs and not at higher risk of resistance (guided by microbiological results when available)\n\nCo‑amoxiclav:\n\nmonth to 11\xa0months, 0.5\xa0ml/kg of 125/31 suspension three times a day for 5\xa0days, then review\n\n\n\nyear to 5\xa0years, 10\xa0ml of 125/31 suspension (or 5\xa0ml of 250/62 suspension) three times a day, or 0.5\xa0ml/kg of 125/31 suspension three times a day for 5\xa0days, then review\n\n\n\nyears to 11\xa0years, 10\xa0ml of 250/62 suspension three times a day or 0.3\xa0ml/kg of 250/62 suspension three times a day for 5\xa0days, then review\n\n\n\nyears to 17\xa0years, 500/125\xa0mg three times a day for 5\xa0days, then review\n\nAlternative oral antibiotic for children aged 1\xa0month and over if non-severe symptoms or signs and not at higher risk of resistance, for penicillin allergy or if co‑amoxiclav unsuitable (other options may be suitable based on specialist microbiological advice and local resistance data)\n\nClarithromycin:\n\nmonth to 11\xa0years:\n\nUnder 8\xa0kg, 7.5\xa0mg/kg twice a day for 5\xa0days, then review\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day for 5\xa0days, then review\n\nkg to 19\xa0kg, 125\xa0mg twice a day for 5\xa0days, then review\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day for 5\xa0days, then review\n\nkg to 40\xa0kg, 250\xa0mg twice a day for 5\xa0days, then review\n\n\n\nyears to 17\xa0years, 500\xa0mg twice a day for 5\xa0days, then review\n\nFirst-choice intravenous antibiotics if severe symptoms or signs (for example, symptoms or signs of sepsis), or at higher risk of resistance (antibiotic choice should be based on specialist microbiological advice and local resistance data)\n\nOptions include:\n\nPiperacillin with tazobactam:\n\nmonth to 11\xa0years, 90\xa0mg/kg three or four times a day (maximum 4.5\xa0g per dose four times a day)\n\nyears to 17\xa0years, 4.5\xa0g three times a day (increased to 4.5\xa0g four times a day if severe infection)\n\n\n\nCeftazidime:\n\nmonth to 17\xa0years, 25\xa0mg/kg three times a day (50\xa0mg/kg three times a day if severe infection; maximum 6\xa0g per day)\n\n\n\nCeftriaxone:\n\nmonth to 11\xa0years (up to 50\xa0kg), 50\xa0mg/kg to 80\xa0mg/kg once a day (use dose at higher end of range if severe infection; maximum 4\xa0g per day)\n\nyears to 11\xa0years (50\xa0kg and above), 2\xa0g once a day\n\nyears to 17\xa0years, 2\xa0g once a day\n\nAntibiotics to be added if suspected or confirmed meticillin-resistant \n \n Staphylococcus aureus\n \n infection (dual therapy with a first-choice intravenous antibiotic)\n\nTeicoplanin:\n\nmonth, initially 16\xa0mg/kg for 1\xa0dose, then 8\xa0mg/kg once daily, subsequent dose to be given 24\xa0hours after initial dose (doses given by intravenous infusion)\n\nmonths to 11\xa0years, initially 10\xa0mg/kg every 12\xa0hours intravenously for 3\xa0doses, then 6\xa0mg/kg to 10\xa0mg/kg once daily intravenously\n\nyears to 17\xa0years, initially 6\xa0mg/kg every 12\xa0hours intravenously for 3\xa0doses, then 6\xa0mg/kg once daily intravenously\n\n(see BNF for children for information on monitoring)\n\n\n\nVancomycin:\n\nmonth to 11\xa0years, 10\xa0mg/kg to 15\xa0mg/kg four times a day intravenously, adjusted according to serum-vancomycin concentration\n\nyears to 17\xa0years, 15\xa0mg/kg to 20\xa0mg/kg two or three times a day intravenously, adjusted according to serum vancomycin concentration (a loading dose of 25\xa0mg/kg to 30\xa0mg/kg can be used in seriously ill people); maximum 2\xa0g per dose\n\n(see BNF for children for information on monitoring)\n\n\n\nLinezolid (if vancomycin cannot be used; off-label use; specialist advice only):\n\nmonths to 11\xa0years, 10\xa0mg/kg three times a day orally or intravenously (maximum 600\xa0mg per dose)\n\nyears to 17\xa0years, 600\xa0mg twice a day orally or intravenously\n\n(see BNF for children for information on monitoring)\n\nSee the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.\n\nHigher risk of resistance includes symptoms or signs starting more than 5\xa0days after hospital admission, relevant comorbidity such as severe lung disease or immunosuppression, recent use of broad-spectrum antibiotics, colonisation with multidrug-resistant bacteria, and recent contact with a health or social care setting before current admission.\n\nReview treatment after a total of 5\xa0days of antibiotics and consider stopping antibiotics if clinically stable. Review intravenous antibiotics by 48\xa0hours and consider switching to oral antibiotics for a total of 5\xa0days, then review.\n\nFor off-label use, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information.\n\nSee the evidence and committee discussions on choice of antibiotic and antibiotic course length, dosage and route of administration.\n\n# Terms used in the guideline\n\n## Hospital-acquired pneumonia\n\nPneumonia that develops 48\xa0hours or more after hospital admission and that was not incubating at hospital admission. When managed in hospital, the diagnosis is usually confirmed by chest X‑ray. For the purpose of this guideline, pneumonia that develops in hospital after intubation (ventilator-associated pneumonia) is excluded from this definition.", 'Summary of the evidence': "This is a summary of the evidence. For full details, see the evidence review.\n\nHospital-acquired pneumonia is a lower respiratory tract infection that may be life threatening.\n\nEarly-onset hospital-acquired pneumonia (less than 5\xa0days after admission to hospital) is usually caused by Streptococcus pneumoniae and late-onset (more than 5\xa0days after admission to hospital) is usually caused by microorganisms that are acquired in hospital, most commonly methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and other non-pseudomonal gram-negative bacteria.\n\nNo evidence from systematic reviews or randomised controlled trials (RCTs) was identified in children or young people under 18\xa0years.\n\n# Antibiotic prescribing strategies\n\nAn antibiotic prescribing strategy (guided by results of immediate bronchoscopy with protected specimen brush sample culture) was not significantly different from immediate antibiotics for clinical cure and mortality up to 28\xa0days in adults with hospital-acquired pneumonia (non-ventilated; Herer et\xa0al. 2009). Bronchoscopy was carried out within 24\xa0hours of clinical diagnosis and gram-stain results (available 4\xa0hours to\xa06\xa0hours after bronchoscopy) were used to modify treatment.\n\nThe total costs (antibiotics and bronchoscopy) of each strategy were not significantly different overall.\n\nAn antibiotic prescribing strategy of using antibiotics with very broad antimicrobial cover (imipenem with cilastatin plus vancomycin) followed by de‑escalation to a broad-spectrum antibiotic based on culture results was significantly better than empirical antibiotics for achieving adequate initial antimicrobial cover. However, there were no significant differences in clinical outcomes, including mortality up to 28\xa0days (Kim et\xa0al. 2012). This study included non-ventilated adults with hospital-acquired pneumonia and a small proportion of adults with ventilator-associated pneumonia (8.3%).\n\nThe overall incidence of multidrug-resistant bacteria was significantly higher with very broad antimicrobial cover followed by de‑escalation, compared with empirical antibiotics.\n\nEvidence for antibiotic prescribing strategies is based on 2\xa0RCTs (Herer et\xa0al. 2009 and Kim\xa0et\xa0al. 2012).\n\nCommittee discussion on antibiotic prescribing strategies\n\nThe committee noted that the bronchoscopy antibiotic prescribing strategy used by Herer et\xa0al. (2009) was not consistent with clinical practice in the UK; culture results are not usually available within 24\xa0hours and sputum cultures are more common than gram staining of bronchoscopy samples.\n\nThe committee noted that overall there were no significant differences in clinical outcomes between the 2\xa0prescribing strategies. Because of the lack of applicability to UK practice, and the small sample size, the committee agreed that there was insufficient evidence to show that the prescribing strategies were equivalent.\n\nThe committee discussed evidence from Kim et\xa0al. (2012) suggesting no difference in clinical outcomes between a prescribing strategy of very-broad-spectrum antibiotics with de‑escalation, compared with empirical antibiotics. However, the committee was concerned that the rate of emergence of multidrug-resistant bacteria was significantly higher with the very-broad-spectrum antibiotics followed by de‑escalation strategy.\n\nThe committee was concerned about the risk of antimicrobial resistance from using very-broad-spectrum antibiotics for longer than necessary, as well as the high rates of adverse effects in some of the included studies. Therefore, the committee concluded that a respiratory sample (for example, sputum sample, nasopharyngeal swab or tracheal aspirate) should be taken and sent for microbiological testing if possible. This reflects current practice.\n\nThe committee agreed that when microbiological results are available, the antibiotic should be reviewed and changed accordingly (for example, if bacteria are found to be resistant), using a narrower-spectrum antibiotic, if appropriate.\n\n# Choice of antibiotics\n\n## Efficacy of antibiotics\n\nOverall, there were no differences in the clinical effectiveness (clinical cure or mortality) in a range of antibiotic comparisons in adults with hospital-acquired pneumonia:\n\n\n\npenicillin with beta-lactamase inhibitor (piperacillin with tazobactam) compared with a carbapenem (imipenem with cilastatin; Schmitt et\xa0al. 2006)\n\ncephalosporin with beta-lactamase inhibitor (ceftazidime with avibactam) compared with a carbapenem (meropenem; Torres et\xa0al. 2017)\n\ntetracycline (tigecycline) compared with a carbapenem (imipenem with cilastatin; Freire et\xa0al. 2010 and Ramirez et\xa0al. 2013)\n\nfluoroquinolone (moxifloxacin) compared with a cephalosporin (ceftriaxone followed by cefuroxime; Hoffken et\xa0al. 2007)\n\ncephalosporin (ceftobiprole) compared with cephalosporin plus oxazolidinone (ceftazidime plus linezolid; Awad et\xa0al. 2014)\n\nglycopeptide (telavancin) compared with glycopeptide (vancomycin; Rubinstein et\xa0al. 2011 reported in Rubinstein et\xa0al. 2014).\n\n\n\nEvidence for efficacy of antibiotics is based on 6\xa0RCTs (Schmitt et\xa0al. 2006, Torres et\xa0al. 2017, Freire et\xa0al. 2010, Ramirez et\xa0al. 2013, Hoffken et\xa0al. 2007 and Awad et\xa0al. 2014) and 1\xa0post-hoc analysis of an RCT (Rubinstein et\xa0al. 2014).\n\n## Safety of antibiotics\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, August 2019).\n\nMacrolides (for example, clarithromycin) should be used with caution in people with a predisposition to QT\xa0interval prolongation (BNF, August 2019).\n\nTetracyclines (for example, doxycycline), can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant or breastfeeding women, and use in children under 12\xa0years is either contraindicated or cautioned for use in severe or life-threatening infections where there are no alternatives (BNF, August 2019).\n\nCo-trimoxazole is associated with rare but serious side effects including blood disorders and Stevens–Johnson syndrome. It is cautioned for use in older people because there is an increased risk of serious adverse effects, and in those with a predisposition to hyperkalaemia. Monitoring of blood counts is recommended with prolonged treatment (BNF, August 2019).\n\nFluoroquinolones have restrictions and precautions around their use because of rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems (MHRA Drug Safety Update, March 2019). They may also be associated with a small increased risk of aortic aneurysm and dissection, particularly in older people (MHRA Drug Safety Update, November 2018).\n\nGlycopeptide (for example, vancomycin and teicoplanin) doses are based on body weight. Therapeutic drug monitoring and monitoring of various patient parameters including blood count, urinalysis, auditory function, hepatic function and renal function is recommended depending on the particular glycopeptide (BNF, August 2019).\n\nSevere optic neuropathy can occur with linezolid, particularly if used for longer than 28\xa0days. Blood disorders have also been reported and weekly full blood counts are recommended (BNF, August 2019).\n\nOverall, there were no significant differences in adverse effects in the studies between antibiotics or classes of antibiotics in people with hospital-acquired pneumonia.\n\nTreatment-related adverse events were significantly higher with moxifloxacin compared with a cephalosporin (intravenous ceftriaxone then oral cefuroxime; 30% versus 16%, number needed to harm [NNH] 7 [range 3 to 84]).\n\nSignificantly more people stopped treatment because of adverse events with tigecycline than with imipenem with cilastatin (10.9% versus 6.6%, NNH 23 [range 12 to 150]).\n\nSee the summaries of product characteristics for information on contraindications, cautions, drug interactions and adverse effects of individual medicines.\n\nCommittee discussion on choice of antibiotics\n\nThe committee agreed that prompt antibiotic treatment should be offered to everyone with hospital-acquired pneumonia.\n\nThe committee discussed the definition of hospital-acquired pneumonia. Because it includes people with pneumonia that develops 48\xa0hours or more after hospital admission and that was not incubating at hospital admission, the committee agreed that the NICE guideline on community-acquired pneumonia should be followed for people with symptoms or signs of pneumonia starting on days\xa01\xa0or\xa02 after hospital admission.\n\nThe committee discussed the timing of antibiotic treatment and was aware of current practice to offer antibiotics within 4\xa0hours. No systematic reviews or RCTs were identified, and the committee agreed that there was no reason to change current practice. However, they noted that the timing should be within 4\xa0hours of an established diagnosis to avoid inappropriate use of broad-spectrum antibiotics.\n\nThe committee noted that evidence was identified in adults only, and for a limited number of head-to-head antibiotic comparisons. They agreed that recommendations for children and young people should be based on its experience and extrapolation of evidence in adults, taking account of any relevant medicines safety concerns.\n\nGiven the clinical expertise needed for assessing and managing hospital-acquired pneumonia in very young children (under 1\xa0month), the committee agreed that the choice of antibiotic in these children should be based on local resistance data and specialist microbiological advice.\n\nOverall, the limited evidence showed no differences in clinical effectiveness between different broad-spectrum antibiotics or classes of antibiotics, with some small differences in the rates of adverse effects. The committee noted the high rates of adverse events for many broad-spectrum antibiotics included in the studies.\n\nThe committee discussed the most common causes of hospital-acquired pneumonia. They agreed that cause is often uncertain because many people do not have a microbiological diagnosis.\n\nThey recognised that S. pneumoniae is the most common cause in people who develop hospital-acquired pneumonia within 5\xa0days of hospital admission. The risk of having a multidrug-resistant infection with P.\xa0aeruginosa, MRSA or extended-spectrum beta-lactamases (ESBLs) increases in people who develop the infection after more than 5\xa0days of being in hospital, although resistance rates vary locally.\n\nTherefore, the committee agreed that for people with symptoms or signs of pneumonia starting on days\xa03\xa0to\xa05 after hospital admission who are not at high risk of resistance, it may be appropriate to follow the NICE guideline on community-acquired pneumonia for recommendations on the choice of antibiotic, based on their clinical judgement. This would give the option to treat some people with amoxicillin, which is a narrower-spectrum antibiotic with activity against S. pneumoniae.\n\nBased on experience, the committee agreed that there are several factors that need to be taken into account when choosing an antibiotic, including the severity of symptoms or signs. The committee did not know of any validated tools for assessing the severity of hospital-acquired pneumonia, and therefore agreed that this should be based on clinical judgement.\n\nThe committee also agreed that some people are at higher risk of developing complications, for example, people with a comorbidity such as severe lung disease or immunosuppression.\n\nThe committee recognised that, when available, local antimicrobial resistance data are an important consideration in hospital-acquired pneumonia, including at hospital and ward-based level (particularly in high-risk areas such as intensive care, high-dependency units, haematology or oncology).\n\nThe committee also agreed that recent use of broad-spectrum antibiotics and recent contact with healthcare services before the current hospital admission were also highly likely to increase the risk of resistant pathogens.\n\nThe committee agreed that taking account of these factors would optimise the appropriate use of broad-spectrum antibiotics and minimise the risk of antimicrobial resistance.\n\nThe committee agreed that an antibiotic should be started empirically, so as not to delay treatment for an infection with a high-mortality risk.\n\nThe committee agreed that the choice of antibiotic should be based on its experience of which antibiotics are effective against likely pathogens and cause the least harm, with the narrowest spectrum possible to minimise the risk of antimicrobial resistance and adverse effects. However, the committee discussed that people with severe symptoms or signs and those at higher risk of resistance will need broad-spectrum antibiotics with high activity against likely organisms.\n\nBased on its experience, the committee recommended co‑amoxiclav as first-choice antibiotic for people with non‑severe symptoms or signs who are not at higher risk of resistance; co‑amoxiclav is a broad-spectrum antibiotic that combines a penicillin with a beta-lactamase inhibitor and has good activity against common pathogens, such as S.\xa0pneumoniae and Haemophilus influenzae. The committee also recognised the extensive clinical experience of its effectiveness in this population.\n\nFor adults with non‑severe symptoms or signs who are not at higher risk of resistance, with penicillin allergy or in whom co‑amoxiclav is unsuitable (for example, because of local resistance data), the committee agreed that the choice of an alternative antibiotic should be based on local resistance data and specialist microbiological advice only. They agreed that options include:\n\n\n\ndoxycycline (a tetracycline)\n\ncefalexin (a cephalosporin; not suitable if there is a risk of penicillin-resistant pneumococci)\n\nco‑trimoxazole (trimethoprim plus a sulfonamide)\n\nlevofloxacin (a fluoroquinolone; only to be used when switching from IV antibiotics, following specialist advice).\n\n\n\nCo‑trimoxazole and levofloxacin are not licensed for hospital-acquired pneumonia, so use would be off-label.\n\nIn children and young people with penicillin allergy or in whom co‑amoxiclav is unsuitable, the alternative antibiotic is clarithromycin (a macrolide); this has good activity against common pathogens and is appropriate for use in children and young people. However, the committee recognised that other options may be suitable based on local resistance data and specialist microbiological advice.\n\nThe committee agreed that specialist advice should be sought for young women who are pregnant with penicillin allergy or in whom co‑amoxiclav is unsuitable, because they were not able to specify an alternative antibiotic for this population.\n\nBased on its experience, the committee recognised that many broad-spectrum antibiotics would be appropriate as first-choice intravenous antibiotics for people with severe symptoms or signs, or who are at higher risk of resistance. It agreed that the choice should be based on local resistance data and following specialist microbiological advice. Options include:\n\n\n\npiperacillin with tazobactam (an antipseudomonal penicillin with a beta-lactamase inhibitor)\n\nceftazidime (a third-generation cephalosporin)\n\nceftriaxone (a third-generation cephalosporin)\n\ncefuroxime (a second-generation cephalosporin; in adults)\n\nmeropenem (a carbapenem; in adults)\n\nceftazidime with avibactam (a third-generation cephalosporin with a beta-lactamase inhibitor; in adults)\n\nlevofloxacin (in adults).\n\n\n\nThese antibiotics have good activity against common pathogens in this population, including multidrug-resistant P.\xa0aeruginosa, ESBLs and some carbapenemase-producing gram-negative bacteria.\n\nThe committee discussed that a small number of people with hospital-acquired pneumonia may have suspected or confirmed infection with MRSA. Therefore, based on their experience, the committee agreed that for these people, 1 of the following antibiotics with activity against MRSA should be added to the treatment regimen:\n\n\n\nvancomycin (a glycopeptide)\n\nteicoplanin (a glycopeptide)\n\nlinezolid (an oxazolidinone; if vancomycin cannot be used, following specialist advice only). Linezolid is not licensed in children and young people under 18\xa0years, so use would be off-label.\n\n\n\nBased on its experience, the committee recommended the same oral antibiotics (discussed above) for people with severe symptoms or signs or at higher risk of resistance who have initially received intravenous antibiotics, to complete the antibiotic course when intravenous antibiotics are no longer required.\n\nThe committee recognised that hospital-acquired pneumonia requires careful monitoring. It agreed by consensus that a person's condition should be reassessed if symptoms do not improve as expected or worsen rapidly or significantly at any time.\n\nThe committee agreed that for people with symptoms that are not improving as expected with antibiotics, or who are known to have multidrug-resistant bacteria, specialist advice from a microbiologist should be sought.\n\n# Antibiotic course length, dosage and route of administration\n\nNo systematic reviews or RCTs were identified that compared antibiotic course lengths, dosage or route of administration.\n\nCommittee discussions on antibiotic course length, dosage and route of administration\n\nThe committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and adverse effects from broad-spectrum antibiotics. However, hospital-acquired pneumonia is a serious infection with a high-mortality risk and needs effective treatment.\n\nBased on its experience and extrapolation of evidence for people with community-acquired pneumonia (see the NICE guideline on community-acquired pneumonia), the committee agreed that a total course of 5\xa0days of antibiotics was the minimum required.\n\nThe committee agreed that antibiotic treatment should be reviewed at 5\xa0days. Stopping the antibiotic should be considered on an individual basis if the person is judged to be clinically stable.\n\nBased on its experience, the committee agreed that usual BNF and BNF for children doses for hospital-acquired pneumonia, or severe susceptible infections should be used.\n\nIn line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, oral antibiotics should be given first line if the person can take them, and if the severity of their infection does not require intravenous antibiotics. The use of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.\n\nFor people with severe symptoms or signs or at higher risk of resistance, the committee agreed that intravenous antibiotics should always be given initially.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).\n\n# Resource implications\n\nRecommended antibiotics (except ceftazidime with avibactam) are available as generic formulations. See the Drug Tariff and the BNF for costs.\n\nSee the evidence review for more information.'}
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https://www.nice.org.uk/guidance/ng139
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This guideline sets out an antimicrobial prescribing strategy for hospital‑acquired pneumonia. It does not cover ventilator‑associated pneumonia. It aims to optimise antibiotic use and reduce antibiotic resistance.
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0548ffe58b7e65c8e7e9cedee2a765acc8144900
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nice
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Attention deficit hyperactivity disorder: diagnosis and management
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Attention deficit hyperactivity disorder: diagnosis and management
This guideline covers recognising, diagnosing and managing attention deficit hyperactivity disorder (ADHD) in children, young people and adults. It aims to improve recognition and diagnosis, as well as the quality of care and support for people with ADHD.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professionals guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Service organisation and training
## Service organisation
People with attention deficit hyperactivity disorder (ADHD) would benefit from improved organisation of care and better integration of child health services, child and adolescent mental health services (CAMHS) and adult mental health services.
Mental health services for children, young people and adults, and child health services, should form multidisciplinary specialist ADHD teams and/or clinics for children and young people, and separate teams and/or clinics for adults. These teams and clinics should have expertise in the diagnosis and management of ADHD, and should:
provide diagnostic, treatment and consultation services for people with ADHD who have complex needs, or where general psychiatric services are in doubt about the diagnosis and/or management of ADHD
put in place systems of communication and protocols for information sharing among paediatric, child and adolescent, forensic, and adult mental health services for people with ADHD, including arrangements for transition between child and adult services
produce local protocols for shared care arrangements with primary care providers, and ensure that clear lines of communication between primary and secondary care are maintained
ensure age-appropriate psychological services are available for children, young people and adults with ADHD, and for parents or carers.The size and time commitment of these teams should depend on local circumstances (for example, the size of the trust, the population covered and the estimated referral rate for people with ADHD).
Every locality should develop a multi-agency group, with representatives from multidisciplinary specialist ADHD teams, paediatrics, mental health and learning disability trusts, forensic services, CAMHS, the Directorate for Children and Young People (DCYP; including services for education and social services), parent support groups and others with a significant local involvement in ADHD services. The group should:
-versee the implementation of this guideline
start and coordinate local training initiatives, including the provision of training and information for teachers about the characteristics of ADHD and its basic behavioural management
-versee the development and coordination of parent-training/education programmes
consider compiling a comprehensive directory of information and services for ADHD including advice on how to contact relevant services and assist in the development of specialist teams.
A young person with ADHD receiving treatment and care from CAMHS or paediatric services should be reassessed at school-leaving age to establish the need for continuing treatment into adulthood. If treatment is necessary, arrangements should be made for a smooth transition to adult services with details of the anticipated treatment and services that the young person will require. Precise timing of arrangements may vary locally but should usually be completed by the time the young person is 18 years. See NICE's guideline on transition from children's to adults' services for young people using health or social care services.
During the transition to adult services, a formal meeting involving CAMHS and/or paediatrics and adult psychiatric services should be considered, and full information provided to the young person about adult services. For young people aged 16 years and older, the care programme approach (CPA) should be used as an aid to transfer between services. The young person, and when appropriate the parent or carer, should be involved in the planning.
After transition to adult services, adult healthcare professionals should carry out a comprehensive assessment of the person with ADHD that includes personal, educational, occupational and social functioning, and assessment of any coexisting conditions, especially drug misuse, personality disorders, emotional problems and learning difficulties.
## Training
Trusts should ensure that specialist ADHD teams for children, young people and adults jointly develop age-appropriate training programmes for the diagnosis and management of ADHD for mental health, paediatric, social care, education, forensic and primary care providers and other professionals who have contact with people with ADHD.
Child and adult psychiatrists, paediatricians, and other child and adult mental health professionals (including those working in forensic services) should undertake training so that they are able to diagnose ADHD and provide treatment and management in accordance with this guideline.
# Recognition, identification and referral
## Recognition
Be aware that people in the following groups may have increased prevalence of ADHD compared with the general population:
people born preterm (see NICE's guideline on developmental follow-up of children and young people born preterm)
looked-after children and young people
children and young people diagnosed with oppositional defiant disorder or conduct disorder
children and young people with mood disorders (for example, anxiety and depression)
people with a close family member diagnosed with ADHD
people with epilepsy
people with other neurodevelopmental disorders (for example, autism spectrum disorder, tic disorders, learning disability and specific learning difficulties)
adults with a mental health condition
people with a history of substance misuse
people known to the Youth Justice System or Adult Criminal Justice System
people with acquired brain injury.
Be aware that ADHD is thought to be under-recognised in girls and women and that:
they are less likely to be referred for assessment for ADHD
they may be more likely to have undiagnosed ADHD
they may be more likely to receive an incorrect diagnosis of another mental health or neurodevelopmental condition.
To find out why the committee made the 2018 recommendations on recognition and how they might affect practice, see the rationale and impact section on recognition .
Full details of the evidence and the committee's discussion are in evidence review A: risk factors.
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## Identification and referral
Universal screening for ADHD should not be undertaken in nursery, primary and secondary schools.
When a child or young person with disordered conduct and suspected ADHD is referred to a school's special educational needs coordinator (SENCO), the SENCO, in addition to helping the child with their behaviour, should inform the parents about local parent-training/education programmes. See NICE's guideline on antisocial behaviour and conduct disorders in children and young people.
Referral from the community to secondary care may involve health, education and social care professionals (for example, GPs, paediatricians, educational psychologists, SENCOs, social workers) and care pathways can vary locally. The person making the referral to secondary care should inform the child or young person's GP.
When a child or young person presents in primary care with behavioural and/or attention problems suggestive of ADHD, primary care practitioners should determine the severity of the problems, how these affect the child or young person and the parents or carers, and the extent to which they pervade different domains and settings.
If the child or young person's behavioural and/or attention problems suggestive of ADHD are having an adverse impact on their development or family life, consider:
a period of watchful waiting of up to 10 weeks
-ffering parents or carers a referral to group-based ADHD-focused support (this should not wait for a formal diagnosis of ADHD). If the behavioural and/or attention problems persist with at least moderate impairment, the child or young person should be referred to secondary care (that is, a child psychiatrist, paediatrician, or specialist ADHD CAMHS) for assessment.
If the child or young person's behavioural and/or attention problems are associated with severe impairment, referral should be made directly to secondary care (that is, a child psychiatrist, paediatrician, or specialist ADHD CAMHS) for assessment.
Primary care practitioners should not make the initial diagnosis or start medication in children or young people with suspected ADHD.
Adults presenting with symptoms of ADHD in primary care or general adult psychiatric services, who do not have a childhood diagnosis of ADHD, should be referred for assessment by a mental health specialist trained in the diagnosis and treatment of ADHD, where there is evidence of typical manifestations of ADHD (hyperactivity/impulsivity and/or inattention) that:
began during childhood and have persisted throughout life
are not explained by other psychiatric diagnoses (although there may be other coexisting psychiatric conditions)
have resulted in or are associated with moderate or severe psychological, social and/or educational or occupational impairment.
Adults who have previously been treated for ADHD as children or young people and present with symptoms suggestive of continuing ADHD should be referred to general adult psychiatric services for assessment. The symptoms should be associated with at least moderate or severe psychological and/or social or educational or occupational impairment.
# Diagnosis
A diagnosis of ADHD should only be made by a specialist psychiatrist, paediatrician or other appropriately qualified healthcare professional with training and expertise in the diagnosis of ADHD, on the basis of:
a full clinical and psychosocial assessment of the person; this should include discussion about behaviour and symptoms in the different domains and settings of the person's everyday life and
a full developmental and psychiatric history and
-bserver reports and assessment of the person's mental state.
A diagnosis of ADHD should not be made solely on the basis of rating scale or observational data. However, rating scales such as the Conners' rating scales and the Strengths and Difficulties Questionnaire are valuable adjuncts, and observations (for example, at school) are useful when there is doubt about symptoms.
For a diagnosis of ADHD, symptoms of hyperactivity/impulsivity and/or inattention should:
meet the diagnostic criteria in DSM‑5 or ICD‑11 (hyperkinetic disorder; but exclusion based on a pervasive developmental disorder or an uncertain time of onset is not recommended) and
cause at least moderate psychological, social and/or educational or occupational impairment based on interview and/or direct observation in multiple settings and
be pervasive, occurring in 2 or more important settings including social, familial, educational and/or occupational settings.As part of the diagnostic process, include an assessment of the person's needs, coexisting conditions, social, familial and educational or occupational circumstances and physical health. For children and young people, there should also be an assessment of their parents' or carers' mental health.
ADHD should be considered in all age groups, with symptom criteria adjusted for age-appropriate changes in behaviour.
In determining the clinical significance of impairment resulting from the symptoms of ADHD in children and young people, their views should be taken into account wherever possible.
# Information and support
Use this guideline with NICE's guidelines on service user experience in adult mental health and patient experience in adult NHS services to improve the experience of care for adults with ADHD. The principles also apply to children and young people, and their parents or carers.
Healthcare professionals working with children and young people with ADHD should follow the recommendations on general principles of care in NICE's guideline on antisocial behaviour and conduct disorder in children and young people. This does not mean that all children and young people with ADHD have coexisting antisocial behaviour and conduct disorder but that the same general principles of care apply when working with children and young people with ADHD.
## Supporting people with ADHD
Following a diagnosis of ADHD, have a structured discussion with people (and their families or carers as appropriate) about how ADHD could affect their life. This could include:
the positive impacts of receiving a diagnosis, such as:
improving their understanding of symptoms
identifying and building on individual strengths
improving access to services
the negative impacts of receiving a diagnosis, such as stigma and labelling
a greater tendency for impulsive behaviour
the importance of environmental modifications to reduce the impact of ADHD symptoms
education issues (for example, reasonable adjustments at school and college)
employment issues (for example, impact on career choices and rights to reasonable adjustments in the workplace)
social relationship issues
the challenges of managing ADHD when a person has coexisting neurodevelopmental or mental health conditions
the increased risk of substance misuse and self-medication
the possible effect on driving (for example, ADHD symptoms may impair a person's driving and ADHD medication may improve this; people with ADHD must declare their diagnosis to the DVLA if their ADHD symptoms or medication affect their ability to drive safely).This structured discussion should inform the shared treatment plan.
Inform people receiving a diagnosis of ADHD (and their families or carers as appropriate) about sources of information, including:
local and national support groups and voluntary organisations
websites
support for education and employment. People who have had an assessment but whose symptoms and impairment fall short of a diagnosis of ADHD may benefit from similar information.
Provide information to people with ADHD (and their families and carers as appropriate) in a form that:
takes into account their developmental level, cognitive style, emotional maturity and cognitive capacity, including any learning disabilities, sight or hearing problems, delays in language development or social communication difficulties
takes into account any coexisting neurodevelopmental and mental health conditions
is tailored to their individual needs and circumstances, including age, gender, educational level and life stage.
## Supporting families and carers
Ask families or carers of people with ADHD how the ADHD affects themselves and other family members, and discuss any concerns they have.
Encourage family members or carers of people with ADHD to seek an assessment of their personal, social and mental health needs, and to join self-help and support groups if appropriate.
Think about the needs of a parent with ADHD who also has a child with ADHD, including whether they need extra support with organisational strategies (for example, with adherence to treatment, daily school routines).
Offer advice to parents and carers of children and young people with ADHD about the importance of:
positive parent– and carer–child contact
clear and appropriate rules about behaviour and consistent management
structure in the child or young person's day.
Offer advice to families and carers of adults with ADHD about:
how ADHD may affect relationships
how ADHD may affect the person's functioning
the importance of structure in daily activities.
Explain to parents and carers that any recommendation of parent-training/education does not imply bad parenting, and that the aim is to optimise parenting skills to meet the above-average parenting needs of children and young people with ADHD.
## Involving schools, colleges and universities
When ADHD is diagnosed, when symptoms change, and when there is transition between schools or from school to college or college to university, obtain consent and then contact the school, college or university to explain:
the validity of a diagnosis of ADHD and how symptoms are likely to affect school, college or university life
-ther coexisting conditions (for example, learning disabilities) are distinct from ADHD and may need different adjustments
the treatment plan and identified special educational needs, including advice for reasonable adjustments and environmental modifications within the educational placement
the value of feedback from schools, colleges and universities to people with ADHD and their healthcare professionals.
## Involving other healthcare professionals
When a person with ADHD has a coexisting condition, contact the relevant healthcare professional, with consent, to explain:
the validity, scope and implications of a diagnosis of ADHD
how ADHD symptoms are likely to affect the person's behaviour (for example, organisation, time management, motivation) and adherence to specific treatments
the treatment plan and the value of feedback from healthcare professionals.
To find out why the committee made the 2018 recommendations on information and support, and how they might affect practice, see the rationale and impact section on information and support .
Full details of the evidence and the committee's discussion are in evidence review B: information and support.
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# Managing ADHD
## Planning treatment
Healthcare providers should ensure continuity of care for people with ADHD.
Ensure that people with ADHD have a comprehensive, holistic shared treatment plan that addresses psychological, behavioural and occupational or educational needs. Take into account:
the severity of ADHD symptoms and impairment, and how these affect or may affect everyday life (including sleep)
their goals
their resilience and protective factors
the relative impact of other neurodevelopmental or mental health conditions.
Regularly discuss with people with ADHD, and their family members or carers, how they want to be involved in treatment planning and decisions; such discussions should take place at intervals to take account of changes in circumstances (for example, the transition from children's to adult services) and developmental level, and should not happen only once.
Before starting any treatment for ADHD, discuss the following with the person, and their family or carers as appropriate, encouraging children and young people to give their own account of how they feel:
the benefits and harms of non-pharmacological and pharmacological treatments (for example, the efficacy of medication compared with no treatment or non-pharmacological treatments, potential adverse effects and non-response rates)
the benefits of a healthy lifestyle, including exercise
their preferences and concerns (it is important to understand that a person's decision to start, change or stop treatment may be influenced by media coverage, teachers, family members, friends and differing opinion on the validity of a diagnosis of ADHD)
how other mental health or neurodevelopmental conditions might affect treatment choices
the importance of adherence to treatment and any factors that may affect this (for example, it may be difficult to take medication at school or work, or to remember appointments). Record the person's preferences and concerns in their treatment plan.
Ask young people and adults with ADHD if they wish a parent, partner, close friend or carer to join discussions on treatment and adherence.
Reassure people with ADHD, and their families or carers as appropriate, that they can revisit decisions about treatments.
To find out why the committee made the 2018 recommendations on managing ADHD – planning treatment, and how they might affect practice, see the rationale and impact section on managing ADHD – planning treatment .
Full details of the evidence and the committee's discussion are in evidence review H: managing treatment.
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## Children under 5 years
These recommendations are for healthcare professionals with training and expertise in diagnosing and managing ADHD. See recommendation 1.4.3 for details of ADHD-focused information.
Offer an ADHD-focused group parent-training programme to parents or carers of children under 5 years with ADHD as first-line treatment. See recommendations 1.5.1 to 1.5.10 in NICE's guideline on antisocial behaviour and conduct disorders in children and young people.This does not imply that all children under 5 years with ADHD have antisocial behaviour or conduct disorder, but that the same general principles of care apply.
If after an ADHD-focused group parent-training programme, ADHD symptoms across settings are still causing a significant impairment in a child under 5 years after environmental modifications have been implemented and reviewed, obtain advice from a specialist ADHD service with expertise in managing ADHD in young children (ideally a tertiary service).
Do not offer medication for ADHD for any child under 5 years without a second specialist opinion from an ADHD service with expertise in managing ADHD in young children (ideally a tertiary service).
To find out why the committee made the 2018 recommendations on managing ADHD – children under 5 years, and how they might affect practice, see the rationale and impact section on managing ADHD – children under 5 years .
Full details of the evidence and the committee's discussion are in evidence review E: non-pharmacological efficacy and adverse events and evidence review F: combination treatment.
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## Children aged 5 years and over and young people
These recommendations, covering children aged 5 years and over and young people, are for healthcare professionals with training and expertise in diagnosing and managing ADHD. March 2018 – medicines used for treating ADHD did not have a UK marketing authorisation for children aged 5 years or under (off-label use). See NICE's information on prescribing medicines.
Give information about ADHD (see recommendation 1.4.3) and offer additional support to parents and carers of all children aged 5 years and over and young people with ADHD. The support should be ADHD focused, can be group based and as few as 1 or 2 sessions. It should include:
education and information on the causes and impact of ADHD
advice on parenting strategies
with consent, liaison with school, college or university (see recommendation 1.4.12)
both parents and carers if feasible.
If a child aged 5 years or over or young person has ADHD and symptoms of oppositional defiant disorder or conduct disorder, offer parents and carers a parent-training programme in line with recommendations 1.5.1 to 1.5.10 in NICE's guideline on antisocial behaviour and conduct disorders in children and young people, as well as group-based ADHD-focused support.
Consider individual parent-training programmes for parents and carers of children and young people with ADHD and symptoms of oppositional defiant disorder or conduct disorder when:
there are particular difficulties for families in attending group sessions (for example, because of disability, needs related to diversity such as language differences, learning disability , parental ill-health, problems with transport, or where other factors suggest poor prospects for therapeutic engagement)
a family's needs are too complex to be met by group-based parent-training programmes.
Offer medication for children aged 5 years and over and young people only if:
their ADHD symptoms are still causing a persistent significant impairment in at least one domain after environmental modifications have been implemented and reviewed
they and their parents and carers have discussed information about ADHD (see recommendation 1.5.4)
a baseline assessment has been carried out (see recommendation 1.7.4).See the recommendations on medication.
Consider a course of cognitive behavioural therapy (CBT) for young people with ADHD who have benefited from medication but whose symptoms are still causing a significant impairment in at least one domain, addressing the following areas:
social skills with peers
problem-solving
self-control
active listening skills
dealing with and expressing feelings.
To find out why the committee made the 2018 recommendations on managing ADHD – children aged 5 years and over and young people, and how they might affect practice, see the rationale and impact section on managing ADHD – children aged 5 years and over and young people .
Full details of the evidence and the committee's discussion are in evidence review E: non-pharmacological efficacy and adverse events and evidence review F: combination treatment.
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## Adults
These recommendations are for healthcare professionals with training and expertise in diagnosing and managing ADHD. See recommendation 1.4.3 for details of ADHD-focused information.
Offer medication to adults with ADHD if their ADHD symptoms are still causing a significant impairment in at least one domain after environmental modifications have been implemented and reviewed. See the recommendations on medication choice.
Consider non-pharmacological treatment for adults with ADHD who have:
made an informed choice not to have medication
difficulty adhering to medication
found medication to be ineffective or cannot tolerate it.
Consider non-pharmacological treatment in combination with medication for adults with ADHD who have benefited from medication but whose symptoms are still causing a significant impairment in at least one domain.
When non-pharmacological treatment is indicated for adults with ADHD, offer the following as a minimum:
a structured supportive psychological intervention focused on ADHD
regular follow‑up either in person or by phone.Treatment may involve elements of or a full course of CBT.
To find out why the committee made the 2018 recommendations on managing ADHD – adults, and how they might affect practice, see the rationale and impact section on managing ADHD – adults .
Full details of the evidence and the committee's discussion are in evidence review E: non-pharmacological efficacy and adverse events and evidence review F: combination treatment.
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# Dietary advice
Healthcare professionals should stress the value of a balanced diet, good nutrition and regular exercise for children, young people and adults with ADHD.
Do not advise elimination of artificial colouring and additives from the diet as a generally applicable treatment for children and young people with ADHD.
Ask about foods or drinks that appear to influence hyperactive behaviour as part of the clinical assessment of ADHD in children and young people, and:
if there is a clear link, advise parents or carers to keep a diary of food and drinks taken and ADHD behaviour
if the diary supports a relationship between specific foods and drinks and behaviour, offer referral to a dietitian
ensure that further management (for example, specific dietary elimination) is jointly undertaken by the dietitian, mental health specialist or paediatrician, and the parent or carer and child or young person.
Do not advise or offer dietary fatty acid supplementation for treating ADHD in children and young people.
Advise the family members or carers of children with ADHD that there is no evidence about the long-term effectiveness or potential harms of a 'few food' diet for children with ADHD, and only limited evidence of short-term benefits.
# Medication
These recommendations, with the exception of recommendation 1.7.29, are for healthcare professionals with training and expertise in diagnosing and managing ADHD.
Use this guideline with NICE's guideline on medicines optimisation: the safe and effective use of medicines to enable the best possible outcomes.
All medication for ADHD should only be initiated by a healthcare professional with training and expertise in diagnosing and managing ADHD.
Healthcare professionals initiating medication for ADHD should:
be familiar with the pharmacokinetic profiles of all the short- and long-acting preparations available for ADHD
ensure that treatment is tailored effectively to the individual needs of the child, young person or adult
take account of variations in bioavailability or pharmacokinetic profiles of different preparations to avoid reduced effect or excessive adverse effects.
## Baseline assessment
Before starting medication for ADHD, people with ADHD should have a full assessment, which should include:
a review to confirm they continue to meet the criteria for ADHD and need treatment
a review of mental health and social circumstances, including:
presence of coexisting mental health and neurodevelopmental conditions
current educational or employment circumstances
risk assessment for substance misuse and drug diversion
care needs
a review of physical health, including:
a medical history, taking into account conditions that may be contraindications for specific medicines
current medication
height and weight (measured and recorded against the normal range for age, height and sex)
baseline pulse and blood pressure (measured with an appropriately sized cuff and compared with the normal range for age)
a cardiovascular assessment.An electrocardiogram (ECG) is not needed before starting stimulants, atomoxetine or guanfacine, unless the person has any of the features in recommendation 1.7.5, or a co-existing condition that is being treated with a medicine that may pose an increased cardiac risk.
Refer for a cardiology opinion before starting medication for ADHD if any of the following apply:
history of congenital heart disease or previous cardiac surgery
history of sudden death in a first-degree relative under 40 years suggesting a cardiac disease
shortness of breath on exertion compared with peers
fainting on exertion or in response to fright or noise
palpitations that are rapid, regular and start and stop suddenly (fleeting occasional bumps are usually ectopic and do not need investigation)
chest pain suggesting cardiac origin
signs of heart failure
a murmur heard on cardiac examination
blood pressure that is classified as hypertensive for adults (see NICE's guideline on hypertension in adults).
Refer to a paediatric hypertension specialist before starting medication for ADHD if blood pressure is consistently above the 95th centile for age and height for children and young people.
To find out why the committee made the 2018 recommendations on medication – baseline assessment, and how they might affect practice, see the rationale and impact section on medication – baseline assessment .
Full details of the evidence and the committee's discussion are in evidence review D: pharmacological safety.
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## Medication choice – children aged 5 years and over and young people
Recommendations 1.7.7 to 1.7.10 update NICE's technology appraisal guidance on methylphenidate, atomoxetine and dexamfetamine for ADHD in children and adolescents (TA98).
Offer methylphenidate (either short or long acting) as the first line pharmacological treatment for children aged 5 years and over and young people with ADHD. March 2018 – this is an off-label use for children aged 5 years. See NICE's information on prescribing medicines.
Consider switching to lisdexamfetamine for children aged 5 years and over and young people who have had a 6‑week trial of methylphenidate at an adequate dose and not derived enough benefit in terms of reduced ADHD symptoms and associated impairment. March 2018 – this is an off-label use for children aged 5 years. See NICE's information on prescribing medicines.
Consider dexamfetamine for children aged 5 years and over and young people whose ADHD symptoms are responding to lisdexamfetamine but who cannot tolerate the longer effect profile. March 2018 – dexamfetamine is only licensed to treat ADHD in children and young people aged 6 to 17 years when response to methylphenidate is clinically inadequate. It is not licensed for children and young people aged 5 to 17 years who have responded to but are intolerant of lisdexamfetamine.See NICE's information on prescribing medicines.
Offer atomoxetine or guanfacine to children aged 5 years and over and young people if:
they cannot tolerate methylphenidate or lisdexamfetamine or
their symptoms have not responded to separate 6‑week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses.March 2018 – this is an off-label use of atomoxetine and guanfacine for children aged 5 years. See NICE's information on prescribing medicines.
## Medication choice – adults
Offer lisdexamfetamine or methylphenidate as first-line pharmacological treatment for adults with ADHD. March 2018 – this is an off-label use of lisdexamfetamine for adults with no ADHD symptoms in childhood. See NICE's information on prescribing medicines. Not all preparations of methylphenidate are licensed for treating symptoms of ADHD in adults.
Consider switching to lisdexamfetamine for adults who have had a 6‑week trial of methylphenidate at an adequate dose but have not derived enough benefit in terms of reduced ADHD symptoms and associated impairment.
Consider switching to methylphenidate for adults who have had a 6‑week trial of lisdexamfetamine at an adequate dose but have not derived enough benefit in terms of reduced ADHD symptoms and associated impairment.
Consider dexamfetamine for adults whose ADHD symptoms are responding to lisdexamfetamine but who cannot tolerate the longer effect profile. March 2018 – this is an off-label use of dexamfetamine. See NICE's information on prescribing medicines.
Offer atomoxetine to adults if:
they cannot tolerate lisdexamfetamine or methylphenidate or
their symptoms have not responded to separate 6‑week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses. March 2018 – this is an off-label use of atomoxetine for adults with no ADHD symptoms in childhood. See NICE's information on prescribing medicines.
## Further medication choices
Obtain a second opinion or refer to a tertiary service if ADHD symptoms in a child aged 5 years or over, a young person or adult are unresponsive to one or more stimulants and one non-stimulant.
Do not offer any of the following medication for ADHD without advice from a tertiary ADHD service:
guanfacine for adults (off-label use)
clonidine for children with ADHD and sleep disturbance, rages or tics (off-label use)
atypical antipsychotics in addition to stimulants for people with ADHD and coexisting pervasive aggression, rages or irritability
medication not included in recommendations 1.7.7 to 1.7.15. See NICE's information on prescribing medicines.
## Medication choice – people with coexisting conditions
Offer the same medication choices to people with ADHD and anxiety disorder, tic disorder or autism spectrum disorder as other people with ADHD.
For children aged 5 years and over, young people and adults with ADHD experiencing an acute psychotic or manic episode:
stop any medication for ADHD
consider restarting or starting new ADHD medication after the episode has resolved, taking into account the individual circumstances, risks and benefits of the ADHD medication.
To find out why the committee made the 2018 recommendations on medication choice, and how they might affect practice, see the rationale and impact section on medication – choice .
Full details of the evidence and the committee's discussion are in evidence review C: pharmacological efficacy and sequencing.
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## Considerations when prescribing ADHD medication
When prescribing stimulants for ADHD, think about modified-release once-daily preparations for the following reasons:
convenience
improving adherence
reducing stigma (because there is no need to take medication at school or in the workplace)
reducing problems of storing and administering controlled drugs at school
the risk of stimulant misuse and diversion with immediate-release preparations
their pharmacokinetic profiles.Immediate-release preparations may be suitable if more flexible dosing regimens are needed, or during initial titration to determine correct dosing levels.
When prescribing stimulants for ADHD, be aware that effect size, duration of effect and adverse effects vary from person to person.
Think about using a modified-release preparation of methylphenidate in the morning and an immediate-release preparation of methylphenidate at another time of the day to extend the duration of effect.
Be cautious about prescribing stimulants for ADHD if there is a risk of diversion for cognitive enhancement or appetite suppression.
Do not offer immediate-release stimulants or modified-release stimulants that can be easily injected or insufflated if there is a risk of stimulant misuse or diversion.
Prescribers should be familiar with the requirements of controlled drug legislation governing the prescription and supply of stimulants. See NICE's guideline on controlled drugs.
## Dose titration
During the titration phase, ADHD symptoms, impairment and adverse effects should be recorded at baseline and at each dose change on standard scales by parents and teachers, and progress reviewed regularly (for example, by weekly telephone contact) with a specialist.
Titrate the dose against symptoms and adverse effects in line with the BNF or BNF for Children until dose optimisation is achieved, that is, reduced symptoms, positive behaviour change, improvements in education, employment and relationships, with tolerable adverse effects.
Ensure that dose titration is slower and monitoring more frequent if any of the following are present in people with ADHD:
neurodevelopmental disorders (for example, autism spectrum disorder, tic disorders, learning disability )
mental health conditions (for example, anxiety disorders , schizophrenia or bipolar disorder, depression, personality disorder, eating disorder, post-traumatic stress disorder, substance misuse)
physical health conditions (for example, cardiac disease, epilepsy or acquired brain injury).
To find out why the committee made the 2018 recommendations on medication – considerations when prescribing and dose titration, and how they might affect practice, see the rationale and impact section on medication – considerations when prescribing and dose titration .
Full details of the evidence and the committee's discussion are in evidence review D: pharmacological safety.
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## Shared care for medication
After titration and dose stabilisation, prescribing and monitoring of ADHD medication should be carried out under Shared Care Protocol arrangements with primary care.
To find out why the committee made the 2018 recommendations on medication – care arrangements, and how they might affect practice, see the rationale and impact section on medication – care arrangements .
Full details of the evidence and the committee's discussion are in evidence review D: pharmacological safety.
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# Maintenance and monitoring
Monitor effectiveness of medication for ADHD and adverse effects, and document in the person's notes.
Encourage people taking medication for ADHD to monitor and record their adverse effects, for example, by using an adverse effect checklist.
Consider using standard symptom and adverse effect rating scales for clinical assessment and throughout the course of treatment for people with ADHD.
Ensure that children, young people and adults receiving treatment for ADHD have review and follow‑up according to the severity of their condition, regardless of whether or not they are taking medication.
## Height and weight
For people taking medication for ADHD:
measure height every 6 months in children and young people
measure weight every 3 months in children 10 years and under
measure weight at 3 and 6 months after starting treatment in children over 10 years and young people, and every 6 months thereafter, or more often if concerns arise
measure weight every 6 months in adults
plot height and weight of children and young people on a growth chart and ensure review by the healthcare professional responsible for treatment.
If weight loss is a clinical concern, consider the following strategies:
taking medication either with or after food, rather than before meals
taking additional meals or snacks early in the morning or late in the evening when stimulant effects have worn off
-btaining dietary advice
consuming high-calorie foods of good nutritional value
taking a planned break from treatment
changing medication.
If a child or young person's height over time is significantly affected by medication (that is, they have not met the height expected for their age), consider a planned break in treatment over school holidays to allow 'catch‑up' growth.
Consider monitoring BMI of adults with ADHD if there has been weight change as a result of their treatment, and changing the medication if weight change persists.
## Cardiovascular
Monitor heart rate and blood pressure and compare with the normal range for age before and after each dose change and every 6 months.
Do not offer routine blood tests (including liver function tests) or ECGs to people taking medication for ADHD unless there is a clinical indication.
If a person taking ADHD medication has sustained resting tachycardia (more than 120 beats per minute), arrhythmia or systolic blood pressure greater than the 95th percentile (or a clinically significant increase) measured on 2 occasions, reduce their dose and refer them to a paediatric hypertension specialist or adult physician.
If a person taking guanfacine has sustained orthostatic hypotension or fainting episodes, reduce their dose or switch to another ADHD medication.
## Tics
If a person taking stimulants develops tics, think about whether:
the tics are related to the stimulant (tics naturally wax and wane) and
the impairment associated with the tics outweighs the benefits of ADHD treatment.
If tics are stimulant related, reduce the stimulant dose, or consider changing to guanfacine (in children aged 5 years and over and young people only), atomoxetine (off-label use for adults with no ADHD symptoms in childhood), clonidine (off-label use for children), or stopping medication. Clonidine should only be considered for people under 18 years after advice from a tertiary ADHD service.
## Sexual dysfunction
Monitor young people and adults with ADHD for sexual dysfunction (that is, erectile and ejaculatory dysfunction) as potential adverse effects of atomoxetine.
## Seizures
If a person with ADHD develops new seizures or a worsening of existing seizures, review their ADHD medication and stop any medication that might be contributing to the seizures. After investigation, cautiously reintroduce ADHD medication if it is unlikely to be the cause of the seizures.
## Sleep
Monitor changes in sleep pattern (for example, with a sleep diary) and adjust medication accordingly.
## Worsening behaviour
Monitor the behavioural response to medication, and if behaviour worsens adjust medication and review the diagnosis.
## Stimulant diversion
Healthcare professionals and parents or carers should monitor changes in the potential for stimulant misuse and diversion, which may come with changes in circumstances and age.
To find out why the committee made the 2018 recommendations on medication – monitoring adverse effects, and how they might affect practice, see the rationale and impact section on medication – monitoring effectiveness and adverse effects .
Full details of the evidence and the committee's discussion are in evidence review D: pharmacological safety.
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# Adherence to treatment
Use this guideline with NICE's guideline on medicines adherence to improve the care for adults with ADHD. The principles also apply to children and young people.
Be aware that the symptoms of ADHD may lead to people having difficulty adhering to treatment plans (for example, remembering to order and collect medication).
Ensure that people are fully informed of the balance of risks and benefits of any treatment for ADHD and check that problems with adherence are not due to misconceptions (for example, tell people that medication does not change personality).
Encourage the person with ADHD to use the following strategies to support adherence to treatment:
being responsible for their own health, including taking their medication as needed
following clear instructions about how to take the medication in picture or written format, which may include information on dose, duration, adverse effects, dosage schedule (the instructions should stay with the medication, for example, a sticker on the side of the packet)
using visual reminders to take medication regularly (for example, apps, alarms, clocks, pill dispensers, or notes on calendars or fridges)
taking medication as part of their daily routine (for example, before meals or after brushing teeth)
attending peer support groups (for both the person with ADHD and for the families and carers).
Encourage parents and carers to oversee ADHD medication for children and young people.
## Supporting adherence to non-pharmacological treatments
Support adherence to non-pharmacological treatments (for example, CBT) by discussing the following:
the balance of risks and benefits (for example, how the treatment can have a positive effect on ADHD symptoms)
the potential barriers to continuing treatment, including:
not being sure if it is making any difference
the time and organisational skills needed to commit to the treatment
the time that might be needed outside of the sessions (for example, to complete homework)
strategies to deal with any identified barriers (for example, scheduling sessions to minimise inconvenience or seeking courses with child care provision)
a possible effect of treatment being increased self-awareness, and the challenging impact this may have on the person and the people around them
the importance of long-term adherence beyond the duration of any initial programme (for example, by attending follow‑up/refresher support to sustain learned strategies).
To find out why the committee made the 2018 recommendations on adherence to treatment and how they might affect practice, see the rationale and impact section on adherence to treatment .
Full details of the evidence and the committee's discussion are in evidence review G: adherence.
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# Review of medication and discontinuation
A healthcare professional with training and expertise in managing ADHD should review ADHD medication at least once a year and discuss with the person with ADHD (and their families and carers as appropriate) whether medication should be continued. The review should include a comprehensive assessment of the:
preference of the child, young person or adult with ADHD (and their family or carers as appropriate)
benefits, including how well the current treatment is working throughout the day
adverse effects
clinical need and whether medication has been optimised
impact on education and employment
effects of missed doses, planned dose reductions and periods of no treatment
effect of medication on existing or new mental health, physical health or neurodevelopmental conditions
need for support and type of support (for example, psychological, educational, social) if medication has been optimised but ADHD symptoms continue to cause a significant impairment.
Encourage people with ADHD to discuss any preferences to stop or change medication and to be involved in any decisions about stopping treatments.
Consider trial periods of stopping medication or reducing the dose when assessment of the overall balance of benefits and harms suggests this may be appropriate. If the decision is made to continue medication, the reasons for this should be documented.
To find out why the committee made the 2018 recommendations on review of medication and discontinuation, and how they might affect practice, see the rationale and impact section on review of medication and discontinuation .
Full details of the evidence and the committee's discussion are in evidence review I: withdrawal and drug holidays.
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# Terms used in this guideline
## Domains
Domains refer to areas of function, for example, interpersonal relationships, education and occupational attainment, and risk awareness.
## Environmental modifications
Environmental modifications are changes that are made to the physical environment in order to minimise the impact of a person's ADHD on their day-to-day life. Appropriate environmental modifications will be specific to the circumstances of each person with ADHD and should be determined from an assessment of their needs. Examples may include changes to seating arrangements, changes to lighting and noise, reducing distractions (for example, using headphones), optimising work or education to have shorter periods of focus with movement breaks (including the use of 'I need a break' cards), reinforcing verbal requests with written instructions and, for children, the appropriate use of teaching assistants at school.
## Reasonable adjustments
Reasonable adjustments is a term that refers to the legal obligations of employers and higher education providers to make sure that workers or students with disabilities, or physical or mental health conditions are not substantially disadvantaged when doing their jobs or during their education.
## Settings
Settings refer to the physical location, for example, home, nursery, friends or family homes.
## Shared treatment plan
A written treatment plan shared between healthcare professional and the person with ADHD; for children, this may be shared more widely (for example, with families, schools or social care, if relevant and agreed).# Recommendations for research
The guideline committee has made the following recommendations for research.
# Children and young people aged 5 to 18 years – brief, group-based, ADHD-focused, parent-training intervention
What is the clinical and cost effectiveness, and optimum length, of a brief parent-training intervention for parents and carers of children and young people with attention deficit hyperactivity disorder (ADHD) aged 5 to 18 years?
## Why this is important
There was no clear evidence identified about the benefit of formal parent-training programmes for ADHD symptoms in children and young people aged 5 to 18 years. The cost effectiveness of these programmes was unclear, partly because of uncertainty over the number of sessions and the length of programme needed to achieve clinical benefit. This research recommendation would help address these uncertainties.
# Medication choice in people with coexisting conditions
What is the clinical and cost effectiveness of ADHD medications in people with ADHD and tic disorders, a history of psychosis or mania, or personality disorder?
## Why is this important
No evidence was identified to justify different medication choices in people with ADHD and tic disorders, a history of psychosis or mania, or emotional dysregulation. These groups are often excluded from trials. There are reasons (for example, mechanism of action of medication options, previous reports of adverse effects) to suspect that these groups may respond differently to different drugs, but a lack of trials to confirm this. Primarily there are some concerns that stimulant medication may worsen the symptoms of any of these coexisting conditions and therefore non-stimulant medication should be preferred.
# Medication choice in people with no previous medication for ADHD
What is the clinical and cost effectiveness of ADHD medications in people with ADHD with no previous medication for the condition?
## Why is this important
Most of the evidence to support the recommendations for medication choices for people with ADHD comes from studies in people who have previously received medication. Therefore, these studies often include a population not representative of the people with newly diagnosed ADHD. There may be differing levels of efficacy of the various treatment options in people who have received no previous medication for ADHD.
# Prescribing beyond monotherapy
What is the clinical and cost effectiveness of various ADHD prescribing strategies when monotherapy has failed?
## Why is this important
This guideline makes recommendations for the medication choices for people with ADHD up to the point at which common monotherapies are exhausted. There is very little evidence to guide healthcare professionals beyond this point, particularly with regard to whether there is a benefit of prescribing stimulant and non-stimulant medication together.# Rationale and impact
# Recognition
Recommendations 1.2.1 and 1.2.2
## Why the committee made the recommendations
Evidence showed that the prevalence of attention deficit hyperactivity disorder (ADHD) is higher in some groups than in the general population. The committee agreed that a recommendation was needed to raise awareness of these groups among non-specialists to help them avoid missing a diagnosis of ADHD. Although no evidence was identified for a higher prevalence in people known to the Youth Justice System or Adult Criminal Justice System and people with acquired brain injury, the committee agreed that in their experience, these groups often receive a late diagnosis of ADHD or a misdiagnosis. No evidence was found on the increased risk of missing a diagnosis of ADHD in girls. But the committee discussed the different symptoms often found in this group, and agreed to make a recommendation to raise awareness.
## How the recommendations might affect practice
The recommendations are to raise awareness among non-specialists of a possible diagnosis of ADHD in groups of people that they are already seeing. The recommendations may increase the rates of diagnosis and referral for ADHD, but these should be accurate and therefore appropriate.
Return to recommendations
# Information and support
Recommendations 1.4.1 to 1.4.13
## Why the committee made the recommendations
Good information and support tailored to needs and circumstances are important for all people using NHS services, but some aspects are particularly important for people with ADHD. Evidence identified the need for information tailored to family circumstances, particularly when a child has ADHD, and to highlight the importance of daily structure for adults with ADHD.
Evidence showed the importance of discussing key areas following a diagnosis of ADHD, particularly the positive impacts of receiving a diagnosis, such as improving understanding of symptoms. The committee used the evidence and their experience to agree other areas for discussion, including driving and possible issues with education and employment. They noted that schools, colleges and universities may sometimes question a diagnosis of ADHD and not understand how symptoms can affect daily functioning. In addition, healthcare professionals treating a coexisting condition may not be aware of how ADHD symptoms may affect behaviour (organisation and time management) and adherence to treatment.
There was evidence that parents of children with ADHD often feel a sense of isolation when attending parent-training programmes. The committee agreed that healthcare professionals should explain to parents that an invitation to attend a parent-training programme does not imply bad parenting. The committee discussed the difficulties in families where parents may also have ADHD and made a recommendation to remind healthcare professionals that these families may need extra support.
In the committee's experience, people who are assessed for ADHD but not given a formal diagnosis are a neglected group who would benefit from advice on where to get support for troublesome symptoms.
## How the recommendations might affect practice
The recommendations should reflect good current practice. Healthcare professionals may spend more time discussing the potential impacts of a diagnosis, but this is likely to mean improved quality of life for the person with ADHD and better management of their symptoms.
Return to recommendations
# Managing ADHD – planning treatment
Recommendations 1.5.1 to 1.5.6
## Why the committee made the recommendations
Evidence showed the importance of joint decision-making when planning treatment; particularly important was the discussion before starting treatment. This was also the committee's experience and they recommended that these discussions should be repeated throughout care.
The committee recommended key areas highlighted in the evidence that should be discussed with the person and their family before starting treatment. This included the benefits and harms of medications and consideration of these alongside other treatment choices.
In the committee's experience, other mental health and neurodevelopmental conditions may affect treatment choices and how successful these are. The committee emphasised the importance of a holistic approach to managing ADHD.
Evidence indicated that parents and carers of children with ADHD found it hard to make decisions about treatment and wanted time to think about the effect of any environmental modifications. The committee recognised that systematic use of environmental modifications is important for limiting the impact of ADHD symptoms. The committee agreed that the effect of environmental modifications should be reviewed and taken into account when considering other treatment options. The committee also recognised the importance of having the opportunity to regularly revisit and discuss earlier decisions and so recommended that healthcare professionals remind people that they can do this if they wish.
The committee acknowledged that it is important to include children and young people in any treatment discussions and recommended they should be encouraged to say how they feel. This should include their views on the aims and effect of any treatments. Healthcare professionals should be aware that these will change as the child matures and will need revisiting. The committee also recognised that it was important that young people and adults should have as much support as they need and should be asked if they would like someone to join discussions about treatment. Decisions around treatment can have many influences, including teachers, peers and the media.
## How the recommendations might affect practice
The recommendations should reflect good current practice. Where practice might change, it is predominantly the approach to care that will be affected.
Return to recommendations
# Managing ADHD – children under 5 years
Recommendations 1.5.7 to 1.5.9
## Why the committee made the recommendations
In a very young child, the impact of ADHD symptoms on behaviour is assessed across different settings. Evidence showed a clinically important benefit on some measures of symptoms of an ADHD-focused group parent-training programme for children under 5 years. There was limited evidence on the efficacy of medication, and because of concerns and lack of evidence about the long-term effects of medication in very young children, particularly in terms of growth and development, the committee agreed to recommend a group-based parent-training programme as first-line treatment. However, the committee agreed that untreated ADHD can have far-reaching, long-lasting negative impacts on a child's life and some children may still have a significant impairment after the programme and environmental modifications. For these exceptional circumstances, the committee drew on their experience to recommend that healthcare professionals should seek further specialist advice, ideally from a tertiary service.
## How the recommendations might affect practice
The recommendations reflect good current practice and do not indicate a change in practice from the 2008 recommendations.
Return to recommendations
# Managing ADHD – children aged 5 years and over and young people
Recommendations 1.5.10 to 1.5.14
## Why the committee made the recommendations
The committee discussed evidence on non-pharmacological interventions and evidence on medication for managing ADHD in children and young people.
Evidence indicated that some parents and carers of children aged 5 years and over and young people can benefit from group support. After discussion of current good practice and consideration of the balance of benefits and costs, the committee decided to recommend offering additional support that could be group-based ADHD-focused support and as few as 1 or 2 sessions for parents and carers of all children and young people with ADHD.
Evidence showed the benefit of medication in this age group in improving ADHD symptoms and this was in line with the committee's experience. The committee acknowledged there are concerns about recommending medication for ADHD and particularly the uncertainty over the long-term adverse effects of medication in growing children. However, the committee agreed that untreated ADHD can have far-reaching, long-lasting negative impacts on a child or young person's life (for example, affecting academic performance, interpersonal relationships, work, personal issues, substance use and driving). Medication offers a better balance of benefits and costs than non-pharmacological interventions, so the committee agreed to recommend it when ADHD symptoms are persistent and still causing a significant impairment in at least one domain of everyday life despite the implementation and review of environmental modifications. The committee was aware of the implications of medication in this young population and made several recommendations to ensure its responsible use. These include recommendations on:
checking that environmental modifications have been done before starting medication
carrying out a thorough baseline assessment
ensuring that medication is initiated only by healthcare professionals with training and expertise in diagnosing and managing ADHD
early review of medication to optimise its use (including checking for adverse effects)
regular review to ensure that medication is continued only for as long as it is needed
-ffering ADHD-focused support for all children and young people with ADHD.
These recommendations are in the sections on planning treatment, baseline assessment, care arrangements and review.
Combining a full parent-training programme with medication did not offer a good balance of benefits and costs for all children and young people in this age group, so the committee decided not to make a recommendation on this.
Some evidence showed a benefit of cognitive behavioural therapy (CBT) in young people with ADHD. The committee agreed that this should be considered when a young person has benefited from medication but still has symptoms that are causing a significant impairment. They used their experience to recommend areas that a programme should address.
## How the recommendations might affect practice
The 2018 recommendations ensure that parents and carers of all children and young people with ADHD receive ADHD-focused information and support. Children and young people aged 5 years and over are offered medication by a healthcare professional with training and expertise in diagnosing and managing ADHD only if ADHD symptoms are still causing a significant impairment in at least one domain of their everyday life despite implementation of environmental modifications. This choice follows discussion with the child or young person and their parents or carers and a full baseline assessment. The recommendations make it clear that where a child has symptoms of oppositional defiant disorder or conduct disorder, parents and carers should be offered a parent-training programme in line with the recommendations in NICE's guideline on antisocial behaviour and conduct disorders.
The current categorisation of ADHD focuses on the presence of significant impairment in the different domains of everyday life and across settings, rather than using the previously used terms of mild, moderate and severe ADHD. There is considerable overlap with the guideline population described in the 2008 recommendation. The 2018 recommendations reflect current practice and are unlikely to result in a substantial increase in prescribing and resource use.
Return to recommendations
# Managing ADHD – adults
Recommendations 1.5.15 to 1.5.18
## Why the committee made the recommendations
Evidence directly comparing medication with non-pharmacological treatment supported the use of medication for first-line treatment of ADHD in adults. The committee acknowledged there are concerns about recommending medication for ADHD and in particular the uncertainty over the long-term benefits and the adverse effects of medication. However, the committee agreed that untreated ADHD can have a negative impact on a person's life, with lower educational attainment, and higher criminality. So they agreed to recommend medication when ADHD symptoms are still causing a significant impairment in at least one domain of everyday life despite environmental modifications.
Evidence indicated a benefit of non-pharmacological treatment, although this was less than for medication. There was also evidence of the importance of offering a choice of treatments, so the committee agreed that non-pharmacological treatment should be considered for adults who have made an informed choice not to have medication, have difficulty adhering to medication or have found they cannot tolerate medication or it is ineffective. Based on their experience, the committee recommended that the treatment may include elements of or a full programme of CBT and should include a structured supportive psychological intervention focused on ADHD, with regular follow‑up and information.
Combining medication with non-pharmacological treatment did not offer the best balance of benefits and costs, so the committee decided that combination treatment should only be considered when medication has offered some benefit but symptoms continue to cause a significant impairment.
## How the recommendations might affect practice
The recommendations reflect good current practice.
Return to recommendations
# Medication – care arrangements
Recommendations 1.7.2 and 1.7.29
## Why the committee made the recommendations
The committee discussed the roles of different healthcare professionals in initiating, monitoring and reviewing medication. They agreed, based on their experience, that medication should only be initiated and titrated by a healthcare professional with training and expertise in diagnosing and managing ADHD. But after dose stabilisation, prescribing and monitoring should be carried out under Shared Care Protocol arrangements with primary care. The exact balance between primary and secondary care will vary depending on the circumstances of the person with ADHD and the available primary and secondary care services.
## How the recommendations might affect practice
The recommendations reflect good current practice.
Return to recommendations 1.7.2 and 1.7.29
# Medication – baseline assessment
Recommendations 1.7.4 to 1.7.6
## Why the committee made the recommendations
The committee noted that it is important to carry out a baseline assessment before starting ADHD medication. Evidence was limited on what should be assessed clinically, but the committee used their experience and expert advice to recommend a general review of health and social circumstances, and a review of physical health. The committee used their experience to outline criteria for referral for a cardiologist opinion.
## How the recommendations might affect practice
The recommendations reflect good current practice.
Return to recommendations
# Medication – choice
Recommendations 1.7.7 to 1.7.19
## Why the committee made the recommendations
Evidence showed a clinically important benefit for monotherapy with the stimulants methylphenidate and lisdexamfetamine compared with placebo or other drugs. This was supported by the committee's experience that stimulants work more quickly than non-stimulant drugs (for example, atomoxetine and guanfacine), which can take longer to have an effect. The committee used the evidence, their experience and the drug licensing to recommend methylphenidate as a treatment for children aged 5 years and over and young people, and lisdexamfetamine or methylphenidate as a treatment for adults.
The committee acknowledged the rising cost of dexamfetamine since 2008 and agreed that it should only be considered when lisdexamfetamine is effective but the longer effect profile is not well tolerated.
The committee agreed that if methylphenidate has not been effective for children aged over 5 years and young people, then lisdexamfetamine could be considered.
Atomoxetine and guanfacine were the non-stimulant drugs with the most convincing evidence. The committee noted that atomoxetine is more widely used and that there was stronger evidence for a benefit of atomoxetine compared with placebo than guanfacine compared with placebo. One trial directly comparing atomoxetine with guanfacine generally showed a clinically important benefit of guanfacine. Taking into account the licensing status of these drugs and the familiarity of most healthcare professionals with them, the committee recommended that in children aged 5 years and over and young people, either drug could be offered after intolerance or a lack of response to stimulants (methylphenidate and lisdexamfetamine). Because guanfacine is not licensed for use in adults and there was no evidence specifically supporting its use in this population, the committee recommended atomoxetine for adults with intolerance or a lack of response to stimulants.
There was not enough evidence to justify specific recommendations for other drugs so the committee recommended that after at least one stimulant and non-stimulant had been tried, healthcare professionals should obtain a second opinion or refer to a tertiary service.
There was very little evidence on medication choice for people with ADHD and coexisting conditions and so the committee made research recommendations to address this gap. The committee agreed that neither the available evidence nor their experience justified a different choice of ADHD medication for people with ADHD and coexisting conditions, but there should be careful consideration of drug interactions and baseline assessments, slower titration, more careful monitoring and recording of adverse effects, and regular weekly telephone contact. However, the committee recommended that ADHD medication should be stopped in people experiencing a psychotic episode because they agreed that ADHD medication could worsen psychotic symptoms.
## How the recommendations might affect practice
The recommendations reflect good current practice.
Return to recommendations
# Medication – considerations when prescribing and dose titration
Recommendations 1.7.20 to 1.7.28
## Why the committee made the recommendations
The committee discussed that the careful initiation of ADHD medication is key to a successful treatment plan. This includes starting and titrating medication according to the BNF or the BNF for Children and the person's tolerance until the dose is optimised (reduced symptoms, positive behaviour change, improvements in education, employment and relationships, and tolerable adverse effects). The committee agreed that healthcare professionals should be aware of the pharmacokinetic profiles of ADHD medication because preparations can vary in their profiles. This is important when considering which medication or formulation to prescribe.
## How the recommendations might affect practice
The recommendations reflect good current practice.
Return to recommendations
# Medication – monitoring effectiveness and adverse effects
Recommendations 1.8.1 to 1.8.19
## Why the committee made the recommendations
Evidence showed clinically important differences in sleep disturbance, decreased appetite and weight changes in people taking ADHD medication. In the committee's experience, these are some of the most troublesome adverse effects. Because of concerns about decreased appetite and weight change, the committee advised that weight should be checked every 3 months in children aged 10 years and under, and at least every 6 months in older children and young people; BMI should be monitored in adults. The committee recommended that changes in sleep pattern should be recorded and medication adjusted accordingly.
There was some evidence that people on atomoxetine may experience sexual dysfunction, in particular erectile dysfunction, and the committee agreed that this should be monitored.
## How the recommendations might affect practice
The committee noted that the recommendations will reinforce current best practice.
Return to recommendations
# Adherence to treatment
Recommendations 1.9.1 to 1.9.6
## Why the committee made the recommendations
The evidence identified several factors that affect adherence to treatment and these were supported by the committee's own experience.
The evidence highlighted time management and forgetfulness as particular issues, so the committee made a recommendation that healthcare professionals should be aware that people with ADHD may have problems remembering to order and collect medication. The committee provided examples of how healthcare professionals might encourage people to follow strategies that support adherence (for example, following clear instructions and using visual reminders).
A common worry about treatment is that it might change personality and the committee agreed that this could affect adherence to both medication and non-pharmacological treatments. Misconceptions about the effects of treatment and worries about adverse effects were common themes identified, and the committee agreed that it was important that healthcare professionals address these.
Evidence identified that the attitudes of people close to a person with ADHD can influence adherence. The committee agreed that it was important that although children and young people should take responsibility for their own health (including taking medication), parents and carers should oversee them.
The committee discussed that adherence to non-pharmacological treatment was an important issue that was rarely addressed. They used their own experience to recommend that healthcare professionals discuss the commitment, time and organisational skills needed for successful adherence to non-pharmacological treatment.
## How the recommendations might affect practice
The committee noted that the recommendations will reinforce current best practice.
Return to recommendations
# Review of medication and discontinuation
Recommendations 1.10.1 to 1.10.3
## Why the committee made the recommendations
Evidence identified concerns around lack of follow‑up and the opportunity to review medication choices and this was supported by the committee's experience. They agreed that a yearly review with an ADHD specialist should be a comprehensive assessment that revisits the areas discussed when starting treatment but also the effect of current treatment. This would ensure that decisions around continuing or stopping treatment are fully informed.
Limited evidence showed possible worsening of ADHD symptoms on stopping medication but supported a reduction in adverse effects after withdrawal. The committee used their experience to make a recommendation on emphasising the importance of assessing the overall benefits and harms of medication as part of a review. The committee agreed that it was important to highlight the elements of a medication review that are important for someone with ADHD; they based the elements on evidence on adverse effects of medication, management of treatment, adherence and information and support.
## How the recommendations might affect practice
The committee noted that the recommendations will reinforce current best practice.
Return to recommendations# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder characterised by the core symptoms of hyperactivity, impulsivity and inattention, which are judged excessive for the person's age or level of overall development. The diagnosis is made on the basis of observed and reported behavioural symptoms. Two main diagnostic systems are in current use, the International Classification of Mental and Behavioural Disorders 10th revision (ICD‑10) and the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM‑5). Both systems require that symptoms are present in several settings such as school/work, home life and leisure activities. Symptoms should be evident in early life, if only in retrospect; for ICD‑10, by age 7 years and for DSM‑5, by age 12 years. ADHD may persist into adult life.
Prevalence rates for ICD‑10 (identifying hyperkinetic disorder) are 1 to 2% in childhood. Under the previous, less stringent DSM‑IV criteria, childhood prevalence rates were 3 to 9% and these may increase under the new DSM‑5 criteria.
The causes of ADHD are not fully understood but a number of risk factors are associated with the condition. Genetic factors can have an influence, with family members frequently affected. The diagnosis of ADHD in older family members such as parents may have previously been missed and should be considered.
Both the ICD‑10 and DSM‑5 require the presence of functional impairment due to symptoms of ADHD, with the symptoms adversely affecting psychological, social and/or educational/occupational functioning. The impact of ADHD may vary considerably in its severity, which is best judged by considering the level of impairment, pervasiveness, and familial and social context. For some people, symptoms may be limited to certain settings and cause minimal impairment in a limited number of domains (for example, ability to complete schoolwork, work tasks, avoiding common hazards and forming positive interpersonal relationships). In other people, multiple symptom areas (hyperactivity, inattention and impulsivity) are present in multiple settings, and this causes significant impairment across multiple domains. Symptoms and impact can also change over time. For some people, symptoms and impairment may be reduced through environmental modifications, such as a modified school curriculum or choice of employment.
Symptoms of ADHD can overlap with those of other related disorders. Therefore, care in differential diagnosis is needed. ADHD may also coexist with other disorders. Common coexisting conditions in children include disorders of mood, conduct, learning, motor control, language and communication, and anxiety disorders; in adults, they include personality disorders, bipolar disorder, obsessive-compulsive disorder and substance misuse. Where there are coexisting conditions, it is important to try to differentiate the level of impairment due to ADHD, because this will guide the treatment plan. In addition, ADHD is under-recognised in some populations, which can mean that a lack of appropriate diagnosis and treatment adversely affects people's quality of life.
The aim of this guideline is to raise awareness of populations at risk and to provide clear advice on managing ADHD.
The guideline covers children under 5 years, children and young people aged 5 to 17 years, and adults aged 18 years or over who are at risk of ADHD or have a diagnosis of ADHD. The guideline covers all primary, secondary and community care settings in which NHS-funded care is provided for people with ADHD.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professionals guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Service organisation and training\n\n## Service organisation\n\nPeople with attention deficit hyperactivity disorder (ADHD) would benefit from improved organisation of care and better integration of child health services, child and adolescent mental health services (CAMHS) and adult mental health services. \n\nMental health services for children, young people and adults, and child health services, should form multidisciplinary specialist ADHD teams and/or clinics for children and young people, and separate teams and/or clinics for adults. These teams and clinics should have expertise in the diagnosis and management of ADHD, and should:\n\nprovide diagnostic, treatment and consultation services for people with ADHD who have complex needs, or where general psychiatric services are in doubt about the diagnosis and/or management of ADHD\n\nput in place systems of communication and protocols for information sharing among paediatric, child and adolescent, forensic, and adult mental health services for people with ADHD, including arrangements for transition between child and adult services\n\nproduce local protocols for shared care arrangements with primary care providers, and ensure that clear lines of communication between primary and secondary care are maintained\n\nensure age-appropriate psychological services are available for children, young people and adults with ADHD, and for parents or carers.The size and time commitment of these teams should depend on local circumstances (for example, the size of the trust, the population covered and the estimated referral rate for people with ADHD). [2008, amended 2018]\n\nEvery locality should develop a multi-agency group, with representatives from multidisciplinary specialist ADHD teams, paediatrics, mental health and learning disability trusts, forensic services, CAMHS, the Directorate for Children and Young People (DCYP; including services for education and social services), parent support groups and others with a significant local involvement in ADHD services. The group should:\n\noversee the implementation of this guideline\n\nstart and coordinate local training initiatives, including the provision of training and information for teachers about the characteristics of ADHD and its basic behavioural management\n\noversee the development and coordination of parent-training/education programmes\n\nconsider compiling a comprehensive directory of information and services for ADHD including advice on how to contact relevant services and assist in the development of specialist teams. [2008, amended 2018]\n\nA young person with ADHD receiving treatment and care from CAMHS or paediatric services should be reassessed at school-leaving age to establish the need for continuing treatment into adulthood. If treatment is necessary, arrangements should be made for a smooth transition to adult services with details of the anticipated treatment and services that the young person will require. Precise timing of arrangements may vary locally but should usually be completed by the time the young person is 18\xa0years. See NICE's guideline on transition from children's to adults' services for young people using health or social care services. [2008, amended 2018]\n\nDuring the transition to adult services, a formal meeting involving CAMHS and/or paediatrics and adult psychiatric services should be considered, and full information provided to the young person about adult services. For young people aged 16\xa0years and older, the care programme approach (CPA) should be used as an aid to transfer between services. The young person, and when appropriate the parent or carer, should be involved in the planning. \n\nAfter transition to adult services, adult healthcare professionals should carry out a comprehensive assessment of the person with ADHD that includes personal, educational, occupational and social functioning, and assessment of any coexisting conditions, especially drug misuse, personality disorders, emotional problems and learning difficulties. \n\n## Training\n\nTrusts should ensure that specialist ADHD teams for children, young people and adults jointly develop age-appropriate training programmes for the diagnosis and management of ADHD for mental health, paediatric, social care, education, forensic and primary care providers and other professionals who have contact with people with ADHD. \n\nChild and adult psychiatrists, paediatricians, and other child and adult mental health professionals (including those working in forensic services) should undertake training so that they are able to diagnose ADHD and provide treatment and management in accordance with this guideline. \n\n# Recognition, identification and referral\n\n## Recognition\n\nBe aware that people in the following groups may have increased prevalence of ADHD compared with the general population:\n\npeople born preterm (see NICE's guideline on developmental follow-up of children and young people born preterm)\n\nlooked-after children and young people\n\nchildren and young people diagnosed with oppositional defiant disorder or conduct disorder\n\nchildren and young people with mood disorders (for example, anxiety and depression)\n\npeople with a close family member diagnosed with ADHD\n\npeople with epilepsy\n\npeople with other neurodevelopmental disorders (for example, autism spectrum disorder, tic disorders, learning disability [intellectual disability] and specific learning difficulties)\n\nadults with a mental health condition\n\npeople with a history of substance misuse\n\npeople known to the Youth Justice System or Adult Criminal Justice System\n\npeople with acquired brain injury. \n\nBe aware that ADHD is thought to be under-recognised in girls and women and that:\n\nthey are less likely to be referred for assessment for ADHD\n\nthey may be more likely to have undiagnosed ADHD\n\nthey may be more likely to receive an incorrect diagnosis of another mental health or neurodevelopmental condition. \n\nTo find out why the committee made the 2018 recommendations on recognition and how they might affect practice, see the rationale and impact section on recognition\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: risk factors.\n\nLoading. Please wait.\n\n## Identification and referral\n\nUniversal screening for ADHD should not be undertaken in nursery, primary and secondary schools. \n\nWhen a child or young person with disordered conduct and suspected ADHD is referred to a school's special educational needs coordinator (SENCO), the SENCO, in addition to helping the child with their behaviour, should inform the parents about local parent-training/education programmes. See NICE's guideline on antisocial behaviour and conduct disorders in children and young people. [2008, amended 2018]\n\nReferral from the community to secondary care may involve health, education and social care professionals (for example, GPs, paediatricians, educational psychologists, SENCOs, social workers) and care pathways can vary locally. The person making the referral to secondary care should inform the child or young person's GP. \n\nWhen a child or young person presents in primary care with behavioural and/or attention problems suggestive of ADHD, primary care practitioners should determine the severity of the problems, how these affect the child or young person and the parents or carers, and the extent to which they pervade different domains and settings. \n\nIf the child or young person's behavioural and/or attention problems suggestive of ADHD are having an adverse impact on their development or family life, consider:\n\na period of watchful waiting of up to 10\xa0weeks\n\noffering parents or carers a referral to group-based ADHD-focused support (this should not wait for a formal diagnosis of ADHD). If the behavioural and/or attention problems persist with at least moderate impairment, the child or young person should be referred to secondary care (that is, a child psychiatrist, paediatrician, or specialist ADHD CAMHS) for assessment. [2008, amended 2018]\n\nIf the child or young person's behavioural and/or attention problems are associated with severe impairment, referral should be made directly to secondary care (that is, a child psychiatrist, paediatrician, or specialist ADHD CAMHS) for assessment. \n\nPrimary care practitioners should not make the initial diagnosis or start medication in children or young people with suspected ADHD. \n\nAdults presenting with symptoms of ADHD in primary care or general adult psychiatric services, who do not have a childhood diagnosis of ADHD, should be referred for assessment by a mental health specialist trained in the diagnosis and treatment of ADHD, where there is evidence of typical manifestations of ADHD (hyperactivity/impulsivity and/or inattention) that:\n\nbegan during childhood and have persisted throughout life\n\nare not explained by other psychiatric diagnoses (although there may be other coexisting psychiatric conditions)\n\nhave resulted in or are associated with moderate or severe psychological, social and/or educational or occupational impairment. \n\nAdults who have previously been treated for ADHD as children or young people and present with symptoms suggestive of continuing ADHD should be referred to general adult psychiatric services for assessment. The symptoms should be associated with at least moderate or severe psychological and/or social or educational or occupational impairment. \n\n# Diagnosis\n\nA diagnosis of ADHD should only be made by a specialist psychiatrist, paediatrician or other appropriately qualified healthcare professional with training and expertise in the diagnosis of ADHD, on the basis of:\n\na full clinical and psychosocial assessment of the person; this should include discussion about behaviour and symptoms in the different domains and settings of the person's everyday life and\n\na full developmental and psychiatric history and\n\nobserver reports and assessment of the person's mental state. \n\nA diagnosis of ADHD should not be made solely on the basis of rating scale or observational data. However, rating scales such as the Conners' rating scales and the Strengths and Difficulties Questionnaire are valuable adjuncts, and observations (for example, at school) are useful when there is doubt about symptoms. \n\nFor a diagnosis of ADHD, symptoms of hyperactivity/impulsivity and/or inattention should:\n\nmeet the diagnostic criteria in DSM‑5 or ICD‑11 (hyperkinetic disorder; but exclusion based on a pervasive developmental disorder or an uncertain time of onset is not recommended) and\n\ncause at least moderate psychological, social and/or educational or occupational impairment based on interview and/or direct observation in multiple settings and\n\nbe pervasive, occurring in 2\xa0or more important settings including social, familial, educational and/or occupational settings.As part of the diagnostic process, include an assessment of the person's needs, coexisting conditions, social, familial and educational or occupational circumstances and physical health. For children and young people, there should also be an assessment of their parents' or carers' mental health. [2008, amended 2018]\n\nADHD should be considered in all age groups, with symptom criteria adjusted for age-appropriate changes in behaviour. \n\nIn determining the clinical significance of impairment resulting from the symptoms of ADHD in children and young people, their views should be taken into account wherever possible. \n\n# Information and support\n\nUse this guideline with NICE's guidelines on service user experience in adult mental health and patient experience in adult NHS services to improve the experience of care for adults with ADHD. The principles also apply to children and young people, and their parents or carers. \n\nHealthcare professionals working with children and young people with ADHD should follow the recommendations on general principles of care in NICE's guideline on antisocial behaviour and conduct disorder in children and young people. This does not mean that all children and young people with ADHD have coexisting antisocial behaviour and conduct disorder but that the same general principles of care apply when working with children and young people with ADHD. \n\n## Supporting people with ADHD\n\nFollowing a diagnosis of ADHD, have a structured discussion with people (and their families or carers as appropriate) about how ADHD could affect their life. This could include:\n\nthe positive impacts of receiving a diagnosis, such as:\n\n\n\nimproving their understanding of symptoms\n\nidentifying and building on individual strengths\n\nimproving access to services\n\n\n\nthe negative impacts of receiving a diagnosis, such as stigma and labelling\n\na greater tendency for impulsive behaviour\n\nthe importance of environmental modifications to reduce the impact of ADHD symptoms\n\neducation issues (for example, reasonable adjustments at school and college)\n\nemployment issues (for example, impact on career choices and rights to reasonable adjustments in the workplace)\n\nsocial relationship issues\n\nthe challenges of managing ADHD when a person has coexisting neurodevelopmental or mental health conditions\n\nthe increased risk of substance misuse and self-medication\n\nthe possible effect on driving (for example, ADHD symptoms may impair a person's driving and ADHD medication may improve this; people with ADHD must declare their diagnosis to the DVLA if their ADHD symptoms or medication affect their ability to drive safely).This structured discussion should inform the shared treatment plan. \n\nInform people receiving a diagnosis of ADHD (and their families or carers as appropriate) about sources of information, including:\n\nlocal and national support groups and voluntary organisations\n\nwebsites\n\nsupport for education and employment. People who have had an assessment but whose symptoms and impairment fall short of a diagnosis of ADHD may benefit from similar information. \n\nProvide information to people with ADHD (and their families and carers as appropriate) in a form that:\n\ntakes into account their developmental level, cognitive style, emotional maturity and cognitive capacity, including any learning disabilities, sight or hearing problems, delays in language development or social communication difficulties\n\ntakes into account any coexisting neurodevelopmental and mental health conditions\n\nis tailored to their individual needs and circumstances, including age, gender, educational level and life stage. \n\n## Supporting families and carers\n\nAsk families or carers of people with ADHD how the ADHD affects themselves and other family members, and discuss any concerns they have. \n\nEncourage family members or carers of people with ADHD to seek an assessment of their personal, social and mental health needs, and to join self-help and support groups if appropriate. \n\nThink about the needs of a parent with ADHD who also has a child with ADHD, including whether they need extra support with organisational strategies (for example, with adherence to treatment, daily school routines). \n\nOffer advice to parents and carers of children and young people with ADHD about the importance of:\n\npositive parent– and carer–child contact\n\nclear and appropriate rules about behaviour and consistent management\n\nstructure in the child or young person's day. \n\nOffer advice to families and carers of adults with ADHD about:\n\nhow ADHD may affect relationships\n\nhow ADHD may affect the person's functioning\n\nthe importance of structure in daily activities. \n\nExplain to parents and carers that any recommendation of parent-training/education does not imply bad parenting, and that the aim is to optimise parenting skills to meet the above-average parenting needs of children and young people with ADHD. \n\n## Involving schools, colleges and universities\n\nWhen ADHD is diagnosed, when symptoms change, and when there is transition between schools or from school to college or college to university, obtain consent and then contact the school, college or university to explain:\n\nthe validity of a diagnosis of ADHD and how symptoms are likely to affect school, college or university life\n\nother coexisting conditions (for example, learning disabilities) are distinct from ADHD and may need different adjustments\n\nthe treatment plan and identified special educational needs, including advice for reasonable adjustments and environmental modifications within the educational placement\n\nthe value of feedback from schools, colleges and universities to people with ADHD and their healthcare professionals. \n\n## Involving other healthcare professionals\n\nWhen a person with ADHD has a coexisting condition, contact the relevant healthcare professional, with consent, to explain:\n\nthe validity, scope and implications of a diagnosis of ADHD\n\nhow ADHD symptoms are likely to affect the person's behaviour (for example, organisation, time management, motivation) and adherence to specific treatments\n\nthe treatment plan and the value of feedback from healthcare professionals. \n\nTo find out why the committee made the 2018 recommendations on information and support, and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: information and support.\n\nLoading. Please wait.\n\n# Managing ADHD\n\n## Planning treatment\n\nHealthcare providers should ensure continuity of care for people with ADHD. \n\nEnsure that people with ADHD have a comprehensive, holistic shared treatment plan that addresses psychological, behavioural and occupational or educational needs. Take into account:\n\nthe severity of ADHD symptoms and impairment, and how these affect or may affect everyday life (including sleep)\n\ntheir goals\n\ntheir resilience and protective factors\n\nthe relative impact of other neurodevelopmental or mental health conditions. \n\nRegularly discuss with people with ADHD, and their family members or carers, how they want to be involved in treatment planning and decisions; such discussions should take place at intervals to take account of changes in circumstances (for example, the transition from children's to adult services) and developmental level, and should not happen only once. \n\nBefore starting any treatment for ADHD, discuss the following with the person, and their family or carers as appropriate, encouraging children and young people to give their own account of how they feel:\n\nthe benefits and harms of non-pharmacological and pharmacological treatments (for example, the efficacy of medication compared with no treatment or non-pharmacological treatments, potential adverse effects and non-response rates)\n\nthe benefits of a healthy lifestyle, including exercise\n\ntheir preferences and concerns (it is important to understand that a person's decision to start, change or stop treatment may be influenced by media coverage, teachers, family members, friends and differing opinion on the validity of a diagnosis of ADHD)\n\nhow other mental health or neurodevelopmental conditions might affect treatment choices\n\nthe importance of adherence to treatment and any factors that may affect this (for example, it may be difficult to take medication at school or work, or to remember appointments). Record the person's preferences and concerns in their treatment plan. \n\nAsk young people and adults with ADHD if they wish a parent, partner, close friend or carer to join discussions on treatment and adherence. \n\nReassure people with ADHD, and their families or carers as appropriate, that they can revisit decisions about treatments. \n\nTo find out why the committee made the 2018 recommendations on managing ADHD – planning treatment, and how they might affect practice, see the rationale and impact section on managing ADHD – planning treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: managing treatment.\n\nLoading. Please wait.\n\n## Children under 5\xa0years\n\nThese recommendations are for healthcare professionals with training and expertise in diagnosing and managing ADHD. See recommendation 1.4.3 for details of ADHD-focused information.\n\nOffer an ADHD-focused group parent-training programme to parents or carers of children under 5\xa0years with ADHD as first-line treatment. See recommendations\xa01.5.1 to\xa01.5.10 in NICE's guideline on antisocial behaviour and conduct disorders in children and young people.This does not imply that all children under 5\xa0years with ADHD have antisocial behaviour or conduct disorder, but that the same general principles of care apply. \n\nIf after an ADHD-focused group parent-training programme, ADHD symptoms across settings are still causing a significant impairment in a child under 5\xa0years after environmental modifications have been implemented and reviewed, obtain advice from a specialist ADHD service with expertise in managing ADHD in young children (ideally a tertiary service). \n\nDo not offer medication for ADHD for any child under 5\xa0years without a second specialist opinion from an ADHD service with expertise in managing ADHD in young children (ideally a tertiary service). \n\nTo find out why the committee made the 2018 recommendations on managing ADHD – children under 5\xa0years, and how they might affect practice, see the rationale and impact section on managing ADHD – children under 5\xa0years\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: non-pharmacological efficacy and adverse events and evidence review\xa0F: combination treatment.\n\nLoading. Please wait.\n\n## Children aged 5\xa0years and over and young people\n\nThese recommendations, covering children aged 5\xa0years and over and young people, are for healthcare professionals with training and expertise in diagnosing and managing ADHD. March 2018 – medicines used for treating ADHD did not have a UK marketing authorisation for children aged 5\xa0years or under (off-label use). See NICE's information on prescribing medicines.\n\nGive information about ADHD (see recommendation 1.4.3) and offer additional support to parents and carers of all children aged 5\xa0years and over and young people with ADHD. The support should be ADHD focused, can be group based and as few as 1\xa0or 2\xa0sessions. It should include:\n\neducation and information on the causes and impact of ADHD\n\nadvice on parenting strategies\n\nwith consent, liaison with school, college or university (see recommendation 1.4.12)\n\nboth parents and carers if feasible. \n\nIf a child aged 5\xa0years or over or young person has ADHD and symptoms of oppositional defiant disorder or conduct disorder, offer parents and carers a parent-training programme in line with recommendations\xa01.5.1 to\xa01.5.10 in NICE's guideline on antisocial behaviour and conduct disorders in children and young people, as well as group-based ADHD-focused support. \n\nConsider individual parent-training programmes for parents and carers of children and young people with ADHD and symptoms of oppositional defiant disorder or conduct disorder when:\n\nthere are particular difficulties for families in attending group sessions (for example, because of disability, needs related to diversity such as language differences, learning disability [intellectual disability], parental ill-health, problems with transport, or where other factors suggest poor prospects for therapeutic engagement)\n\na family's needs are too complex to be met by group-based parent-training programmes. \n\nOffer medication for children aged 5\xa0years and over and young people only if:\n\ntheir ADHD symptoms are still causing a persistent significant impairment in at least one domain after environmental modifications have been implemented and reviewed\n\nthey and their parents and carers have discussed information about ADHD (see recommendation 1.5.4)\n\na baseline assessment has been carried out (see recommendation 1.7.4).See the recommendations on medication. \n\nConsider a course of cognitive behavioural therapy (CBT) for young people with ADHD who have benefited from medication but whose symptoms are still causing a significant impairment in at least one domain, addressing the following areas:\n\nsocial skills with peers\n\nproblem-solving\n\nself-control\n\nactive listening skills\n\ndealing with and expressing feelings. \n\nTo find out why the committee made the 2018 recommendations on managing ADHD – children aged 5\xa0years and over and young people, and how they might affect practice, see the rationale and impact section on managing ADHD – children aged 5\xa0years and over and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: non-pharmacological efficacy and adverse events and evidence review\xa0F: combination treatment.\n\nLoading. Please wait.\n\n## Adults\n\nThese recommendations are for healthcare professionals with training and expertise in diagnosing and managing ADHD. See recommendation 1.4.3 for details of ADHD-focused information.\n\nOffer medication to adults with ADHD if their ADHD symptoms are still causing a significant impairment in at least one domain after environmental modifications have been implemented and reviewed. See the recommendations on medication choice. \n\nConsider non-pharmacological treatment for adults with ADHD who have:\n\nmade an informed choice not to have medication\n\ndifficulty adhering to medication\n\nfound medication to be ineffective or cannot tolerate it. \n\nConsider non-pharmacological treatment in combination with medication for adults with ADHD who have benefited from medication but whose symptoms are still causing a significant impairment in at least one domain. \n\nWhen non-pharmacological treatment is indicated for adults with ADHD, offer the following as a minimum:\n\na structured supportive psychological intervention focused on ADHD\n\nregular follow‑up either in person or by phone.Treatment may involve elements of or a full course of CBT. \n\nTo find out why the committee made the 2018 recommendations on managing ADHD – adults, and how they might affect practice, see the rationale and impact section on managing ADHD – adults\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: non-pharmacological efficacy and adverse events and evidence review\xa0F: combination treatment.\n\nLoading. Please wait.\n\n# Dietary advice\n\nHealthcare professionals should stress the value of a balanced diet, good nutrition and regular exercise for children, young people and adults with ADHD. \n\nDo not advise elimination of artificial colouring and additives from the diet as a generally applicable treatment for children and young people with ADHD. \n\nAsk about foods or drinks that appear to influence hyperactive behaviour as part of the clinical assessment of ADHD in children and young people, and:\n\nif there is a clear link, advise parents or carers to keep a diary of food and drinks taken and ADHD behaviour\n\nif the diary supports a relationship between specific foods and drinks and behaviour, offer referral to a dietitian\n\nensure that further management (for example, specific dietary elimination) is jointly undertaken by the dietitian, mental health specialist or paediatrician, and the parent or carer and child or young person. \n\nDo not advise or offer dietary fatty acid supplementation for treating ADHD in children and young people. \n\nAdvise the family members or carers of children with ADHD that there is no evidence about the long-term effectiveness or potential harms of a 'few food' diet for children with ADHD, and only limited evidence of short-term benefits. \n\n# Medication\n\nThese recommendations, with the exception of\xa0recommendation 1.7.29, are for healthcare professionals with training and expertise in diagnosing and managing ADHD.\n\nUse this guideline with NICE's guideline on medicines optimisation: the safe and effective use of medicines to enable the best possible outcomes. \n\nAll medication for ADHD should only be initiated by a healthcare professional with training and expertise in diagnosing and managing ADHD. \n\nHealthcare professionals initiating medication for ADHD should:\n\nbe familiar with the pharmacokinetic profiles of all the short- and long-acting preparations available for ADHD\n\nensure that treatment is tailored effectively to the individual needs of the child, young person or adult\n\ntake account of variations in bioavailability or pharmacokinetic profiles of different preparations to avoid reduced effect or excessive adverse effects. \n\n## Baseline assessment\n\nBefore starting medication for ADHD, people with ADHD should have a full assessment, which should include:\n\na review to confirm they continue to meet the criteria for ADHD and need treatment\n\na review of mental health and social circumstances, including:\n\n\n\npresence of coexisting mental health and neurodevelopmental conditions\n\ncurrent educational or employment circumstances\n\nrisk assessment for substance misuse and drug diversion\n\ncare needs\n\n\n\na review of physical health, including:\n\n\n\na medical history, taking into account conditions that may be contraindications for specific medicines\n\ncurrent medication\n\nheight and weight (measured and recorded against the normal range for age, height and sex)\n\nbaseline pulse and blood pressure (measured with an appropriately sized cuff and compared with the normal range for age)\n\na cardiovascular assessment.An electrocardiogram (ECG) is not needed before starting stimulants, atomoxetine or guanfacine, unless the person has any of the features in recommendation 1.7.5, or a co-existing condition that is being treated with a medicine that may pose an increased cardiac risk. [2018, amended 2019]\n\n\n\nRefer for a cardiology opinion before starting medication for ADHD if any of the following apply:\n\nhistory of congenital heart disease or previous cardiac surgery\n\nhistory of sudden death in a first-degree relative under 40\xa0years suggesting a cardiac disease\n\nshortness of breath on exertion compared with peers\n\nfainting on exertion or in response to fright or noise\n\npalpitations that are rapid, regular and start and stop suddenly (fleeting occasional bumps are usually ectopic and do not need investigation)\n\nchest pain suggesting cardiac origin\n\nsigns of heart failure\n\na murmur heard on cardiac examination\n\nblood pressure that is classified as hypertensive for adults (see NICE's guideline on hypertension in adults). \n\nRefer to a paediatric hypertension specialist before starting medication for ADHD if blood pressure is consistently above the 95th centile for age and height for children and young people. \n\nTo find out why the committee made the 2018 recommendations on medication – baseline assessment, and how they might affect practice, see the rationale and impact section on medication – baseline assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological safety.\n\nLoading. Please wait.\n\n## Medication choice – children aged 5\xa0years and over and young people\n\nRecommendations 1.7.7 to 1.7.10 update NICE's technology appraisal guidance on methylphenidate, atomoxetine and dexamfetamine for ADHD in children and adolescents (TA98).\n\nOffer methylphenidate (either short or long acting) as the first line pharmacological treatment for children aged 5\xa0years and over and young people with ADHD. March 2018 – this is an off-label use for children aged 5\xa0years. See NICE's information on prescribing medicines. \n\nConsider switching to lisdexamfetamine for children aged 5\xa0years and over and young people who have had a 6‑week trial of methylphenidate at an adequate dose and not derived enough benefit in terms of reduced ADHD symptoms and associated impairment. March 2018 – this is an off-label use for children aged 5\xa0years. See NICE's information on prescribing medicines. \n\nConsider dexamfetamine for children aged 5\xa0years and over and young people whose ADHD symptoms are responding to lisdexamfetamine but who cannot tolerate the longer effect profile. March 2018 – dexamfetamine is only licensed to treat ADHD in children and young people aged 6\xa0to 17\xa0years when response to methylphenidate is clinically inadequate. It is not licensed for children and young people aged 5\xa0to 17\xa0years who have responded to but are intolerant of lisdexamfetamine.See NICE's information on prescribing medicines. \n\nOffer atomoxetine or guanfacine to children aged 5\xa0years and over and young people if:\n\nthey cannot tolerate methylphenidate or lisdexamfetamine or\n\ntheir symptoms have not responded to separate 6‑week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses.March 2018 – this is an off-label use of atomoxetine and guanfacine for children aged 5\xa0years. See NICE's information on prescribing medicines. \n\n## Medication choice – adults\n\nOffer lisdexamfetamine or methylphenidate as first-line pharmacological treatment for adults with ADHD. March 2018 – this is an off-label use of lisdexamfetamine for adults with no ADHD symptoms in childhood. See NICE's information on prescribing medicines. Not all preparations of methylphenidate are licensed for treating symptoms of ADHD in adults. \n\nConsider switching to lisdexamfetamine for adults who have had a 6‑week trial of methylphenidate at an adequate dose but have not derived enough benefit in terms of reduced ADHD symptoms and associated impairment. \n\nConsider switching to methylphenidate for adults who have had a 6‑week trial of lisdexamfetamine at an adequate dose but have not derived enough benefit in terms of reduced ADHD symptoms and associated impairment. \n\nConsider dexamfetamine for adults whose ADHD symptoms are responding to lisdexamfetamine but who cannot tolerate the longer effect profile. March 2018 – this is an off-label use of dexamfetamine. See NICE's information on prescribing medicines. \n\nOffer atomoxetine to adults if:\n\nthey cannot tolerate lisdexamfetamine or methylphenidate or\n\ntheir symptoms have not responded to separate 6‑week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses. March 2018 – this is an off-label use of atomoxetine for adults with no ADHD symptoms in childhood. See NICE's information on prescribing medicines. \n\n## Further medication choices\n\nObtain a second opinion or refer to a tertiary service if ADHD symptoms in a child aged 5\xa0years or over, a young person or adult are unresponsive to one or more stimulants and one non-stimulant. \n\nDo not offer any of the following medication for ADHD without advice from a tertiary ADHD service:\n\nguanfacine for adults (off-label use)\n\nclonidine for children with ADHD and sleep disturbance, rages or tics (off-label use)\n\natypical antipsychotics in addition to stimulants for people with ADHD and coexisting pervasive aggression, rages or irritability\n\nmedication not included in recommendations\xa01.7.7 to\xa01.7.15. See NICE's information on prescribing medicines. \n\n## Medication choice – people with coexisting conditions\n\nOffer the same medication choices to people with ADHD and anxiety disorder, tic disorder or autism spectrum disorder as other people with ADHD. \n\nFor children aged 5\xa0years and over, young people and adults with ADHD experiencing an acute psychotic or manic episode:\n\nstop any medication for ADHD\n\nconsider restarting or starting new ADHD medication after the episode has resolved, taking into account the individual circumstances, risks and benefits of the ADHD medication. \n\nTo find out why the committee made the 2018 recommendations on medication choice, and how they might affect practice, see the rationale and impact section on medication – choice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: pharmacological efficacy and sequencing.\n\nLoading. Please wait.\n\n## Considerations when prescribing ADHD medication\n\nWhen prescribing stimulants for ADHD, think about modified-release once-daily preparations for the following reasons:\n\nconvenience\n\nimproving adherence\n\nreducing stigma (because there is no need to take medication at school or in the workplace)\n\nreducing problems of storing and administering controlled drugs at school\n\nthe risk of stimulant misuse and diversion with immediate-release preparations\n\ntheir pharmacokinetic profiles.Immediate-release preparations may be suitable if more flexible dosing regimens are needed, or during initial titration to determine correct dosing levels. \n\nWhen prescribing stimulants for ADHD, be aware that effect size, duration of effect and adverse effects vary from person to person. \n\nThink about using a modified-release preparation of methylphenidate in the morning and an immediate-release preparation of methylphenidate at another time of the day to extend the duration of effect. \n\nBe cautious about prescribing stimulants for ADHD if there is a risk of diversion for cognitive enhancement or appetite suppression. \n\nDo not offer immediate-release stimulants or modified-release stimulants that can be easily injected or insufflated if there is a risk of stimulant misuse or diversion. \n\nPrescribers should be familiar with the requirements of controlled drug legislation governing the prescription and supply of stimulants. See NICE's guideline on controlled drugs. \n\n## Dose titration\n\nDuring the titration phase, ADHD symptoms, impairment and adverse effects should be recorded at baseline and at each dose change on standard scales by parents and teachers, and progress reviewed regularly (for example, by weekly telephone contact) with a specialist. \n\nTitrate the dose against symptoms and adverse effects in line with the BNF or BNF for Children until dose optimisation is achieved, that is, reduced symptoms, positive behaviour change, improvements in education, employment and relationships, with tolerable adverse effects. \n\nEnsure that dose titration is slower and monitoring more frequent if any of the following are present in people with ADHD:\n\nneurodevelopmental disorders (for example, autism spectrum disorder, tic disorders, learning disability [intellectual disability])\n\nmental health conditions (for example, anxiety disorders [including obsessive–compulsive disorder], schizophrenia or bipolar disorder, depression, personality disorder, eating disorder, post-traumatic stress disorder, substance misuse)\n\nphysical health conditions (for example, cardiac disease, epilepsy or acquired brain injury). \n\nTo find out why the committee made the 2018 recommendations on medication – considerations when prescribing and dose titration, and how they might affect practice, see the rationale and impact section on medication – considerations when prescribing and dose titration\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological safety.\n\nLoading. Please wait.\n\n## Shared care for medication\n\nAfter titration and dose stabilisation, prescribing and monitoring of ADHD medication should be carried out under Shared Care Protocol arrangements with primary care. \n\nTo find out why the committee made the 2018 recommendations on medication – care arrangements, and how they might affect practice, see the rationale and impact section on medication – care arrangements\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological safety.\n\nLoading. Please wait.\n\n# Maintenance and monitoring\n\nMonitor effectiveness of medication for ADHD and adverse effects, and document in the person's notes. \n\nEncourage people taking medication for ADHD to monitor and record their adverse effects, for example, by using an adverse effect checklist. \n\nConsider using standard symptom and adverse effect rating scales for clinical assessment and throughout the course of treatment for people with ADHD. \n\nEnsure that children, young people and adults receiving treatment for ADHD have review and follow‑up according to the severity of their condition, regardless of whether or not they are taking medication. \n\n## Height and weight\n\nFor people taking medication for ADHD:\n\nmeasure height every 6\xa0months in children and young people\n\nmeasure weight every 3\xa0months in children 10\xa0years and under\n\nmeasure weight at 3\xa0and 6\xa0months after starting treatment in children over 10\xa0years and young people, and every 6\xa0months thereafter, or more often if concerns arise\n\nmeasure weight every 6\xa0months in adults\n\nplot height and weight of children and young people on a growth chart and ensure review by the healthcare professional responsible for treatment. \n\nIf weight loss is a clinical concern, consider the following strategies:\n\ntaking medication either with or after food, rather than before meals\n\ntaking additional meals or snacks early in the morning or late in the evening when stimulant effects have worn off\n\nobtaining dietary advice\n\nconsuming high-calorie foods of good nutritional value\n\ntaking a planned break from treatment\n\nchanging medication. \n\nIf a child or young person's height over time is significantly affected by medication (that is, they have not met the height expected for their age), consider a planned break in treatment over school holidays to allow 'catch‑up' growth. \n\nConsider monitoring BMI of adults with ADHD if there has been weight change as a result of their treatment, and changing the medication if weight change persists. \n\n## Cardiovascular\n\nMonitor heart rate and blood pressure and compare with the normal range for age before and after each dose change and every 6\xa0months. \n\nDo not offer routine blood tests (including liver function tests) or ECGs to people taking medication for ADHD unless there is a clinical indication. \n\nIf a person taking ADHD medication has sustained resting tachycardia (more than 120\xa0beats per minute), arrhythmia or systolic blood pressure greater than the 95th percentile (or a clinically significant increase) measured on 2\xa0occasions, reduce their dose and refer them to a paediatric hypertension specialist or adult physician. \n\nIf a person taking guanfacine has sustained orthostatic hypotension or fainting episodes, reduce their dose or switch to another ADHD medication. \n\n## Tics\n\nIf a person taking stimulants develops tics, think about whether:\n\nthe tics are related to the stimulant (tics naturally wax and wane) and\n\nthe impairment associated with the tics outweighs the benefits of ADHD treatment. \n\nIf tics are stimulant related, reduce the stimulant dose, or consider changing to guanfacine (in children aged 5\xa0years and over and young people only), atomoxetine (off-label use for adults with no ADHD symptoms in childhood), clonidine (off-label use for children), or stopping medication. Clonidine should only be considered for people under 18\xa0years after advice from a tertiary ADHD service. \n\n## Sexual dysfunction\n\nMonitor young people and adults with ADHD for sexual dysfunction (that is, erectile and ejaculatory dysfunction) as potential adverse effects of atomoxetine. \n\n## Seizures\n\nIf a person with ADHD develops new seizures or a worsening of existing seizures, review their ADHD medication and stop any medication that might be contributing to the seizures. After investigation, cautiously reintroduce ADHD medication if it is unlikely to be the cause of the seizures. \n\n## Sleep\n\nMonitor changes in sleep pattern (for example, with a sleep diary) and adjust medication accordingly. \n\n## Worsening behaviour\n\nMonitor the behavioural response to medication, and if behaviour worsens adjust medication and review the diagnosis. \n\n## Stimulant diversion\n\nHealthcare professionals and parents or carers should monitor changes in the potential for stimulant misuse and diversion, which may come with changes in circumstances and age. \n\nTo find out why the committee made the 2018 recommendations on medication – monitoring adverse effects, and how they might affect practice, see the rationale and impact section on medication – monitoring effectiveness and adverse effects\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological safety.\n\nLoading. Please wait.\n\n# Adherence to treatment\n\nUse this guideline with NICE's guideline on medicines adherence to improve the care for adults with ADHD. The principles also apply to children and young people. \n\nBe aware that the symptoms of ADHD may lead to people having difficulty adhering to treatment plans (for example, remembering to order and collect medication). \n\nEnsure that people are fully informed of the balance of risks and benefits of any treatment for ADHD and check that problems with adherence are not due to misconceptions (for example, tell people that medication does not change personality). \n\nEncourage the person with ADHD to use the following strategies to support adherence to treatment:\n\nbeing responsible for their own health, including taking their medication as needed\n\nfollowing clear instructions about how to take the medication in picture or written format, which may include information on dose, duration, adverse effects, dosage schedule (the instructions should stay with the medication, for example, a sticker on the side of the packet)\n\nusing visual reminders to take medication regularly (for example, apps, alarms, clocks, pill dispensers, or notes on calendars or fridges)\n\ntaking medication as part of their daily routine (for example, before meals or after brushing teeth)\n\nattending peer support groups (for both the person with ADHD and for the families and carers). \n\nEncourage parents and carers to oversee ADHD medication for children and young people. \n\n## Supporting adherence to non-pharmacological treatments\n\nSupport adherence to non-pharmacological treatments (for example, CBT) by discussing the following:\n\nthe balance of risks and benefits (for example, how the treatment can have a positive effect on ADHD symptoms)\n\nthe potential barriers to continuing treatment, including:\n\n\n\nnot being sure if it is making any difference\n\nthe time and organisational skills needed to commit to the treatment\n\nthe time that might be needed outside of the sessions (for example, to complete homework)\n\n\n\nstrategies to deal with any identified barriers (for example, scheduling sessions to minimise inconvenience or seeking courses with child care provision)\n\na possible effect of treatment being increased self-awareness, and the challenging impact this may have on the person and the people around them\n\nthe importance of long-term adherence beyond the duration of any initial programme (for example, by attending follow‑up/refresher support to sustain learned strategies). \n\nTo find out why the committee made the 2018 recommendations on adherence to treatment and how they might affect practice, see the rationale and impact section on adherence to treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: adherence.\n\nLoading. Please wait.\n\n# Review of medication and discontinuation\n\nA healthcare professional with training and expertise in managing ADHD should review ADHD medication at least once a year and discuss with the person with ADHD (and their families and carers as appropriate) whether medication should be continued. The review should include a comprehensive assessment of the:\n\npreference of the child, young person or adult with ADHD (and their family or carers as appropriate)\n\nbenefits, including how well the current treatment is working throughout the day\n\nadverse effects\n\nclinical need and whether medication has been optimised\n\nimpact on education and employment\n\neffects of missed doses, planned dose reductions and periods of no treatment\n\neffect of medication on existing or new mental health, physical health or neurodevelopmental conditions\n\nneed for support and type of support (for example, psychological, educational, social) if medication has been optimised but ADHD symptoms continue to cause a significant impairment. \n\nEncourage people with ADHD to discuss any preferences to stop or change medication and to be involved in any decisions about stopping treatments. \n\nConsider trial periods of stopping medication or reducing the dose when assessment of the overall balance of benefits and harms suggests this may be appropriate. If the decision is made to continue medication, the reasons for this should be documented. \n\nTo find out why the committee made the 2018 recommendations on review of medication and discontinuation, and how they might affect practice, see the rationale and impact section on review of medication and discontinuation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: withdrawal and drug holidays.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Domains\n\nDomains refer to areas of function, for example, interpersonal relationships, education and occupational attainment, and risk awareness.\n\n## Environmental modifications\n\nEnvironmental modifications are changes that are made to the physical environment in order to minimise the impact of a person's ADHD on their day-to-day life. Appropriate environmental modifications will be specific to the circumstances of each person with ADHD and should be determined from an assessment of their needs. Examples may include changes to seating arrangements, changes to lighting and noise, reducing distractions (for example, using headphones), optimising work or education to have shorter periods of focus with movement breaks (including the use of 'I need a break' cards), reinforcing verbal requests with written instructions and, for children, the appropriate use of teaching assistants at school.\n\n## Reasonable adjustments\n\nReasonable adjustments is a term that refers to the legal obligations of employers and higher education providers to make sure that workers or students with disabilities, or physical or mental health conditions are not substantially disadvantaged when doing their jobs or during their education.\n\n## Settings\n\nSettings refer to the physical location, for example, home, nursery, friends or family homes.\n\n## Shared treatment plan\n\nA written treatment plan shared between healthcare professional and the person with ADHD; for children, this may be shared more widely (for example, with families, schools or social care, if relevant and agreed).", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Children and young people aged 5\xa0to 18\xa0years – brief, group-based, ADHD-focused, parent-training intervention\n\nWhat is the clinical and cost effectiveness, and optimum length, of a brief parent-training intervention for parents and carers of children and young people with attention deficit hyperactivity disorder (ADHD) aged 5\xa0to 18\xa0years?\n\n## Why this is important\n\nThere was no clear evidence identified about the benefit of formal parent-training programmes for ADHD symptoms in children and young people aged 5\xa0to 18\xa0years. The cost effectiveness of these programmes was unclear, partly because of uncertainty over the number of sessions and the length of programme needed to achieve clinical benefit. This research recommendation would help address these uncertainties.\n\n# Medication choice in people with coexisting conditions\n\nWhat is the clinical and cost effectiveness of ADHD medications in people with ADHD and tic disorders, a history of psychosis or mania, or personality disorder?\n\n## Why is this important\n\nNo evidence was identified to justify different medication choices in people with ADHD and tic disorders, a history of psychosis or mania, or emotional dysregulation. These groups are often excluded from trials. There are reasons (for example, mechanism of action of medication options, previous reports of adverse effects) to suspect that these groups may respond differently to different drugs, but a lack of trials to confirm this. Primarily there are some concerns that stimulant medication may worsen the symptoms of any of these coexisting conditions and therefore non-stimulant medication should be preferred.\n\n# Medication choice in people with no previous medication for ADHD\n\nWhat is the clinical and cost effectiveness of ADHD medications in people with ADHD with no previous medication for the condition?\n\n## Why is this important\n\nMost of the evidence to support the recommendations for medication choices for people with ADHD comes from studies in people who have previously received medication. Therefore, these studies often include a population not representative of the people with newly diagnosed ADHD. There may be differing levels of efficacy of the various treatment options in people who have received no previous medication for ADHD.\n\n# Prescribing beyond monotherapy\n\nWhat is the clinical and cost effectiveness of various ADHD prescribing strategies when monotherapy has failed?\n\n## Why is this important\n\nThis guideline makes recommendations for the medication choices for people with ADHD up to the point at which common monotherapies are exhausted. There is very little evidence to guide healthcare professionals beyond this point, particularly with regard to whether there is a benefit of prescribing stimulant and non-stimulant medication together.', 'Rationale and impact': "# Recognition\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nEvidence showed that the prevalence of attention deficit hyperactivity disorder (ADHD) is higher in some groups than in the general population. The committee agreed that a recommendation was needed to raise awareness of these groups among non-specialists to help them avoid missing a diagnosis of ADHD. Although no evidence was identified for a higher prevalence in people known to the Youth Justice System or Adult Criminal Justice System and people with acquired brain injury, the committee agreed that in their experience, these groups often receive a late diagnosis of ADHD or a misdiagnosis. No evidence was found on the increased risk of missing a diagnosis of ADHD in girls. But the committee discussed the different symptoms often found in this group, and agreed to make a recommendation to raise awareness.\n\n## How the recommendations might affect practice\n\nThe recommendations are to raise awareness among non-specialists of a possible diagnosis of ADHD in groups of people that they are already seeing. The recommendations may increase the rates of diagnosis and referral for ADHD, but these should be accurate and therefore appropriate.\n\nReturn to recommendations\n\n# Information and support\n\nRecommendations 1.4.1 to 1.4.13\n\n## Why the committee made the recommendations\n\nGood information and support tailored to needs and circumstances are important for all people using NHS services, but some aspects are particularly important for people with ADHD. Evidence identified the need for information tailored to family circumstances, particularly when a child has ADHD, and to highlight the importance of daily structure for adults with ADHD.\n\nEvidence showed the importance of discussing key areas following a diagnosis of ADHD, particularly the positive impacts of receiving a diagnosis, such as improving understanding of symptoms. The committee used the evidence and their experience to agree other areas for discussion, including driving and possible issues with education and employment. They noted that schools, colleges and universities may sometimes question a diagnosis of ADHD and not understand how symptoms can affect daily functioning. In addition, healthcare professionals treating a coexisting condition may not be aware of how ADHD symptoms may affect behaviour (organisation and time management) and adherence to treatment.\n\nThere was evidence that parents of children with ADHD often feel a sense of isolation when attending parent-training programmes. The committee agreed that healthcare professionals should explain to parents that an invitation to attend a parent-training programme does not imply bad parenting. The committee discussed the difficulties in families where parents may also have ADHD and made a recommendation to remind healthcare professionals that these families may need extra support.\n\nIn the committee's experience, people who are assessed for ADHD but not given a formal diagnosis are a neglected group who would benefit from advice on where to get support for troublesome symptoms.\n\n## How the recommendations might affect practice\n\nThe recommendations should reflect good current practice. Healthcare professionals may spend more time discussing the potential impacts of a diagnosis, but this is likely to mean improved quality of life for the person with ADHD and better management of their symptoms.\n\nReturn to recommendations\n\n# Managing ADHD – planning treatment\n\nRecommendations 1.5.1 to 1.5.6\n\n## Why the committee made the recommendations\n\nEvidence showed the importance of joint decision-making when planning treatment; particularly important was the discussion before starting treatment. This was also the committee's experience and they recommended that these discussions should be repeated throughout care.\n\nThe committee recommended key areas highlighted in the evidence that should be discussed with the person and their family before starting treatment. This included the benefits and harms of medications and consideration of these alongside other treatment choices.\n\nIn the committee's experience, other mental health and neurodevelopmental conditions may affect treatment choices and how successful these are. The committee emphasised the importance of a holistic approach to managing ADHD.\n\nEvidence indicated that parents and carers of children with ADHD found it hard to make decisions about treatment and wanted time to think about the effect of any environmental modifications. The committee recognised that systematic use of environmental modifications is important for limiting the impact of ADHD symptoms. The committee agreed that the effect of environmental modifications should be reviewed and taken into account when considering other treatment options. The committee also recognised the importance of having the opportunity to regularly revisit and discuss earlier decisions and so recommended that healthcare professionals remind people that they can do this if they wish.\n\nThe committee acknowledged that it is important to include children and young people in any treatment discussions and recommended they should be encouraged to say how they feel. This should include their views on the aims and effect of any treatments. Healthcare professionals should be aware that these will change as the child matures and will need revisiting. The committee also recognised that it was important that young people and adults should have as much support as they need and should be asked if they would like someone to join discussions about treatment. Decisions around treatment can have many influences, including teachers, peers and the media.\n\n## How the recommendations might affect practice\n\nThe recommendations should reflect good current practice. Where practice might change, it is predominantly the approach to care that will be affected.\n\nReturn to recommendations\n\n# Managing ADHD – children under 5\xa0years\n\nRecommendations 1.5.7 to 1.5.9\n\n## Why the committee made the recommendations\n\nIn a very young child, the impact of ADHD symptoms on behaviour is assessed across different settings. Evidence showed a clinically important benefit on some measures of symptoms of an ADHD-focused group parent-training programme for children under 5\xa0years. There was limited evidence on the efficacy of medication, and because of concerns and lack of evidence about the long-term effects of medication in very young children, particularly in terms of growth and development, the committee agreed to recommend a group-based parent-training programme as first-line treatment. However, the committee agreed that untreated ADHD can have far-reaching, long-lasting negative impacts on a child's life and some children may still have a significant impairment after the programme and environmental modifications. For these exceptional circumstances, the committee drew on their experience to recommend that healthcare professionals should seek further specialist advice, ideally from a tertiary service.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect good current practice and do not indicate a change in practice from the 2008 recommendations.\n\nReturn to recommendations\n\n# Managing ADHD – children aged 5\xa0years and over and young people\n\nRecommendations 1.5.10 to 1.5.14\n\n## Why the committee made the recommendations\n\nThe committee discussed evidence on non-pharmacological interventions and evidence on medication for managing ADHD in children and young people.\n\nEvidence indicated that some parents and carers of children aged 5\xa0years and over and young people can benefit from group support. After discussion of current good practice and consideration of the balance of benefits and costs, the committee decided to recommend offering additional support that could be group-based ADHD-focused support and as few as 1\xa0or 2\xa0sessions for parents and carers of all children and young people with ADHD.\n\nEvidence showed the benefit of medication in this age group in improving ADHD symptoms and this was in line with the committee's experience. The committee acknowledged there are concerns about recommending medication for ADHD and particularly the uncertainty over the long-term adverse effects of medication in growing children. However, the committee agreed that untreated ADHD can have far-reaching, long-lasting negative impacts on a child or young person's life (for example, affecting academic performance, interpersonal relationships, work, personal issues, substance use and driving). Medication offers a better balance of benefits and costs than non-pharmacological interventions, so the committee agreed to recommend it when ADHD symptoms are persistent and still causing a significant impairment in at least one domain of everyday life despite the implementation and review of environmental modifications. The committee was aware of the implications of medication in this young population and made several recommendations to ensure its responsible use. These include recommendations on:\n\nchecking that environmental modifications have been done before starting medication\n\ncarrying out a thorough baseline assessment\n\nensuring that medication is initiated only by healthcare professionals with training and expertise in diagnosing and managing ADHD\n\nearly review of medication to optimise its use (including checking for adverse effects)\n\nregular review to ensure that medication is continued only for as long as it is needed\n\noffering ADHD-focused support for all children and young people with ADHD.\n\nThese recommendations are in the sections on planning treatment, baseline assessment, care arrangements and review.\n\nCombining a full parent-training programme with medication did not offer a good balance of benefits and costs for all children and young people in this age group, so the committee decided not to make a recommendation on this.\n\nSome evidence showed a benefit of cognitive behavioural therapy (CBT) in young people with ADHD. The committee agreed that this should be considered when a young person has benefited from medication but still has symptoms that are causing a significant impairment. They used their experience to recommend areas that a programme should address.\n\n## How the recommendations might affect practice\n\nThe 2018 recommendations ensure that parents and carers of all children and young people with ADHD receive ADHD-focused information and support. Children and young people aged 5\xa0years and over are offered medication by a healthcare professional with training and expertise in diagnosing and managing ADHD only if ADHD symptoms are still causing a significant impairment in at least one domain of their everyday life despite implementation of environmental modifications. This choice follows discussion with the child or young person and their parents or carers and a full baseline assessment. The recommendations make it clear that where a child has symptoms of oppositional defiant disorder or conduct disorder, parents and carers should be offered a parent-training programme in line with the recommendations in NICE's guideline on antisocial behaviour and conduct disorders.\n\nThe current categorisation of ADHD focuses on the presence of significant impairment in the different domains of everyday life and across settings, rather than using the previously used terms of mild, moderate and severe ADHD. There is considerable overlap with the guideline population described in the 2008 recommendation. The 2018 recommendations reflect current practice and are unlikely to result in a substantial increase in prescribing and resource use.\n\nReturn to recommendations\n\n# Managing ADHD – adults\n\nRecommendations 1.5.15 to 1.5.18\n\n## Why the committee made the recommendations\n\nEvidence directly comparing medication with non-pharmacological treatment supported the use of medication for first-line treatment of ADHD in adults. The committee acknowledged there are concerns about recommending medication for ADHD and in particular the uncertainty over the long-term benefits and the adverse effects of medication. However, the committee agreed that untreated ADHD can have a negative impact on a person's life, with lower educational attainment, and higher criminality. So they agreed to recommend medication when ADHD symptoms are still causing a significant impairment in at least one domain of everyday life despite environmental modifications.\n\nEvidence indicated a benefit of non-pharmacological treatment, although this was less than for medication. There was also evidence of the importance of offering a choice of treatments, so the committee agreed that non-pharmacological treatment should be considered for adults who have made an informed choice not to have medication, have difficulty adhering to medication or have found they cannot tolerate medication or it is ineffective. Based on their experience, the committee recommended that the treatment may include elements of or a full programme of CBT and should include a structured supportive psychological intervention focused on ADHD, with regular follow‑up and information.\n\nCombining medication with non-pharmacological treatment did not offer the best balance of benefits and costs, so the committee decided that combination treatment should only be considered when medication has offered some benefit but symptoms continue to cause a significant impairment.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect good current practice.\n\nReturn to recommendations\n\n# Medication – care arrangements\n\nRecommendations 1.7.2 and 1.7.29\n\n## Why the committee made the recommendations\n\nThe committee discussed the roles of different healthcare professionals in initiating, monitoring and reviewing medication. They agreed, based on their experience, that medication should only be initiated and titrated by a healthcare professional with training and expertise in diagnosing and managing ADHD. But after dose stabilisation, prescribing and monitoring should be carried out under Shared Care Protocol arrangements with primary care. The exact balance between primary and secondary care will vary depending on the circumstances of the person with ADHD and the available primary and secondary care services.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect good current practice.\n\nReturn to recommendations 1.7.2 and 1.7.29\n\n# Medication – baseline assessment\n\nRecommendations 1.7.4 to 1.7.6\n\n## Why the committee made the recommendations\n\nThe committee noted that it is important to carry out a baseline assessment before starting ADHD medication. Evidence was limited on what should be assessed clinically, but the committee used their experience and expert advice to recommend a general review of health and social circumstances, and a review of physical health. The committee used their experience to outline criteria for referral for a cardiologist opinion.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect good current practice.\n\nReturn to recommendations\n\n# Medication – choice\n\nRecommendations 1.7.7 to 1.7.19\n\n## Why the committee made the recommendations\n\nEvidence showed a clinically important benefit for monotherapy with the stimulants methylphenidate and lisdexamfetamine compared with placebo or other drugs. This was supported by the committee's experience that stimulants work more quickly than non-stimulant drugs (for example, atomoxetine and guanfacine), which can take longer to have an effect. The committee used the evidence, their experience and the drug licensing to recommend methylphenidate as a treatment for children aged 5\xa0years and over and young people, and lisdexamfetamine or methylphenidate as a treatment for adults.\n\nThe committee acknowledged the rising cost of dexamfetamine since 2008 and agreed that it should only be considered when lisdexamfetamine is effective but the longer effect profile is not well tolerated.\n\nThe committee agreed that if methylphenidate has not been effective for children aged over 5\xa0years and young people, then lisdexamfetamine could be considered.\n\nAtomoxetine and guanfacine were the non-stimulant drugs with the most convincing evidence. The committee noted that atomoxetine is more widely used and that there was stronger evidence for a benefit of atomoxetine compared with placebo than guanfacine compared with placebo. One trial directly comparing atomoxetine with guanfacine generally showed a clinically important benefit of guanfacine. Taking into account the licensing status of these drugs and the familiarity of most healthcare professionals with them, the committee recommended that in children aged 5\xa0years and over and young people, either drug could be offered after intolerance or a lack of response to stimulants (methylphenidate and lisdexamfetamine). Because guanfacine is not licensed for use in adults and there was no evidence specifically supporting its use in this population, the committee recommended atomoxetine for adults with intolerance or a lack of response to stimulants.\n\nThere was not enough evidence to justify specific recommendations for other drugs so the committee recommended that after at least one stimulant and non-stimulant had been tried, healthcare professionals should obtain a second opinion or refer to a tertiary service.\n\nThere was very little evidence on medication choice for people with ADHD and coexisting conditions and so the committee made research recommendations to address this gap. The committee agreed that neither the available evidence nor their experience justified a different choice of ADHD medication for people with ADHD and coexisting conditions, but there should be careful consideration of drug interactions and baseline assessments, slower titration, more careful monitoring and recording of adverse effects, and regular weekly telephone contact. However, the committee recommended that ADHD medication should be stopped in people experiencing a psychotic episode because they agreed that ADHD medication could worsen psychotic symptoms.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect good current practice.\n\nReturn to recommendations\n\n# Medication – considerations when prescribing and dose titration\n\nRecommendations 1.7.20 to 1.7.28\n\n## Why the committee made the recommendations\n\nThe committee discussed that the careful initiation of ADHD medication is key to a successful treatment plan. This includes starting and titrating medication according to the BNF or the BNF for Children and the person's tolerance until the dose is optimised (reduced symptoms, positive behaviour change, improvements in education, employment and relationships, and tolerable adverse effects). The committee agreed that healthcare professionals should be aware of the pharmacokinetic profiles of ADHD medication because preparations can vary in their profiles. This is important when considering which medication or formulation to prescribe.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect good current practice.\n\nReturn to recommendations\n\n# Medication – monitoring effectiveness and adverse effects\n\nRecommendations 1.8.1 to 1.8.19\n\n## Why the committee made the recommendations\n\nEvidence showed clinically important differences in sleep disturbance, decreased appetite and weight changes in people taking ADHD medication. In the committee's experience, these are some of the most troublesome adverse effects. Because of concerns about decreased appetite and weight change, the committee advised that weight should be checked every 3\xa0months in children aged 10\xa0years and under, and at least every 6\xa0months in older children and young people; BMI should be monitored in adults. The committee recommended that changes in sleep pattern should be recorded and medication adjusted accordingly.\n\nThere was some evidence that people on atomoxetine may experience sexual dysfunction, in particular erectile dysfunction, and the committee agreed that this should be monitored.\n\n## How the recommendations might affect practice\n\nThe committee noted that the recommendations will reinforce current best practice.\n\nReturn to recommendations\n\n# Adherence to treatment\n\nRecommendations 1.9.1 to 1.9.6\n\n## Why the committee made the recommendations\n\nThe evidence identified several factors that affect adherence to treatment and these were supported by the committee's own experience.\n\nThe evidence highlighted time management and forgetfulness as particular issues, so the committee made a recommendation that healthcare professionals should be aware that people with ADHD may have problems remembering to order and collect medication. The committee provided examples of how healthcare professionals might encourage people to follow strategies that support adherence (for example, following clear instructions and using visual reminders).\n\nA common worry about treatment is that it might change personality and the committee agreed that this could affect adherence to both medication and non-pharmacological treatments. Misconceptions about the effects of treatment and worries about adverse effects were common themes identified, and the committee agreed that it was important that healthcare professionals address these.\n\nEvidence identified that the attitudes of people close to a person with ADHD can influence adherence. The committee agreed that it was important that although children and young people should take responsibility for their own health (including taking medication), parents and carers should oversee them.\n\nThe committee discussed that adherence to non-pharmacological treatment was an important issue that was rarely addressed. They used their own experience to recommend that healthcare professionals discuss the commitment, time and organisational skills needed for successful adherence to non-pharmacological treatment.\n\n## How the recommendations might affect practice\n\nThe committee noted that the recommendations will reinforce current best practice.\n\nReturn to recommendations\n\n# Review of medication and discontinuation\n\nRecommendations 1.10.1 to 1.10.3\n\n## Why the committee made the recommendations\n\nEvidence identified concerns around lack of follow‑up and the opportunity to review medication choices and this was supported by the committee's experience. They agreed that a yearly review with an ADHD specialist should be a comprehensive assessment that revisits the areas discussed when starting treatment but also the effect of current treatment. This would ensure that decisions around continuing or stopping treatment are fully informed.\n\nLimited evidence showed possible worsening of ADHD symptoms on stopping medication but supported a reduction in adverse effects after withdrawal. The committee used their experience to make a recommendation on emphasising the importance of assessing the overall benefits and harms of medication as part of a review. The committee agreed that it was important to highlight the elements of a medication review that are important for someone with ADHD; they based the elements on evidence on adverse effects of medication, management of treatment, adherence and information and support.\n\n## How the recommendations might affect practice\n\nThe committee noted that the recommendations will reinforce current best practice.\n\nReturn to recommendations", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder characterised by the core symptoms of hyperactivity, impulsivity and inattention, which are judged excessive for the person's age or level of overall development. The diagnosis is made on the basis of observed and reported behavioural symptoms. Two main diagnostic systems are in current use, the International Classification of Mental and Behavioural Disorders 10th revision (ICD‑10) and the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM‑5). Both systems require that symptoms are present in several settings such as school/work, home life and leisure activities. Symptoms should be evident in early life, if only in retrospect; for ICD‑10, by age 7\xa0years and for DSM‑5, by age 12\xa0years. ADHD may persist into adult life.\n\nPrevalence rates for ICD‑10 (identifying hyperkinetic disorder) are 1\xa0to\xa02% in childhood. Under the previous, less stringent DSM‑IV criteria, childhood prevalence rates were 3\xa0to\xa09% and these may increase under the new DSM‑5 criteria.\n\nThe causes of ADHD are not fully understood but a number of risk factors are associated with the condition. Genetic factors can have an influence, with family members frequently affected. The diagnosis of ADHD in older family members such as parents may have previously been missed and should be considered.\n\nBoth the ICD‑10 and DSM‑5 require the presence of functional impairment due to symptoms of ADHD, with the symptoms adversely affecting psychological, social and/or educational/occupational functioning. The impact of ADHD may vary considerably in its severity, which is best judged by considering the level of impairment, pervasiveness, and familial and social context. For some people, symptoms may be limited to certain settings and cause minimal impairment in a limited number of domains (for example, ability to complete schoolwork, work tasks, avoiding common hazards and forming positive interpersonal relationships). In other people, multiple symptom areas (hyperactivity, inattention and impulsivity) are present in multiple settings, and this causes significant impairment across multiple domains. Symptoms and impact can also change over time. For some people, symptoms and impairment may be reduced through environmental modifications, such as a modified school curriculum or choice of employment.\n\nSymptoms of ADHD can overlap with those of other related disorders. Therefore, care in differential diagnosis is needed. ADHD may also coexist with other disorders. Common coexisting conditions in children include disorders of mood, conduct, learning, motor control, language and communication, and anxiety disorders; in adults, they include personality disorders, bipolar disorder, obsessive-compulsive disorder and substance misuse. Where there are coexisting conditions, it is important to try to differentiate the level of impairment due to ADHD, because this will guide the treatment plan. In addition, ADHD is under-recognised in some populations, which can mean that a lack of appropriate diagnosis and treatment adversely affects people's quality of life.\n\nThe aim of this guideline is to raise awareness of populations at risk and to provide clear advice on managing ADHD.\n\nThe guideline covers children under 5\xa0years, children and young people aged 5\xa0to 17\xa0years, and adults aged 18\xa0years or over who are at risk of ADHD or have a diagnosis of ADHD. The guideline covers all primary, secondary and community care settings in which NHS-funded care is provided for people with ADHD."}
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https://www.nice.org.uk/guidance/ng87
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This guideline covers recognising, diagnosing and managing attention deficit hyperactivity disorder (ADHD) in children, young people and adults. It aims to improve recognition and diagnosis, as well as the quality of care and support for people with ADHD.
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85a80f631bb21eb38c62adf0ca5d1519f413085d
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nice
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Tuberculosis
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Tuberculosis
This guideline covers preventing, identifying and managing latent and active tuberculosis (TB) in children, young people and adults. It aims to improve ways of finding people who have TB in the community and recommends that everyone under 65 with latent TB should be treated. It describes how TB services should be organised, including the role of the TB control board.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Preventing TB
## Raising and sustaining awareness of TB
Multidisciplinary TB teams (in collaboration with Public Health England, primary care, the voluntary sector and Health Education England) should identify and support an ongoing TB education programme for local professionals in contact with the general public, and at‑risk groups in particular. This includes, for example, staff in emergency departments, GPs and wider primary care staff, people who work in housing support services, staff who support migrants and those working in walk‑in centres, hostels, substance misuse projects and prisons.
Multidisciplinary TB teams should ensure the education programme increases other professionals' awareness of the possibility of TB and reduces the stigma associated with it. The programme should include detail on:
causes of TB, how it is transmitted, and the signs and symptoms
lifestyle factors that may mask symptoms
local epidemiology, highlighting under-served groups, other high-risk groups and the fact that TB also occurs in people without risk factors
principles of TB control:
early diagnosis and active case-finding
how to support treatment (including directly observed therapy)
drug resistance
awareness of drug interactions (including factors such as effect on contraception efficacy)
contact investigation after diagnosing an active case
the importance of adhering to treatment
treatment for TB is free for everyone (irrespective of eligibility for other NHS care)
social and cultural barriers to accessing health services (for example, fear of stigma and staff attitudes)
local referral pathways, including details of who to refer and how
the role of allied professionals in awareness‑raising, identifying cases and helping people complete treatment
misinformation that causes fear about TB, including concerns about housing people with the condition
the best ways to effectively communicate all the above topics with different groups.
Statutory, community and voluntary organisations and advocates working with the general public, and under‑served and high‑risk groups in particular, should share information on TB education and awareness training with all frontline staff. (They should get information on this from the local multidisciplinary TB team.)
If possible, statutory, community and voluntary organisations should ensure peers from under‑served groups and anyone else with experience of TB contribute to, or lead, awareness‑raising activities. (Peers who lead such activities will need training and support.)
Multidisciplinary TB teams should help professionals working in relevant statutory, community and voluntary organisations to raise awareness of TB among under‑served and other high‑risk groups. These professionals should be able to explain that treatment for TB is free and confidential for everyone (irrespective of eligibility for other NHS care). They should also be able to provide people with details of:
how to recognise symptoms in adults and children
how people get TB
the benefits of diagnosis and treatment (including the fact that TB is treatable and curable)
location and opening hours of testing services
referral pathways, including self‑referral
the potential interaction of TB medication with other drugs, for example, oral contraceptives and opioids (especially methadone) and HIV treatment
TB/HIV co‑infection
how to address the myths about TB infection and treatment (for example, to counter the belief that TB is hereditary)
how to address the stigma associated with TB
the risk of migrants from high‑incidence countries developing active TB, even if they have already screened negative for it
contact tracing.
Multidisciplinary TB teams and others working with at‑risk groups should use high quality material to raise awareness of TB (see section 1.1.2).
Multidisciplinary TB teams and others working with the general public, and with under‑served and other high‑risk groups in particular, should include information on TB with other health‑related messages and existing health promotion programmes tailored to the target group.
Multidisciplinary TB teams should work in partnership with voluntary organisations and 'community champions' to increase awareness of TB, in particular among under‑served groups at risk of infection but also in the general population. If possible, peers who have experience of TB should contribute to awareness‑raising activities and support people in treatment.
## Providing information for the public about TB
National organisations (for example, National Knowledge Service: Tuberculosis, TB Alert, Public Health England, Department of Health and NHS Choices) should work together to develop generic, quality‑assured template materials with consistent up‑to‑date messages. These materials should be made freely available and designed so that they can be adapted to local needs.
Multidisciplinary TB teams should use these templates for general awareness raising and targeted activities in under‑served and other high‑risk groups. Involve the target group in developing and piloting the materials.
The content of any materials should:
be up‑to‑date and attractively designed, including pictures and colour if possible
be culturally appropriate, taking into account the language, actions, customs, beliefs and values of the group they are aimed at
be tailored to the target population's needs
include risks and benefits of treatment, and how to access services, advice and support
dispel myths
show that, by deciding to be tested and treated for TB, a person can be empowered to take responsibility for their own health
use language that encourages the person to believe that they can change their behaviour
be simple and succinct.
Make the material available in a range of formats such as written, braille, text messages, electronic, audio (including podcasts), pictorial and video. Make them freely available in a variety of ways, for example, online, as print materials or on memory sticks.
Disseminate materials in ways likely to reach target groups, for example, via culturally specific radio or TV stations, at shelters, and at community, commercial or religious venues that target groups attend regularly.
## BCG vaccination
To improve the uptake of BCG vaccination, identify eligible groups (in line with the Department of Health's Green Book) opportunistically through several routes, for example:
new registrations in primary care and with antenatal services, or other points of contact with secondary or tertiary care
people entering education, including university
links with statutory and voluntary groups working with new entrants and looked‑after children and young people
during contact investigations.
When BCG vaccination is being recommended, discuss the benefits and risks of vaccination or remaining unvaccinated with the person (or, if a child, with the parents), so that they can make an informed decision. Tailor this discussion to the person, use appropriate language, and take into account cultural sensitivities and stigma.
If people identified for BCG vaccination through occupational health, contact tracing or new entrant screening are also considered to be at increased risk of being HIV‑positive, offer them HIV testing before BCG vaccination.
Identify babies eligible for vaccination (in line with the Green Book) before birth, ideally through antenatal services.
Discuss neonatal BCG vaccination for any baby at increased risk of TB with the parents or legal guardian.
Preferably vaccinate babies at increased risk of TB before discharge from hospital or before handover from midwifery to primary care. Otherwise, vaccinate as soon as possible afterwards, for example, at the 6‑week postnatal check.
Incorporate computer reminders into maternity service (obstetrics) IT systems for staff, to identify and offer BCG vaccination to babies eligible for vaccination.
Provide education and training for postnatal ward staff, midwives, health visitors and other clinicians on identifying babies eligible for vaccination, local service information and providing BCG vaccination, including:
case definition for at‑risk groups to be offered vaccination
information about the local BCG vaccination policy that can be given verbally, in writing or in any other appropriate format (see sections 1.1.1 and 1.1.2) to parents and carers at the routine examination of the baby before discharge
local service information about BCG vaccination, such as pre‑discharge availability of neonatal vaccination, local BCG clinics and referral for BCG vaccination if this is not available in maternity services
administration of BCG vaccination and contraindications.
Primary care organisations with a high incidence of TB should consider vaccinating all neonates soon after birth.
In areas with a low incidence of TB (see Public Health England's TB rate bands, published in their annual tuberculosis report), primary care organisations should offer BCG vaccination to selected neonates who:
were born in an area with a high incidence of TB or
have 1 or more parents or grandparents who were born in a high‑incidence country or
have a family history of TB in the past 5 years.
Routine BCG vaccination is not recommended for children aged 10 to 14 years.
Healthcare professionals should opportunistically identify unvaccinated children older than 4 weeks and younger than 16 years at increased risk of TB who would have qualified for neonatal BCG (see recommendation 1.1.3.4) and provide Mantoux testing (see the section on diagnosing latent TB in children and young people) and BCG vaccination (if Mantoux‑negative).At the time of publication (January 2016) the BNF states: 'The Mantoux test is recommended for tuberculin skin testing, but no licensed preparation is currently available.' For further guidance, see immunisation against infectious disease (the Green book).
This opportunistic vaccination should be in line with the Green Book.
Mantoux testing should not be done routinely before BCG vaccination in children younger than 6 years unless they have a history of residence or prolonged stay (more than 1 month) in a country with a high incidence of TB.
Offer BCG vaccination to new entrants who are Mantoux‑negative who:
are from high‑incidence countries and
are previously unvaccinated (that is, without adequate documentation or a BCG scar) and
are aged:
younger than 16 years or
to 35 years from sub‑Saharan Africa or a country with a TB incidence of 500 per 100,000 or more.
Deliver the following interventions in primary care settings to improve uptake of BCG vaccination in people from eligible groups (as outlined in the Green Book):
education and support for practice staff, including:
raising awareness of relevant guidelines and case definition for at‑risk groups
promoting BCG and TB testing in eligible groups
incorporating reminders for staff (prompts about eligibility for BCG) on practice computers (for example, embedded in medical records)
consider financial incentives for practices for identifying eligible groups for BCG and TB testing
reminders ('immunisations due') and recall ('immunisations overdue') for people who are eligible for vaccination or for parents of infants and children who are eligible, as outlined in the Green Book. (This could include written reminders, telephone calls from a member of staff or a computerised auto dialler, text messages or a combination of these approaches.)
Use home visits to give information and advice to people who are disadvantaged on the importance of immunisation. This should be delivered by trained lay health workers, community‑based healthcare staff or nurses.
Offer BCG vaccination to healthcare workers and other NHS employees as advised in the Green Book.
Offer BCG vaccination to Mantoux‑negative contacts of people with pulmonary and laryngeal TB (see the section on diagnosing latent TB in all age groups) if they:
have not been vaccinated previously (that is, there is no adequate documentation or a BCG scar) and
are aged 35 years or younger or
are aged 36 years and older and a healthcare or laboratory worker who has contact with patients or clinical materials.
Offer BCG vaccination to previously unvaccinated, Mantoux‑negative people aged 35 years or younger in the following groups at increased risk of exposure to TB, in accordance with the Green Book:
veterinary and other staff such as abattoir workers who handle animal species known to be susceptible to TB, such as simians
prison staff working directly with prisoners
staff of care homes for older people
staff of hostels for people who are homeless and facilities accommodating refugees and asylum seekers
people going to live or work with local people for more than 3 months in a high‑incidence country.
## Preventing infection in specific settings
Employees new to the NHS who will be working with patients or clinical specimens should not start work until they have completed a TB screen or health check, or documentary evidence is provided of such screening having taken place within the preceding 12 months.
Employees new to the NHS who will not have contact with patients or clinical specimens should not start work if they have signs or symptoms of TB.
Health checks for employees new to the NHS who will have contact with patients or clinical materials should include:
assessment of personal or family history of TB
asking about symptoms and signs, possibly by questionnaire
documentary evidence of TB skin (or interferon‑gamma release assay) testing within the past 5 years and/or BCG scar check by an occupational health professional, not relying on the applicant's personal assessment.
See the section on healthcare workers for screening new NHS employees for latent TB.
Employees who will be working with patients or clinical specimens and who are Mantoux‑ or interferon‑gamma release assay‑negative (see section 1.2.1) should have an individual risk assessment for HIV infection before BCG vaccination is given.
Offer BCG vaccination to employees of any age who are new to the NHS and are from countries of high TB incidence, or who have had contact with patients in settings with a high TB prevalence, and who are Mantoux‑negative.
If a new employee from the UK or other low‑incidence setting, who has not had a BCG vaccination, has a positive Mantoux test and a positive interferon‑gamma release assay, they should have a medical assessment and a chest X‑ray. They should be referred to a TB clinic to determine whether they need TB treatment if the chest X‑ray is abnormal, or to determine whether they need treatment of latent TB infection if the chest X‑ray is normal.
If a prospective or current healthcare worker who is Mantoux‑negative (see the section on healthcare workers) declines BCG vaccination, explain the risks and supplement the oral explanation with written advice. If the person still declines BCG vaccination, he or she should not work where there is a risk of exposure to TB. The employer will need to consider each case individually, taking account of employment and health and safety obligations.
Screen clinical students, agency and locum staff and contract ancillary workers who have contact with patients or clinical materials for TB to the same standard as new employees in healthcare environments, according to the recommendations set out above. Seek documentary evidence of screening to this standard from locum agencies and contractors who carry out their own screening.
NHS trusts arranging care for NHS patients in non‑NHS settings should ensure that healthcare workers who have contact with patients or clinical materials in these settings have been screened for TB to the same standard as new employees in NHS settings.
Include reminders of the symptoms of TB, and the need for prompt reporting of such symptoms, with annual reminders about occupational health for staff who:
are in regular contact with TB patients or clinical materials or
have worked in a high‑risk clinical setting for 4 weeks or longer. Give one‑off reminders after a TB incident on a ward.
If no documentary evidence of previous screening is available, screen staff in contact with patients or clinical material who are transferring jobs within the NHS as for new employees (see recommendations 1.2.1.5 to 1.2.1.7 in the section on healthcare workers).
Assess the risk of TB for a new healthcare worker who knows he or she is HIV‑positive at the time of recruitment as part of the occupational health checks.
The employer, through the occupational health department, should be aware of the settings with increased risk of exposure to TB, and that these pose increased risks to HIV‑positive healthcare workers.
Healthcare workers who are found to be HIV‑positive during employment should have medical and occupational assessments of TB risk, and may need to modify their work to reduce exposure.
# Latent TB
## Diagnosing latent TB in adults
Offer Mantoux testing to diagnose latent TB in adults aged 18 to 65 who are close contacts of a person with pulmonary or laryngeal TB.
If the Mantoux test is inconclusive, refer the person to a TB specialist.
If the Mantoux test is positive (an induration of 5 mm or larger, regardless of BCG history) assess for active TB (see the sections on diagnosing active TB in all age groups, diagnosing pulmonary (including laryngeal) TB in all age groups, diagnosing pulmonary (including laryngeal) TB in adults and diagnosing extrapulmonary TB in all age groups).
If the Mantoux test is positive but a diagnosis of active TB is excluded, consider an interferon gamma release assay if more evidence of infection is needed to decide on treatment. This could be, for example, if the person needs enhanced case management or if there could be adverse events from treatment.
If the Mantoux is positive, and if an IGRA was done and that is also positive, offer them treatment for latent TB infection (see the sections on managing latent TB in all age groups and managing latent TB in adults). At the time of publication (January 2016) the BNF states: 'The Mantoux test is recommended for tuberculin skin testing, but no licensed preparation is currently available.' For further guidance, see immunisation against infectious disease (the Green book).
In adults who are anticipated to be or are currently immunocompromised, do a risk assessment to establish whether testing should be offered, taking into account their:
risk of progression to active TB based on how severely they are immunocompromised and for how long they have been immunocompromised
risk factors for TB infection, such as country of birth or recent contact with an index case with suspected infectious or confirmed pulmonary or laryngeal TB.
For adults who are severely immunocompromised, such as those with HIV and CD4 counts of fewer than 200 cells/mm3, or after solid organ or allogeneic stem cell transplant, offer an interferon‑gamma release assay and a concurrent Mantoux test.
If either test is positive (for Mantoux, this is an induration of 5 mm or larger, regardless of BCG history), assess for active TB.
If this assessment is negative, offer them treatment for latent TB infection.
For other adults who are immunocompromised, consider an interferon‑gamma release assay alone or an interferon‑gamma release assay with a concurrent Mantoux test.
If either test is positive (for Mantoux, this is an induration of 5 mm or larger, regardless of BCG history), assess for active TB.
If this assessment is negative, offer them treatment for latent TB infection.
Offer a Mantoux test to new NHS employees who will be in contact with patients or clinical materials, if the employees:
are not new entrants from high‑incidence countries and
have not had BCG vaccination (for example, they are without a BCG scar, other documentation or a reliable history). If the Mantoux test is positive, offer an interferon‑gamma release assay. If this is positive, assess for active TB; if this assessment is negative, offer them treatment for latent TB infection.
Offer a Mantoux test to new NHS employees who are from a high‑incidence country.
If the Mantoux test is positive (5 mm or larger, regardless of BCG history), assess for active TB; if this assessment is negative, offer them treatment for latent TB infection.
If Mantoux testing is unavailable, offer an interferon‑gamma release assay.
Offer an interferon‑gamma release assay to new NHS employees who have had contact with patients in settings where TB is highly prevalent:
If the interferon‑gamma release assay is positive, assess for active TB and
if this assessment is negative, offer them treatment for latent TB infection.
Healthcare workers who are immunocompromised should be screened in the same way as other people who are immunocompromised (see recommendations 1.2.1.2 to 1.2.1.4).
## Diagnosing latent TB in children and young people
Only consider using interferon‑gamma release assays alone in children and young people if Mantoux testing is not available or is impractical. This includes for example, situations in which large numbers need to be tested (see the section on incident and outbreak response and recommendation 1.2.3.2).
Refer children younger than 2 years and in close contact with people with smear‑negative pulmonary or laryngeal TB to a specialist to determine what testing strategy for latent TB should be done. This should be a paediatrician with experience and training in TB, or a general paediatrician with advice from a specialised clinician.
If a neonate has been in close contact with people with smear‑positive pulmonary or laryngeal TB who have not had at least 2 weeks of anti‑TB treatment:
Assess for active TB (see the sections on diagnosing active TB in all age groups, diagnosing pulmonary (including laryngeal) TB in all age groups and diagnosing pulmonary (including laryngeal) TB in children and young people).
Start isoniazid (with pyridoxine).
Carry out a Mantoux test after 6 weeks of treatment.
If the Mantoux test is inconclusive, refer the child to a TB specialist.
If the Mantoux test is positive (5 mm or larger, regardless of BCG history), reassess for active TB; if this assessment is negative, continue isoniazid (with pyridoxine) for a total of 6 months.
If the Mantoux test is negative, reassess for active TB and consider an interferon‑gamma release assay:
if the interferon‑gamma release assay is negative then stop isoniazid (and pyridoxine) and give a BCG vaccination
if the interferon‑gamma release assay is positive, reassess for active TB; if this assessment for active TB is negative, continue isoniazid (with pyridoxine) for a total of 6 months.
If a child aged between 4 weeks and 2 years has been in close contact with people with smear‑positive pulmonary or laryngeal TB who have not had at least 2 weeks of anti‑TB treatment:
Assess for active TB.
Start treatment for latent TB (see the sections on managing latent TB in all age groups and managing latent TB in children and young people) and carry out a Mantoux test.
If the Mantoux test is inconclusive, refer the child to a TB specialist.
If the Mantoux test is positive (5 mm or larger, regardless of BCG history), reassess for active TB; if this assessment is negative, complete treatment for latent TB.
If the Mantoux test is negative, continue treatment for latent TB, reassess for active TB after 6 weeks and repeat the Mantoux test:
if the Mantoux test is negative, consider an interferon‑gamma release assay
if the interferon‑gamma release assay is negative, treatment for latent TB may be stopped; give a BCG vaccination if the child has not already had one
if either test is positive, reassess for active TB; if this assessment is negative, complete treatment for latent TB.
If a child or young person aged between 2 and 17 years has been in close contact with people with pulmonary or laryngeal TB:
Offer Mantoux testing.
If the Mantoux test is inconclusive, refer the child or young person to a TB specialist.
If the Mantoux test is positive (5 mm or larger, regardless of BCG history), assess for active TB; if this assessment is negative, offer them treatment for latent TB infection.
If the initial Mantoux test is negative, offer an interferon‑gamma release assay after 6 weeks and repeat the Mantoux test.
If latent TB is suspected in children and young people who are anticipated to be or are currently immunocompromised (for example, if they are from a high incidence country or have been in close contact with people with suspected infectious or confirmed pulmonary or laryngeal TB), refer to a TB specialist.
## Diagnosing latent TB in all age groups
Offer Mantoux testing as the initial diagnostic test for latent TB infection in people who have recently arrived from a high‑incidence country who present to healthcare services. If the Mantoux test is positive (5 mm or larger, regardless of BCG history):
assess for active TB (see recommendations 1.3.1 to 1.3.5 in the section on active TB) and
if this assessment is negative, offer them treatment for latent TB infection (see the section on managing latent TB in all age groups to the section on managing latent TB in children and young people).If Mantoux testing is unavailable, offer an interferon‑gamma release assay.
In an incident situation when large numbers of people may need to be screened, consider a single interferon‑gamma release assay for people aged 18 to 65 years. For children and young people, follow the recommendations in the sections on diagnosing latent TB in children and young people and immunocompromised children and young people.
Offer people younger than 65 years from under-served groups a single interferon‑gamma release assay.
Substance misuse services with access to an interferon‑gamma release assay should provide testing for people younger than 65 years who misuse substances if they:
live in a high incidence area
are likely to be involved with substance misuse services or other support services on a regular basis (for example, for opioid substitution therapy), when support should be available for directly observed preventive therapy.
In high incidence areas (and at prisons that receive prisoners from high incidence areas), prison health services should offer an interferon‑gamma release assay for TB to inmates younger than 65 years who are in regular contact with substance misuse services or other support services. This is provided arrangements have been made for this support to continue after release.
Substance misuse services and prison health services should incorporate interferon‑gamma release assay testing with screening for hepatitis B and C, and HIV testing. They should refer prisoners and people who misuse substances with positive interferon‑gamma release assays to local multidisciplinary TB teams for further clinical investigations. For prisoners, these investigations should be done in the prison if practically possible.
If the interferon‑gamma release assay is positive, assess for active TB (see the sections on diagnosing active TB in all age groups to diagnosing extrapulmonary TB in all age groups); if this assessment is negative, offer them treatment for latent TB infection (see sections on managing latent TB in all age groups to managing latent TB in children and young people).
## Managing latent TB in all age groups
Be aware that certain groups of people with latent TB are at increased risk of going on to develop active TB, including people who:
are HIV‑positive
are younger than 5 years
have excessive alcohol intake
are injecting drug users
have had solid organ transplantation
have a haematological malignancy
are having chemotherapy
have had a jejunoileal bypass
have diabetes
have chronic kidney disease or receive haemodialysis
have had a gastrectomy
are having treatment with anti‑tumour necrosis factor‑alpha or other biologic agents
have silicosis.
For people, including those with HIV, aged younger than 65 years with evidence of latent TB who have been in close contact with people who have suspected infectious or confirmed active pulmonary or laryngeal drug‑sensitive TB, offer either of the following drug treatments:
months of isoniazid (with pyridoxine) and rifampicin or
months of isoniazid (with pyridoxine).
Base the choice of regimen on the person's clinical circumstances. Offer:
months of isoniazid (with pyridoxine) and rifampicin to people younger than 35 years if hepatotoxicity is a concern after an assessment of both liver function (including transaminase levels) and risk factors
months of isoniazid (with pyridoxine) if interactions with rifamycins are a concern, for example, in people with HIV or who have had a transplant.
Clearly explain the risks and potential benefits of each treatment regimen. In discussion with the person, select a suitable regimen if they wish to proceed with preventive treatment.
If a person also has severe liver disease, for example, Child‑Pugh level B or C, work with a specialist multidisciplinary team with experience of managing TB and liver disease.
Manage treatment with caution, ensuring careful monitoring of liver function, in:
people with non‑severe liver disease
people with abnormal liver function (including abnormal transaminase levels) before starting treatment for latent TB infection
people who misuse alcohol or drugs.
Ensure people having treatment for latent TB who also have social risk factors, such as misusing alcohol or drugs or being homeless, are linked to support services. They should also have an assessment of social needs and stability, including potential barriers to adherence or treatment completion (see the section on adherence, treatment completion and follow‑up).
People in the groups listed in recommendation 1.2.4.1 who do not have treatment for latent TB, as specified in recommendations 1.2.4.2 to 1.2.4.8, for any reason should be advised of the risks and symptoms of TB (on the basis of an individual risk assessment), usually in a standard letter of the type referred to as 'Inform and advise' information (see section 1.1.2).
## Managing latent TB in adults
For adults between the ages of 35 and 65 years, offer drug treatments only if hepatotoxicity is not a concern.
Offer testing for HIV before starting treatment for latent TB. See the NICE guidelines on increasing the uptake of HIV testing among black Africans in England and increasing the uptake of HIV testing among men who have sex with men.
Offer adults testing for hepatitis B and C before starting treatment for latent TB. See the NICE guidelines on hepatitis B and C: ways to promote and offer testing to people at increased risk of infection and hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults.
## Managing latent TB in children and young people
Consider testing children and young people for hepatitis B and C before starting treatment for latent TB. See the NICE guidelines on hepatitis B and C: ways to promote and offer testing to people at increased risk of infection and hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults.
# Active TB
## Diagnosing active TB in all age groups
If TB is a possibility, microbiology staff should consider carrying out TB culture on samples (see recommendations 1.3.2.2 and 1.3.2.3), even if it is not requested.
If there are clinical signs and symptoms consistent with a diagnosis of TB, start treatment without waiting for culture results.
Consider completing the standard recommended regimen (see recommendations 1.3.7.2 and 1.3.7.3 in the section on standard treatment), even if subsequent culture results are negative.
## Diagnosing pulmonary (including laryngeal) TB in all age groups
Take a chest X‑ray; do further diagnostic investigations (as detailed below and summarised in table 1) if chest X‑ray appearances suggest TB.
Send multiple respiratory samples (3 deep cough sputum samples, preferably including 1 early morning sample) for TB microscopy and culture.
This should be before starting treatment if possible or, failing that, within 7 days of starting treatment in people with life‑threatening disease.
Obtain spontaneously‑produced, deep cough sputum samples if possible, otherwise use:
gastric lavages or 3 inductions of sputum in children and young people (see recommendation 1.5.1.10 in the section on infection control in healthcare settings) or
induction of sputum or bronchoscopy and lavage in adults.
Laboratory practices should be in accordance with the UK's Standards for Microbiology Investigations.
Send samples for TB culture from autopsy samples if pulmonary or laryngeal TB is a possibility.
## Diagnosing pulmonary (including laryngeal) TB in adults
Request rapid diagnostic nucleic acid amplification tests for the M. tuberculosis complex (M. tuberculosis, M. bovis, M. africanum) on primary specimens (listed in table 1) if there is clinical suspicion of TB disease, and:
the person has HIV or
rapid information about mycobacterial species would alter the person's care or
the need for a large contact‑tracing initiative is being explored.
## Diagnosing pulmonary (including laryngeal) TB in children and young people
In children aged 15 years or younger with suspected pulmonary TB, offer rapid diagnostic nucleic acid amplification tests for the M. tuberculosis complex (M. tuberculosis, M. bovis, M. africanum). Usually only 1 nucleic acid amplification test is needed per specimen type (for example, spontaneous sputum, induced sputum or gastric lavage; see table 1).
In young people aged 16 to 18 years use the same criteria as in adults to decide whether to request rapid diagnostic nucleic acid amplification tests (see table 1).
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional tests (if it would alter management)
Pulmonary (adult)
X‑ray (Routine test, see recommendation 1.3.2.1.)
CT thoraxTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
respiratory samples:
preferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or bronchoscopy and lavage
preferably 1 early morning sample
Microscopy Culture
Histology
Nucleic acid amplification test
Pulmonary (young people aged 16 to 17 years)
X‑ray (Routine test, see recommendation 1.3.2.1.)
CT thoraxTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
respiratory samples:
preferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or gastric lavage
preferably 1 early morning sample
Microscopy Culture
Histology
Nucleic acid amplification test
Pulmonary (children aged 15 years or younger)
X‑ray (Routine test, see recommendation 1.3.2.1.)
CT thoraxTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
respiratory samples:
preferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or gastric lavage
preferably 1 early morning sample
Microscopy
Culture
Histology
Nucleic acid amplification tests (1 per specimen type)
Interferon‑gamma release assay and/or tuberculin skin test (with expert input)
Either a paediatrician with experience and training in TB or a general paediatrician with advice from a specialised clinician should investigate and manage TB in children and young people.
An expert in paediatric TB may request interferon‑gamma release assays and tuberculin skin tests. Interpret these together with other diagnostic tools (such as history taking, clinical examination and imaging).
## Diagnosing extrapulmonary TB in all age groups
Discuss the advantages and disadvantages of both biopsy and needle aspiration with the patient, with the aim of obtaining adequate material for diagnosis.
Do not place part or all of any of the samples in formalin (or other fixative agent) when sending for TB culture.
Think about a diagnosis of extrapulmonary TB even if rapid diagnostic tests in, for example, cerebrospinal fluid, pleural fluid or ascitic fluid are negative.
Offer all patients presenting with extrapulmonary TB a chest X‑ray and, if possible, culture of a spontaneously‑produced respiratory sample to exclude or confirm coexisting pulmonary TB (see recommendations 1.3.1 to 1.3.3 in the section on active TB). Also, consider site‑specific tests as described below to exclude or confirm additional sites of TB.
Refer to an expert for sites not listed here, including TB of the eye and other rare sites of disease.
Use the site‑specific investigations listed in table 2 to diagnose and assess pleural TB.
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional tests on primary specimen (if it would alter management)
Pleural
X‑ray
BronchoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
respiratory samples:
preferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or gastric lavage
preferably 1 early morning sample
Pleural biopsy
Microscopy
Culture
Histology
Pleural
X‑ray
BronchoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Pleural fluid
Microscopy
Culture
Cytology
Adenosine deaminase assay
Use the site‑specific investigations listed in table 3 to diagnose and assess central nervous system TB.
Suspected site of disease
Possible imaging techniquesa
Specimen
Routine test
Additional tests on primary specimen (if it would alter management)
Central nervous system
CT (Routine test, see recommendation 1.3.5.8)
MRI (Routine test, see recommendation 1.3.5.8)Taking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Biopsy of suspected tuberculoma
Microscopy
Culture
Histology
Central nervous system
CT (Routine test, see recommendation 1.3.5.8)
MRI (Routine test, see recommendation 1.3.5.8)Taking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Cerebrospinal fluid
Microscopy
Culture
Cytology
Adenosine deaminase assay
Meningeal
CT (Routine test, see recommendation 1.3.5.8)
MRI (Routine test, see recommendation 1.3.5.8)Taking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Cerebrospinal fluid
Microscopy
Culture
Cytology
Nucleic acid amplification test
Adenosine deaminase assay
Offer a CT or MRI scan to people in whom central nervous system involvement is suspected.
Offer treatment for TB meningitis if clinical signs and other laboratory findings are consistent with the diagnosis, even if a rapid diagnostic test is negative.
Use the site‑specific investigations listed in table 4 to diagnose and assess lymph node TB (including intrathoracic mediastinal adenopathy).
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional tests on primary specimen (if it would alter management)
Lymph node (including intrathoracic mediastinal adenopathy)
Ultrasound
CT
MRITaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Biopsy
Microscopy
Culture
Histology
Nucleic acid amplification test
Aspirate
Microscopy
Culture
Cytology
Nucleic acid amplification test
Use the site‑specific investigations listed in table 5 to diagnose and assess pericardial TB.
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional tests on primary specimen (if it would alter management)
Pericardial
EchocardiogramTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Biopsy of pericardium
Microscopy
Culture
Histology
Pericardial
EchocardiogramTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Pericardial fluid
Microscopy
Culture
Cytology
Nucleic acid amplification test
Adenosine deaminase assay
Use the site‑specific investigations listed in table 6 to diagnose and assess gastrointestinal TB.
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional tests on primary specimen (if it would alter management)
Gastrointestinal
Ultrasound
CT
LaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Biopsy of omentum
Biopsy of bowel
Biopsy of liver
Microscopy
Culture
Histology
Gastrointestinal
Ultrasound
CT
LaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Ascitic fluid
Microscopy
Culture
Cytology
Adenosine deaminase assay
Use the site‑specific investigations listed in table 7 to diagnose and assess genitourinary TB.
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional tests on primary specimen (if it would alter management)
Genitourinary
Ultrasound
Intravenous urography
LaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Early morning urine
Culture
Genitourinary
Ultrasound
Intravenous urography
LaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Biopsy from site of disease, such as endometrial curettings or renal biopsy
Microscopy
Culture
Histology
Use the site‑specific investigations listed in table 8 to diagnose and assess bone and joint TB.
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional test on primary specimen (if it would alter management)
Bone or joint TB
X‑ray
CT
MRITaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment
Biopsy or aspirate of paraspinal abscess
Biopsy of joint
Aspiration of joint fluid
Culture
Use the site‑specific investigations listed in table 9 to diagnose and assess disseminated TB.
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional tests on primary specimen (if it would alter management)
Disseminated
CT of the thorax and head
MRI
Ultrasound of the abdomenTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Biopsy of site of disease, including lung, liver and bone marrow
Microscopy
Culture
Histology
Additional tests appropriate to site
Disseminated
CT of the thorax and head
MRI
Ultrasound of the abdomenTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Aspirate bone marrow
Bronchial wash
Cerebrospinal fluid
Microscopy (if sample available)
Culture
Cytology
Additional tests appropriate to site
Disseminated
CT of the thorax and head
MRI
Ultrasound of the abdomenTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.
Blood
Culture
Additional tests appropriate to site
Use the site‑specific investigations listed in table 10 to diagnose and assess skin TB.
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional tests on primary specimen (if it would alter management)
Skin
Biopsy
Microscopy
Culture
Histology
Use the site‑specific investigations listed in table 11 to diagnose and assess TB in a localised, tuberculous abscess at a site other than a lymph node.
Suspected site of disease
Possible imaging techniques
Specimen
Routine test
Additional tests on primary specimen (if it would alter management)
Abscess outside of the lymph nodes
Ultrasound or other appropriate imagingTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment
Aspirate
Microscopy
Culture
Cytology
Abscess outside of the lymph nodes
Ultrasound or other appropriate imagingTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment
Biopsy
Microscopy
Culture
Histology
## Rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process
Local hospitals, clinical commissioning groups and the local multidisciplinary team should consider developing a local pathway for people with imaging highly suggestive of active TB. The pathway should enable them to be referred by the radiology department by the next working day to multidisciplinary TB teams. Consider including the following in the pathway:
Agreed standardised radiology codes to identify imaging investigations highly suggestive of active TB.
Regular liaison between multidisciplinary TB teams and the radiology department (for example, weekly) to ensure all patients have been referred to the multidisciplinary team for triage using the agreed local mechanism or pathway.
Report results of all pathology or other diagnostic results suggesting TB to the multidisciplinary TB team and clinicians who ask for them.
Commissioners and multidisciplinary teams should consider working with emergency departments to develop direct referral pathways for people with suspected active TB so that:
the local multidisciplinary team is informed of all suspected cases of TB using the appropriate process
referral is accepted from any appropriate healthcare professional, for example an on‑call radiologist.
Emergency department clinicians should ensure first‑line diagnostic tests for TB are performed on anyone presenting with suspected TB (see table 1 on diagnostic investigations for pulmonary TB).
Emergency departments should consider carrying out audits of their direct referrals because of suspected active TB and the outcomes of diagnosis.
Multidisciplinary TB teams should consider training emergency department staff in:
using approaches that do not stigmatise people with TB
giving people with TB appropriate advice (see recommendations 1.1.1 and 1.1.2 in the section on raising and sustaining awareness of TB and the section on infection control).
## Managing active TB in all age groups
Once a diagnosis of active TB is made:
the clinician responsible for care should refer the person with TB to a clinician with training in, and experience of, the specialised care of people with TB
the TB service should include specialised nurses and health visitors
active TB in children should be managed by a TB specialist (see recommendation 1.3.4.3 in the section on diagnosing pulmonary (including laryngeal) TB in children and young people), and by paediatric trained nursing staff, where possible.If these arrangements are not possible, seek advice from more specialised colleagues throughout the treatment period.
For people with active TB without central nervous system involvement, offer:
isoniazid (with pyridoxine), rifampicin, pyrazinamide and ethambutol for 2 months then
isoniazid (with pyridoxine) and rifampicin for a further 4 months.Modify the treatment regimen according to drug susceptibility testing.
For people with active TB of the central nervous system, offer:
isoniazid (with pyridoxine), rifampicin, pyrazinamide and ethambutol for 2 months then
isoniazid (with pyridoxine) and rifampicin for a further 10 months.Modify the treatment regimen according to drug susceptibility testing.
Test people with active spinal TB who have neurological signs or symptoms for central nervous system involvement (see recommendation 1.3.5.8 in the section on central nervous system TB). Manage direct spinal cord involvement (for example, a spinal cord tuberculoma) as TB of the central nervous system.
For people with active spinal TB without central nervous system involvement, do not extend treatment beyond 6 months for residual effects (for example, persistent bending of the spine or vertebral loss).
Test people with disseminated (including miliary) TB who have neurological signs or symptoms for central nervous system involvement. If there is evidence of central nervous system involvement, treat as for TB of the central nervous system.
Treat active peripheral lymph node TB in people who have had an affected gland surgically removed with the standard recommended regimen.
For people with active TB of the lymph nodes, do not routinely extend treatment beyond 6 months for newly enlarged lymph nodes or sinus formation, or for residual enlargement of the lymph nodes or sinuses.
Use fixed‑dose combination tablets as part of any TB treatment regimen.
Do not offer anti‑TB treatment dosing regimens of fewer than 3 times per week.
Offer a daily dosing schedule to people with active pulmonary TB.
Consider a daily dosing schedule as first choice in people with active extrapulmonary TB.
Consider 3 times weekly dosing for people with active TB only if:
a risk assessment identifies a need for directly observed therapy and enhanced case management (see section on adherence, treatment completion and follow‑up) and
daily directly observed therapy is not possible.
If the person has a comorbidity or coexisting condition such as:
HIV or
severe liver disease, for example, Child‑Pugh level B or C or
stage 4 or 5 chronic kidney disease (a glomerular filtration rate of <30 ml/minute/1.73m2) or
diabetes or
eye disease or impaired vision or
pregnancy or breastfeeding or
a history of alcohol or substance misusework with a specialist multidisciplinary team with experience of managing TB and the comorbidity or coexisting condition.
For people with HIV and active TB without central nervous system involvement, do not routinely extend treatment beyond 6 months.
For people with HIV and active TB with central nervous system involvement, do not routinely extend treatment beyond 12 months.
Take into account drug‑to‑drug interactions when co‑prescribing antiretroviral and anti‑TB drugs.
At the start of an anti‑TB treatment regimen, offer people with active TB of the central nervous system dexamethasone or prednisolone, initially at a high dose with gradual withdrawal over 4 to 8 weeks. An example of a suitable regimen is listed in table 12.
Dose of dexamethasone by week
Stage 1
Stage 2 or 3
Week 1
mg/kg/day (intravenous)
mg/kg/day (intravenous)
Week 2
mg/kg/day (intravenous)
mg/kg/day (intravenous)
Week 3
mg/kg/day (oral)
mg/kg/day (intravenous)
Week 4
mg/day (oral)
mg/kg/day (intravenous)
Week 5
mg/day (oral)
mg/day (oral)
Week 6
mg/day (oral)
mg/day (oral)
Week 7
mg/day (oral)
Week 8
mg/day (oral)
According to the modified British Medical Research Council criteria for disease severity:
Stage 1: Glasgow coma score of 15 without focal neurological deficits; alert and oriented.
Stage 2: Glasgow coma score of 14 to 11 or 15 with focal neurological deficits.
Stage 3: Glasgow coma score of 10 or less, with or without focal neurological deficits.
At the start of an anti‑TB treatment regimen, offer children and young people with active TB of the central nervous system dexamethasone or prednisolone. This should initially be at a high dose with gradual withdrawal over 4 to 8 weeks in line with the British National Formulary for Children.
At the start of an anti‑TB treatment regimen, offer adults with active pericardial TB oral prednisolone at a starting dose of 60 mg/day, gradually withdrawing it 2 to 3 weeks after starting treatment.
At the start of an anti‑TB treatment regimen, offer children and young people with active pericardial TB oral prednisolone in line with the British National Formulary for Children. Gradually withdraw prednisolone 2 to 3 weeks after starting treatment.
If surgery is indicated, the surgeon should fully explain what is involved to the person, either with or after consulting a TB specialist. Discuss the possible benefits and risks with the person and their family members or carers, as appropriate, so that they can make an informed decision.
Consider referring people with TB of the central nervous system for surgery as a therapeutic intervention only if there is evidence of raised intracranial pressure.
Do not routinely refer people with spinal TB for surgery to eradicate the disease.
Consider referring people with spinal TB for surgery if there is spinal instability or evidence of spinal cord compression.
# Drug resistant TB
## Multidrug‑resistant TB
For people with clinically suspected TB, a TB specialist should request rapid diagnostic nucleic acid amplification tests for rifampicin resistance on primary specimens if a risk assessment for multidrug resistance identifies any of the following risk factors:
history of previous TB drug treatment, particularly if there was known to be poor adherence to that treatment
contact with a known case of multidrug-resistant TB
birth or residence in a country in which the World Health Organization reports that a high proportion (5% or more) of new TB cases are multidrug‑resistant.Start infection control measures (see section 1.5).
If the rapid diagnostic nucleic acid amplification test for rifampicin resistance is positive:
continue infection control measures until pulmonary or laryngeal disease has been excluded
manage treatment along with a multidisciplinary team with experience of managing multidrug‑resistant TB (see the section on service organisation)
-ffer a treatment regimen involving at least 6 drugs to which the mycobacterium is likely to be sensitive
test for resistance to second‑line drugs.
If the rapid diagnostic nucleic acid amplification test for the M. tuberculosis complex is positive but rifampicin resistance is not detected, treat as drug‑susceptible TB with the standard regimen (see the section on managing active TB in all age groups).
If the rapid diagnostic nucleic acid amplification test for the M. tuberculosis complex is negative in a person at high risk of multidrug‑resistant TB:
-btain further specimens for nucleic acid amplification testing and culture, if possible
use rapid rifampicin resistance detection on cultures that become positive for the M. tuberculosis complex
consider waiting for the results of further tests before starting treatment if the person is well
if urgent treatment is needed, consider managing as multidrug‑resistant TB until sensitivity results are available.
When definitive phenotypic susceptibility results are available, modify treatment as needed (see sections on managing active TB in all age groups and drug‑resistant TB).
Consider more intensive clinical follow‑up for people with multidrug‑resistant TB. This includes people having directly observed therapy (see the section on adherence, treatment completion and follow‑up) throughout treatment because of the complexity of treatment and risk of adverse events.
Discuss the options for organising care for people with multidrug‑resistant TB with clinicians who specialise in this. Seek the person's views and take them into account, and consider shared care (see the section on service organisation).
Consider surgery as a therapeutic intervention in people with potentially resectable multidrug‑resistant disease if:
-ptimal medical therapy under direct observation has not worked or
medical therapy is likely to fail because of extensively drug-resistant TB.
## Drug‑resistant TB (excluding multidrug‑ and extensively drug‑resistant TB)
For people with TB, without central nervous system involvement, that is resistant to just 1 drug consider the treatments in table 13.
Drug resistance
First 2 months (initial phase)
Continue with (continuation phase)
Isoniazid
Rifampicin, pyrazinamide and ethambutol
Rifampicin and ethambutol for 7 months (up to 10 months for extensive disease)
Pyrazinamide
Rifampicin, isoniazid (with pyridoxine) and ethambutol
Rifampicin and isoniazid (with pyridoxine) for 7 months
Ethambutol
Rifampicin, isoniazid (with pyridoxine) and pyrazinamide
Rifampicin and isoniazid (with pyridoxine) for 4 months
Rifampicin
As for multidrug‑resistant TB
As for multidrug‑resistant TB
For people with drug‑resistant TB and central nervous system involvement, involve a TB specialist with experience in managing drug‑resistant TB in decisions about the most appropriate regimen and the duration of treatment.
# Infection control
NICE has also produced general guidelines on the prevention and control of healthcare-associated infections in primary and community care, and the prevention and control of healthcare-associated infections.
## Healthcare settings
Ensure healthcare settings can promptly identify people with suspected infectious or confirmed pulmonary or laryngeal TB before or at presentation. Ensure people working in the settings follow the recommendations about testing and treatments (see the sections on latent TB, active TB and drug resistant TB).
Put people with suspected infectious or confirmed pulmonary or laryngeal TB who will remain in a hospital setting (including emergency, outpatients or inpatient care) in a single room. If this is not possible, keep the person's waiting times to a minimum. This may involve prioritising their care above that of other patients.
Minimise the number and duration of visits a person with TB makes to an outpatient department while they are still infectious. To minimise the risk of infection, people with infectious TB should be seen at times or in places away from other people.
In hospital settings, risk assess people with suspected infectious or confirmed pulmonary TB for multidrug‑resistant TB (see the section on multidrug‑resistant TB). Care for people deemed to be at low risk in a single room, as a minimum. For people deemed to be at high risk:
provide care in a negative pressure room and
have specimens sent for rapid diagnostic tests, such as nucleic acid amplification tests.
Unless there is a clear clinical or public health need, such as homelessness, people with suspected infectious or confirmed pulmonary TB should not be admitted to hospital for diagnostic tests or for care.
Do not admit people with suspected infectious or confirmed pulmonary TB to a ward containing people who are immunocompromised, such as transplant recipients, people with HIV and those on anti‑tumour necrosis factor alpha or other biologics, unless they can be cared for in a negative pressure room on the same ward.
Assess any visitors to a child with suspected active TB in hospital for symptoms of infectious TB, and keep them separate from other people until they have been excluded as a source of infection (see recommendations 1.2.1 to 1.2.3 in the section on latent TB and the section on contact tracing).
Care for people with a continuing clinical or public health need for admission with pulmonary TB in a single room (as a minimum) until they have completed 2 weeks of the standard treatment regimen (see the section on managing active TB in all age groups) if they:
are unlikely to be rifampicin resistant (that is, do not have risk factors for multidrug‑resistant TB) or
have negative rifampicin resistance on nucleic acid amplification test or culture.
Consider de‑escalating isolation after 2 weeks of treatment, taking into account the risks and benefits, if:
the person is showing tolerance to the prescribed treatment
there is agreement to adhere to treatment
there is resolution of cough
there is definite clinical improvement on treatment; for example, remaining afebrile for a week
there are not immunocompromised people, such as transplant recipients, people with HIV and those on anti‑tumour necrosis factor alpha or other biologics, in the same accommodation
the person's initial smear grade was not high; for example, 2 or less
there is not extensive pulmonary involvement, including cavitation
there is no laryngeal TB.
In people who may have TB, only carry out aerosol‑generating procedures such as bronchoscopy, sputum induction or nebuliser treatment in an appropriately engineered and ventilated area (ideally a negative pressure room).
Consider discharging from hospital people:
who do not have a continuing clinical or public health need for admission with pulmonary TB and
who are unlikely to be rifampicin resistant (that is, do not have risk factors for multidrug‑resistant TB) or
who have negative rifampicin resistance on nucleic acid amplification test or culture.If discharged, the person should avoid congregate settings for the first 2 weeks of their treatment.
Explain to inpatients with suspected infectious or confirmed pulmonary or laryngeal TB that they will need to wear a surgical mask in the hospital whenever they leave their room. Ask them to continue wearing it until they have had at least 2 weeks of treatment.
Offer people advice on simple respiratory hygiene measures.
## Non‑healthcare settings
In non‑healthcare settings catering for large numbers of people and populations at high risk of TB (such as detention settings, residential hostels and day centres):
promote simple respiratory hygiene
ensure awareness of symptoms of potentially infectious TB to enable prompt healthcare referral
work with the local public health team and the local authority to ensure accommodation for people with TB
ensure adequate ventilation.
In prisons or immigration removal centres, everyone with X‑ray changes indicative of active TB, as well as those with symptoms who are awaiting X‑ray, should be isolated in an adequately ventilated individual room or cell. Prisoners and detainees should be retained on medical hold until they have:
proven smear‑negative and had an X‑ray that does not suggest active TB or
had a negative risk assessment for multidrug‑resistant TB and completed 2 weeks of the standard treatment regimen.
## Multidrug‑resistant TB
If people with suspected or known infectious multidrug‑resistant TB are admitted to hospital, admit them to a negative pressure room. If none is available locally, transfer them to a hospital that has these facilities and a clinician experienced in managing complex drug‑resistant cases. Carry out care in a negative pressure room for people with:
suspected multidrug‑resistant TB, until non‑resistance is confirmed
confirmed multidrug‑resistant TB, until they have 3 negative smears at weekly intervals and ideally have a negative culture.
As soon as possible, explore options to reduce the psychosocial impact of prolonged isolation. For example, through providing free access to internet, telephone and television, and accompanied walks in the open air.
Consider earlier discharge for people with confirmed multidrug‑resistant TB, if there are suitable facilities for home isolation and the person will adhere to the care plan.
For people with confirmed multidrug‑resistant TB whose symptoms have improved and who are unable to produce sputum, discharge decisions should be taken by the multidisciplinary team and the health protection team.
Staff and visitors should wear filtering face piece (FFP3) masks during contact with a person with suspected or known multidrug‑resistant TB while the person is thought to be infectious.
Before deciding to discharge a person with suspected or known multidrug‑resistant TB from hospital, agree with the person and their carers secure arrangements for supervising and administering all anti‑TB therapy.
Discuss the decision to discharge a person with suspected or known multidrug‑resistant TB with:
the infection control team and
the local microbiologist and
the local TB service and
the health protection team.
Ensure negative pressure rooms used for infection control in multidrug‑resistant TB meet the standards of the Interdepartmental Working Group on Tuberculosis, and are clearly identified for staff, for example by a standard sign. Keep such signs up to date.
# Case finding
## Contact tracing
Once a person has been diagnosed with active TB, the diagnosing physician should inform relevant colleagues so that the need for contact tracing can be assessed without delay. Contact tracing should not be delayed until notification.
Offer screening to the close contacts of any person with pulmonary or laryngeal TB.
Assess symptomatic close contacts for active TB (see recommendations 1.3.1 to 1.3.4 in the section on active TB).
In asymptomatic close contacts younger than 65 years, consider standard testing for latent TB (see recommendations 1.2.1 to 1.2.3 in the section on latent TB), followed by consideration of BCG vaccination in line with the section on BCG vaccination or treatment for latent TB infection (see recommendations 1.2.4 to 1.2.6 in the section on latent TB) once active TB has been ruled out for people who:
are previously unvaccinated and
are contacts of a person with smear‑positive pulmonary or laryngeal TB and
are Mantoux‑negative.At the time of publication (January 2016) the BNF states: 'The Mantoux test is recommended for tuberculin skin testing, but no licensed preparation is currently available.' For further guidance, see immunisation against infectious disease (the Green book).
In asymptomatic close contacts older than 65 years, consider a chest X‑ray (if there are no contraindications), possibly leading to further investigation for active TB.
Do not routinely assess social contacts of people with TB, who will include most workplace contacts.
Assess the need for tracing social contacts of people with pulmonary or laryngeal TB if:
the index case is judged to be particularly infectious (for example, evidenced by transmission to close contacts) or
any social contacts are known to possess features that put them at high risk of going on to develop active TB.
Offer 'inform and advise' information to close and social contacts of people with smear‑positive TB (see section on providing information for the public about TB).
After diagnosis of TB in an aircraft traveller, do not routinely carry out contact tracing of fellow passengers.
The notifying clinician should inform the relevant consultant in communicable disease control or health protection if:
less than 3 months has elapsed since the flight and the flight was longer than 8 hours and
the index case is smear‑positive and either
the index case has multidrug‑resistant TB or
the index case coughed frequently during the flight.
The consultant in communicable disease control or health protection should provide the airline with 'inform and advise' information to send to passengers seated in the same part of the aircraft as the index case.
If the TB index case is an aircraft crew member, contact tracing of passengers should not routinely take place.
If the TB index case is an aircraft crew member, contact tracing of other members of staff is appropriate, in accordance with the usual principles for screening workplace colleagues.
After diagnosis of TB in a school pupil or member of staff, the consultant in communicable disease control or health protection should be prepared to explain the prevention and control procedures to staff, parents and the press. Advice on managing these incidents and their public relations is available from the Public Health England health protection team and the local authority.
If a school pupil is diagnosed with smear‑positive TB, carry out a risk assessment of the need to test the rest of his or her class (if there is a single class group), or the rest of the year group who share classes, as part of contact tracing.
If a teacher has smear‑positive TB, assess the pupils in his or her classes during the preceding 3 months as part of contact tracing.
Consider extending contact tracing in schools to include children and teachers involved in extracurricular activities, and non‑teaching staff, on the basis of:
the degree of infectivity of the index case
the length of time the index case was in contact with others
whether contacts are unusually susceptible to infection
the proximity of contact.
Treat secondary cases of smear‑positive TB as index cases for contact tracing.
If the index case of a school pupil's TB infection is not found, and the child is not in a high‑risk group for TB, contact tracing and screening (by either symptom enquiry or chest X‑ray) should be considered for all relevant members of staff at the school.
When an adult who works in childcare (including people who provide childcare informally) is diagnosed with smear‑positive TB, follow recommendations 1.6.1.1 to 1.6.1.8.
If TB is diagnosed in a hospital inpatient, do a risk assessment. This should take into account:
the degree of infectivity of the index case
the length of time before the infectious patient was isolated
whether other patients are unusually susceptible to infection
the proximity of contact.
Carry out contact tracing and testing only for patients for whom the risk is regarded as significant.
Regard patients as at risk of infection if they spent more than 8 hours in the same bay as an inpatient with smear‑positive TB who had a cough. Document the risk in the contact's clinical notes, for the attention of the contact's consultant. Give the contact 'inform and advise' information, and inform their GP.
If patients were exposed to a patient with smear‑positive TB for long enough to be equivalent to close contacts (as determined by the risk assessment), or an exposed patient is known to be particularly susceptible to infection, manage their TB risk in the same way as close contacts.
If an inpatient with smear‑positive TB is found to have multidrug‑resistant TB, or if exposed patients are HIV positive, trace contacts following the Interdepartmental Working Group on Tuberculosis guidelines.
In cases of doubt when planning contact tracing after diagnosing smear‑positive TB in an inpatient, seek further advice from the local or national Public Health England or Wales unit or people experienced in the field.
## Opportunistic case finding
Assess and manage TB in new entrants from high incidence countries who present to healthcare services as follows:
assess risk of HIV, including HIV prevalence rates in the country of origin, and take this into account when deciding whether to give a BCG vaccination
-ffer testing for latent TB (see recommendations 1.2.1 to 1.2.3 in the section on latent TB)
assess for active TB if the test for latent TB is positive (see recommendations 1.3.1 to 1.3.5 in the section on active TB)
-ffer treatment to people aged 65 years or younger in whom active TB has been excluded but who have a positive Mantoux test or a positive interferon‑gamma release assay for latent TB infection (see recommendations 1.2.4 to 1.2.6 in the section on latent TB)
consider offering BCG for unvaccinated people who are Mantoux‑ or interferon‑gamma release assay‑negative (see the section on BCG vaccination)
give 'inform and advise' information to people who do not have active TB and are not being offered BCG or treatment for latent TB infection (see the section on providing information for the public about TB).
Primary care services should support local, community‑based and voluntary organisations that work with vulnerable migrants to ensure they:
register with a primary care provider
know how to use NHS services (emergency or primary care).
Healthcare professionals, including primary care staff, responsible for testing new entrants should test all vulnerable migrants who have not previously been checked. This is regardless of when they arrived in England. People born in countries with an incidence of more than 150 per 100,000 per year should be made a priority for latent TB testing when they arrive here.
In areas of identified need (see the section on local needs assessment), including major urban centres with a high incidence of TB, commissioners should:
ensure there is a programme of active case‑finding using mobile X‑ray in places where homeless people and people who misuse substances congregate (this includes: homeless day centres, rolling shelters, hostels and temporary shelters established as part of cold weather initiatives and venues housing needle and syringe programmes)
base the frequency of screening at any 1 location on population turnover
where local demand does not warrant a mobile X‑ray team, consider commissioning mobile X‑ray capacity from another area.
Multidisciplinary TB teams should consider using simple incentives, such as providing hot drinks and snacks, to encourage people to attend for testing.
Commissioners of TB prevention and control programmes should consider offering people who are homeless and people who misuse substances other health interventions when they are screened for TB at a mobile X‑ray unit. (Examples may include blood‑borne virus screening, dentistry and podiatry services.)
Multidisciplinary TB teams should work closely with mobile X‑ray teams and frontline staff in hostels and day centres to promote TB screening and to ensure appropriate onward referrals and follow‑up.
Multidisciplinary TB teams should consider using peer educators to promote the uptake of TB screening in hostels and day centres.
Multidisciplinary TB teams should provide routine data to TB control boards on: screening uptake, referrals and the number of active TB cases identified.
Healthcare professionals in prisons and immigration removal centres should ensure prisoners and detainees are screened for TB within 48 hours of arrival.
Prisons with Department of Health‑funded static digital X‑ray facilities for TB screening should X‑ray all new prisoners and detainees (including those being transferred from other establishments) if they have not had a chest X‑ray in the past 6 months. This should take place within 48 hours of arrival.
Prison and immigration removal centre health staff should report all suspected and confirmed TB cases to the local multidisciplinary TB team within 1 working day.
Multidisciplinary TB staff should visit every confirmed TB case in a prison or immigration removal centre in their locality within 5 working days.
If a case of active TB is identified, the local Public Health England unit, in conjunction with the multidisciplinary TB team, should plan a contact investigations exercise. They should also consider using mobile X‑ray to check for further cases.
## Active case finding in under‑served groups
Multidisciplinary TB teams should follow NICE recommendations on contact tracing (see the section on contact tracing).They should coordinate contact investigations at places where the person with TB spends significant amounts of time. Examples could include pubs, crack houses, parks and community centres. The aim is to help identify people who have been living with them and people they frequently socialise with.
Multidisciplinary TB teams dealing with someone from an under-served group should work alongside health and social care professionals known to them to help trace relevant contacts. They should also work in partnership with voluntary, community and statutory organisations to conduct outreach contact investigations.
Multidisciplinary TB teams should, if available and appropriate, encourage peer educators or TB programme support workers to help with contact investigations involving under‑served people who have complex social networks.
Multidisciplinary TB teams in discussion with local Public Health England health protection teams should consider using digital mobile X‑ray for active case‑finding in settings identified by looking at social networks as places where under‑served people at risk congregate. They should also provide the necessary support so that multidisciplinary TB teams can use strain‑typing and social network analysis to ascertain where transmission is occurring in the community. (Examples of transmission sites may include pubs, crack houses, hostels and day centres.) They should focus on active case‑finding in the settings identified.
## Incident and outbreak response
Multidisciplinary TB teams should coordinate incident or outbreak contact investigations at places where the person with active TB spends significant amounts of time. Examples include workplaces, schools, colleges, universities, childcare settings. Identify people that the person with TB frequently spends substantial time with, as outlined in the section on contact tracing.
Multidisciplinary TB teams should refer any incident in a congregate setting to the local Public Health England health protection team for risk assessment within 5 working days of suspicion of a potential incident.
TB control boards working with local health protection teams should, through local arrangements, mobilise existing staff or have access to an incident team that will:
undertake an incident risk assessment and provide advice
support or undertake contact investigations
provide information and communication support to the multidisciplinary TB team, the local director of public health, the setting in which the incident has occurred and the people affected including:
written advice, printed or by email
question and answer sessions
telephone advice
media engagement
gather and collate data, and report on outcomes to measure the effectiveness of the investigation (for example, offering testing to all people identified at risk and monitoring uptake)
report back to TB control boards at appropriate times. This includes when outcomes of initial investigation of people classified as close contacts are available. It also includes when a decision is made to broaden the investigation to the next stage using the concentric circle method for risk assessment.
When incidents have been identified, multidisciplinary TB teams in discussion with local Public Health England health protection teams should consider providing support for strain‑typing and other analysis to ascertain where transmission is occurring. (Examples of transmission sites may include workplaces, schools, colleges, universities, childcare settings.)
In all types of contact investigation scenarios (active case finding, incident or outbreak investigations) multidisciplinary TB teams should investigate all people who have been in contact with children who have pulmonary or extrapulmonary TB to identify the primary source of infection. If necessary, they should look beyond immediate close contacts to find the source.
# Adherence, treatment completion and follow‑up
## Improving adherence: case management including directly observed therapy
Allocate a named TB case manager to everyone with active TB as soon as possible after diagnosis (and within 5 days). The clinical team should tell each person who their named TB case manager is and provide contact details.
The TB case managers should work with the person diagnosed with TB to develop a health and social care plan, and support them to complete therapy successfully. The TB case manager should:
-ffer a risk assessment to every person with TB, to identify their needs and whether they should have enhanced case management including directly observed therapy
educate the person about TB and the treatment
develop an individual care plan after discussion with the person
gain the person's consent to the plan and agree a review date (for example, when moving from initiation to maintenance, or at each contact to ensure the person's needs are being met)
coordinate discharge planning, especially for people on directly observed therapy
involve representatives from other allied professions and key workers from all organisations who work with the person, if appropriate
explore appropriate ways that peers and voluntary organisations can provide support.
Offer directly observed therapy as part of enhanced case management in people who:
do not adhere to treatment (or have not in the past)
have been treated previously for TB
have a history of homelessness, drug or alcohol misuse
are currently in prison, or have been in the past 5 years
have a major psychiatric, memory or cognitive disorder
are in denial of the TB diagnosis
have multidrug‑resistant TB
request directly observed therapy after discussion with the clinical team
are too ill to administer the treatment themselves.
In children whose parents are members of any of the above groups, offer directly observed therapy as part of enhanced case management and include advice and support for parents to assist with treatment completion.
Re‑evaluate the need for directly observed therapy throughout the course of TB treatment whenever the person's (or in the case of children, parents') circumstances change.
TB case managers should ensure the health and social care plan (particularly if directly observed therapy is needed) identifies why a person may not attend for diagnostic testing or follow a treatment plan, and how they can be encouraged to do so. It should also include ways to address issues such as fear of stigmatisation, support needs and/or cultural beliefs, and may include information on:
demographics (for example, age, nationality, place of birth, length of time in UK)
all current prescribing regimens
housing needs and living situation, including looked‑after children
substance misuse (drugs or alcohol)
any contact with the criminal justice system
the need for hepatitis B and C or HIV testing (see recommendations 1.2.5.2 and 1.2.5.3 in the section on managing latent TB in adults and recommendation 1.2.6.1 in the section on managing latent TB in children and young people)
HIV status
-ther health conditions (physical or mental)
communication factors (for example, language and literacy levels)
ability to access treatment (mobility and transport needs)
employment or entitlement to benefits
legal or immigration status (including risk of removal or relocation within the UK)
any enablers or incentives to overcome anything that is stopping diagnosis or treatment.
The health and social care plan should:
state who will be observing treatment and where (if the person is having directly observed therapy this should be provided at a location that is convenient and accessible to them, for example, at a methadone clinic)
include actions to take if contact with the person is lost (for example, keeping details of people who might be able to help re‑establish contact)
refer to, and be coordinated with, any other care plan already established for the person
define the support needed to address any unmet health and social care needs (for example, support to gain housing or other benefits, or to help them access other health or social care services)
include a commitment from the person to complete their TB treatment
be supported by frequent contact with any key workers who work with the person.
Multidisciplinary TB teams should aim to find people with active TB who are lost to follow-up, or who stop using services before completing diagnostic investigations. They should report all those lost to follow‑up to local Public Health England teams, GPs, the referring organisation and specialist outreach teams.
## Other strategies to encourage people to follow their treatment plan
To encourage people to follow their treatment plan, involve people in treatment decisions for active or latent TB from the start. Emphasise the importance of following the treatment plan when agreeing the regimen.
Multidisciplinary TB teams should implement strategies for active and latent TB to encourage people to follow the treatment plan and prevent people stopping treatment early. These could include:
reminder letters, printed information, telephone calls, texts and apps using an appropriate language
health education counselling and patient‑centred interviews
tailored health education booklets from quality sources (see section on providing information for the public about TB)
home visits
random urine tests and other monitoring (for example, pill counts)
access to free TB treatment for everyone (irrespective of eligibility for other NHS care) and information about help with paying for prescriptions
social and psychological support (including cultural case management and broader social support)
advice and support for parents and carers
incentives and enablers to help people follow their treatment regimen.
TB control boards should ensure services take into account the barriers facing vulnerable migrants who may need treatment, and in particular the stigma they may face. Other issues include the location of services (both geographically and in terms of opening times) and people's language and cultural needs, in terms of the format of advice and the type of information given.
## Strategies in prisons or immigration removal centres
On arrival at a prison or immigration removal centre, healthcare professionals should ask all prisoners and detainees (including those being transferred from other establishments) if they are taking TB medication, to ensure continuity of treatment.
All prisoners and immigration removal centre detainees having treatment for active TB should have a named TB case manager. The case manager should be responsible for contingency planning for discharge from prison or detention.
Prisons and immigration removal centres should ensure multidisciplinary TB staff have access to prisoners and detainees who need treatment (for example, by being given security clearance).
All prisoners having treatment for active TB should have directly observed therapy.
Prison health services should have contingency, liaison and handover arrangements to ensure continuity of care before any prisoner on TB treatment is transferred between prisons or released. In addition, other agencies working with prisoners or detainees should also be involved in this planning.
Prison and immigration removal centre healthcare services should liaise with the named TB case manager (from the multidisciplinary TB team) to ensure contingency plans for continuation of treatment are drawn up for prisoners and immigration removal centre detainees with TB.
Multidisciplinary TB teams should ensure accommodation is available for the duration of TB treatment after the prisoner or detainee's release (see section on Identifying and managing active TB in prisons, custody suites or immigration removal centres: organisational factors).
Multidisciplinary TB teams should ensure directly observed therapy is arranged for prisoners or detainees being treated for TB after their release. This should be available close to where they will live in the community.
## Re‑establishing treatment for active or latent TB after interruptions because of adverse events
In people who have experienced a treatment interruption because of drug‑induced hepatotoxicity:
investigate other causes of acute liver reactions and
wait until aspartate or alanine transaminase levels fall below twice the upper limit of normal, bilirubin levels return to the normal range and hepatotoxic symptoms have resolved then
sequentially reintroduce each of the anti‑TB drugs at full dose over a period of no more than 10 days, starting with ethambutol and either isoniazid (with pyridoxine) or rifampicin.
In people with severe or highly infectious TB who need to interrupt standard therapy because of a reaction, consider continuing treatment:
for hepatotoxicity, a combination of at least 2 anti‑TB drugs of low hepatotoxicity (such as ethambutol and streptomycin, with or without a fluoroquinolone antibiotic, such as levofloxacin or moxifloxacin) and monitor with a liver specialist for further reactions See MHRA advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).Not licensed for tuberculosis, so use would be off label. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information.
for a cutaneous reaction, a combination of at least 2 anti‑TB drugs with a low risk of cutaneous reactions (such as ethambutol and streptomycin) and monitor with a dermatologist for further reactions.
If another reaction of a similar or greater severity occurs because of reintroducing a particular drug, do not give that drug in future regimens and consider extending the total regimen accordingly.
## Follow‑up after treatment completion
Follow‑up clinic visits should not be conducted routinely after treatment completion.
Tell patients to watch for symptoms of relapse and how to contact the TB service rapidly through primary care or a TB clinic. Key workers should ensure that patients at increased risk of relapse are particularly well informed about symptoms.
Patients who have had drug‑resistant TB should be considered for follow‑up for 12 months after completing treatment. Patients who have had multidrug‑resistant TB should be considered for prolonged follow‑up.
# Service organisation
When using the recommendations in this section with under served groups, also check sections 1.1.1 on raising and sustaining awareness, 1.1.2 on providing information for the public, 1.6.2 on opportunistic case finding, 1.6.3 on active case finding in under served groups and 1.7 on adherence, treatment completion and follow up. See also, recommendations on under served groups in section 1.2.3 on diagnosing latent TB in all age groups.
## Strategic oversight and commissioning of TB prevention and control activities
Public Health England, in partnership with NHS England, should take responsibility for national oversight of TB prevention and control activities. This includes setting up TB control boards (see section 1.8.2).
Public Health England and NHS England should consider working together to establish control boards in agreed geographical areas and employ appropriate staff (see recommendation 1.8.2.3).
Clinical commissioning groups and local authority public health teams working in partnership with Public Health England and NHS England should consider collaborative commissioning arrangements through TB control boards. This could, for example, include working with 1 or more clinical commissioning groups to cover a major metropolitan district, region or TB control board area taking into account:
local TB incidence
local at‑risk populations and their movements across different geographical areas
existing service configurations for organisations involved in TB prevention and control
the need to share services, such as mobile X‑ray facilities, and outreach incident teams across different geographical areas.
TB control boards should develop TB prevention and control programmes working with commissioners, Public Health England and NHS England. The board could include clinical, commissioning (from clinical commissioning groups, local government and the voluntary sector) and public health leaders and people with TB or groups who advocate on their behalf from across the control board area. This may include identifying a lead clinical commissioning group, which could be led by an executive director of that commissioning group working with the board. Feedback mechanisms between local commissioning groups and the TB control board should be developed.
An executive director of local commissioning groups, working with the local director of public health or another nominated public health consultant, should lead implementation of the programme in their locality. The lead should ensure a comprehensive prevention and control programme is commissioned to support the level of need (see section on local needs assessment) and that they work with the control board regularly.
Working together through TB control boards and local networks, commissioners, local government and Public Health England should ensure TB prevention and control programmes set up multidisciplinary TB teams to provide all TB services (see section on commissioning multidisciplinary TB support). They should ensure that local strategy and service commissioning focuses on an end-to-end pathway.
Working together through TB control boards, commissioners and Public Health England should ensure the TB prevention and control programme is informed by relevant NICE guidance and developed in collaboration with clinical services. It should also be informed by the standard minimum data set collected through local needs assessment and service audit.
Working together through TB control boards, commissioners and Public Health England should ensure the TB prevention and control programme targets all ages, including children, and covers all aspects of TB prevention and control (see recommendations 1.8.2.1 and 1.8.2.2), including but not limited to:
active case finding (contact investigations and identifying latent TB in high‑risk groups)
awareness‑raising activities
standard and enhanced case management (including providing directly observed therapy and free treatment)
finding people lost to follow‑up and encouraging them back into treatment
incident and outbreak control
monitoring, evaluating and gathering surveillance and outcome data.
Working together through TB control boards, commissioners, Public Health England and the voluntary sector should ensure TB prevention and control programmes take account of the need to work with other programmes targeting specific high‑risk groups, such as those who are under-served. Examples include programmes focused on the health of asylum seekers and refugees, under-served children, homelessness and housing, offenders and people who misuse substances.
TB control boards should consider integrating TB and HIV services, joint clinics and training opportunities.
Commissioners should consider commissioning support and advice to all groups diagnosed with TB irrespective of whether they are under‑served.
## Developing the TB prevention and control programme
TB control boards should be responsible for developing a TB prevention and control programme based on the national strategy and evidence‑based models.
TB control boards should plan, oversee, support and monitor local TB control, including clinical and public health services and workforce planning.
TB control boards should assess services in their area, identify gaps in provision and develop plans to meet these, including:
undertaking a workforce review to support local or regional commissioning of TB services to meet the needs of their population (see sections on local needs assessment and cohort review)
supporting development of appropriate services and pathways to improve access and early diagnosis (see the sections on rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process, non‑clinical roles including TB support workers and rapid‑access TB services)
negotiating arrangements to cover the cost of additional services to address specific gaps in current TB control arrangements.
TB control boards should ensure cohort review is undertaken at least quarterly, and the results are fed back to local clinical and TB networks. These should be agreed by accountable bodies such as clinical commissioning groups, trust management, regional Public Health England and centre directors and local authority directors of public health as agreed, all of whom should make sure appropriate action is taken.
TB control boards should enable full and consistent use of national guidelines including:
ensuring the needs of all people with TB, particularly under‑served populations, are addressed
ensuring contact tracing arrangements are appropriate to the needs of the population (see the section on case finding)
assuring themselves that TB control in low‑incidence areas is established and delivered appropriately (see the section on rural services: organisational and support factors)
assuring themselves that multidrug‑resistant TB is managed appropriately (see the section on multidrug‑resistant TB) and mechanisms are in place to ensure:
there is sufficient clinical expertise available to manage cases
regional multidrug‑resistant TB networks take account of expert advice (see section 1.8.3).
TB control boards should develop links and partnerships and establish agreed relationships and lines of accountability between TB control boards and local clinical and TB networks. This includes engaging with other key stakeholders to ensure universal coverage of TB control efforts.
TB control boards should collaborate with their local and regional partners. They should agree and establish regular monitoring, surveillance and reporting arrangements with all partners to support needs assessment (see the section on local needs assessment) and regular audit and evaluation.
TB control board staff should have clearly defined roles and responsibilities. Their roles and responsibilities could include:
Establishing the links, partnerships and relationships between all aspects of the control board area within their remit (if necessary across usual geographical commissioning boundaries).
Developing and supporting adoption and implementation of evidence‑based model service specifications for the clinical and public health actions needed to control TB including:
improving access and early diagnosis (see the sections on raising and sustaining awareness of TB, providing information for the public about TB, rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process and non‑clinical roles including TB support workers)
diagnostics, treatment and care services (see the sections on latent TB and active TB)
contact investigations and tracing (see the sections on diagnosing latent TB in adults and case finding)
cohort review
vaccination (see the section on BCG vaccination)
drug resistance (see the section on multidrug‑resistant TB)
tackling TB in under‑served populations
surveillance, monitoring and quality assurance
workforce development and commissioning (see the sections on commissioning multidisciplinary TB support and non‑clinical roles including TB support workers).
TB control boards should ensure there is sufficient capacity available to them to manage a sudden increase in demand such as:
TB contact investigations, (such as incidents in congregate settings)
large scale active case‑finding initiatives in under‑served groups in the community
-utbreaks in a variety of settings or sites where transmission risk may be high, including but not limited to schools, workplaces, hostels and prisons.
To set up, monitor and evaluate a TB control programme, TB control boards should:
agree plans within their partnerships to assess local services against the service specifications
develop plans and quality standards to secure improvements
establish quality assurance mechanisms and regular audits including, but not limited to, cohort review for all aspects of the TB control board partnership plans.
TB control boards should (in collaboration with commissioners) consider the need for a TB network local coordinator, particularly if working across multiple clinical commissioning group areas (see recommendation 1.8.1.3).
The coordinator should work in close collaboration with clinicians and all relevant multidisciplinary TB teams to develop the network and be responsible for:
setting up the network and developing it based on needs, reporting back to the TB control board regularly
establishing the links, partnerships and relationships across their local network (if necessary across usual geographical commissioning boundaries).
## Regional multidrug‑resistant TB network
TB control boards should consider setting up a regional multidisciplinary TB network to oversee management of multidrug‑resistant TB. This could:
Identify and designate regional expert centres.
Ensure all healthcare professionals who suspect or treat a case of multidrug‑resistant TB are informed about and have access to specialist advisory services for multidrug‑resistant TB. This includes the designated expert centre in their regional network and may also include the national advisory service for multidrug-resistant TB (currently provided by the British Thoracic Society).
Ensure all cases of multidrug‑resistant TB are discussed at the regional multidisciplinary TB team meeting in the local clinical network.
Formally consider and record the advice from the specialist advisory services for multidrug‑resistant TB provided by the designated regional expert centre or the national advisory service for multidrug‑resistant TB.
## Rural services: organisational and support factors
Commissioners in rural areas (working with the TB control board) should consider collaborative approaches to deliver and manage TB services. They could, for example, set up a network including areas with high and low incidence of TB.
## Local needs assessment
Directors of public health, in discussion with local health protection teams, should ensure that TB is part of the joint strategic needs assessment.
Directors of public health should provide commissioners of TB prevention and control programmes and TB control boards with local needs assessment information annually using data provided by Public Health England.
Commissioners of TB prevention and control programmes should ensure services reflect the needs of their area, identified by needs assessment. Health and wellbeing boards should ensure that local TB services have been commissioned based on local needs identified through needs assessment.
Directors of public health and TB control boards should use cohort review (see section 1.8.6) and other methods to collect data on the following, to inform local needs assessment:
Number of annual notified TB cases (see Public Health England's enhanced TB surveillance data and annual 'suite of indicators').
Size, composition (for example, age and ethnicity) and distribution of local at‑risk groups.
Indices of social deprivation.
Local statutory and non‑statutory services working with these groups.
Organisation of local TB services, including the composition and capacity of the local multidisciplinary TB team(see the results of local audit) and location of services. This may also include data to support evaluating the need for integrated TB/HIV services including joint clinics.
Numbers needing enhanced case management (see the section on adherence, treatment completion and follow‑up).
Numbers receiving directly observed therapy from the start of, or at any point during, treatment (see Public Health England's enhanced TB surveillance data).
Evidence of recent transmission (for example, using DNA fingerprinting or surrogate markers such as number of cases in children under 5 years (see UK TB national strain-typing database and local incident and outbreak reports).
Completeness and yield of contact investigations. This includes: proportion of smear‑positive cases with 0, 5 or more contacts identified; proportion of identified contacts clinically assessed; and proportion of contacts with latent TB infection who successfully complete treatment.
Active case‑finding initiatives, incident contact investigations and identification of latent TB infection in high‑risk groups.
Treatment outcomes for everyone grouped according to social risk factors and by the use of directly observed therapy (including rates of loss to follow‑up and treatment interruptions, see Public Health England's enhanced TB surveillance data).
Local education and awareness‑raising programmes for under‑served groups, professionals and practitioners working with them.
Views and experiences of people with TB, carers and the services working with them.
Local needs assessments should also be equity proofed to assess the potential effect of planning, commissioning and policy decisions on health inequalities (see planning and commissioning services in NICE's local government briefing on health inequalities and population health).
## Cohort review
TB control boards and prevention and control programme leads should initiate, audit and evaluate cohort reviews in their commissioning area. Quarterly cohort review meetings should take place in the area covered by the programme. Combine these meetings with others if possible, or use technology to make it easier for clinicians and case managers to attend.
TB case managers should present standardised information on each case, including: demographic information, HIV test results, pre‑treatment and ongoing status (clinical, laboratory, radiology), adherence to treatment and the results of contact investigations.
TB case managers and key allied professionals from the TB prevention and control programme should attend cohort review meetings. This could include the lead clinician (who may or may not be the case manager). Either a paediatrician with experience and training in the treatment of TB or a general paediatrician with advice from a specialised clinician should be present when cases of children with TB are presented.
The chair of the cohort review should not work for any of the TB services included in the review. Examples of possible chairs include a public health consultant, a specialist physician or a senior TB nurse, preferably from a different geographical area. Alternatively the chair could be a representative from the local Public Health England health protection team or the TB control board.
Multidisciplinary TB teams, in conjunction with Public Health England units, should collate and present cohort review data on TB treatment and the outcome of contact investigations at the review meetings. In addition, progress towards national, regional and local service targets should be presented.
TB control boards, directors of public health and local public health consultants should ensure outputs from the cohort review feed into the needs assessment for TB services. TB control board directors should attend the cohort review at least once a year.
TB case managers should feed back promptly to multidisciplinary TB teams on issues identified as a result of cohort review. The results of the cohort review should be collated locally and agreed by the chair before being fed back to TB control boards, commissioners and health and wellbeing boards regularly and via needs assessment.
People participating in a cohort review should review the results and evaluate local services (for example, auditing adverse outcomes, rates of culture confirmation, treatment completion rates or time to diagnosis).
## Commissioning multidisciplinary TB support
Commissioners should ensure multidisciplinary TB teams:
Have the skills and resources to manage the care of people with active TB who are not from under‑served groups.
Include at least 1 TB case manager with responsibility for planning and coordinating the care of under‑served people and those with active TB who receive enhanced case management.
Have the resources to manage latent TB care in under‑served groups and the wider population.
Include a range of clinical specialties in the multidisciplinary TB team, including paediatrics, infection control and respiratory medicine.
Have regular attendance at these multidisciplinary team and cohort review meetings for all team members included as a programmed activity as part of their work planning.
Have the skills and resources necessary to manage the care of people with complex social and clinical needs (either directly or via an established route). This includes the ability to provide prompt access (or if necessary, referral) to skilled outreach and advocacy workers who can draw on the services of allied practitioners. The aim is to address people's housing, asylum, immigration, welfare, substance dependency and other health and social care needs. (The allied practitioner support should include both a specified housing officer and a social worker.)
Can provide rapid access TB clinics for all cases, including under‑served groups.
Consider providing administration support for TB nurses and case managers so they have capacity for clinical and case management work. This could include giving TB nurses access to computer hardware and software.
Have the resources to provide a continuous service throughout the year, ensuring the TB service accounts for the following to manage continuity of care:
planned absence (for example, professional development, mandatory training, annual, maternity or paternity leave)
unplanned absence (such as sickness absence).
Can provide prompt access to a professional who has training and experience in assessing and protecting children and vulnerable adults at risk of abuse or neglect.
Have access to funds through local government and clinical commissioning groups that can be used flexibly to improve adherence to treatment among under‑served groups. For example, funds could be used to provide transport to clinics, to provide support or enablers for treatment, or for paying outreach workers or community services to support directly observed therapy. Funds may also be used to provide accommodation during treatment.
Have the resources to provide ongoing TB awareness‑raising activities for professional, community and voluntary (including advocacy) groups that work with populations at high risk of TB (see the section on raising and sustaining awareness of TB). These resources could be financed by local government or clinical commissioning groups.
Commissioners should ensure NHS England's safe staffing principles are applied when commissioning TB services. The staffing ratios used in Public Health England and NHS England's collaborative tuberculosis strategy for England (published in 2015) came from NICE's guideline on tuberculosis: identification and management in under-served groups (published in 2012) which has been replaced by this guideline.NICE's 2012 guideline on tuberculosis: identification and management in under-served groups recommended 1 WTE case manager per 40 incident cases needing standard management and 1 WTE case manager per 20 incident cases needing enhanced case management.
## Non‑clinical roles including TB support workers
TB control boards and local TB services should consider employing trained, non‑clinically qualified professionals to work alongside clinical teams to agreed protocols, and to contribute to a variety of activities. Examples of this may include awareness raising and supporting people to attend appointments (including other health and social care appointments). They could also help with collecting samples, contact tracing, case management including directly observed therapy and cohort review, or any other aspect of the service if:
they are trained to deliver the intervention or processes effectively
they are supported, mentored and supervised by a named case manager, such as a TB nurse
they have the skills to monitor, evaluate and report on their work practices and outcomes to maintain a process of ongoing evaluation and service improvement in relation to cohort review (see the section on cohort review).
TB control boards should ensure that people working in the TB service have the right knowledge, engagement, advocacy and communication skills to meet the needs (for example, language, cultural or other requirements) of all the groups they may work with.
Commissioners should consider taking into account different needs across traditional geographical and organisational boundaries. Put agreements in place so that staff can work across these boundaries, covering the whole service or TB control board area if appropriate.
Commissioners and TB control boards should ensure they put in place appropriate governance (including clear lines of accountability and extension of scope of practice) and data sharing practices and agreements. This includes ensuring they are part of service level agreements between NHS and non‑NHS services, for example, the third sector or local government, and appropriate training has been completed.
## Rapid‑access TB services
Multidisciplinary TB teams should establish relationships with statutory, community and voluntary organisations that work with people at risk of TB to develop appropriate TB referral pathways. They should ensure these organisations know how to refer people to local TB services.
Multidisciplinary TB teams should accept referrals from healthcare providers and allied organisations working in the community with under‑served groups. This includes voluntary and statutory organisations (for example, mobile X‑ray teams or community organisations or outreach workers working with vulnerable migrants).
Multidisciplinary TB teams should accept self‑referrals to TB clinics by people who suspect they have TB or have recently been in contact with someone with TB.
Multidisciplinary TB teams should consider accepting direct referrals from emergency departments (see the section on rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process).
Healthcare professionals should consider urgent referral to TB clinics for people with suspected active TB. They should also ensure the results from first‑line diagnostic tests (including a sputum smear and chest X‑ray) are available before the person sees a specialist. (Note: this should not delay the referral.)
Multidisciplinary TB teams should have pathways to triage referrals, start investigations and collect clinical information before the person is seen by a physician.
While triaging, multidisciplinary TB teams should ensure everyone is given information about TB as part of the process (see the section on providing information for the public about TB). This should include who the person should contact if they have any questions and how to access advice or information from support groups, national charities such as TB Alert and other sources such as local government (for example, public health or social care teams).
Multidisciplinary TB teams should ensure people who have a smear‑positive result or imaging features highly suggestive of smear‑positive TB (for example, evidence of cavitation on chest X‑ray) are assessed the next working day. This is so that case management and infection control procedures start promptly.
The multidisciplinary TB team should assess people who are not smear‑positive but have imaging that suggests pulmonary or laryngeal TB as soon as possible. This should be no later than 5 working days after a referral.
Multidisciplinary TB teams should, where necessary, be able to provide or arrange outreach services to ensure sputum samples or other assessments such as contact investigations can be arranged in the community.
## Identifying and managing active TB in prisons, custody suites or immigration removal centres: organisational factors
Multidisciplinary TB teams, prisons, custody suites and immigration removal centre healthcare services should have named TB liaison leads to ensure they can communicate effectively with each other.
Prison, custody suites and immigration removal centre healthcare services should develop a TB policy by working with the TB control board and multidisciplinary TB team and the local Public Health England health protection team.
Multidisciplinary TB teams, in conjunction with prisons, custody suites and immigration removal centre healthcare services, should agree a care pathway for TB. This is to ensure that any suspected or confirmed cases are reported to, and managed by, the multidisciplinary TB team.
Multidisciplinary TB teams, in liaison with prisons, custody suites or immigration removal centre healthcare providers, should manage all cases of active TB. Investigations and follow‑up should be undertaken within the prison or immigration removal centre if possible.
## Accommodation during treatment
Multidisciplinary TB teams should assess the living circumstances of people with TB. Where there is a housing need they should work with allied agencies to ensure that all those who are entitled to state‑funded accommodation receive it as early as possible during their treatment, for example, as a result of a statutory homelessness review and identified need.
Multidisciplinary TB teams, commissioners, local authority housing lead officers and other social landlords, providers of hostel accommodation, hospital discharge teams, Public Health England and the Local Government Association should work together to agree a process for identifying and providing accommodation for homeless people diagnosed with active pulmonary TB who are otherwise ineligible for state‑funded accommodation. This includes people who are not sleeping rough but do not have access to housing or recourse to public funds. The process should detail the person's eligibility and ensure they are given accommodation for the duration of their TB treatment.
Local government and clinical commissioning groups should fund accommodation for homeless people diagnosed with active TB who are otherwise ineligible for state‑funded accommodation. Use health and public health resources, in line with the Care Act 2014.
Multidisciplinary TB teams should make people who would not otherwise be entitled to state‑funded accommodation aware that they may lose this accommodation if they do not comply with treatment. They should ensure plans are made to continue housing people once their TB treatment is completed.
Public Health England, working with the Local Government Association and their special interest groups, should consider working with national housing organisations such as the Chartered Institute of Housing, Homeless Link, Sitra and the National Housing Federation to raise the profile of TB. This is to ensure people with TB are considered a priority for housing.
Consider training housing commissioners and frontline staff on TB and the need for housing support, so that they understand that a stable home life is a prerequisite to successful TB treatment.
# Terms used in this guideline
## Active case‑finding
Systematically identifying people with active or latent TB using tests, examinations or other procedures.
## Adherence
The term adherence refers to the person's ability or willingness to keep to a treatment regimen as directed.
## Adults
People aged 18 or older.
## Case management
Case management involves follow‑up of a person suspected or confirmed to have TB. It needs a collaborative, multidisciplinary approach and should start as soon as possible after a suspected case is discovered.
## Case manager
Standard and enhanced case management is overseen by a case manager who will usually be a specialist TB nurse or (in low‑incidence areas) a nurse with responsibilities that include TB. Depending on the person's circumstances and needs, case management can also be provided by appropriately trained and supported non‑clinical members of the TB multidisciplinary team.
## Children
People aged 15 or younger.
## Children and young people
People aged 17 or younger.
## Close contacts
'Close contacts' are people who have had prolonged, frequent or intense contact with a person with infectious TB. For example, these could include 'household contacts', those who share a bedroom, kitchen, bathroom or sitting room with the index case. Close contacts may also include boyfriends or girlfriends and frequent visitors to the home of the index case. Depending in the circumstances, occasionally coworkers are classed as 'close contacts although they are more usually classed as 'social contacts'.
## Cohort review
Cohort review is a systematic quarterly audit of the management and treatment of all TB patients and their contacts. The 'cohort' is a group of cases counted over a specific time, usually 3 months. Brief details of the management and outcomes of each case are reviewed in a group setting. The case manager presents the cases they are responsible for, giving the opportunity to discuss problems and difficulties in case management, service strengths and weaknesses, and staff training needs.
## Congregate setting
A place where people congregate or an institutional setting such as a workplace, prison, hostel, or childcare or educational setting, where social contacts might have had significant exposure to TB.
## Contact
A person who has spent time with someone with infectious TB. See also 'close contact' and 'social contact'.
## Contact investigation
Clinical investigations (diagnostic testing) of people identified as having had significant exposure to a case of TB, including tests to diagnose latent or active TB. The aims of contact investigations are to:
detect active TB earlier to offer treatment and prevent further transmission
detect latent TB that may benefit from drug treatment
detect people not infected but for whom BCG vaccination might be appropriate.
## Contact tracing
Identifying people who may have come into contact with a person with infectious TB and assessing them for risk of significant exposure to TB. The aim is to find associated cases, to detect people with latent TB and to identify those not infected but for whom BCG vaccination might be appropriate.
## Disseminated TB
Blood‑borne spread of TB that may or may not be accompanied by chest X‑ray or high resolution CT changes.
## Enablers
Methods of helping someone to overcome barriers to completing diagnostic investigations and TB treatment. Examples of barriers include: transport, housing, nutrition and immigration status.
## Enhanced case management
Management of TB for someone with clinically or socially complex needs. It starts as soon as TB is suspected. As part of enhanced case management, the need for directly observed treatment is considered, along with a package of supportive care tailored to the person's needs.
## Equity proofed
Tools such as health equity audit and health impact assessment have been used systematically to assess the potential effect of all policies, programmes and activities (including those without an explicit health focus) on health inequalities. Equity proofing helps ensure all policies and programmes address the social determinants of health and health inequalities. Including a health equity audit as part of the joint strategic needs assessment can help local authorities and their partners to:
develop strategy and plans according to need
identify and work with community and health partners
commission activities based on the best available evidence
implement interventions to tackle inequity.
## End‑to‑end pathway
The pathway from awareness raising and primary prevention, through diagnosis to treatment completion, incorporating all aspects such as contact tracing and other infection control mechanisms, for example, access to isolation facilities. This includes governance and commissioning considerations so that a comprehensive clinical and public health service is developed and delivered across any agreed geographical footprint.
## Extrapulmonary TB
Active TB disease in any site other than the lungs or tracheobronchial tree.
## Extensively drug‑resistant TB
Resistance to at least isoniazid and rifampicin, 1 injectable agent (capreomycin, kanamycin or amikacin) and 1 fluoroquinolone.
## High incidence
A high‑incidence country or area has more than 40 cases of TB per 100,000 people per year. Public Health England lists high‑incidence countries and areas of the UK on its website.
## High‑risk groups
The term 'high‑risk groups' is used in this guideline to mean adults, young people and children from any ethnic background, regardless of migration status, who are at increased risk of having or contracting TB. This includes people classified as under‑served, people identified as contacts according to the case finding recommendations, new entrants from high‑incidence countries and people who are immunocompromised.
## Homelessness
For the purposes of TB control, a broad and inclusive definition of homelessness has been adopted that incorporates overcrowded and substandard accommodation. It includes people:
who share an enclosed air space with people at high risk of undetected active pulmonary TB (that is, people with a history of rough sleeping, hostel residence or substance misuse)
without the means to securely store prescribed medication
without private space in which to self‑administer TB treatment
without secure accommodation in which to rest and recuperate in safety and dignity for the full duration of planned treatment.
## Immigration removal centres
Immigration removal centres are private or prison‑run holding centres for migrants waiting to be accepted by, or deported from, the UK. Immigration removal centres are also known as immigration detention centres and pre‑departure accommodation.
## Immunocompromised
In this guideline, immunocompromised refers to a person who has a significantly impaired immune system. For instance, this may be because of prolonged corticosteroid use, tumour necrosis factor‑alpha antagonists, antirejection therapy, immunosuppression‑causing medication or comorbid states that affect the immune system, for example, HIV, chronic renal disease, many haematological and solid cancers, and diabetes.
## Incident risk assessment
Assessment of risk of exposure to TB in a congregate setting to decide on the need for and extent of contact investigation. The risk assessment would take into consideration factors such as infectiousness of the index case, vulnerability of contacts to TB infection, length of contact with or exposure to an infectious case and the built environment (for example, size of the rooms, ventilation and overcrowding).
## Index case
The initial person found to have TB, whose contacts are screened. The source of their infection may be found to be 1 of the contacts, but the person who presents first is regarded as the index case.
## Induration
The firm skin reaction occurring after a tuberculin skin test to diagnose latent TB infection. It is measured, and the result used to determine whether the test result is classified as positive or negative. This guideline recommends a threshold of 5 mm for tuberculin skin test positivity.
## Infectious TB
Active smear‑positive pulmonary TB, that is with acid fast bacilli visible on microscopy. Active TB affecting other parts of the respiratory tract or oral cavity, though rare, is also considered infectious.
## Isolation
An infection control measure in which people with infectious TB are kept away from others who may be at risk of infection. This guideline deals with 3 levels of isolation for infection control in hospital settings:
negative pressure rooms, which have air pressure continuously or automatically measured, as defined by NHS Property Services
single rooms that are not negative pressure but are vented to the outside of the building
beds on a ward, for which no particular engineering standards are needed.
## Lost to follow‑up
People are defined as 'lost to follow‑up' if they cannot be contacted within 10 working days of:
their first missed outpatient appointment (if they are on self‑administered treatment)
their first missed directly observed therapy appointment (if they are on directly observed therapy).
## Multidisciplinary TB teams
A team of professionals with a mix of skills to meet the needs of someone with TB who also has complex physical and psychosocial issues (that is, someone who is under‑served). Team members will include a social worker, voluntary sector and local housing representatives, TB lead physician and nurse, a case manager, a pharmacist, an infectious disease doctor or consultant in communicable disease control or health protection, a peer supporter or advocate and a psychiatrist.
## Multidrug‑resistant TB
TB resistant to isoniazid and rifampicin, with or without any other resistance.
## Negative pressure room
Used to isolate some patients known or suspected to have infectious TB. A negative pressure room is one where the air from the room is sucked out into dedicated ducting through a filter and into the outside air, at a distance from all other air intakes. The pressure should be 10 pascals below the ambient air pressure.
## Neonates
Children aged 4 weeks or younger.
## New entrant
Anyone coming to work or settle in the UK. This includes immigrants, refugees, asylum seekers, students and people on work permits. It also includes UK‑born people, or UK citizens, re‑entering the country after a prolonged stay in a high‑incidence country.
## Opportunistic case‑finding
Opportunistic identification of people with active or latent TB using tests, examinations or other procedures in the course of existing appointments or interactions, rather than identification through formal screening programmes.
## Outbreak
There is no robust, widely accepted threshold for an outbreak of a disease, but in practical terms an outbreak is the occurrence of an unusually high number of cases in associated people, in a small geographical area, or in a relatively short period of time.
## Peers
Peers are people who may have experienced TB. They are often in a good position to help convey, with empathy, the need for testing or treatment. They may be recruited from specific populations. With support they can communicate health messages, assist with contact investigations or testing and offer people support while they are being tested or treated.
## Prisons
Any state prison establishments, including young offender institutions.
## Rapid access
In the context of TB services, rapid access refers to timely support from a specialist team.
## Smear grade
The number of bacilli found in a sputum sample, believed to relate to the degree of infectivity of the person. There are several systems but in general recording goes from no mycobacteria in 100 fields (0 or negative) to more than 10 acid‑fast bacilli per field in at least 20 fields (grade 3).
## Social contacts
Someone who has had contact with a person with infectious TB but has not been in prolonged, frequent or intense contact.
## Substance misuse
Substance misuse is defined as intoxication by, or regular excessive consumption of or dependence on, psychoactive substances, leading to social, psychological, physical or legal problems. It includes problematic use of both legal and illegal drugs.
## TB control board
A partnership of mixed professionals and lay people who have experience of leading, commissioning, managing or supporting people with TB. Board members are likely to include the voluntary sector, housing representatives, TB specialists and other clinicians, consultants in communicable disease control or health protection, peer supporter and advocate groups, clinical commissioning groups, executive officers, local government commissioners and an independent chair. This list is not intended to be exhaustive; membership should be determined based on an area's needs, agreements and commissioning arrangements.
## Treatment interruption
A break in the prescribed anti‑TB regimen for 2 weeks or more in the initial phase, or more than 20% of prescribed doses missed intermittently.
## Under‑served groups
This term is used in this guideline to mean groups of adults, young people and children from any ethnic background, regardless of migration status. They are 'under‑served' if their social circumstances, language, culture or lifestyle (or those of their parents or carers) make it difficult to:
recognise the clinical onset of TB
access diagnostic and treatment services
self‑administer treatment (or, in the case of children and young people, have treatment administered by a parent or carer)
attend regular appointments for clinical follow‑up.
The groups classified as under‑served in this guideline are:
people who are homeless
people who misuse substances
prisoners
vulnerable migrants.
## Under‑served children
Groups of children identified as potentially under served include:
unaccompanied minors
children whose parents are under served, including vulnerable migrants
children whose parents are in prison or who abuse substances
children from Gypsy and Traveller communities
looked‑after children.
## Vulnerable migrants
Vulnerable migrants may include undocumented migrants and those with no recourse to public funds. Some refugees, asylum seekers and new entrants to the country may also fall into this category.
## Young people
People aged 16 or 17.# Context
Tuberculosis (TB) is a curable infectious disease caused by a type of bacterium called Mycobacterium tuberculosis ('M. tuberculosis' or 'M.Tb'), or other bacterium in the M. tuberculosis complex (that is, M. bovis or M. africanum). It is spread by droplets containing the bacteria being coughed out by someone with infectious TB, and then being inhaled by other people.
The initial infection clears in over 80% of people but, in a few cases, a defensive barrier is built round the infection and the TB bacteria lie dormant. This is called latent TB; the person is not ill and is not infectious. If the immune system fails to build the defensive barrier, or the barrier fails later, latent TB can spread in the lung (pulmonary TB) or develop in the other parts of the body it has spread to (extrapulmonary TB). Only a small proportion of people with latent TB will develop symptoms ('active TB').
Many cases of TB can be prevented by public health measures and, when clinical disease does occur, most people can be cured if treated properly. Taking medication in the wrong dose or combination, irregularly or for too short a time can lead to drug resistance. Drug‑resistant strains of TB are much harder to treat and significantly increase a person's risk of long‑term complications or death. If left untreated, 1 person with active pulmonary TB may infect as many as 10 to 15 people every year.
TB incidence in the UK has increased since the early 1990s, but has remained relatively stable since 2005. Despite this, it remains high compared with many other western European countries. Cases tend to cluster in urban areas where populations of at‑risk groups are high. These include areas with many people born in countries with a high incidence of TB, areas with a high level of homelessness, poor housing or poverty, and areas with high rates of problem drug use.
The NHS and Public Health England, as well as a local authority public health teams and many third sector organisations, have been working to reduce the harm caused by TB to many individuals and communities. TB is a notifiable disease, meaning that clinicians have a statutory duty to notify local authorities or a local Public Health England centre of suspected cases, and efforts have been made to strengthen services and ensure clear lines of accountability and responsibility. However, a stronger approach to TB control is now needed to build on this work. Indicators of TB incidence and TB treatment outcomes have been included in the Public Health Outcomes Framework. In addition, Public Health England and NHS England have designed a collaborative tuberculosis strategy for England that brings together best practice in clinical care, social support and public health. Agencies at all levels, including national and local government, clinical commissioning groups and third sector partners, are committed to working in partnership to decrease the incidence of TB, fight the spread of drug‑resistant forms of the disease, reduce current health inequality and, ultimately, eliminate TB as a public health problem in England.# Recommendations for research
The guideline committee has made the following recommendations for research. The guideline committee's full set of research recommendations is detailed in the full guideline.
# Universal compared with risk‑based approach to using rapid diagnostic tests
In people with suspected TB, what is the relative clinical and cost effectiveness of universal and risk‑based use of rapid nucleic acid amplification tests?
## Why this is important
The guideline committee noted that there were 2 possible approaches to using rapid nucleic acid amplification tests for suspected TB. The current approach is to use them only if TB is strongly suspected and rapid information about mycobacterial species would alter the person's care. Another approach is to use them in anyone with a possible diagnosis of TB. There is a trade‑off between ensuring that all people with active TB are diagnosed and avoiding a large number of false positives, which leads to unnecessary treatment. This trade‑off may lead to differences in the cost effectiveness of each approach. NICE's systematic review of the diagnosis of active TB did not identify any robust evidence on this, nor did the health technology assessment on using nucleic acid amplification tests to detect drug resistance. Cost‑effectiveness studies are needed to improve understanding in this area.
# Diagnosis in children
Apart from culture, what other diagnostic tests or combinations of tests are effective in establishing an accurate diagnosis of active respiratory TB in children and young people with suspected active TB?
## Why this is important
The guideline committee noted the lack of evidence on the diagnosis of active TB in children. The disease manifests differently in children than in adults, and more evidence would have been useful to the committee. Cross‑sectional studies are needed to examine the relative accuracy of different tests, and the most appropriate specimen type for these tests, compared with tests currently in use. In particular, the poor accuracy of many tests in children means that diagnostic strategies that is, combinations of tests, should be investigated, including both tests with high sensitivity and tests based on host response.
# Treating isoniazid‑resistant TB
For isoniazid‑resistant TB, what is the most effective regimen for reducing mortality and morbidity?
## Why this is important
There is little evidence for the treatment of isoniazid resistant TB. This is the most common form of drug resistance in the UK, occurring in 7.5% of TB cases. Currently, treatment is not always successful, even when the recommended drugs are given for the recommended time and there are no adherence issues. It is particularly difficult to treat if there are treatment interruptions or if the central nervous system is involved. Randomised controlled trials are needed to compare different anti‑TB regimens for isoniazid‑resistant TB, assessing mortality, treatment success or treatment failure, rates of relapse and adverse events.
# Impact of infection control measures on quality of life
What effects does isolation have on the quality of life of people being treated for TB?
## Why this is important
Isolation is known to significantly affect a person's quality of life. Despite this, the guideline committee identified no reliable data on the impact of isolation on quality of life. This information is essential in producing economic models that reflect the real costs of isolation. Data on the impact of isolation on quality of life need to be collected and reported.
# Treatment interruptions caused by adverse events (specifically hepatotoxicity)
For people with active, drug susceptible TB who experience treatment interruptions because of adverse events, particularly hepatotoxicity, what approach to re‑establishing treatment is most effective in reducing mortality and morbidity?
## Why this is important
There is little evidence on re‑establishing treatment after interruptions because of adverse events. This is key to ensuring treatment success without relapse or the emergence of drug resistance, but avoiding further adverse events is also important. Randomised controlled trials are needed to compare approaches to re‑establishing treatment for active, drug susceptible TB after it is interrupted because of adverse events, particularly hepatotoxicity. These trials should assess mortality, treatment success or failure, rates of relapse, the recurrence of adverse events and the emergence of drug resistance. Approaches evaluated could compare, for example, restarting regimens with lengthening their duration, as well as sequential reintroduction. Approaches should vary depending on the proportion of doses missed and the stage of treatment (initial or continuation phase) in which the interruption occurred. Prospective observational cohort studies with multivariable analyses may also be useful.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Preventing TB\n\n## Raising and sustaining awareness of TB\n\nMultidisciplinary TB teams (in collaboration with Public Health England, primary care, the voluntary sector and Health Education England) should identify and support an ongoing TB education programme for local professionals in contact with the general public, and at‑risk groups in particular. This includes, for example, staff in emergency departments, GPs and wider primary care staff, people who work in housing support services, staff who support migrants and those working in walk‑in centres, hostels, substance misuse projects and prisons. [2012, amended 2016]\n\nMultidisciplinary TB teams should ensure the education programme increases other professionals' awareness of the possibility of TB and reduces the stigma associated with it. The programme should include detail on:\n\ncauses of TB, how it is transmitted, and the signs and symptoms\n\nlifestyle factors that may mask symptoms\n\nlocal epidemiology, highlighting under-served groups, other high-risk groups and the fact that TB also occurs in people without risk factors\n\nprinciples of TB control:\n\n\n\nearly diagnosis and active case-finding\n\nhow to support treatment (including directly observed therapy)\n\ndrug resistance\n\nawareness of drug interactions (including factors such as effect on contraception efficacy)\n\ncontact investigation after diagnosing an active case\n\nthe importance of adhering to treatment\n\ntreatment for TB is free for everyone (irrespective of eligibility for other NHS care)\n\nsocial and cultural barriers to accessing health services (for example, fear of stigma and staff attitudes)\n\nlocal referral pathways, including details of who to refer and how\n\nthe role of allied professionals in awareness‑raising, identifying cases and helping people complete treatment\n\nmisinformation that causes fear about TB, including concerns about housing people with the condition\n\n\n\nthe best ways to effectively communicate all the above topics with different groups. [2012, amended 2016]\n\nStatutory, community and voluntary organisations and advocates working with the general public, and under‑served and high‑risk groups in particular, should share information on TB education and awareness training with all frontline staff. (They should get information on this from the local multidisciplinary TB team.) [2012, amended 2016]\n\nIf possible, statutory, community and voluntary organisations should ensure peers from under‑served groups and anyone else with experience of TB contribute to, or lead, awareness‑raising activities. (Peers who lead such activities will need training and support.) [2012, amended 2016]\n\nMultidisciplinary TB teams should help professionals working in relevant statutory, community and voluntary organisations to raise awareness of TB among under‑served and other high‑risk groups. These professionals should be able to explain that treatment for TB is free and confidential for everyone (irrespective of eligibility for other NHS care). They should also be able to provide people with details of:\n\nhow to recognise symptoms in adults and children\n\nhow people get TB\n\nthe benefits of diagnosis and treatment (including the fact that TB is treatable and curable)\n\nlocation and opening hours of testing services\n\nreferral pathways, including self‑referral\n\nthe potential interaction of TB medication with other drugs, for example, oral contraceptives and opioids (especially methadone) and HIV treatment\n\nTB/HIV co‑infection\n\nhow to address the myths about TB infection and treatment (for example, to counter the belief that TB is hereditary)\n\nhow to address the stigma associated with TB\n\nthe risk of migrants from high‑incidence countries developing active TB, even if they have already screened negative for it\n\ncontact tracing. [2012, amended 2016]\n\nMultidisciplinary TB teams and others working with at‑risk groups should use high quality material to raise awareness of TB (see section\xa01.1.2). [2012, amended 2016]\n\nMultidisciplinary TB teams and others working with the general public, and with under‑served and other high‑risk groups in particular, should include information on TB with other health‑related messages and existing health promotion programmes tailored to the target group. [2012, amended 2016]\n\nMultidisciplinary TB teams should work in partnership with voluntary organisations and 'community champions' to increase awareness of TB, in particular among under‑served groups at risk of infection but also in the general population. If possible, peers who have experience of TB should contribute to awareness‑raising activities and support people in treatment. [2012, amended 2016]\n\n## Providing information for the public about TB\n\nNational organisations (for example, National Knowledge Service: Tuberculosis, TB Alert, Public Health England, Department of Health and NHS Choices) should work together to develop generic, quality‑assured template materials with consistent up‑to‑date messages. These materials should be made freely available and designed so that they can be adapted to local needs. [new 2016]\n\nMultidisciplinary TB teams should use these templates for general awareness raising and targeted activities in under‑served and other high‑risk groups. Involve the target group in developing and piloting the materials. [new 2016]\n\nThe content of any materials should:\n\nbe up‑to‑date and attractively designed, including pictures and colour if possible\n\nbe culturally appropriate, taking into account the language, actions, customs, beliefs and values of the group they are aimed at\n\nbe tailored to the target population's needs\n\ninclude risks and benefits of treatment, and how to access services, advice and support\n\ndispel myths\n\nshow that, by deciding to be tested and treated for TB, a person can be empowered to take responsibility for their own health\n\nuse language that encourages the person to believe that they can change their behaviour\n\nbe simple and succinct. [new 2016]\n\nMake the material available in a range of formats such as written, braille, text messages, electronic, audio (including podcasts), pictorial and video. Make them freely available in a variety of ways, for example, online, as print materials or on memory sticks. [new 2016]\n\nDisseminate materials in ways likely to reach target groups, for example, via culturally specific radio or TV stations, at shelters, and at community, commercial or religious venues that target groups attend regularly. [new 2016]\n\n## BCG vaccination\n\nTo improve the uptake of BCG vaccination, identify eligible groups (in line with the Department of Health's Green Book) opportunistically through several routes, for example:\n\nnew registrations in primary care and with antenatal services, or other points of contact with secondary or tertiary care\n\npeople entering education, including university\n\nlinks with statutory and voluntary groups working with new entrants and looked‑after children and young people\n\nduring contact investigations. [new 2016]\n\nWhen BCG vaccination is being recommended, discuss the benefits and risks of vaccination or remaining unvaccinated with the person (or, if a child, with the parents), so that they can make an informed decision. Tailor this discussion to the person, use appropriate language, and take into account cultural sensitivities and stigma. \n\nIf people identified for BCG vaccination through occupational health, contact tracing or new entrant screening are also considered to be at increased risk of being HIV‑positive, offer them HIV testing before BCG vaccination. \n\nIdentify babies eligible for vaccination (in line with the Green Book) before birth, ideally through antenatal services. [new 2016]\n\nDiscuss neonatal BCG vaccination for any baby at increased risk of TB with the parents or legal guardian. \n\nPreferably vaccinate babies at increased risk of TB before discharge from hospital or before handover from midwifery to primary care. Otherwise, vaccinate as soon as possible afterwards, for example, at the 6‑week postnatal check. [new 2016]\n\nIncorporate computer reminders into maternity service (obstetrics) IT systems for staff, to identify and offer BCG vaccination to babies eligible for vaccination. [new 2016]\n\nProvide education and training for postnatal ward staff, midwives, health visitors and other clinicians on identifying babies eligible for vaccination, local service information and providing BCG vaccination, including:\n\ncase definition for at‑risk groups to be offered vaccination\n\ninformation about the local BCG vaccination policy that can be given verbally, in writing or in any other appropriate format (see sections\xa01.1.1 and 1.1.2) to parents and carers at the routine examination of the baby before discharge\n\nlocal service information about BCG vaccination, such as pre‑discharge availability of neonatal vaccination, local BCG clinics and referral for BCG vaccination if this is not available in maternity services\n\nadministration of BCG vaccination and contraindications. [new 2016]\n\nPrimary care organisations with a high incidence of TB should consider vaccinating all neonates soon after birth. \n\nIn areas with a low incidence of TB (see Public Health England's TB rate bands, published in their annual tuberculosis report), primary care organisations should offer BCG vaccination to selected neonates who:\n\nwere born in an area with a high incidence of TB or\n\nhave 1 or more parents or grandparents who were born in a high‑incidence country or\n\nhave a family history of TB in the past 5\xa0years. [2006, amended 2016]\n\nRoutine BCG vaccination is not recommended for children aged 10 to 14\xa0years.\n\nHealthcare professionals should opportunistically identify unvaccinated children older than 4\xa0weeks and younger than 16\xa0years at increased risk of TB who would have qualified for neonatal BCG (see recommendation 1.1.3.4) and provide Mantoux testing (see the section on diagnosing latent TB in children and young people) and BCG vaccination (if Mantoux‑negative).At the time of publication (January 2016) the BNF states: 'The Mantoux test is recommended for tuberculin skin testing, but no licensed preparation is currently available.' For further guidance, see immunisation against infectious disease (the Green book).\n\nThis opportunistic vaccination should be in line with the Green Book. [2006, amended 2016]\n\nMantoux testing should not be done routinely before BCG vaccination in children younger than 6\xa0years unless they have a history of residence or prolonged stay (more than 1\xa0month) in a country with a high incidence of TB. \n\nOffer BCG vaccination to new entrants who are Mantoux‑negative who:\n\nare from high‑incidence countries and\n\nare previously unvaccinated (that is, without adequate documentation or a BCG scar) and\n\nare aged:\n\n\n\nyounger than 16\xa0years or\n\n\n\nto 35\xa0years from sub‑Saharan Africa or a country with a TB incidence of 500\xa0per\xa0100,000 or more. [2006, amended 2016]\n\nDeliver the following interventions in primary care settings to improve uptake of BCG vaccination in people from eligible groups (as outlined in the Green Book):\n\neducation and support for practice staff, including:\n\n\n\nraising awareness of relevant guidelines and case definition for at‑risk groups\n\npromoting BCG and TB testing in eligible groups\n\n\n\nincorporating reminders for staff (prompts about eligibility for BCG) on practice computers (for example, embedded in medical records)\n\nconsider financial incentives for practices for identifying eligible groups for BCG and TB testing\n\nreminders ('immunisations due') and recall ('immunisations overdue') for people who are eligible for vaccination or for parents of infants and children who are eligible, as outlined in the Green Book. (This could include written reminders, telephone calls from a member of staff or a computerised auto dialler, text messages or a combination of these approaches.) [new 2016]\n\nUse home visits to give information and advice to people who are disadvantaged on the importance of immunisation. This should be delivered by trained lay health workers, community‑based healthcare staff or nurses. [new 2016]\n\nOffer BCG vaccination to healthcare workers and other NHS employees as advised in the Green Book. [2006, amended 2016]\n\nOffer BCG vaccination to Mantoux‑negative contacts of people with pulmonary and laryngeal TB (see the section on diagnosing latent TB in all age groups) if they:\n\nhave not been vaccinated previously (that is, there is no adequate documentation or a BCG scar) and\n\nare aged 35\xa0years or younger or\n\nare aged 36\xa0years and older and a healthcare or laboratory worker who has contact with patients or clinical materials. [2006, amended 2016]\n\nOffer BCG vaccination to previously unvaccinated, Mantoux‑negative people aged 35\xa0years or younger in the following groups at increased risk of exposure to TB, in accordance with the Green Book:\n\nveterinary and other staff such as abattoir workers who handle animal species known to be susceptible to TB, such as simians\n\nprison staff working directly with prisoners\n\nstaff of care homes for older people\n\nstaff of hostels for people who are homeless and facilities accommodating refugees and asylum seekers\n\npeople going to live or work with local people for more than 3\xa0months in a high‑incidence country. [2006, amended 2016]\n\n## Preventing infection in specific settings\n\nEmployees new to the NHS who will be working with patients or clinical specimens should not start work until they have completed a TB screen or health check, or documentary evidence is provided of such screening having taken place within the preceding 12\xa0months. \n\nEmployees new to the NHS who will not have contact with patients or clinical specimens should not start work if they have signs or symptoms of TB. \n\nHealth checks for employees new to the NHS who will have contact with patients or clinical materials should include:\n\nassessment of personal or family history of TB\n\nasking about symptoms and signs, possibly by questionnaire\n\ndocumentary evidence of TB skin (or interferon‑gamma release assay) testing within the past 5 years and/or BCG scar check by an occupational health professional, not relying on the applicant's personal assessment. \n\nSee the section on\xa0healthcare workers for screening new NHS employees for latent TB. [2006, amended 2011]\n\nEmployees who will be working with patients or clinical specimens and who are Mantoux‑ or interferon‑gamma release assay‑negative (see section\xa01.2.1) should have an individual risk assessment for HIV infection before BCG vaccination is given. [2006, amended 2016]\n\nOffer BCG vaccination to employees of any age who are new to the NHS and are from countries of high TB incidence, or who have had contact with patients in settings with a high TB prevalence, and who are Mantoux‑negative. [2006, amended 2011]\n\nIf a new employee from the UK or other low‑incidence setting, who has not had a BCG vaccination, has a positive Mantoux test and a positive interferon‑gamma release assay, they should have a medical assessment and a chest X‑ray. They should be referred to a TB clinic to determine whether they need TB treatment if the chest X‑ray is abnormal, or to determine whether they need treatment of latent TB infection if the chest X‑ray is normal. [2006, amended 2011, amended 2016]\n\nIf a prospective or current healthcare worker who is Mantoux‑negative (see the section on healthcare workers) declines BCG vaccination, explain the risks and supplement the oral explanation with written advice. If the person still declines BCG vaccination, he or she should not work where there is a risk of exposure to TB. The employer will need to consider each case individually, taking account of employment and health and safety obligations. [2006, amended 2016]\n\nScreen clinical students, agency and locum staff and contract ancillary workers who have contact with patients or clinical materials for TB to the same standard as new employees in healthcare environments, according to the recommendations set out above. Seek documentary evidence of screening to this standard from locum agencies and contractors who carry out their own screening. \n\nNHS trusts arranging care for NHS patients in non‑NHS settings should ensure that healthcare workers who have contact with patients or clinical materials in these settings have been screened for TB to the same standard as new employees in NHS settings. \n\nInclude reminders of the symptoms of TB, and the need for prompt reporting of such symptoms, with annual reminders about occupational health for staff who:\n\nare in regular contact with TB patients or clinical materials or\n\nhave worked in a high‑risk clinical setting for 4\xa0weeks or longer. Give one‑off reminders after a TB incident on a ward. \n\nIf no documentary evidence of previous screening is available, screen staff in contact with patients or clinical material who are transferring jobs within the NHS as for new employees (see recommendations 1.2.1.5 to 1.2.1.7 in the section on healthcare workers). \n\nAssess the risk of TB for a new healthcare worker who knows he or she is HIV‑positive at the time of recruitment as part of the occupational health checks. \n\nThe employer, through the occupational health department, should be aware of the settings with increased risk of exposure to TB, and that these pose increased risks to HIV‑positive healthcare workers. \n\nHealthcare workers who are found to be HIV‑positive during employment should have medical and occupational assessments of TB risk, and may need to modify their work to reduce exposure. \n\n# Latent TB\n\n## Diagnosing latent TB in adults\n\nOffer Mantoux testing to diagnose latent TB in adults aged 18\xa0to\xa065 who are close contacts of a person with pulmonary or laryngeal TB.\n\nIf the Mantoux test is inconclusive, refer the person to a TB specialist.\n\nIf the Mantoux test is positive (an induration of 5\xa0mm or larger, regardless of BCG history) assess for active TB (see the sections on diagnosing active TB in all age groups, diagnosing pulmonary (including laryngeal) TB in all age groups, diagnosing pulmonary (including laryngeal) TB in adults and diagnosing extrapulmonary TB in all age groups).\n\nIf the Mantoux test is positive but a diagnosis of active TB is excluded, consider an interferon gamma release assay if more evidence of infection is needed to decide on treatment. This could be, for example, if the person needs enhanced case management or if there could be adverse events from treatment.\n\nIf the Mantoux is positive, and if an IGRA was done and that is also positive, offer them treatment for latent TB infection (see the sections on managing latent TB in all age groups and managing latent TB in adults). At the time of publication (January 2016) the BNF states: 'The Mantoux test is recommended for tuberculin skin testing, but no licensed preparation is currently available.' For further guidance, see immunisation against infectious disease (the Green book).[2011, amended 2016]\n\nIn adults who are anticipated to be or are currently immunocompromised, do a risk assessment to establish whether testing should be offered, taking into account their:\n\nrisk of progression to active TB based on how severely they are immunocompromised and for how long they have been immunocompromised\n\nrisk factors for TB infection, such as country of birth or recent contact with an index case with suspected infectious or confirmed pulmonary or laryngeal TB. [new 2016]\n\nFor adults who are severely immunocompromised, such as those with HIV and CD4 counts of fewer than 200\xa0cells/mm3, or after solid organ or allogeneic stem cell transplant, offer an interferon‑gamma release assay and a concurrent Mantoux test.\n\nIf either test is positive (for Mantoux, this is an induration of 5\xa0mm or larger, regardless of BCG history), assess for active TB.\n\nIf this assessment is negative, offer them treatment for latent TB infection. [new 2016]\n\nFor other adults who are immunocompromised, consider an interferon‑gamma release assay alone or an interferon‑gamma release assay with a concurrent Mantoux test.\n\nIf either test is positive (for Mantoux, this is an induration of 5\xa0mm or larger, regardless of BCG history), assess for active TB.\n\nIf this assessment is negative, offer them treatment for latent TB infection. [new 2016]\n\nOffer a Mantoux test to new NHS employees who will be in contact with patients or clinical materials, if the employees:\n\nare not new entrants from high‑incidence countries and\n\nhave not had BCG vaccination (for example, they are without a BCG scar, other documentation or a reliable history). If the Mantoux test is positive, offer an interferon‑gamma release assay. If this is positive, assess for active TB; if this assessment is negative, offer them treatment for latent TB infection. [2011, amended 2016]\n\nOffer a Mantoux test to new NHS employees who are from a high‑incidence country.\n\nIf the Mantoux test is positive (5\xa0mm or larger, regardless of BCG history), assess for active TB; if this assessment is negative, offer them treatment for latent TB infection.\n\nIf Mantoux testing is unavailable, offer an interferon‑gamma release assay. [new 2016]\n\nOffer an interferon‑gamma release assay to new NHS employees who have had contact with patients in settings where TB is highly prevalent:\n\nIf the interferon‑gamma release assay is positive, assess for active TB and\n\nif this assessment is negative, offer them treatment for latent TB infection. [2011, amended 2016]\n\nHealthcare workers who are immunocompromised should be screened in the same way as other people who are immunocompromised (see recommendations 1.2.1.2 to 1.2.1.4). \n\n## Diagnosing latent TB in children and young people\n\nOnly consider using interferon‑gamma release assays alone in children and young people if Mantoux testing is not available or is impractical. This includes for example, situations in which large numbers need to be tested (see the section on incident and outbreak response and recommendation 1.2.3.2). [new 2016]\n\nRefer children younger than 2\xa0years and in close contact with people with smear‑negative pulmonary or laryngeal TB to a specialist to determine what testing strategy for latent TB should be done. This should be a paediatrician with experience and training in TB, or a general paediatrician with advice from a specialised clinician. [new 2016]\n\nIf a neonate has been in close contact with people with smear‑positive pulmonary or laryngeal TB who have not had at least 2\xa0weeks of anti‑TB treatment:\n\nAssess for active TB (see the sections on diagnosing active TB in all age groups, diagnosing pulmonary (including laryngeal) TB in all age groups and diagnosing pulmonary (including laryngeal) TB in children and young people).\n\nStart isoniazid (with pyridoxine).\n\nCarry out a Mantoux test after 6 weeks of treatment.\n\nIf the Mantoux test is inconclusive, refer the child to a TB specialist.\n\nIf the Mantoux test is positive (5\xa0mm or larger, regardless of BCG history), reassess for active TB; if this assessment is negative, continue isoniazid (with pyridoxine) for a total of 6\xa0months.\n\nIf the Mantoux test is negative, reassess for active TB and consider an interferon‑gamma release assay:\n\n\n\nif the interferon‑gamma release assay is negative then stop isoniazid (and pyridoxine) and give a BCG vaccination\n\nif the interferon‑gamma release assay is positive, reassess for active TB; if this assessment for active TB is negative, continue isoniazid (with pyridoxine) for a total of 6\xa0months. [new 2016]\n\n\n\nIf a child aged between 4\xa0weeks and 2\xa0years has been in close contact with people with smear‑positive pulmonary or laryngeal TB who have not had at least 2\xa0weeks of anti‑TB treatment:\n\nAssess for active TB.\n\nStart treatment for latent TB (see the sections on managing latent TB in all age groups and managing latent TB in children and young people) and carry out a Mantoux test.\n\nIf the Mantoux test is inconclusive, refer the child to a TB specialist.\n\nIf the Mantoux test is positive (5\xa0mm or larger, regardless of BCG history), reassess for active TB; if this assessment is negative, complete treatment for latent TB.\n\nIf the Mantoux test is negative, continue treatment for latent TB, reassess for active TB after 6\xa0weeks and repeat the Mantoux test:\n\n\n\nif the Mantoux test is negative, consider an interferon‑gamma release assay\n\nif the interferon‑gamma release assay is negative, treatment for latent TB may be stopped; give a BCG vaccination if the child has not already had one\n\nif either test is positive, reassess for active TB; if this assessment is negative, complete treatment for latent TB. [new 2016]\n\n\n\nIf a child or young person aged between 2\xa0and 17\xa0years has been in close contact with people with pulmonary or laryngeal TB:\n\nOffer Mantoux testing.\n\nIf the Mantoux test is inconclusive, refer the child or young person to a TB specialist.\n\nIf the Mantoux test is positive (5\xa0mm or larger, regardless of BCG history), assess for active TB; if this assessment is negative, offer them treatment for latent TB infection.\n\nIf the initial Mantoux test is negative, offer an interferon‑gamma release assay after 6\xa0weeks and repeat the Mantoux test. [new 2016]\n\nIf latent TB is suspected in children and young people who are anticipated to be or are currently immunocompromised (for example, if they are from a high incidence country or have been in close contact with people with suspected infectious or confirmed pulmonary or laryngeal TB), refer to a TB specialist. \n\n## Diagnosing latent TB in all age groups\n\nOffer Mantoux testing as the initial diagnostic test for latent TB infection in people who have recently arrived from a high‑incidence country who present to healthcare services. If the Mantoux test is positive (5\xa0mm or larger, regardless of BCG history):\n\nassess for active TB (see recommendations 1.3.1 to 1.3.5 in the section on active TB) and\n\nif this assessment is negative, offer them treatment for latent TB infection (see the section on managing latent TB in all age groups to the section on managing latent TB in children and young people).If Mantoux testing is unavailable, offer an interferon‑gamma release assay. [new 2016]\n\nIn an incident situation when large numbers of people may need to be screened, consider a single interferon‑gamma release assay for people aged 18 to 65\xa0years. For children and young people, follow the recommendations in the sections on diagnosing latent TB in children and young people and immunocompromised children and young people. [2011, amended 2016]\n\nOffer people younger than 65\xa0years from under-served groups a single interferon‑gamma release assay. [2011, amended 2016]\n\nSubstance misuse services with access to an interferon‑gamma release assay should provide testing for people younger than 65\xa0years who misuse substances if they:\n\nlive in a high incidence area\n\nare likely to be involved with substance misuse services or other support services on a regular basis (for example, for opioid substitution therapy), when support should be available for directly observed preventive therapy. [2012, amended 2016]\n\nIn high incidence areas (and at prisons that receive prisoners from high incidence areas), prison health services should offer an interferon‑gamma release assay for TB to inmates younger than 65\xa0years who are in regular contact with substance misuse services or other support services. This is provided arrangements have been made for this support to continue after release. [2012, amended 2016]\n\nSubstance misuse services and prison health services should incorporate interferon‑gamma release assay testing with screening for hepatitis\xa0B and\xa0C, and HIV testing. They should refer prisoners and people who misuse substances with positive interferon‑gamma release assays to local multidisciplinary TB teams for further clinical investigations. For prisoners, these investigations should be done in the prison if practically possible. [2012, amended 2016]\n\nIf the interferon‑gamma release assay is positive, assess for active TB (see the sections on diagnosing active TB in all age groups to diagnosing extrapulmonary TB in all age groups); if this assessment is negative, offer them treatment for latent TB infection (see sections on managing latent TB in all age groups to managing latent TB in children and young people). [new 2016]\n\n## Managing latent TB in all age groups\n\nBe aware that certain groups of people with latent TB are at increased risk of going on to develop active TB, including people who:\n\nare HIV‑positive\n\nare younger than 5\xa0years\n\nhave excessive alcohol intake\n\nare injecting drug users\n\nhave had solid organ transplantation\n\nhave a haematological malignancy\n\nare having chemotherapy\n\nhave had a jejunoileal bypass\n\nhave diabetes\n\nhave chronic kidney disease or receive haemodialysis\n\nhave had a gastrectomy\n\nare having treatment with anti‑tumour necrosis factor‑alpha or other biologic agents\n\nhave silicosis. [new 2016]\n\nFor people, including those with HIV, aged younger than 65\xa0years with evidence of latent TB who have been in close contact with people who have suspected infectious or confirmed active pulmonary or laryngeal drug‑sensitive TB, offer either of the following drug treatments:\n\nmonths of isoniazid (with pyridoxine) and rifampicin or\n\nmonths of isoniazid (with pyridoxine). [new 2016]\n\nBase the choice of regimen on the person's clinical circumstances. Offer:\n\nmonths of isoniazid (with pyridoxine) and rifampicin to people younger than 35\xa0years if hepatotoxicity is a concern after an assessment of both liver function (including transaminase levels) and risk factors\n\nmonths of isoniazid (with pyridoxine) if interactions with rifamycins are a concern, for example, in people with HIV or who have had a transplant. [new 2016]\n\nClearly explain the risks and potential benefits of each treatment regimen. In discussion with the person, select a suitable regimen if they wish to proceed with preventive treatment. [new 2016]\n\nIf a person also has severe liver disease, for example, Child‑Pugh level\xa0B\xa0or\xa0C, work with a specialist multidisciplinary team with experience of managing TB and liver disease. [new 2016]\n\nManage treatment with caution, ensuring careful monitoring of liver function, in:\n\npeople with non‑severe liver disease\n\npeople with abnormal liver function (including abnormal transaminase levels) before starting treatment for latent TB infection\n\npeople who misuse alcohol or drugs. [new 2016]\n\nEnsure people having treatment for latent TB who also have social risk factors, such as misusing alcohol or drugs or being homeless, are linked to support services. They should also have an assessment of social needs and stability, including potential barriers to adherence or treatment completion (see the section on adherence, treatment completion and follow‑up). [new 2016]\n\nPeople in the groups listed in recommendation 1.2.4.1 who do not have treatment for latent TB, as specified in recommendations 1.2.4.2 to 1.2.4.8, for any reason should be advised of the risks and symptoms of TB (on the basis of an individual risk assessment), usually in a standard letter of the type referred to as 'Inform and advise' information (see section\xa01.1.2). [new 2016]\n\n## Managing latent TB in adults\n\nFor adults between the ages of 35\xa0and\xa065\xa0years, offer drug treatments only if hepatotoxicity is not a concern. [new 2016]\n\nOffer testing for HIV before starting treatment for latent TB. See the NICE guidelines on increasing the uptake of HIV testing among black Africans in England and increasing the uptake of HIV testing among men who have sex with men. [new 2016]\n\nOffer adults testing for hepatitis\xa0B\xa0and\xa0C before starting treatment for latent TB. See the NICE guidelines on hepatitis B and C: ways to promote and offer testing to people at increased risk of infection and hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. [new 2016]\n\n## Managing latent TB in children and young people\n\nConsider testing children and young people for hepatitis B and C before starting treatment for latent TB. See the NICE guidelines on hepatitis B and C: ways to promote and offer testing to people at increased risk of infection and hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. [new 2016]\n\n# Active TB\n\n## Diagnosing active TB in all age groups\n\nIf TB is a possibility, microbiology staff should consider carrying out TB culture on samples (see recommendations 1.3.2.2 and 1.3.2.3), even if it is not requested. [2006, amended 2016]\n\nIf there are clinical signs and symptoms consistent with a diagnosis of TB, start treatment without waiting for culture results. \n\nConsider completing the standard recommended regimen (see recommendations 1.3.7.2 and 1.3.7.3 in the section on standard treatment), even if subsequent culture results are negative. [2006, amended 2016]\n\n## Diagnosing pulmonary (including laryngeal) TB in all age groups\n\nTake a chest X‑ray; do further diagnostic investigations (as detailed below and summarised in table\xa01) if chest X‑ray appearances suggest TB. \n\nSend multiple respiratory samples (3 deep cough sputum samples, preferably including 1 early morning sample) for TB microscopy and culture. \n\nThis should be before starting treatment if possible or, failing that, within 7\xa0days of starting treatment in people with life‑threatening disease. [2006, amended 2016]\n\nObtain spontaneously‑produced, deep cough sputum samples if possible, otherwise use:\n\n\n\ngastric lavages or 3 inductions of sputum in children and young people (see recommendation 1.5.1.10 in the section on infection control in healthcare settings) [new 2016] or\n\ninduction of sputum or bronchoscopy and lavage in adults. [2006, amended 2016]\n\n\n\nLaboratory practices should be in accordance with the UK's Standards for Microbiology Investigations. [new 2016]\n\nSend samples for TB culture from autopsy samples if pulmonary or laryngeal TB is a possibility. [2006, amended 2016]\n\n## Diagnosing pulmonary (including laryngeal) TB in adults\n\nRequest rapid diagnostic nucleic acid amplification tests for the M.\xa0tuberculosis complex (M.\xa0tuberculosis, M.\xa0bovis, M.\xa0africanum) on primary specimens (listed in table\xa01) if there is clinical suspicion of TB disease, and:\n\nthe person has HIV or\n\nrapid information about mycobacterial species would alter the person's care or\n\nthe need for a large contact‑tracing initiative is being explored. [new 2016]\n\n## Diagnosing pulmonary (including laryngeal) TB in children and young people\n\nIn children aged 15\xa0years or younger with suspected pulmonary TB, offer rapid diagnostic nucleic acid amplification tests for the M.\xa0tuberculosis complex (M.\xa0tuberculosis, M.\xa0bovis, M.\xa0africanum). Usually only 1 nucleic acid amplification test is needed per specimen type (for example, spontaneous sputum, induced sputum or gastric lavage; see table\xa01). [new 2016]\n\nIn young people aged 16 to 18\xa0years use the same criteria as in adults to decide whether to request rapid diagnostic nucleic acid amplification tests (see table\xa01). [new 2016]\n\nSuspected site of disease\n\nPossible\xa0imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional tests (if it would alter management)\n\nPulmonary (adult)\n\nX‑ray (Routine test, see recommendation 1.3.2.1.)\n\nCT thoraxTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nrespiratory samples:\n\npreferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or bronchoscopy and lavage\n\npreferably 1\xa0early morning sample\n\nMicroscopy Culture\n\nHistology\n\nNucleic acid amplification test\n\nPulmonary (young people aged 16 to 17\xa0years)\n\nX‑ray (Routine test, see recommendation 1.3.2.1.)\n\nCT thoraxTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nrespiratory samples:\n\npreferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or gastric lavage\n\npreferably 1\xa0early morning sample\n\nMicroscopy Culture\n\nHistology\n\nNucleic acid amplification test\n\nPulmonary (children aged 15\xa0years or younger)\n\nX‑ray (Routine test, see recommendation 1.3.2.1.)\n\nCT thoraxTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nrespiratory samples:\n\npreferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or gastric lavage\n\npreferably 1\xa0early morning sample\n\nMicroscopy\n\nCulture\n\nHistology\n\nNucleic acid amplification tests (1\xa0per specimen type)\n\nInterferon‑gamma release assay and/or tuberculin skin test (with expert input)\n\nEither a paediatrician with experience and training in TB or a general paediatrician with advice from a specialised clinician should investigate and manage TB in children and young people. [new 2016]\n\nAn expert in paediatric TB may request interferon‑gamma release assays and tuberculin skin tests. Interpret these together with other diagnostic tools (such as history taking, clinical examination and imaging). [new 2016]\n\n## Diagnosing extrapulmonary TB in all age groups\n\nDiscuss the advantages and disadvantages of both biopsy and needle aspiration with the patient, with the aim of obtaining adequate material for diagnosis. \n\nDo not place part or all of any of the samples in formalin (or other fixative agent) when sending for TB culture. [2006, amended 2016]\n\nThink about a diagnosis of extrapulmonary TB even if rapid diagnostic tests in, for example, cerebrospinal fluid, pleural fluid or ascitic fluid are negative. [new 2016]\n\nOffer all patients presenting with extrapulmonary TB a chest X‑ray and, if possible, culture of a spontaneously‑produced respiratory sample to exclude or confirm coexisting pulmonary TB (see\xa0recommendations 1.3.1 to 1.3.3 in the section on active TB). Also, consider site‑specific tests as described below to exclude or confirm additional sites of TB. [new 2016]\n\nRefer to an expert for sites not listed here, including TB of the eye and other rare sites of disease. [new 2016]\n\nUse the site‑specific investigations listed in table\xa02 to diagnose and assess pleural TB.\n\nSuspected site of disease\n\nPossible imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional tests on primary specimen (if it would alter management)\n\nPleural\n\nX‑ray\n\nBronchoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nrespiratory samples:\n\npreferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or gastric lavage\n\npreferably 1\xa0early morning sample\n\nPleural biopsy\n\nMicroscopy\n\nCulture\n\nHistology\n\n-\n\nPleural\n\nX‑ray\n\nBronchoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nPleural fluid\n\nMicroscopy\n\nCulture\n\nCytology\n\nAdenosine deaminase assay\n\n[new 2016]\n\nUse the site‑specific investigations listed in table\xa03 to diagnose and assess central nervous system TB.\n\nSuspected site of disease\n\nPossible imaging techniquesa\n\nSpecimen\n\nRoutine test\n\nAdditional tests on primary specimen (if it would alter management)\n\nCentral nervous system\n\nCT (Routine test, see recommendation 1.3.5.8)\n\nMRI (Routine test, see recommendation 1.3.5.8)Taking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nBiopsy of suspected tuberculoma\n\nMicroscopy\n\nCulture\n\nHistology\n\n-\n\nCentral nervous system\n\nCT (Routine test, see recommendation 1.3.5.8)\n\nMRI (Routine test, see recommendation 1.3.5.8)Taking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nCerebrospinal fluid\n\nMicroscopy\n\nCulture\n\nCytology\n\nAdenosine deaminase assay\n\nMeningeal\n\nCT (Routine test, see recommendation 1.3.5.8)\n\nMRI (Routine test, see recommendation 1.3.5.8)Taking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nCerebrospinal fluid\n\nMicroscopy\n\nCulture\n\nCytology\n\nNucleic acid amplification test\n\nAdenosine deaminase assay\n\n[new 2016]\n\nOffer a CT or MRI scan to people in whom central nervous system involvement is suspected. \n\nOffer treatment for TB meningitis if clinical signs and other laboratory findings are consistent with the diagnosis, even if a rapid diagnostic test is negative. [new 2016]\n\nUse the site‑specific investigations listed in table\xa04 to diagnose and assess lymph node TB (including intrathoracic mediastinal adenopathy).\n\nSuspected site of disease\n\nPossible imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional tests on primary specimen (if it would alter management)\n\nLymph node (including intrathoracic mediastinal adenopathy)\n\nUltrasound\n\nCT\n\nMRITaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nBiopsy\n\nMicroscopy\n\nCulture\n\nHistology\n\nNucleic acid amplification test\n\nAspirate\n\nMicroscopy\n\nCulture\n\nCytology\n\nNucleic acid amplification test\n\n[new 2016]\n\nUse the site‑specific investigations listed in table\xa05 to diagnose and assess pericardial TB.\n\nSuspected site of disease\n\nPossible imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional tests on primary specimen (if it would alter management)\n\nPericardial\n\nEchocardiogramTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nBiopsy of pericardium\n\nMicroscopy\n\nCulture\n\nHistology\n\n-\n\nPericardial\n\nEchocardiogramTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nPericardial fluid\n\nMicroscopy\n\nCulture\n\nCytology\n\nNucleic acid amplification test\n\nAdenosine deaminase assay\n\n[new 2016]\n\nUse the site‑specific investigations listed in table\xa06 to diagnose and assess gastrointestinal TB.\n\nSuspected site of disease\n\nPossible imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional tests on primary specimen (if it would alter management)\n\nGastrointestinal\n\nUltrasound\n\nCT\n\nLaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nBiopsy of omentum\n\nBiopsy of bowel\n\nBiopsy of liver\n\nMicroscopy\n\nCulture\n\nHistology\n\n-\n\nGastrointestinal\n\nUltrasound\n\nCT\n\nLaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nAscitic fluid\n\nMicroscopy\n\nCulture\n\nCytology\n\nAdenosine deaminase assay\n\n[new 2016]\n\nUse the site‑specific investigations listed in table\xa07 to diagnose and assess genitourinary TB.\n\nSuspected site of disease\n\nPossible imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional tests on primary specimen (if it would alter management)\n\nGenitourinary\n\nUltrasound\n\nIntravenous urography\n\nLaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nEarly morning urine\n\nCulture\n\n-\n\nGenitourinary\n\nUltrasound\n\nIntravenous urography\n\nLaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nBiopsy from site of disease, such as endometrial curettings or renal biopsy\n\nMicroscopy\n\nCulture\n\nHistology\n\n-\n\n[new 2016]\n\nUse the site‑specific investigations listed in table\xa08 to diagnose and assess bone and joint TB.\n\n\n\nSuspected site of disease\n\nPossible imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional test on primary specimen (if it would alter management)\n\nBone or joint TB\n\nX‑ray\n\nCT\n\nMRITaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment\n\nBiopsy or aspirate of paraspinal abscess\n\nBiopsy of joint\n\nAspiration of joint fluid\n\nCulture\n\n-\n\n[new 2016]\n\nUse the site‑specific investigations listed in table\xa09 to diagnose and assess disseminated TB.\n\nSuspected site of disease\n\nPossible\xa0imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional tests on primary specimen (if it would alter management)\n\nDisseminated\n\nCT of the thorax and head\n\nMRI\n\nUltrasound of the abdomenTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nBiopsy of site of disease, including lung, liver and bone marrow\n\nMicroscopy\n\nCulture\n\nHistology\n\nAdditional tests appropriate to site\n\nDisseminated\n\nCT of the thorax and head\n\nMRI\n\nUltrasound of the abdomenTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nAspirate bone marrow\n\nBronchial wash\n\nCerebrospinal fluid\n\nMicroscopy (if sample available)\n\nCulture\n\nCytology\n\nAdditional tests appropriate to site\n\nDisseminated\n\nCT of the thorax and head\n\nMRI\n\nUltrasound of the abdomenTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\n\nBlood\n\nCulture\n\nAdditional tests appropriate to site\n\n[new 2016]\n\nUse the site‑specific investigations listed in table\xa010 to diagnose and assess skin TB.\n\nSuspected site of disease\n\nPossible imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional tests on primary specimen (if it would alter management)\n\nSkin\n\n‑\n\nBiopsy\n\nMicroscopy\n\nCulture\n\nHistology\n\n‑\n\n\n\nUse the site‑specific investigations listed in table\xa011 to diagnose and assess TB in a localised, tuberculous abscess at a site other than a lymph node.\n\nSuspected site of disease\n\nPossible imaging techniques\n\nSpecimen\n\nRoutine test\n\nAdditional tests on primary specimen (if it would alter management)\n\nAbscess outside of the lymph nodes\n\nUltrasound or other appropriate imagingTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment\n\nAspirate\n\nMicroscopy\n\nCulture\n\nCytology\n\n-\n\nAbscess outside of the lymph nodes\n\nUltrasound or other appropriate imagingTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment\n\nBiopsy\n\nMicroscopy\n\nCulture\n\nHistology\n\n-\n\n\n\n## Rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process\n\nLocal hospitals, clinical commissioning groups and the local multidisciplinary team should consider developing a local pathway for people with imaging highly suggestive of active TB. The pathway should enable them to be referred by the radiology department by the next working day to multidisciplinary TB teams. Consider including the following in the pathway:\n\nAgreed standardised radiology codes to identify imaging investigations highly suggestive of active TB.\n\nRegular liaison between multidisciplinary TB teams and the radiology department (for example, weekly) to ensure all patients have been referred to the multidisciplinary team for triage using the agreed local mechanism or pathway. [new 2016]\n\nReport results of all pathology or other diagnostic results suggesting TB to the multidisciplinary TB team and clinicians who ask for them. [new 2016]\n\nCommissioners and multidisciplinary teams should consider working with emergency departments to develop direct referral pathways for people with suspected active TB so that:\n\nthe local multidisciplinary team is informed of all suspected cases of TB using the appropriate process\n\nreferral is accepted from any appropriate healthcare professional, for example an on‑call radiologist. [new 2016]\n\nEmergency department clinicians should ensure first‑line diagnostic tests for TB are performed on anyone presenting with suspected TB (see table\xa01 on diagnostic investigations for pulmonary TB). [new 2016]\n\nEmergency departments should consider carrying out audits of their direct referrals because of suspected active TB and the outcomes of diagnosis. [new 2016]\n\nMultidisciplinary TB teams should consider training emergency department staff in:\n\nusing approaches that do not stigmatise people with TB\n\ngiving people with TB appropriate advice (see recommendations 1.1.1 and 1.1.2 in the section on raising and sustaining awareness of TB and the section on infection control). [new 2016]\n\n## Managing active TB in all age groups\n\nOnce a diagnosis of active TB is made:\n\nthe clinician responsible for care should refer the person with TB to a clinician with training in, and experience of, the specialised care of people with TB\n\nthe TB service should include specialised nurses and health visitors\n\nactive TB in children should be managed by a TB specialist (see recommendation 1.3.4.3 in the section on diagnosing pulmonary (including laryngeal) TB in children and young people), and by paediatric trained nursing staff, where possible.If these arrangements are not possible, seek advice from more specialised colleagues throughout the treatment period. \n\nFor people with active TB without central nervous system involvement, offer:\n\nisoniazid (with pyridoxine), rifampicin, pyrazinamide and ethambutol for 2\xa0months then\n\nisoniazid (with pyridoxine) and rifampicin for a further 4\xa0months.Modify the treatment regimen according to drug susceptibility testing. \n\nFor people with active TB of the central nervous system, offer:\n\nisoniazid (with pyridoxine), rifampicin, pyrazinamide and ethambutol for 2\xa0months then\n\nisoniazid (with pyridoxine) and rifampicin for a further 10\xa0months.Modify the treatment regimen according to drug susceptibility testing. \n\nTest people with active spinal TB who have neurological signs or symptoms for central nervous system involvement (see recommendation 1.3.5.8 in the section on central nervous system TB). Manage direct spinal cord involvement (for example, a spinal cord tuberculoma) as TB of the central nervous system. \n\nFor people with active spinal TB without central nervous system involvement, do not extend treatment beyond 6\xa0months for residual effects (for example, persistent bending of the spine or vertebral loss). \n\nTest people with disseminated (including miliary) TB who have neurological signs or symptoms for central nervous system involvement. If there is evidence of central nervous system involvement, treat as for TB of the central nervous system. \n\nTreat active peripheral lymph node TB in people who have had an affected gland surgically removed with the standard recommended regimen. [new 2016]\n\nFor people with active TB of the lymph nodes, do not routinely extend treatment beyond 6\xa0months for newly enlarged lymph nodes or sinus formation, or for residual enlargement of the lymph nodes or sinuses. [new 2016]\n\nUse fixed‑dose combination tablets as part of any TB treatment regimen. \n\nDo not offer anti‑TB treatment dosing regimens of fewer than 3\xa0times per week. [2006, amended 2016]\n\nOffer a daily dosing schedule to people with active pulmonary TB. [2006, amended 2016]\n\nConsider a daily dosing schedule as first choice in people with active extrapulmonary TB. [2006, amended 2016]\n\nConsider 3\xa0times weekly dosing for people with active TB only if:\n\na risk assessment identifies a need for directly observed therapy and enhanced case management (see section on adherence, treatment completion and follow‑up) and\n\ndaily directly observed therapy is not possible. [2006, amended 2016]\n\nIf the person has a comorbidity or coexisting condition such as:\n\nHIV or\n\nsevere liver disease, for example, Child‑Pugh level\xa0B or\xa0C or\n\nstage\xa04\xa0or\xa05 chronic kidney disease (a glomerular filtration rate of <30\xa0ml/minute/1.73m2) or\n\ndiabetes or\n\neye disease or impaired vision or\n\npregnancy or breastfeeding or\n\na history of alcohol or substance misusework with a specialist multidisciplinary team with experience of managing TB and the comorbidity or coexisting condition. [new 2016]\n\nFor people with HIV and active TB without central nervous system involvement, do not routinely extend treatment beyond 6\xa0months. [new 2016]\n\nFor people with HIV and active TB with central nervous system involvement, do not routinely extend treatment beyond 12\xa0months. [new 2016]\n\nTake into account drug‑to‑drug interactions when co‑prescribing antiretroviral and anti‑TB drugs. [new 2016]\n\nAt the start of an anti‑TB treatment regimen, offer people with active TB of the central nervous system dexamethasone or prednisolone, initially at a high dose with gradual withdrawal over 4 to 8\xa0weeks. An example of a suitable regimen is listed in table\xa012.\n\nDose of dexamethasone by week\n\nStage 1\n\nStage 2 or 3\n\nWeek 1\n\nmg/kg/day (intravenous)\n\nmg/kg/day (intravenous)\n\nWeek 2\n\nmg/kg/day (intravenous)\n\nmg/kg/day (intravenous)\n\nWeek 3\n\nmg/kg/day (oral)\n\nmg/kg/day (intravenous)\n\nWeek 4\n\nmg/day (oral)\n\nmg/kg/day (intravenous)\n\nWeek 5\n\nmg/day (oral)\n\nmg/day (oral)\n\nWeek 6\n\nmg/day (oral)\n\nmg/day (oral)\n\nWeek 7\n\n-\n\nmg/day (oral)\n\nWeek 8\n\n-\n\nmg/day (oral)\n\nAccording to the modified British Medical Research Council criteria for disease severity:\n\nStage 1: Glasgow coma score of 15 without focal neurological deficits; alert and oriented.\n\nStage 2: Glasgow coma score of 14 to 11 or 15 with focal neurological deficits.\n\nStage 3: Glasgow coma score of 10 or less, with or without focal neurological deficits.\n\n[new 2016]\n\nAt the start of an anti‑TB treatment regimen, offer children and young people with active TB of the central nervous system dexamethasone or prednisolone. This should initially be at a high dose with gradual withdrawal over 4 to 8\xa0weeks in line with the British National Formulary for Children. [new 2016]\n\nAt the start of an anti‑TB treatment regimen, offer adults with active pericardial TB oral prednisolone at a starting dose of 60\xa0mg/day, gradually withdrawing it 2 to 3\xa0weeks after starting treatment. \n\nAt the start of an anti‑TB treatment regimen, offer children and young people with active pericardial TB oral prednisolone in line with the British National Formulary for Children. Gradually withdraw prednisolone 2 to 3\xa0weeks after starting treatment. \n\nIf surgery is indicated, the surgeon should fully explain what is involved to the person, either with or after consulting a TB specialist. Discuss the possible benefits and risks with the person and their family members or carers, as appropriate, so that they can make an informed decision. [new 2016]\n\nConsider referring people with TB of the central nervous system for surgery as a therapeutic intervention only if there is evidence of raised intracranial pressure. [new 2016]\n\nDo not routinely refer people with spinal TB for surgery to eradicate the disease. [new 2016]\n\nConsider referring people with spinal TB for surgery if there is spinal instability or evidence of spinal cord compression. [new 2016]\n\n# Drug resistant TB\n\n## Multidrug‑resistant TB\n\nFor people with clinically suspected TB, a TB specialist should request rapid diagnostic nucleic acid amplification tests for rifampicin resistance on primary specimens if a risk assessment for multidrug resistance identifies any of the following risk factors:\n\nhistory of previous TB drug treatment, particularly if there was known to be poor adherence to that treatment\n\ncontact with a known case of multidrug-resistant TB\n\nbirth or residence in a country in which the World Health Organization reports that a high proportion (5% or more) of new TB cases are multidrug‑resistant.Start infection control measures (see section\xa01.5). [new 2016]\n\nIf the rapid diagnostic nucleic acid amplification test for rifampicin resistance is positive:\n\ncontinue infection control measures until pulmonary or laryngeal disease has been excluded\n\nmanage treatment along with a multidisciplinary team with experience of managing multidrug‑resistant TB (see the section on service organisation)\n\noffer a treatment regimen involving at least 6\xa0drugs to which the mycobacterium is likely to be sensitive\n\ntest for resistance to second‑line drugs. [new 2016]\n\nIf the rapid diagnostic nucleic acid amplification test for the M.\xa0tuberculosis complex is positive but rifampicin resistance is not detected, treat as drug‑susceptible TB with the standard regimen (see the section on managing active TB in all age groups). [new 2016]\n\nIf the rapid diagnostic nucleic acid amplification test for the M.\xa0tuberculosis complex is negative in a person at high risk of multidrug‑resistant TB:\n\nobtain further specimens for nucleic acid amplification testing and culture, if possible\n\nuse rapid rifampicin resistance detection on cultures that become positive for the M.\xa0tuberculosis complex\n\nconsider waiting for the results of further tests before starting treatment if the person is well\n\nif urgent treatment is needed, consider managing as multidrug‑resistant TB until sensitivity results are available. [new 2016]\n\nWhen definitive phenotypic susceptibility results are available, modify treatment as needed (see sections on managing active TB in all age groups and drug‑resistant TB). [new 2016]\n\nConsider more intensive clinical follow‑up for people with multidrug‑resistant TB. This includes people having directly observed therapy (see the section on adherence, treatment completion and follow‑up) throughout treatment because of the complexity of treatment and risk of adverse events. [new 2016]\n\nDiscuss the options for organising care for people with multidrug‑resistant TB with clinicians who specialise in this. Seek the person's views and take them into account, and consider shared care (see the section on service organisation). \n\nConsider surgery as a therapeutic intervention in people with potentially resectable multidrug‑resistant disease if:\n\noptimal medical therapy under direct observation has not worked or\n\nmedical therapy is likely to fail because of extensively drug-resistant TB. [new 2016]\n\n## Drug‑resistant TB (excluding multidrug‑ and extensively drug‑resistant TB)\n\nFor people with TB, without central nervous system involvement, that is resistant to just 1\xa0drug consider the treatments in table\xa013.\n\nDrug resistance\n\nFirst 2\xa0months (initial phase)\n\nContinue with (continuation phase)\n\nIsoniazid\n\nRifampicin, pyrazinamide and ethambutol\n\nRifampicin and ethambutol for 7\xa0months (up to 10\xa0months for extensive disease)\n\nPyrazinamide\n\nRifampicin, isoniazid (with pyridoxine) and ethambutol\n\nRifampicin and isoniazid (with pyridoxine) for 7\xa0months\n\nEthambutol\n\nRifampicin, isoniazid (with pyridoxine) and pyrazinamide\n\nRifampicin and isoniazid (with pyridoxine) for 4\xa0months\n\nRifampicin\n\nAs for multidrug‑resistant TB\n\nAs for multidrug‑resistant TB\n\n[new 2016]\n\nFor people with drug‑resistant TB and central nervous system involvement, involve a TB specialist with experience in managing drug‑resistant TB in decisions about the most appropriate regimen and the duration of treatment. [new 2016]\n\n# Infection control\n\nNICE has also produced general guidelines on the prevention and control of healthcare-associated infections in primary and community care, and the prevention and control of healthcare-associated infections.\n\n## Healthcare settings\n\nEnsure healthcare settings can promptly identify people with suspected infectious or confirmed pulmonary or laryngeal TB before or at presentation. Ensure people working in the settings follow the recommendations about testing and treatments (see the sections on latent TB, active TB and drug resistant TB). [new 2016]\n\nPut people with suspected infectious or confirmed pulmonary or laryngeal TB who will remain in a hospital setting (including emergency, outpatients or inpatient care) in a single room. If this is not possible, keep the person's waiting times to a minimum. This may involve prioritising their care above that of other patients. [new 2016]\n\nMinimise the number and duration of visits a person with TB makes to an outpatient department while they are still infectious. To minimise the risk of infection, people with infectious TB should be seen at times or in places away from other people. [new 2016]\n\nIn hospital settings, risk assess people with suspected infectious or confirmed pulmonary TB for multidrug‑resistant TB (see the section on multidrug‑resistant TB). Care for people deemed to be at low risk in a single room, as a minimum. For people deemed to be at high risk:\n\nprovide care in a negative pressure room and\n\nhave specimens sent for rapid diagnostic tests, such as nucleic acid amplification tests. [new 2016]\n\nUnless there is a clear clinical or public health need, such as homelessness, people with suspected infectious or confirmed pulmonary TB should not be admitted to hospital for diagnostic tests or for care. [2006, amended 2016]\n\nDo not admit people with suspected infectious or confirmed pulmonary TB to a ward containing people who are immunocompromised, such as transplant recipients, people with HIV and those on anti‑tumour necrosis factor alpha or other biologics, unless they can be cared for in a negative pressure room on the same ward. [new 2016]\n\nAssess any visitors to a child with suspected active TB in hospital for symptoms of infectious TB, and keep them separate from other people until they have been excluded as a source of infection (see recommendations 1.2.1 to 1.2.3 in the section on latent TB and the section on contact tracing). [new 2016]\n\nCare for people with a continuing clinical or public health need for admission with pulmonary TB in a single room (as a minimum) until they have completed 2\xa0weeks of the standard treatment regimen (see the section on managing active TB in all age groups) if they:\n\nare unlikely to be rifampicin resistant (that is, do not have risk factors for multidrug‑resistant TB) or\n\nhave negative rifampicin resistance on nucleic acid amplification test or culture. [new 2016]\n\nConsider de‑escalating isolation after 2\xa0weeks of treatment, taking into account the risks and benefits, if:\n\nthe person is showing tolerance to the prescribed treatment\n\nthere is agreement to adhere to treatment\n\nthere is resolution of cough\n\nthere is definite clinical improvement on treatment; for example, remaining afebrile for a week\n\nthere are not immunocompromised people, such as transplant recipients, people with HIV and those on anti‑tumour necrosis factor alpha or other biologics, in the same accommodation\n\nthe person's initial smear grade was not high; for example, 2\xa0or\xa0less\n\nthere is not extensive pulmonary involvement, including cavitation\n\nthere is no laryngeal TB. [new 2016]\n\nIn people who may have TB, only carry out aerosol‑generating procedures such as bronchoscopy, sputum induction or nebuliser treatment in an appropriately engineered and ventilated area (ideally a negative pressure room). [new 2016]\n\nConsider discharging from hospital people:\n\nwho do not have a continuing clinical or public health need for admission with pulmonary TB and\n\nwho are unlikely to be rifampicin resistant (that is, do not have risk factors for multidrug‑resistant TB) or\n\nwho have negative rifampicin resistance on nucleic acid amplification test or culture.If discharged, the person should avoid congregate settings for the first 2\xa0weeks of their treatment. [new 2016]\n\nExplain to inpatients with suspected infectious or confirmed pulmonary or laryngeal TB that they will need to wear a surgical mask in the hospital whenever they leave their room. Ask them to continue wearing it until they have had at least 2\xa0weeks of treatment. \n\nOffer people advice on simple respiratory hygiene measures. [new 2016]\n\n## Non‑healthcare settings\n\nIn non‑healthcare settings catering for large numbers of people and populations at high risk of TB (such as detention settings, residential hostels and day centres):\n\npromote simple respiratory hygiene\n\nensure awareness of symptoms of potentially infectious TB to enable prompt healthcare referral\n\nwork with the local public health team and the local authority to ensure accommodation for people with TB\n\nensure adequate ventilation. [new 2016]\n\nIn prisons or immigration removal centres, everyone with X‑ray changes indicative of active TB, as well as those with symptoms who are awaiting X‑ray, should be isolated in an adequately ventilated individual room or cell. Prisoners and detainees should be retained on medical hold until they have:\n\nproven smear‑negative and had an X‑ray that does not suggest active TB or\n\nhad a negative risk assessment for multidrug‑resistant TB and completed 2\xa0weeks of the standard treatment regimen. [2012, amended 2016]\n\n## Multidrug‑resistant TB\n\nIf people with suspected or known infectious multidrug‑resistant TB are admitted to hospital, admit them to a negative pressure room. If none is available locally, transfer them to a hospital that has these facilities and a clinician experienced in managing complex drug‑resistant cases. Carry out care in a negative pressure room for people with:\n\nsuspected multidrug‑resistant TB, until non‑resistance is confirmed\n\nconfirmed multidrug‑resistant TB, until they have 3 negative smears at weekly intervals and ideally have a negative culture. [new 2016]\n\nAs soon as possible, explore options to reduce the psychosocial impact of prolonged isolation. For example, through providing free access to internet, telephone and television, and accompanied walks in the open air. [new 2016]\n\nConsider earlier discharge for people with confirmed multidrug‑resistant TB, if there are suitable facilities for home isolation and the person will adhere to the care plan. [new 2016]\n\nFor people with confirmed multidrug‑resistant TB whose symptoms have improved and who are unable to produce sputum, discharge decisions should be taken by the multidisciplinary team and the health protection team. [new 2016]\n\nStaff and visitors should wear filtering face piece (FFP3) masks during contact with a person with suspected or known multidrug‑resistant TB while the person is thought to be infectious. \n\nBefore deciding to discharge a person with suspected or known multidrug‑resistant TB from hospital, agree with the person and their carers secure arrangements for supervising and administering all anti‑TB therapy. \n\nDiscuss the decision to discharge a person with suspected or known multidrug‑resistant TB with:\n\nthe infection control team and\n\nthe local microbiologist and\n\nthe local TB service and\n\nthe health protection team. \n\nEnsure negative pressure rooms used for infection control in multidrug‑resistant TB meet the standards of the Interdepartmental Working Group on Tuberculosis, and are clearly identified for staff, for example by a standard sign. Keep such signs up to date. \n\n# Case finding\n\n## Contact tracing\n\nOnce a person has been diagnosed with active TB, the diagnosing physician should inform relevant colleagues so that the need for contact tracing can be assessed without delay. Contact tracing should not be delayed until notification. \n\nOffer screening to the close contacts of any person with pulmonary or laryngeal TB. [2006, amended 2016]\n\nAssess symptomatic close contacts for active TB (see recommendations 1.3.1 to 1.3.4 in the section on active TB). [new 2016]\n\nIn asymptomatic close contacts younger than 65\xa0years, consider standard testing for latent TB (see recommendations 1.2.1 to 1.2.3 in the section on latent TB), followed by consideration of BCG vaccination in line with the section on BCG vaccination or treatment for latent TB infection (see recommendations 1.2.4 to 1.2.6 in the section on latent TB) once active TB has been ruled out for people who:\n\nare previously unvaccinated and\n\nare contacts of a person with smear‑positive pulmonary or laryngeal TB and\n\nare Mantoux‑negative.At the time of publication (January 2016) the BNF states: 'The Mantoux test is recommended for tuberculin skin testing, but no licensed preparation is currently available.' For further guidance, see immunisation against infectious disease (the Green book). [2006, amended 2016]\n\nIn asymptomatic close contacts older than 65\xa0years, consider a chest X‑ray (if there are no contraindications), possibly leading to further investigation for active TB. [2006, amended 2016]\n\nDo not routinely assess social contacts of people with TB, who will include most workplace contacts. [2006, amended 2016]\n\nAssess the need for tracing social contacts of people with pulmonary or laryngeal TB if:\n\nthe index case is judged to be particularly infectious (for example, evidenced by transmission to close contacts) or\n\nany social contacts are known to possess features that put them at high risk of going on to develop active TB. [2006, amended 2016]\n\nOffer 'inform and advise' information to close and social contacts of people with smear‑positive TB (see section on providing information for the public about TB). \n\nAfter diagnosis of TB in an aircraft traveller, do not routinely carry out contact tracing of fellow passengers. [2006, amended 2016]\n\nThe notifying clinician should inform the relevant consultant in communicable disease control or health protection if:\n\nless than 3\xa0months has elapsed since the flight and the flight was longer than 8\xa0hours and\n\nthe index case is smear‑positive and either\n\n\n\nthe index case has multidrug‑resistant TB or\n\nthe index case coughed frequently during the flight. \n\n\n\nThe consultant in communicable disease control or health protection should provide the airline with 'inform and advise' information to send to passengers seated in the same part of the aircraft as the index case. [2006, amended 2016]\n\nIf the TB index case is an aircraft crew member, contact tracing of passengers should not routinely take place. \n\nIf the TB index case is an aircraft crew member, contact tracing of other members of staff is appropriate, in accordance with the usual principles for screening workplace colleagues. \n\nAfter diagnosis of TB in a school pupil or member of staff, the consultant in communicable disease control or health protection should be prepared to explain the prevention and control procedures to staff, parents and the press. Advice on managing these incidents and their public relations is available from the Public Health England health protection team and the local authority. [2006, amended 2016]\n\nIf a school pupil is diagnosed with smear‑positive TB, carry out a risk assessment of the need to test the rest of his or her class (if there is a single class group), or the rest of the year group who share classes, as part of contact tracing. \n\nIf a teacher has smear‑positive TB, assess the pupils in his or her classes during the preceding 3\xa0months as part of contact tracing. \n\nConsider extending contact tracing in schools to include children and teachers involved in extracurricular activities, and non‑teaching staff, on the basis of:\n\nthe degree of infectivity of the index case\n\nthe length of time the index case was in contact with others\n\nwhether contacts are unusually susceptible to infection\n\nthe proximity of contact. [2006, amended 2016]\n\nTreat secondary cases of smear‑positive TB as index cases for contact tracing. \n\nIf the index case of a school pupil's TB infection is not found, and the child is not in a high‑risk group for TB, contact tracing and screening (by either symptom enquiry or chest X‑ray) should be considered for all relevant members of staff at the school. \n\nWhen an adult who works in childcare (including people who provide childcare informally) is diagnosed with smear‑positive TB, follow recommendations 1.6.1.1 to 1.6.1.8. [2006, amended 2016]\n\nIf TB is diagnosed in a hospital inpatient, do a risk assessment. This should take into account:\n\nthe degree of infectivity of the index case\n\nthe length of time before the infectious patient was isolated\n\nwhether other patients are unusually susceptible to infection\n\nthe proximity of contact. [2006, amended 2016]\n\nCarry out contact tracing and testing only for patients for whom the risk is regarded as significant. \n\nRegard patients as at risk of infection if they spent more than 8\xa0hours in the same bay as an inpatient with smear‑positive TB who had a cough. Document the risk in the contact's clinical notes, for the attention of the contact's consultant. Give the contact 'inform and advise' information, and inform their GP. \n\nIf patients were exposed to a patient with smear‑positive TB for long enough to be equivalent to close contacts (as determined by the risk assessment), or an exposed patient is known to be particularly susceptible to infection, manage their TB risk in the same way as close contacts. [2006, amended 2016]\n\nIf an inpatient with smear‑positive TB is found to have multidrug‑resistant TB, or if exposed patients are HIV positive, trace contacts following the Interdepartmental Working Group on Tuberculosis guidelines. \n\nIn cases of doubt when planning contact tracing after diagnosing smear‑positive TB in an inpatient, seek further advice from the local or national Public Health England or Wales unit or people experienced in the field. [2006, amended 2016]\n\n## Opportunistic case finding\n\nAssess and manage TB in new entrants from high incidence countries who present to healthcare services as follows:\n\nassess risk of HIV, including HIV prevalence rates in the country of origin, and take this into account when deciding whether to give a BCG vaccination\n\noffer testing for latent TB (see recommendations 1.2.1 to 1.2.3 in the section on latent TB)\n\nassess for active TB if the test for latent TB is positive (see recommendations 1.3.1 to 1.3.5 in the section on active TB)\n\noffer treatment to people aged 65\xa0years or younger in whom active TB has been excluded but who have a positive Mantoux test or a positive interferon‑gamma release assay for latent TB infection (see recommendations 1.2.4 to 1.2.6 in the section on latent TB)\n\nconsider offering BCG for unvaccinated people who are Mantoux‑ or interferon‑gamma release assay‑negative (see the section on BCG vaccination)\n\ngive 'inform and advise' information to people who do not have active TB and are not being offered BCG or treatment for latent TB infection (see the section on providing information for the public about TB). [2006, amended 2011 and 2016]\n\nPrimary care services should support local, community‑based and voluntary organisations that work with vulnerable migrants to ensure they:\n\nregister with a primary care provider\n\nknow how to use NHS services (emergency or primary care). \n\nHealthcare professionals, including primary care staff, responsible for testing new entrants should test all vulnerable migrants who have not previously been checked. This is regardless of when they arrived in England. People born in countries with an incidence of more than 150\xa0per\xa0100,000 per year should be made a priority for latent TB testing when they arrive here. [2012, amended 2016]\n\nIn areas of identified need (see the section on local needs assessment), including major urban centres with a high incidence of TB, commissioners should:\n\nensure there is a programme of active case‑finding using mobile X‑ray in places where homeless people and people who misuse substances congregate (this includes: homeless day centres, rolling shelters, hostels and temporary shelters established as part of cold weather initiatives and venues housing needle and syringe programmes)\n\nbase the frequency of screening at any 1 location on population turnover\n\nwhere local demand does not warrant a mobile X‑ray team, consider commissioning mobile X‑ray capacity from another area. [2006, amended 2012]\n\nMultidisciplinary TB teams should consider using simple incentives, such as providing hot drinks and snacks, to encourage people to attend for testing. [2006, amended 2012, amended 2016]\n\nCommissioners of TB prevention and control programmes should consider offering people who are homeless and people who misuse substances other health interventions when they are screened for TB at a mobile X‑ray unit. (Examples may include blood‑borne virus screening, dentistry and podiatry services.) \n\nMultidisciplinary TB teams should work closely with mobile X‑ray teams and frontline staff in hostels and day centres to promote TB screening and to ensure appropriate onward referrals and follow‑up. \n\nMultidisciplinary TB teams should consider using peer educators to promote the uptake of TB screening in hostels and day centres. \n\nMultidisciplinary TB teams should provide routine data to TB control boards on: screening uptake, referrals and the number of active TB cases identified. \n\nHealthcare professionals in prisons and immigration removal centres should ensure prisoners and detainees are screened for TB within 48\xa0hours of arrival. \n\nPrisons with Department of Health‑funded static digital X‑ray facilities for TB screening should X‑ray all new prisoners and detainees (including those being transferred from other establishments) if they have not had a chest X‑ray in the past 6\xa0months. This should take place within 48\xa0hours of arrival. \n\nPrison and immigration removal centre health staff should report all suspected and confirmed TB cases to the local multidisciplinary TB team within 1 working day. \n\nMultidisciplinary TB staff should visit every confirmed TB case in a prison or immigration removal centre in their locality within 5 working days. \n\nIf a case of active TB is identified, the local Public Health England unit, in conjunction with the multidisciplinary TB team, should plan a contact investigations exercise. They should also consider using mobile X‑ray to check for further cases. \n\n## Active case finding in under‑served groups\n\nMultidisciplinary TB teams should follow NICE recommendations on contact tracing (see the section on contact tracing).They should coordinate contact investigations at places where the person with TB spends significant amounts of time. Examples could include pubs, crack houses, parks and community centres. The aim is to help identify people who have been living with them and people they frequently socialise with. \n\nMultidisciplinary TB teams dealing with someone from an under-served group should work alongside health and social care professionals known to them to help trace relevant contacts. They should also work in partnership with voluntary, community and statutory organisations to conduct outreach contact investigations. \n\nMultidisciplinary TB teams should, if available and appropriate, encourage peer educators or TB programme support workers to help with contact investigations involving under‑served people who have complex social networks. \n\nMultidisciplinary TB teams in discussion with local Public Health England health protection teams should consider using digital mobile X‑ray for active case‑finding in settings identified by looking at social networks as places where under‑served people at risk congregate. They should also provide the necessary support so that multidisciplinary TB teams can use strain‑typing and social network analysis to ascertain where transmission is occurring in the community. (Examples of transmission sites may include pubs, crack houses, hostels and day centres.) They should focus on active case‑finding in the settings identified. [2012, amended 2016]\n\n## Incident and outbreak response\n\nMultidisciplinary TB teams should coordinate incident or outbreak contact investigations at places where the person with active TB spends significant amounts of time. Examples include workplaces, schools, colleges, universities, childcare settings. Identify people that the person with TB frequently spends substantial time with, as outlined in the section on contact tracing. [new 2016]\n\nMultidisciplinary TB teams should refer any incident in a congregate setting to the local Public Health England health protection team for risk assessment within 5 working days of suspicion of a potential incident. [new 2016]\n\nTB control boards working with local health protection teams should, through local arrangements, mobilise existing staff or have access to an incident team that will:\n\nundertake an incident risk assessment and provide advice\n\nsupport or undertake contact investigations\n\nprovide information and communication support to the multidisciplinary TB team, the local director of public health, the setting in which the incident has occurred and the people affected including:\n\n\n\nwritten advice, printed or by email\n\nquestion and answer sessions\n\ntelephone advice\n\nmedia engagement\n\n\n\ngather and collate data, and report on outcomes to measure the effectiveness of the investigation (for example, offering testing to all people identified at risk and monitoring uptake)\n\nreport back to TB control boards at appropriate times. This includes when outcomes of initial investigation of people classified as close contacts are available. It also includes when a decision is made to broaden the investigation to the next stage using the concentric circle method for risk assessment. [new 2016]\n\nWhen incidents have been identified, multidisciplinary TB teams in discussion with local Public Health England health protection teams should consider providing support for strain‑typing and other analysis to ascertain where transmission is occurring. (Examples of transmission sites may include workplaces, schools, colleges, universities, childcare settings.) [new 2016]\n\nIn all types of contact investigation scenarios (active case finding, incident or outbreak investigations) multidisciplinary TB teams should investigate all people who have been in contact with children who have pulmonary or extrapulmonary TB to identify the primary source of infection. If necessary, they should look beyond immediate close contacts to find the source. [2012, amended 2016]\n\n# Adherence, treatment completion and follow‑up\n\n## Improving adherence: case management including directly observed therapy\n\nAllocate a named TB case manager to everyone with active TB as soon as possible after diagnosis (and within 5\xa0days). The clinical team should tell each person who their named TB case manager is and provide contact details. [2006, 2012 amended 2016]\n\nThe TB case managers should work with the person diagnosed with TB to develop a health and social care plan, and support them to complete therapy successfully. The TB case manager should:\n\noffer a risk assessment to every person with TB, to identify their needs and whether they should have enhanced case management including directly observed therapy\n\neducate the person about TB and the treatment\n\ndevelop an individual care plan after discussion with the person\n\ngain the person's consent to the plan and agree a review date (for example, when moving from initiation to maintenance, or at each contact to ensure the person's needs are being met)\n\ncoordinate discharge planning, especially for people on directly observed therapy\n\ninvolve representatives from other allied professions and key workers from all organisations who work with the person, if appropriate\n\nexplore appropriate ways that peers and voluntary organisations can provide support. [2006, 2012, amended 2016]\n\nOffer directly observed therapy as part of enhanced case management in people who:\n\ndo not adhere to treatment (or have not in the past)\n\nhave been treated previously for TB\n\nhave a history of homelessness, drug or alcohol misuse\n\nare currently in prison, or have been in the past 5\xa0years\n\nhave a major psychiatric, memory or cognitive disorder\n\nare in denial of the TB diagnosis\n\nhave multidrug‑resistant TB\n\nrequest directly observed therapy after discussion with the clinical team\n\nare too ill to administer the treatment themselves. [2012, amended 2016]\n\nIn children whose parents are members of any of the above groups, offer directly observed therapy as part of enhanced case management and include advice and support for parents to assist with treatment completion. \n\nRe‑evaluate the need for directly observed therapy throughout the course of TB treatment whenever the person's (or in the case of children, parents') circumstances change. [new 2016]\n\nTB case managers should ensure the health and social care plan (particularly if directly observed therapy is needed) identifies why a person may not attend for diagnostic testing or follow a treatment plan, and how they can be encouraged to do so. It should also include ways to address issues such as fear of stigmatisation, support needs and/or cultural beliefs, and may include information on:\n\ndemographics (for example, age, nationality, place of birth, length of time in UK)\n\nall current prescribing regimens\n\nhousing needs and living situation, including looked‑after children\n\nsubstance misuse (drugs or alcohol)\n\nany contact with the criminal justice system\n\nthe need for hepatitis\xa0B and\xa0C or HIV testing (see recommendations 1.2.5.2 and 1.2.5.3 in the section on managing latent TB in adults and recommendation 1.2.6.1 in the section on managing latent TB in children and young people)\n\nHIV status\n\nother health conditions (physical or mental)\n\ncommunication factors (for example, language and literacy levels)\n\nability to access treatment (mobility and transport needs)\n\nemployment or entitlement to benefits\n\nlegal or immigration status (including risk of removal or relocation within the UK)\n\nany enablers or incentives to overcome anything that is stopping diagnosis or treatment. [2012, amended 2016]\n\nThe health and social care plan should:\n\nstate who will be observing treatment and where (if the person is having directly observed therapy this should be provided at a location that is convenient and accessible to them, for example, at a methadone clinic) [2012, amended 2016]\n\ninclude actions to take if contact with the person is lost (for example, keeping details of people who might be able to help re‑establish contact) \n\nrefer to, and be coordinated with, any other care plan already established for the person \n\ndefine the support needed to address any unmet health and social care needs (for example, support to gain housing or other benefits, or to help them access other health or social care services) [2012, amended 2016]\n\ninclude a commitment from the person to complete their TB treatment [2012, amended 2016]\n\nbe supported by frequent contact with any key workers who work with the person. [2006 amended 2011, amended 2016]\n\nMultidisciplinary TB teams should aim to find people with active TB who are lost to follow-up, or who stop using services before completing diagnostic investigations. They should report all those lost to follow‑up to local Public Health England teams, GPs, the referring organisation and specialist outreach teams. \n\n## Other strategies to encourage people to follow their treatment plan\n\nTo encourage people to follow their treatment plan, involve people in treatment decisions for active or latent TB from the start. Emphasise the importance of following the treatment plan when agreeing the regimen. \n\nMultidisciplinary TB teams should implement strategies for active and latent TB to encourage people to follow the treatment plan and prevent people stopping treatment early. These could include:\n\nreminder letters, printed information, telephone calls, texts and apps using an appropriate language [2006, amended 2016]\n\nhealth education counselling and patient‑centred interviews [2006, amended 2016]\n\ntailored health education booklets from quality sources (see\xa0section on providing information for the public about TB) [2006, amended 2016]\n\nhome visits \n\nrandom urine tests and other monitoring (for example, pill counts) \n\naccess to free TB treatment for everyone (irrespective of eligibility for other NHS care) and information about help with paying for prescriptions [2006, 2012, amended 2016]\n\nsocial and psychological support (including cultural case management and broader social support) [new 2016]\n\nadvice and support for parents and carers [new 2016]\n\nincentives and enablers to help people follow their treatment regimen. [new 2016]\n\nTB control boards should ensure services take into account the barriers facing vulnerable migrants who may need treatment, and in particular the stigma they may face. Other issues include the location of services (both geographically and in terms of opening times) and people's language and cultural needs, in terms of the format of advice and the type of information given. [2012, amended 2016]\n\n## Strategies in prisons or immigration removal centres\n\nOn arrival at a prison or immigration removal centre, healthcare professionals should ask all prisoners and detainees (including those being transferred from other establishments) if they are taking TB medication, to ensure continuity of treatment. \n\nAll prisoners and immigration removal centre detainees having treatment for active TB should have a named TB case manager. The case manager should be responsible for contingency planning for discharge from prison or detention. \n\nPrisons and immigration removal centres should ensure multidisciplinary TB staff have access to prisoners and detainees who need treatment (for example, by being given security clearance). \n\nAll prisoners having treatment for active TB should have directly observed therapy. \n\nPrison health services should have contingency, liaison and handover arrangements to ensure continuity of care before any prisoner on TB treatment is transferred between prisons or released. In addition, other agencies working with prisoners or detainees should also be involved in this planning. \n\nPrison and immigration removal centre healthcare services should liaise with the named TB case manager (from the multidisciplinary TB team) to ensure contingency plans for continuation of treatment are drawn up for prisoners and immigration removal centre detainees with TB. \n\nMultidisciplinary TB teams should ensure accommodation is available for the duration of TB treatment after the prisoner or detainee's release (see section on Identifying and managing active TB in prisons, custody suites or immigration removal centres: organisational factors). \n\nMultidisciplinary TB teams should ensure directly observed therapy is arranged for prisoners or detainees being treated for TB after their release. This should be available close to where they will live in the community. \n\n## Re‑establishing treatment for active or latent TB after interruptions because of adverse events\n\nIn people who have experienced a treatment interruption because of drug‑induced hepatotoxicity:\n\ninvestigate other causes of acute liver reactions and\n\nwait until aspartate or alanine transaminase levels fall below twice the upper limit of normal, bilirubin levels return to the normal range and hepatotoxic symptoms have resolved then\n\nsequentially reintroduce each of the anti‑TB drugs at full dose over a period of no more than 10\xa0days, starting with ethambutol and either isoniazid (with pyridoxine) or rifampicin. [new 2016]\n\nIn people with severe or highly infectious TB who need to interrupt standard therapy because of a reaction, consider continuing treatment:\n\nfor hepatotoxicity, a combination of at least 2 anti‑TB drugs of low hepatotoxicity (such as ethambutol and streptomycin, with or without a fluoroquinolone antibiotic, such as levofloxacin or moxifloxacin) and monitor with a liver specialist for further reactions See MHRA advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).Not licensed for tuberculosis, so use would be off label. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information.\n\nfor a cutaneous reaction, a combination of at least 2 anti‑TB drugs with a low risk of cutaneous reactions (such as ethambutol and streptomycin) and monitor with a dermatologist for further reactions. [new 2016, amended 2019]\n\nIf another reaction of a similar or greater severity occurs because of reintroducing a particular drug, do not give that drug in future regimens and consider extending the total regimen accordingly. [new 2016]\n\n## Follow‑up after treatment completion\n\nFollow‑up clinic visits should not be conducted routinely after treatment completion. \n\nTell patients to watch for symptoms of relapse and how to contact the TB service rapidly through primary care or a TB clinic. Key workers should ensure that patients at increased risk of relapse are particularly well informed about symptoms. \n\nPatients who have had drug‑resistant TB should be considered for follow‑up for 12\xa0months after completing treatment. Patients who have had multidrug‑resistant TB should be considered for prolonged follow‑up. \n\n# Service organisation\n\nWhen using the recommendations in this section with under served groups, also check sections 1.1.1 on raising and sustaining awareness, 1.1.2 on providing information for the public, 1.6.2 on opportunistic case finding, 1.6.3 on active case finding in under served groups and 1.7 on adherence, treatment completion and follow up. See also, recommendations on under served groups in section 1.2.3 on diagnosing latent TB in all age groups.\n\n## Strategic oversight and commissioning of TB prevention and control activities\n\nPublic Health England, in partnership with NHS England, should take responsibility for national oversight of TB prevention and control activities. This includes setting up TB control boards (see section\xa01.8.2). [2012, amended 2016]\n\nPublic Health England and NHS England should consider working together to establish control boards in agreed geographical areas and employ appropriate staff (see recommendation 1.8.2.3). [new 2016]\n\nClinical commissioning groups and local authority public health teams working in partnership with Public Health England and NHS England should consider collaborative commissioning arrangements through TB control boards. This could, for example, include working with 1 or more clinical commissioning groups to cover a major metropolitan district, region or TB control board area taking into account:\n\nlocal TB incidence\n\nlocal at‑risk populations and their movements across different geographical areas\n\nexisting service configurations for organisations involved in TB prevention and control\n\nthe need to share services, such as mobile X‑ray facilities, and outreach incident teams across different geographical areas. [2012, amended 2016]\n\nTB control boards should develop TB prevention and control programmes working with commissioners, Public Health England and NHS England. The board could include clinical, commissioning (from clinical commissioning groups, local government and the voluntary sector) and public health leaders and people with TB or groups who advocate on their behalf from across the control board area. This may include identifying a lead clinical commissioning group, which could be led by an executive director of that commissioning group working with the board. Feedback mechanisms between local commissioning groups and the TB control board should be developed. [new 2016]\n\nAn executive director of local commissioning groups, working with the local director of public health or another nominated public health consultant, should lead implementation of the programme in their locality. The lead should ensure a comprehensive prevention and control programme is commissioned to support the level of need (see section on local needs assessment) and that they work with the control board regularly. [2012, amended 2016]\n\nWorking together through TB control boards and local networks, commissioners, local government and Public Health England should ensure TB prevention and control programmes set up multidisciplinary TB teams to provide all TB services (see section on\xa0commissioning multidisciplinary TB support). They should ensure that local strategy and service commissioning focuses on an end-to-end pathway. [2012, amended 2016]\n\nWorking together through TB control boards, commissioners and Public Health England should ensure the TB prevention and control programme is informed by relevant NICE guidance and developed in collaboration with clinical services. It should also be informed by the standard minimum data set collected through local needs assessment and service audit. [2012, amended 2016]\n\nWorking together through TB control boards, commissioners and Public Health England should ensure the TB prevention and control programme targets all ages, including children, and covers all aspects of TB prevention and control (see recommendations\xa01.8.2.1 and 1.8.2.2), including but not limited to:\n\nactive case finding (contact investigations and identifying latent TB in high‑risk groups)\n\nawareness‑raising activities\n\nstandard and enhanced case management (including providing directly observed therapy and free treatment)\n\nfinding people lost to follow‑up and encouraging them back into treatment\n\nincident and outbreak control\n\nmonitoring, evaluating and gathering surveillance and outcome data. [2012, amended 2016]\n\nWorking together through TB control boards, commissioners, Public Health England and the voluntary sector should ensure TB prevention and control programmes take account of the need to work with other programmes targeting specific high‑risk groups, such as those who are under-served. Examples include programmes focused on the health of asylum seekers and refugees, under-served children, homelessness and housing, offenders and people who misuse substances. [2012, amended 2016]\n\nTB control boards should consider integrating TB and HIV services, joint clinics and training opportunities. [new 2016]\n\nCommissioners should consider commissioning support and advice to all groups diagnosed with TB irrespective of whether they are under‑served. [new 2016]\n\n## Developing the TB prevention and control programme\n\nTB control boards should be responsible for developing a TB prevention and control programme based on the national strategy and evidence‑based models. [new 2016]\n\nTB control boards should plan, oversee, support and monitor local TB control, including clinical and public health services and workforce planning. [new 2016]\n\nTB control boards should assess services in their area, identify gaps in provision and develop plans to meet these, including:\n\nundertaking a workforce review to support local or regional commissioning of TB services to meet the needs of their population (see sections on local needs assessment and cohort review)\n\nsupporting development of appropriate services and pathways to improve access and early diagnosis (see the sections on rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process, non‑clinical roles including TB support workers and rapid‑access TB services)\n\nnegotiating arrangements to cover the cost of additional services to address specific gaps in current TB control arrangements. [new 2016]\n\nTB control boards should ensure cohort review is undertaken at least quarterly, and the results are fed back to local clinical and TB networks. These should be agreed by accountable bodies such as clinical commissioning groups, trust management, regional Public Health England and centre directors and local authority directors of public health as agreed, all of whom should make sure appropriate action is taken. [new 2016]\n\nTB control boards should enable full and consistent use of national guidelines including:\n\nensuring the needs of all people with TB, particularly under‑served populations, are addressed\n\nensuring contact tracing arrangements are appropriate to the needs of the population (see the section on case finding)\n\nassuring themselves that TB control in low‑incidence areas is established and delivered appropriately (see the section on rural services: organisational and support factors)\n\nassuring themselves that multidrug‑resistant TB is managed appropriately (see the section on multidrug‑resistant TB) and mechanisms are in place to ensure:\n\n\n\nthere is sufficient clinical expertise available to manage cases\n\nregional multidrug‑resistant TB networks take account of expert advice (see section\xa01.8.3). [new 2016]\n\n\n\nTB control boards should develop links and partnerships and establish agreed relationships and lines of accountability between TB control boards and local clinical and TB networks. This includes engaging with other key stakeholders to ensure universal coverage of TB control efforts. [new 2016]\n\nTB control boards should collaborate with their local and regional partners. They should agree and establish regular monitoring, surveillance and reporting arrangements with all partners to support needs assessment (see the section on local needs assessment) and regular audit and evaluation. [new 2016]\n\nTB control board staff should have clearly defined roles and responsibilities. Their roles and responsibilities could include:\n\nEstablishing the links, partnerships and relationships between all aspects of the control board area within their remit (if necessary across usual geographical commissioning boundaries).\n\nDeveloping and supporting adoption and implementation of evidence‑based model service specifications for the clinical and public health actions needed to control TB including:\n\n\n\nimproving access and early diagnosis (see the sections on raising and sustaining awareness of TB, providing information for the public about TB, rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process and non‑clinical roles including TB support workers)\n\ndiagnostics, treatment and care services (see the sections on latent TB and active TB)\n\ncontact investigations and tracing (see the sections on diagnosing latent TB in adults and case finding)\n\ncohort review\n\nvaccination (see the section on BCG vaccination)\n\ndrug resistance (see the\xa0section on multidrug‑resistant TB)\n\ntackling TB in under‑served populations\n\nsurveillance, monitoring and quality assurance\n\nworkforce development and commissioning (see the sections on commissioning multidisciplinary TB support and non‑clinical roles including TB support workers). [new 2016]\n\n\n\nTB control boards should ensure there is sufficient capacity available to them to manage a sudden increase in demand such as:\n\nTB contact investigations, (such as incidents in congregate settings)\n\nlarge scale active case‑finding initiatives in under‑served groups in the community\n\noutbreaks in a variety of settings or sites where transmission risk may be high, including but not limited to schools, workplaces, hostels and prisons. [new 2016]\n\nTo set up, monitor and evaluate a TB control programme, TB control boards should:\n\nagree plans within their partnerships to assess local services against the service specifications\n\ndevelop plans and quality standards to secure improvements\n\nestablish quality assurance mechanisms and regular audits including, but not limited to, cohort review for all aspects of the TB control board partnership plans. [new 2016]\n\nTB control boards should (in collaboration with commissioners) consider the need for a TB network local coordinator, particularly if working across multiple clinical commissioning group areas (see recommendation\xa01.8.1.3). [new 2016]\n\nThe coordinator should work in close collaboration with clinicians and all relevant multidisciplinary TB teams to develop the network and be responsible for:\n\nsetting up the network and developing it based on needs, reporting back to the TB control board regularly\n\nestablishing the links, partnerships and relationships across their local network (if necessary across usual geographical commissioning boundaries). [new 2016]\n\n## Regional multidrug‑resistant TB network\n\nTB control boards should consider setting up a regional multidisciplinary TB network to oversee management of multidrug‑resistant TB. This could:\n\nIdentify and designate regional expert centres.\n\nEnsure all healthcare professionals who suspect or treat a case of multidrug‑resistant TB are informed about and have access to specialist advisory services for multidrug‑resistant TB. This includes the designated expert centre in their regional network and may also include the national advisory service for multidrug-resistant TB (currently provided by the British Thoracic Society).\n\nEnsure all cases of multidrug‑resistant TB are discussed at the regional multidisciplinary TB team meeting in the local clinical network.\n\nFormally consider and record the advice from the specialist advisory services for multidrug‑resistant TB provided by the designated regional expert centre or the national advisory service for multidrug‑resistant TB. [new 2016]\n\n## Rural services: organisational and support factors\n\nCommissioners in rural areas (working with the TB control board) should consider collaborative approaches to deliver and manage TB services. They could, for example, set up a network including areas with high and low incidence of TB. [new 2016]\n\n## Local needs assessment\n\nDirectors of public health, in discussion with local health protection teams, should ensure that TB is part of the joint strategic needs assessment. [2012, amended 2016]\n\nDirectors of public health should provide commissioners of TB prevention and control programmes and TB control boards with local needs assessment information annually using data provided by Public Health England. [2012, amended 2016]\n\nCommissioners of TB prevention and control programmes should ensure services reflect the needs of their area, identified by needs assessment. Health and wellbeing boards should ensure that local TB services have been commissioned based on local needs identified through needs assessment. [2012, amended 2016]\n\nDirectors of public health and TB control boards should use cohort review (see section\xa01.8.6) and other methods to collect data on the following, to inform local needs assessment:\n\nNumber of annual notified TB cases (see Public Health England's enhanced TB surveillance data and annual 'suite of indicators').\n\nSize, composition (for example, age and ethnicity) and distribution of local at‑risk groups.\n\nIndices of social deprivation.\n\nLocal statutory and non‑statutory services working with these groups.\n\nOrganisation of local TB services, including the composition and capacity of the local multidisciplinary TB team(see the results of local audit) and location of services. This may also include data to support evaluating the need for integrated TB/HIV services including joint clinics.\n\nNumbers needing enhanced case management (see the section on adherence, treatment completion and follow‑up).\n\nNumbers receiving directly observed therapy from the start of, or at any point during, treatment (see Public Health England's enhanced TB surveillance data).\n\nEvidence of recent transmission (for example, using DNA fingerprinting or surrogate markers such as number of cases in children under 5\xa0years (see UK TB national strain-typing database and local incident and outbreak reports).\n\nCompleteness and yield of contact investigations. This includes: proportion of smear‑positive cases with 0, 5 or more contacts identified; proportion of identified contacts clinically assessed; and proportion of contacts with latent TB infection who successfully complete treatment.\n\nActive case‑finding initiatives, incident contact investigations and identification of latent TB infection in high‑risk groups.\n\nTreatment outcomes for everyone grouped according to social risk factors and by the use of directly observed therapy (including rates of loss to follow‑up and treatment interruptions, see Public Health England's enhanced TB surveillance data).\n\nLocal education and awareness‑raising programmes for under‑served groups, professionals and practitioners working with them.\n\nViews and experiences of people with TB, carers and the services working with them. [2012, amended 2016]\n\nLocal needs assessments should also be equity proofed to assess the potential effect of planning, commissioning and policy decisions on health inequalities (see planning and commissioning services in NICE's local government briefing on health inequalities and population health). [new 2016]\n\n## Cohort review\n\nTB control boards and prevention and control programme leads should initiate, audit and evaluate cohort reviews in their commissioning area. Quarterly cohort review meetings should take place in the area covered by the programme. Combine these meetings with others if possible, or use technology to make it easier for clinicians and case managers to attend. [2012, amended 2016]\n\nTB case managers should present standardised information on each case, including: demographic information, HIV test results, pre‑treatment and ongoing status (clinical, laboratory, radiology), adherence to treatment and the results of contact investigations. [2012, amended 2016]\n\nTB case managers and key allied professionals from the TB prevention and control programme should attend cohort review meetings. This could include the lead clinician (who may or may not be the case manager). Either a paediatrician with experience and training in the treatment of TB or a general paediatrician with advice from a specialised clinician should be present when cases of children with TB are presented. [2012, amended 2016]\n\nThe chair of the cohort review should not work for any of the TB services included in the review. Examples of possible chairs include a public health consultant, a specialist physician or a senior TB nurse, preferably from a different geographical area. Alternatively the chair could be a representative from the local Public Health England health protection team or the TB control board. [2012, amended 2016]\n\nMultidisciplinary TB teams, in conjunction with Public Health England units, should collate and present cohort review data on TB treatment and the outcome of contact investigations at the review meetings. In addition, progress towards national, regional and local service targets should be presented. [2012, amended 2016]\n\nTB control boards, directors of public health and local public health consultants should ensure outputs from the cohort review feed into the needs assessment for TB services. TB control board directors should attend the cohort review at least once a year. [2012, amended 2016]\n\nTB case managers should feed back promptly to multidisciplinary TB teams on issues identified as a result of cohort review. The results of the cohort review should be collated locally and agreed by the chair before being fed back to TB control boards, commissioners and health and wellbeing boards regularly and via needs assessment. [2012, amended 2016]\n\nPeople participating in a cohort review should review the results and evaluate local services (for example, auditing adverse outcomes, rates of culture confirmation, treatment completion rates or time to diagnosis). [2012, amended 2016]\n\n## Commissioning multidisciplinary TB support\n\nCommissioners should ensure multidisciplinary TB teams:\n\nHave the skills and resources to manage the care of people with active TB who are not from under‑served groups. [2012, amended 2016]\n\nInclude at least 1 TB case manager with responsibility for planning and coordinating the care of under‑served people and those with active TB who receive enhanced case management. [2012, amended 2016]\n\nHave the resources to manage latent TB care in under‑served groups and the wider population. [new 2016]\n\nInclude a range of clinical specialties in the multidisciplinary TB team, including paediatrics, infection control and respiratory medicine. \n\nHave regular attendance at these multidisciplinary team and cohort review meetings for all team members included as a programmed activity as part of their work planning. [new 2016]\n\nHave the skills and resources necessary to manage the care of people with complex social and clinical needs (either directly or via an established route). This includes the ability to provide prompt access (or if necessary, referral) to skilled outreach and advocacy workers who can draw on the services of allied practitioners. The aim is to address people's housing, asylum, immigration, welfare, substance dependency and other health and social care needs. (The allied practitioner support should include both a specified housing officer and a social worker.) \n\nCan provide rapid access TB clinics for all cases, including under‑served groups. \n\nConsider providing administration support for TB nurses and case managers so they have capacity for clinical and case management work. This could include giving TB nurses access to computer hardware and software. [new 2016]\n\nHave the resources to provide a continuous service throughout the year, ensuring the TB service accounts for the following to manage continuity of care:\n\n\n\nplanned absence (for example, professional development, mandatory training, annual, maternity or paternity leave)\n\nunplanned absence (such as sickness absence). [2012, amended 2016]\n\n\n\nCan provide prompt access to a professional who has training and experience in assessing and protecting children and vulnerable adults at risk of abuse or neglect. \n\nHave access to funds through local government and clinical commissioning groups that can be used flexibly to improve adherence to treatment among under‑served groups. For example, funds could be used to provide transport to clinics, to provide support or enablers for treatment, or for paying outreach workers or community services to support directly observed therapy. Funds may also be used to provide accommodation during treatment. [2012, amended 2016]\n\nHave the resources to provide ongoing TB awareness‑raising activities for professional, community and voluntary (including advocacy) groups that work with populations at high risk of TB (see the section on raising and sustaining awareness of TB). These resources could be financed by local government or clinical commissioning groups. [2012, amended 2016]\n\nCommissioners should ensure NHS England's safe staffing principles are applied when commissioning TB services. The staffing ratios used in Public Health England and NHS England's collaborative tuberculosis strategy for England (published in 2015) came from NICE's guideline on tuberculosis: identification and management in under-served groups (published in 2012) which has been replaced by this guideline.NICE's 2012 guideline on tuberculosis: identification and management in under-served groups recommended 1 WTE case manager per 40 incident cases needing standard management and 1 WTE case manager per 20 incident cases needing enhanced case management. [new 2016]\n\n## Non‑clinical roles including TB support workers\n\nTB control boards and local TB services should consider employing trained, non‑clinically qualified professionals to work alongside clinical teams to agreed protocols, and to contribute to a variety of activities. Examples of this may include awareness raising and supporting people to attend appointments (including other health and social care appointments). They could also help with collecting samples, contact tracing, case management including directly observed therapy and cohort review, or any other aspect of the service if:\n\nthey are trained to deliver the intervention or processes effectively\n\nthey are supported, mentored and supervised by a named case manager, such as a TB nurse\n\nthey have the skills to monitor, evaluate and report on their work practices and outcomes to maintain a process of ongoing evaluation and service improvement in relation to cohort review (see the\xa0section on cohort review). [new 2016]\n\nTB control boards should ensure that people working in the TB service have the right knowledge, engagement, advocacy and communication skills to meet the needs (for example, language, cultural or other requirements) of all the groups they may work with. [new 2016]\n\nCommissioners should consider taking into account different needs across traditional geographical and organisational boundaries. Put agreements in place so that staff can work across these boundaries, covering the whole service or TB control board area if appropriate. [new 2016]\n\nCommissioners and TB control boards should ensure they put in place appropriate governance (including clear lines of accountability and extension of scope of practice) and data sharing practices and agreements. This includes ensuring they are part of service level agreements between NHS and non‑NHS services, for example, the third sector or local government, and appropriate training has been completed. [new 2016]\n\n## Rapid‑access TB services\n\nMultidisciplinary TB teams should establish relationships with statutory, community and voluntary organisations that work with people at risk of TB to develop appropriate TB referral pathways. They should ensure these organisations know how to refer people to local TB services. \n\nMultidisciplinary TB teams should accept referrals from healthcare providers and allied organisations working in the community with under‑served groups. This includes voluntary and statutory organisations (for example, mobile X‑ray teams or community organisations or outreach workers working with vulnerable migrants). \n\nMultidisciplinary TB teams should accept self‑referrals to TB clinics by people who suspect they have TB or have recently been in contact with someone with TB. [2012, amended 2016]\n\nMultidisciplinary TB teams should consider accepting direct referrals from emergency departments (see the section on rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process). [new 2016]\n\nHealthcare professionals should consider urgent referral to TB clinics for people with suspected active TB. They should also ensure the results from first‑line diagnostic tests (including a sputum smear and chest X‑ray) are available before the person sees a specialist. (Note: this should not delay the referral.) [2012, amended 2016]\n\nMultidisciplinary TB teams should have pathways to triage referrals, start investigations and collect clinical information before the person is seen by a physician. [new 2016]\n\nWhile triaging, multidisciplinary TB teams should ensure everyone is given information about TB as part of the process (see the\xa0section on providing information for the public about TB). This should include who the person should contact if they have any questions and how to access advice or information from support groups, national charities such as TB Alert and other sources such as local government (for example, public health or social care teams). \n\nMultidisciplinary TB teams should ensure people who have a smear‑positive result or imaging features highly suggestive of smear‑positive TB (for example, evidence of cavitation on chest X‑ray) are assessed the next working day. This is so that case management and infection control procedures start promptly. [2012, amended 2016]\n\nThe multidisciplinary TB team should assess people who are not smear‑positive but have imaging that suggests pulmonary or laryngeal TB as soon as possible. This should be no later than 5\xa0working\xa0days after a referral. [2012, amended 2016]\n\nMultidisciplinary TB teams should, where necessary, be able to provide or arrange outreach services to ensure sputum samples or other assessments such as contact investigations can be arranged in the community. \n\n## Identifying and managing active TB in prisons, custody suites or immigration removal centres: organisational factors\n\nMultidisciplinary TB teams, prisons, custody suites and immigration removal centre healthcare services should have named TB liaison leads to ensure they can communicate effectively with each other. [2012, amended 2016]\n\nPrison, custody suites and immigration removal centre healthcare services should develop a TB policy by working with the TB control board and multidisciplinary TB team and the local Public Health England health protection team. [2012, amended 2016]\n\nMultidisciplinary TB teams, in conjunction with prisons, custody suites and immigration removal centre healthcare services, should agree a care pathway for TB. This is to ensure that any suspected or confirmed cases are reported to, and managed by, the multidisciplinary TB team. [2012, amended 2016]\n\nMultidisciplinary TB teams, in liaison with prisons, custody suites or immigration removal centre healthcare providers, should manage all cases of active TB. Investigations and follow‑up should be undertaken within the prison or immigration removal centre if possible. [2012, amended 2016]\n\n## Accommodation during treatment\n\nMultidisciplinary TB teams should assess the living circumstances of people with TB. Where there is a housing need they should work with allied agencies to ensure that all those who are entitled to state‑funded accommodation receive it as early as possible during their treatment, for example, as a result of a statutory homelessness review and identified need. [2012, amended 2016]\n\nMultidisciplinary TB teams, commissioners, local authority housing lead officers and other social landlords, providers of hostel accommodation, hospital discharge teams, Public Health England and the Local Government Association should work together to agree a process for identifying and providing accommodation for homeless people diagnosed with active pulmonary TB who are otherwise ineligible for state‑funded accommodation. This includes people who are not sleeping rough but do not have access to housing or recourse to public funds. The process should detail the person's eligibility and ensure they are given accommodation for the duration of their TB treatment. [2012, amended 2016]\n\nLocal government and clinical commissioning groups should fund accommodation for homeless people diagnosed with active TB who are otherwise ineligible for state‑funded accommodation. Use health and public health resources, in line with the Care Act 2014. [2012, amended 2016]\n\nMultidisciplinary TB teams should make people who would not otherwise be entitled to state‑funded accommodation aware that they may lose this accommodation if they do not comply with treatment. They should ensure plans are made to continue housing people once their TB treatment is completed. \n\nPublic Health England, working with the Local Government Association and their special interest groups, should consider working with national housing organisations such as the Chartered Institute of Housing, Homeless Link, Sitra and the National Housing Federation to raise the profile of TB. This is to ensure people with TB are considered a priority for housing. [new 2016]\n\nConsider training housing commissioners and frontline staff on TB and the need for housing support, so that they understand that a stable home life is a prerequisite to successful TB treatment. [new 2016]\n\n# Terms used in this guideline\n\n## Active case‑finding\n\nSystematically identifying people with active or latent TB using tests, examinations or other procedures.\n\n## Adherence\n\nThe term adherence refers to the person's ability or willingness to keep to a treatment regimen as directed.\n\n## Adults\n\nPeople aged 18\xa0or older.\n\n## Case management\n\nCase management involves follow‑up of a person suspected or confirmed to have TB. It needs a collaborative, multidisciplinary approach and should start as soon as possible after a suspected case is discovered.\n\n## Case manager\n\nStandard and enhanced case management is overseen by a case manager who will usually be a specialist TB nurse or (in low‑incidence areas) a nurse with responsibilities that include TB. Depending on the person's circumstances and needs, case management can also be provided by appropriately trained and supported non‑clinical members of the TB multidisciplinary team.\n\n## Children\n\nPeople aged\xa015 or younger.\n\n## Children and young people\n\nPeople aged\xa017 or younger.\n\n## Close contacts\n\n'Close contacts' are people who have had prolonged, frequent or intense contact with a person with infectious TB. For example, these could include 'household contacts', those who share a bedroom, kitchen, bathroom or sitting room with the index case. Close contacts may also include boyfriends or girlfriends and frequent visitors to the home of the index case. Depending in the circumstances, occasionally coworkers are classed as 'close contacts although they are more usually classed as 'social contacts'.\n\n## Cohort review\n\nCohort review is a systematic quarterly audit of the management and treatment of all TB patients and their contacts. The 'cohort' is a group of cases counted over a specific time, usually 3\xa0months. Brief details of the management and outcomes of each case are reviewed in a group setting. The case manager presents the cases they are responsible for, giving the opportunity to discuss problems and difficulties in case management, service strengths and weaknesses, and staff training needs.\n\n## Congregate setting\n\nA place where people congregate or an institutional setting such as a workplace, prison, hostel, or childcare or educational setting, where social contacts might have had significant exposure to TB.\n\n## Contact\n\nA person who has spent time with someone with infectious TB. See also 'close contact' and 'social contact'.\n\n## Contact investigation\n\nClinical investigations (diagnostic testing) of people identified as having had significant exposure to a case of TB, including tests to diagnose latent or active TB. The aims of contact investigations are to:\n\ndetect active TB earlier to offer treatment and prevent further transmission\n\ndetect latent TB that may benefit from drug treatment\n\ndetect people not infected but for whom BCG vaccination might be appropriate.\n\n## Contact tracing\n\nIdentifying people who may have come into contact with a person with infectious TB and assessing them for risk of significant exposure to TB. The aim is to find associated cases, to detect people with latent TB and to identify those not infected but for whom BCG vaccination might be appropriate.\n\n## Disseminated TB\n\nBlood‑borne spread of TB that may or may not be accompanied by chest X‑ray or high resolution CT changes.\n\n## Enablers\n\nMethods of helping someone to overcome barriers to completing diagnostic investigations and TB treatment. Examples of barriers include: transport, housing, nutrition and immigration status.\n\n## Enhanced case management\n\nManagement of TB for someone with clinically or socially complex needs. It starts as soon as TB is suspected. As part of enhanced case management, the need for directly observed treatment is considered, along with a package of supportive care tailored to the person's needs.\n\n## Equity proofed\n\nTools such as health equity audit and health impact assessment have been used systematically to assess the potential effect of all policies, programmes and activities (including those without an explicit health focus) on health inequalities. Equity proofing helps ensure all policies and programmes address the social determinants of health and health inequalities. Including a health equity audit as part of the joint strategic needs assessment can help local authorities and their partners to:\n\ndevelop strategy and plans according to need\n\nidentify and work with community and health partners\n\ncommission activities based on the best available evidence\n\nimplement interventions to tackle inequity.\n\n## End‑to‑end pathway\n\nThe pathway from awareness raising and primary prevention, through diagnosis to treatment completion, incorporating all aspects such as contact tracing and other infection control mechanisms, for example, access to isolation facilities. This includes governance and commissioning considerations so that a comprehensive clinical and public health service is developed and delivered across any agreed geographical footprint.\n\n## Extrapulmonary TB\n\nActive TB disease in any site other than the lungs or tracheobronchial tree.\n\n## Extensively drug‑resistant TB\n\nResistance to at least isoniazid and rifampicin, 1\xa0injectable agent (capreomycin, kanamycin or amikacin) and 1\xa0fluoroquinolone.\n\n## High incidence\n\nA high‑incidence country or area has more than 40\xa0cases of TB per\xa0100,000\xa0people per year. Public Health England lists high‑incidence countries and areas of the UK on its website.\n\n## High‑risk groups\n\nThe term 'high‑risk groups' is used in this guideline to mean adults, young people and children from any ethnic background, regardless of migration status, who are at increased risk of having or contracting TB. This includes people classified as under‑served, people identified as contacts according to the case finding recommendations, new entrants from high‑incidence countries and people who are immunocompromised.\n\n## Homelessness\n\nFor the purposes of TB control, a broad and inclusive definition of homelessness has been adopted that incorporates overcrowded and substandard accommodation. It includes people:\n\nwho share an enclosed air space with people at high risk of undetected active pulmonary TB (that is, people with a history of rough sleeping, hostel residence or substance misuse)\n\nwithout the means to securely store prescribed medication\n\nwithout private space in which to self‑administer TB treatment\n\nwithout secure accommodation in which to rest and recuperate in safety and dignity for the full duration of planned treatment.\n\n## Immigration removal centres\n\nImmigration removal centres are private or prison‑run holding centres for migrants waiting to be accepted by, or deported from, the UK. Immigration removal centres are also known as immigration detention centres and pre‑departure accommodation.\n\n## Immunocompromised\n\nIn this guideline, immunocompromised refers to a person who has a significantly impaired immune system. For instance, this may be because of prolonged corticosteroid use, tumour necrosis factor‑alpha antagonists, antirejection therapy, immunosuppression‑causing medication or comorbid states that affect the immune system, for example, HIV, chronic renal disease, many haematological and solid cancers, and diabetes.\n\n## Incident risk assessment\n\nAssessment of risk of exposure to TB in a congregate setting to decide on the need for and extent of contact investigation. The risk assessment would take into consideration factors such as infectiousness of the index case, vulnerability of contacts to TB infection, length of contact with or exposure to an infectious case and the built environment (for example, size of the rooms, ventilation and overcrowding).\n\n## Index case\n\nThe initial person found to have TB, whose contacts are screened. The source of their infection may be found to be 1 of the contacts, but the person who presents first is regarded as the index case.\n\n## Induration\n\nThe firm skin reaction occurring after a tuberculin skin test to diagnose latent TB infection. It is measured, and the result used to determine whether the test result is classified as positive or negative. This guideline recommends a threshold of 5\xa0mm for tuberculin skin test positivity.\n\n## Infectious TB\n\nActive smear‑positive pulmonary TB, that is with acid fast bacilli visible on microscopy. Active TB affecting other parts of the respiratory tract or oral cavity, though rare, is also considered infectious.\n\n## Isolation\n\nAn infection control measure in which people with infectious TB are kept away from others who may be at risk of infection. This guideline deals with 3 levels of isolation for infection control in hospital settings:\n\nnegative pressure rooms, which have air pressure continuously or automatically measured, as defined by NHS Property Services\n\nsingle rooms that are not negative pressure but are vented to the outside of the building\n\nbeds on a ward, for which no particular engineering standards are needed.\n\n## Lost to follow‑up\n\nPeople are defined as 'lost to follow‑up' if they cannot be contacted within 10 working days of:\n\ntheir first missed outpatient appointment (if they are on self‑administered treatment)\n\ntheir first missed directly observed therapy appointment (if they are on directly observed therapy).\n\n## Multidisciplinary TB teams\n\nA team of professionals with a mix of skills to meet the needs of someone with TB who also has complex physical and psychosocial issues (that is, someone who is under‑served). Team members will include a social worker, voluntary sector and local housing representatives, TB lead physician and nurse, a case manager, a pharmacist, an infectious disease doctor or consultant in communicable disease control or health protection, a peer supporter or advocate and a psychiatrist.\n\n## Multidrug‑resistant TB\n\nTB resistant to isoniazid and rifampicin, with or without any other resistance.\n\n## Negative pressure room\n\nUsed to isolate some patients known or suspected to have infectious TB. A negative pressure room is one where the air from the room is sucked out into dedicated ducting through a filter and into the outside air, at a distance from all other air intakes. The pressure should be 10\xa0pascals below the ambient air pressure.\n\n## Neonates\n\nChildren aged 4\xa0weeks or younger.\n\n## New entrant\n\nAnyone coming to work or settle in the UK. This includes immigrants, refugees, asylum seekers, students and people on work permits. It also includes UK‑born people, or UK citizens, re‑entering the country after a prolonged stay in a high‑incidence country.\n\n## Opportunistic case‑finding\n\nOpportunistic identification of people with active or latent TB using tests, examinations or other procedures in the course of existing appointments or interactions, rather than identification through formal screening programmes.\n\n## Outbreak\n\nThere is no robust, widely accepted threshold for an outbreak of a disease, but in practical terms an outbreak is the occurrence of an unusually high number of cases in associated people, in a small geographical area, or in a relatively short period of time.\n\n## Peers\n\nPeers are people who may have experienced TB. They are often in a good position to help convey, with empathy, the need for testing or treatment. They may be recruited from specific populations. With support they can communicate health messages, assist with contact investigations or testing and offer people support while they are being tested or treated.\n\n## Prisons\n\nAny state prison establishments, including young offender institutions.\n\n## Rapid access\n\nIn the context of TB services, rapid access refers to timely support from a specialist team.\n\n## Smear grade\n\nThe number of bacilli found in a sputum sample, believed to relate to the degree of infectivity of the person. There are several systems but in general recording goes from no mycobacteria in 100\xa0fields (0\xa0or\xa0negative) to more than 10\xa0acid‑fast bacilli per field in at least 20\xa0fields (grade\xa03).\n\n## Social contacts\n\nSomeone who has had contact with a person with infectious TB but has not been in prolonged, frequent or intense contact.\n\n## Substance misuse\n\nSubstance misuse is defined as intoxication by, or regular excessive consumption of or dependence on, psychoactive substances, leading to social, psychological, physical or legal problems. It includes problematic use of both legal and illegal drugs.\n\n## TB control board\n\nA partnership of mixed professionals and lay people who have experience of leading, commissioning, managing or supporting people with TB. Board members are likely to include the voluntary sector, housing representatives, TB specialists and other clinicians, consultants in communicable disease control or health protection, peer supporter and advocate groups, clinical commissioning groups, executive officers, local government commissioners and an independent chair. This list is not intended to be exhaustive; membership should be determined based on an area's needs, agreements and commissioning arrangements.\n\n## Treatment interruption\n\nA break in the prescribed anti‑TB regimen for 2\xa0weeks or more in the initial phase, or more than 20% of prescribed doses missed intermittently.\n\n## Under‑served groups\n\nThis term is used in this guideline to mean groups of adults, young people and children from any ethnic background, regardless of migration status. They are 'under‑served' if their social circumstances, language, culture or lifestyle (or those of their parents or carers) make it difficult to:\n\nrecognise the clinical onset of TB\n\naccess diagnostic and treatment services\n\nself‑administer treatment (or, in the case of children and young people, have treatment administered by a parent or carer)\n\nattend regular appointments for clinical follow‑up.\n\nThe groups classified as under‑served in this guideline are:\n\npeople who are homeless\n\npeople who misuse substances\n\nprisoners\n\nvulnerable migrants.\n\n## Under‑served children\n\nGroups of children identified as potentially under served include:\n\nunaccompanied minors\n\nchildren whose parents are under served, including vulnerable migrants\n\nchildren whose parents are in prison or who abuse substances\n\nchildren from Gypsy and Traveller communities\n\nlooked‑after children.\n\n## Vulnerable migrants\n\nVulnerable migrants may include undocumented migrants and those with no recourse to public funds. Some refugees, asylum seekers and new entrants to the country may also fall into this category.\n\n## Young people\n\nPeople aged 16 or 17.", 'Context': "Tuberculosis (TB) is a curable infectious disease caused by a type of bacterium called Mycobacterium tuberculosis ('M.\xa0tuberculosis' or 'M.Tb'), or other bacterium in the M.\xa0tuberculosis complex (that is, M.\xa0bovis or M.\xa0africanum). It is spread by droplets containing the bacteria being coughed out by someone with infectious TB, and then being inhaled by other people.\n\nThe initial infection clears in over 80% of people but, in a few cases, a defensive barrier is built round the infection and the TB bacteria lie dormant. This is called latent TB; the person is not ill and is not infectious. If the immune system fails to build the defensive barrier, or the barrier fails later, latent TB can spread in the lung (pulmonary TB) or develop in the other parts of the body it has spread to (extrapulmonary TB). Only a small proportion of people with latent TB will develop symptoms ('active TB').\n\nMany cases of TB can be prevented by public health measures and, when clinical disease does occur, most people can be cured if treated properly. Taking medication in the wrong dose or combination, irregularly or for too short a time can lead to drug resistance. Drug‑resistant strains of TB are much harder to treat and significantly increase a person's risk of long‑term complications or death. If left untreated, 1\xa0person with active pulmonary TB may infect as many as 10 to 15\xa0people every year.\n\nTB incidence in the UK has increased since the early 1990s, but has remained relatively stable since 2005. Despite this, it remains high compared with many other western European countries. Cases tend to cluster in urban areas where populations of at‑risk groups are high. These include areas with many people born in countries with a high incidence of TB, areas with a high level of homelessness, poor housing or poverty, and areas with high rates of problem drug use.\n\nThe NHS and Public Health England, as well as a local authority public health teams and many third sector organisations, have been working to reduce the harm caused by TB to many individuals and communities. TB is a notifiable disease, meaning that clinicians have a statutory duty to notify local authorities or a local Public Health England centre of suspected cases, and efforts have been made to strengthen services and ensure clear lines of accountability and responsibility. However, a stronger approach to TB control is now needed to build on this work. Indicators of TB incidence and TB treatment outcomes have been included in the Public Health Outcomes Framework. In addition, Public Health England and NHS England have designed a collaborative tuberculosis strategy for England that brings together best practice in clinical care, social support and public health. Agencies at all levels, including national and local government, clinical commissioning groups and third sector partners, are committed to working in partnership to decrease the incidence of TB, fight the spread of drug‑resistant forms of the disease, reduce current health inequality and, ultimately, eliminate TB as a public health problem in England.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The guideline committee's full set of research recommendations is detailed in the full guideline.\n\n# Universal compared with risk‑based approach to using rapid diagnostic tests\n\nIn people with suspected TB, what is the relative clinical and cost effectiveness of universal and risk‑based use of rapid nucleic acid amplification tests?\n\n## Why this is important\n\nThe guideline committee noted that there were 2 possible approaches to using rapid nucleic acid amplification tests for suspected TB. The current approach is to use them only if TB is strongly suspected and rapid information about mycobacterial species would alter the person's care. Another approach is to use them in anyone with a possible diagnosis of TB. There is a trade‑off between ensuring that all people with active TB are diagnosed and avoiding a large number of false positives, which leads to unnecessary treatment. This trade‑off may lead to differences in the cost effectiveness of each approach. NICE's systematic review of the diagnosis of active TB did not identify any robust evidence on this, nor did the health technology assessment on using nucleic acid amplification tests to detect drug resistance. Cost‑effectiveness studies are needed to improve understanding in this area.\n\n# Diagnosis in children\n\nApart from culture, what other diagnostic tests or combinations of tests are effective in establishing an accurate diagnosis of active respiratory TB in children and young people with suspected active TB?\n\n## Why this is important\n\nThe guideline committee noted the lack of evidence on the diagnosis of active TB in children. The disease manifests differently in children than in adults, and more evidence would have been useful to the committee. Cross‑sectional studies are needed to examine the relative accuracy of different tests, and the most appropriate specimen type for these tests, compared with tests currently in use. In particular, the poor accuracy of many tests in children means that diagnostic strategies that is, combinations of tests, should be investigated, including both tests with high sensitivity and tests based on host response.\n\n# Treating isoniazid‑resistant TB\n\nFor isoniazid‑resistant TB, what is the most effective regimen for reducing mortality and morbidity?\n\n## Why this is important\n\nThere is little evidence for the treatment of isoniazid resistant TB. This is the most common form of drug resistance in the UK, occurring in 7.5% of TB cases. Currently, treatment is not always successful, even when the recommended drugs are given for the recommended time and there are no adherence issues. It is particularly difficult to treat if there are treatment interruptions or if the central nervous system is involved. Randomised controlled trials are needed to compare different anti‑TB regimens for isoniazid‑resistant TB, assessing mortality, treatment success or treatment failure, rates of relapse and adverse events.\n\n# Impact of infection control measures on quality of life\n\nWhat effects does isolation have on the quality of life of people being treated for TB?\n\n## Why this is important\n\nIsolation is known to significantly affect a person's quality of life. Despite this, the guideline committee identified no reliable data on the impact of isolation on quality of life. This information is essential in producing economic models that reflect the real costs of isolation. Data on the impact of isolation on quality of life need to be collected and reported.\n\n# Treatment interruptions caused by adverse events (specifically hepatotoxicity)\n\nFor people with active, drug susceptible TB who experience treatment interruptions because of adverse events, particularly hepatotoxicity, what approach to re‑establishing treatment is most effective in reducing mortality and morbidity?\n\n## Why this is important\n\nThere is little evidence on re‑establishing treatment after interruptions because of adverse events. This is key to ensuring treatment success without relapse or the emergence of drug resistance, but avoiding further adverse events is also important. Randomised controlled trials are needed to compare approaches to re‑establishing treatment for active, drug susceptible TB after it is interrupted because of adverse events, particularly hepatotoxicity. These trials should assess mortality, treatment success or failure, rates of relapse, the recurrence of adverse events and the emergence of drug resistance. Approaches evaluated could compare, for example, restarting regimens with lengthening their duration, as well as sequential reintroduction. Approaches should vary depending on the proportion of doses missed and the stage of treatment (initial or continuation phase) in which the interruption occurred. Prospective observational cohort studies with multivariable analyses may also be useful."}
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https://www.nice.org.uk/guidance/ng33
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This guideline covers preventing, identifying and managing latent and active tuberculosis (TB) in children, young people and adults. It aims to improve ways of finding people who have TB in the community and recommends that everyone under 65 with latent TB should be treated. It describes how TB services should be organised, including the role of the TB control board.
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1aa8d955313f65df9385c96282bbe1056331ca2d
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nice
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Implant insertion for prominent ears
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Implant insertion for prominent ears
Evidence-based recommendations on implant insertion for prominent ears in children, young people and adults. This involves inserting small curved implants under the skin of each ear.
# Recommendations
Current evidence on the safety and efficacy of implant insertion for prominent ears is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should include comparisons of this procedure with current best therapy. It should address issues of patient selection, such as age and type of ear shape, nature of ear implants used, long-term efficacy and safety outcomes, and patient-reported outcomes using validated quality-of-life measures.# The condition, current treatments and procedure
# The condition
Protruding or prominent ears result when cartilaginous folds fail to form within the ear.
# Current treatments
Surgery to correct protruding ears aims to reposition the elastic cartilage permanently while preserving a natural appearance. Cartilage-sparing techniques such as scoring, drilling and suturing of the cartilage may be used. Most techniques involve a post-auricular skin incision, although there has been a report of an incisionless otoplasty.
# The procedure
This procedure is done under local anaesthesia. One or more implants (gold-coated curved nitinol devices) are used to create or reshape the antihelical fold of the ear. The aim is to correct any ear prominence resulting from either poor definition or a lack of this fold.
The position of any implants is discussed and agreed with the patient before the procedure and marked on the ear. The implant is inserted using an introducer and released onto the anterior surface of the cartilage, immediately reshaping it and correcting the ear prominence. The incision is closed using 1 or 2 dissolvable sutures, and the wound is then dressed with sterile tape.
Typically, 1 implant is used in each ear, but more may be needed. The procedure usually takes about 20 minutes for both ears.
|
{'Recommendations': 'Current evidence on the safety and efficacy of implant insertion for prominent ears is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include comparisons of this procedure with current best therapy. It should address issues of patient selection, such as age and type of ear shape, nature of ear implants used, long-term efficacy and safety outcomes, and patient-reported outcomes using validated quality-of-life measures.', 'The condition, current treatments and procedure': '# The condition\n\nProtruding or prominent ears result when cartilaginous folds fail to form within the ear.\n\n# Current treatments\n\nSurgery to correct protruding ears aims to reposition the elastic cartilage permanently while preserving a natural appearance. Cartilage-sparing techniques such as scoring, drilling and suturing of the cartilage may be used. Most techniques involve a post-auricular skin incision, although there has been a report of an incisionless otoplasty.\n\n# The procedure\n\nThis procedure is done under local anaesthesia. One or more implants (gold-coated curved nitinol devices) are used to create or reshape the antihelical fold of the ear. The aim is to correct any ear prominence resulting from either poor definition or a lack of this fold.\n\nThe position of any implants is discussed and agreed with the patient before the procedure and marked on the ear. The implant is inserted using an introducer and released onto the anterior surface of the cartilage, immediately reshaping it and correcting the ear prominence. The incision is closed using 1\xa0or\xa02 dissolvable sutures, and the wound is then dressed with sterile tape.\n\nTypically, 1\xa0implant is used in each ear, but more may be needed. The procedure usually takes about 20\xa0minutes for both ears.'}
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https://www.nice.org.uk/guidance/ipg660
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Evidence-based recommendations on implant insertion for prominent ears in children, young people and adults. This involves inserting small curved implants under the skin of each ear.
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566990e83d358ec45047a5a4d54e174174437d94
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nice
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Twin and triplet pregnancy
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Twin and triplet pregnancy
This guideline covers the care that should be offered to women with a twin or triplet pregnancy in addition to the routine care that is offered to all women during pregnancy. It aims to reduce the risk of complications and improve outcomes for women and their babies.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidance explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Type of pregnancy
Chorionicity and amnionicity
Dichorionic diamniotic twins
Both babies have a separate placenta and amniotic sac.
Monochorionic diamniotic twins
Both babies share a placenta but have separate amniotic sacs.
Monochorionic monoamniotic twins
Both babies share a placenta and amniotic sac.
Trichorionic triamniotic triplets
Each baby has a separate placenta and amniotic sac.
Dichorionic triamniotic triplets
One baby has a separate placenta and 2 of the babies share a placenta.
All 3 babies have separate amniotic sacs.
Dichorionic diamniotic triplets
One baby has a separate placenta and amniotic.
Two of the babies share a placenta and amniotic sac.
Monochorionic triamniotic triplets
All 3 babies share 1 placenta.
All 3 babies have separate amniotic sacs.
Monochorionic diamniotic triplets
All 3 babies share 1 placenta.
One baby has a separate amniotic sac and 2 babies share 1 sac.
Monochorionic monoamniotic triplets
All 3 babies share a placenta and amniotic sac.
# Determining gestational age and chorionicity
## Gestational age
Offer women with a twin or triplet pregnancy a first trimester ultrasound scan to estimate gestational age and determine chorionicity and amnionicity (ideally, these should all be performed at the same scan; see the recommendations on determining chorionicity and amnionicity and assigning nomenclature). See the recommendations on screening for chromosomal conditions.
Estimate gestational age from the largest baby in a twin or triplet pregnancy to avoid the risk of estimating it from a baby with early growth pathology.
## Chorionicity and amnionicity
Determine chorionicity and amnionicity at the time of detecting a twin or triplet pregnancy by ultrasound using:
the number of placental masses
the presence of amniotic membrane(s) and membrane thickness
the lambda or T‑sign.
Assign nomenclature to babies (for example, upper and lower, or left and right) in a twin or triplet pregnancy, and document this clearly in the woman's notes to ensure consistency throughout pregnancy.
If a woman with a twin or triplet pregnancy presents after 14+0 weeks, determine chorionicity and amnionicity at the earliest opportunity by ultrasound using all of the following:
the number of placental masses
the presence of amniotic membrane(s) and membrane thickness
the lambda or T-sign
discordant fetal sex.
If it is not possible to determine chorionicity or amnionicity by ultrasound at the time of detecting the twin or triplet pregnancy, seek a second opinion from a senior sonographer or refer the woman to a healthcare professional who is competent in determining chorionicity and amnionicity by ultrasound scan as soon as possible.
If it is difficult to determine chorionicity, even after referral (for example, because the woman has booked late in pregnancy), manage the pregnancy as a monochorionic pregnancy until proved otherwise.
Provide regular training so that sonographers can identify the lambda or T-sign accurately and confidently. Less experienced sonographers should have support from senior colleagues.
Training should cover ultrasound scan measurements needed for women who book after 14+0 weeks and should emphasise that the risks associated with twin and triplet pregnancy are determined by chorionicity and not zygosity.
Conduct regular clinical audits to evaluate the accuracy of determining chorionicity and amnionicity.
If transabdominal ultrasound scan views are poor because of a retroverted uterus or a high BMI, use a transvaginal ultrasound scan to determine chorionicity and amnionicity.
Do not use 3‑dimensional (3‑D) ultrasound scans to determine chorionicity and amnionicity.
Networks should agree care pathways for managing all twin and triplet pregnancies to ensure that each woman has a care plan in place that is appropriate for the chorionicity and amnionicity of her pregnancy.
# General care
## Information and emotional support
Explain sensitively the aims and possible outcomes of all screening and diagnostic tests to women with a twin or triplet pregnancy to minimise their anxiety.
## Diet, lifestyle and nutritional supplements
Give women with a twin or triplet pregnancy the same advice about diet, lifestyle and nutritional supplements as in routine antenatal care (see NICE's guideline on antenatal care for uncomplicated pregnancies).
Be aware of the higher incidence of anaemia in women with a twin or triplet pregnancy compared with women with a singleton pregnancy.
Perform a full blood count at 20 to 24 weeks to identify women with a twin or triplet pregnancy who need early supplementation with iron or folic acid (this is in addition to the test for anaemia at the routine booking appointment recommended in NICE's guideline on antenatal care for uncomplicated pregnancies). Repeat at 28 weeks as in routine antenatal care.
# Delivery of antenatal and intrapartum care
## Antenatal care
Antenatal clinical care for women with a twin or triplet pregnancy should be provided by a nominated multidisciplinary team consisting of:
a core team of named specialist obstetricians, specialist midwives and sonographers, all of whom have experience and knowledge of managing twin and triplet pregnancies
an enhanced team for referrals, which should include:
a perinatal mental health professional
a women's health physiotherapist
an infant feeding specialist
a dietitian.
Members of the enhanced team should have experience and knowledge relevant to twin and triplet pregnancies.
Do not routinely refer all women with a twin or triplet pregnancy to the enhanced team but base the decision to refer on each woman's needs.
Coordinate clinical care for women with a twin or triplet pregnancy to:
minimise the number of hospital visits
provide care as close to the woman's home as possible
provide continuity of care within and between hospitals and the community.
The core team should offer information and emotional support specific to twin and triplet pregnancies at their first contact with the woman and provide ongoing opportunities for further discussion and advice including:
antenatal and postnatal mental health and wellbeing
antenatal nutrition (see the recommendation on giving advice in the section on diet, lifestyle and nutritional supplements)
the risks, symptoms and signs of preterm labour and the potential need for corticosteroids for fetal lung maturation
likely timing of birth (see the section on timing of birth) and possible modes of birth (see the section on mode of birth)
breastfeeding
parenting.
## Intrapartum care
Intrapartum care for women with a twin or triplet pregnancy should be provided by a multidisciplinary team of obstetricians and midwives who have experience and knowledge of managing twin and triplet pregnancies in the intrapartum period.
For a short explanation of why the committee made the 2019 recommendation and how it might affect practice, see the rationale and impact on intrapartum care .
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## Schedule of specialist antenatal appointments
The schedule of specialist appointments is also shown as part of a multiple pregnancy antenatal care resource produced by Twins Trust and endorsed by NICE.
Offer women with an uncomplicated dichorionic diamniotic twin pregnancy at least 8 antenatal appointments with a healthcare professional from the core team. At least 2 of these appointments should be with the specialist obstetrician.
Combine appointments with scans when crown–rump length measures from 45.0 mm to 84.0 mm (at approximately 11+2 weeks to 14+1 weeks) and then at estimated gestations of 20, 24, 28, 32 and 36 weeks.
Offer additional appointments without scans at 16 and 34 weeks.
Offer women with an uncomplicated monochorionic diamniotic twin pregnancy at least 11 antenatal appointments with a healthcare professional from the core team. At least 2 of these appointments should be with the specialist obstetrician.
Combine appointments with scans when crown–rump length measures from 45.0 mm to 84.0 mm (at approximately 11+2 weeks to 14+1 weeks) and then at estimated gestations of 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34 weeks.
Offer women with an uncomplicated trichorionic triamniotic triplet pregnancy at least 9 antenatal appointments with a healthcare professional from the core team. At least 2 of these appointments should be with the specialist obstetrician.
Combine appointments with scans when crown–rump length measures from 45.0 mm to 84.0 mm (at approximately 11+2 weeks to 14+1 weeks) and then at estimated gestations of 20, 24, 26, 28, 30, 32 and 34 weeks.
Offer an additional appointment without a scan at 16 weeks.
Offer women with a dichorionic triamniotic or monochorionic triamniotic triplet pregnancy at least 11 antenatal appointments with a healthcare professional from the core team. At least 5 of these appointments should be with the specialist obstetrician.
Combine appointments with scans when crown–rump length measures from 45.0 mm to 84.0 mm (at approximately 11+2 weeks to 14+1 weeks) and then at estimated gestations of 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34 weeks.
Offer women with a twin or triplet pregnancy involving a shared amnion individualised care from a consultant in a tertiary level fetal medicine centre (see the recommendation on indications for referral to a tertiary level fetal medicine centre).
# Fetal complications
## Information about screening
A healthcare professional with experience of caring for women with twin and triplet pregnancies should offer information and counselling to women before and after every screening test.
Inform women with a twin or triplet pregnancy about the complexity of decisions they may need to make depending on the outcomes of screening, including different options according to the chorionicity and amnionicity of the pregnancy.
## Screening for chromosomal conditions
Offer women with a twin pregnancy information on and screening for Down's syndrome, Edwards' syndrome and Patau's syndrome as outlined in the NHS fetal anomaly screening programme (FASP).
Before offering screening for Down's syndrome, Edwards' syndrome and Patau's syndrome, give women with a triplet pregnancy information about:
the greater likelihood of Down's syndrome, Edwards' syndrome and Patau's syndrome in triplet pregnancy
the different options for screening
the increased false positive rate of screening tests in triplet pregnancy
their greater likelihood of being offered invasive testing
their greater likelihood of complications of invasive testing
the physical risks and psychological implications in the short and long term relating to selective fetal reduction.
Healthcare professionals who screen for Down's syndrome, Edwards' syndrome and Patau's syndrome in trichorionic triplet pregnancy should:
map the fetal positions
use nuchal translucency and maternal age to screen for Down's syndrome, Edwards' syndrome and Patau's syndrome when crown–rump length measures from 45.0 mm to 84.0 mm (at approximately 11+2 weeks to 14+1 weeks)
calculate the chance of Down's syndrome, Edwards' syndrome and Patau's syndrome for each fetus.
Refer women with a dichorionic and monochorionic triplet pregnancy who want to have screening for Down's syndrome, Edwards' syndrome and Patau's syndrome to a tertiary level fetal medicine centre.
Do not use second trimester serum screening for Down's syndrome in triplet pregnancies.
Refer women with any type of triplet pregnancy who have a higher chance of Down's syndrome, Edwards' syndrome or Patau's syndrome (use a threshold of 1 in 150 at term) to a fetal medicine specialist in a tertiary-level fetal medicine centre.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on screening for chromosomal conditions .
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## Screening for structural abnormalities
Offer screening for structural abnormalities (such as cardiac abnormalities) in twin and triplet pregnancies as in routine antenatal care; see NICE's guideline on antenatal care for uncomplicated pregnancies and the NHS fetal anomaly screening programme.
Consider scheduling ultrasound scans in twin and triplet pregnancies at a slightly later gestational age than in singleton pregnancies and be aware that the scans will take longer to perform.
Allow 45 minutes for the anomaly scan in twin and triplet pregnancies (as recommended by FASP).
Allow 30 minutes for growth scans in twin and triplet pregnancies.
## Screening for preterm birth
Also see the section on preventing preterm birth.
Explain to women and their family members or carers (as appropriate) that:
they have a higher risk of spontaneous preterm birth (see the section on timing of birth) than women with a singleton pregnancy and
this risk is further increased if they have other risk factors, such as a spontaneous preterm birth in a previous pregnancy.
Do not use fetal fibronectin testing alone to predict the risk of spontaneous preterm birth in twin and triplet pregnancy.
Do not use home uterine activity monitoring to predict the risk of spontaneous preterm birth in twin and triplet pregnancy.
For a short explanation of why the committee made the 2019 recommendations (and why they did not make a recommendation on cervical length screening) and how they might affect practice, see the rationale and impact section on screening for preterm birth .
Full details of the evidence and the committee's discussion are in evidence review D: screening for spontaneous preterm birth.
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## Screening for fetal growth restriction and feto-fetal transfusion syndrome in the first trimester
Do not offer women with a twin or triplet pregnancy screening for fetal growth restriction or feto-fetal transfusion syndrome in the first trimester.
For a short explanation of why the committee made this 2019 recommendation and how it might affect practice, see the rationale and impact section on screening for fetal growth restriction and feto-fetal transfusion syndrome in the first trimester .
Full details of the evidence and the committee's discussion are in evidence review A: screening for feto-fetal transfusion syndrome and evidence review B: screening for fetal growth restriction.
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## Diagnostic monitoring for fetal growth restriction in dichorionic twin and trichorionic triplet pregnancies
Do not use abdominal palpation or symphysis–fundal height measurements to monitor for fetal growth restriction in a dichorionic twin or trichorionic triplet pregnancy.
At each ultrasound scan from 24 weeks, offer women with a dichorionic twin or trichorionic triplet pregnancy diagnostic monitoring for fetal weight discordance using 2 or more biometric parameters and amniotic fluid levels. To assess amniotic fluid levels, measure the deepest vertical pocket (DVP) on either side of the amniotic membrane.
Continue monitoring for fetal weight discordance at intervals that do not exceed:
days for women with a dichorionic twin pregnancy
days for women with a trichorionic triplet pregnancy.
Calculate and document estimated fetal weight (EFW) discordance for dichorionic twins using the formula below : ( ÷ EFW larger fetus) × 100
Calculate and document EFW discordance for trichorionic triplets using the formula below :( ÷ EFW largest fetus) × 100and( ÷ EFW largest fetus) × 100
Increase diagnostic monitoring in the second and third trimesters to at least weekly, and include doppler assessment of the umbilical artery flow for each baby, if:
there is an EFW discordance of 20% or more and/or
the EFW of any of the babies is below the 10th centile for gestational age.
Refer women with a dichorionic twin or trichorionic triplet pregnancy to a tertiary level fetal medicine centre if there is an EFW discordance of 25% or more and the EFW of any of the babies is below the 10th centile for gestational age because this is a clinically important indicator of selective fetal growth restriction.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on diagnostic monitoring for fetal growth restriction in dichorionic twin and trichorionic triplet pregnancies .
Full details of the evidence and the committee's discussion are in evidence review B: screening for fetal growth restriction.
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## Diagnostic monitoring for complications of monochorionicity in twin and triplet pregnancy
A monochorionic twin or triplet pregnancy is one in which any of the babies share a placenta and a chorionic (outer) membrane. This includes monochorionic twins and dichorionic and monochorionic triplets.
Offer women simultaneous monitoring for feto-fetal transfusion syndrome, fetal growth restriction and advanced-stage twin anaemia polycythaemia sequence (TAPS) at every ultrasound assessment to monitor effectively for all complications of monochorionicity. Explain that the relative likelihood of each complication changes with advancing gestation but that they can all occur at any gestational age.
Offer diagnostic monitoring for feto-fetal transfusion syndrome to women with a monochorionic twin or triplet pregnancy. Monitor with ultrasound every 14 days from 16 weeks until birth.
Use ultrasound assessment, with a visible amniotic membrane within the measurement image, to monitor for feto-fetal transfusion syndrome. Measure the DVP depths of amniotic fluid on either side of the amniotic membrane.
Increase the frequency of diagnostic monitoring for feto-fetal transfusion syndrome in the woman's second and third trimester to at least weekly if there are concerns about differences between the babies' amniotic fluid level (a difference in DVP depth of 4 cm or more). Include doppler assessment of the umbilical artery flow for each baby.
Refer the woman to a tertiary level fetal medicine centre if feto-fetal transfusion syndrome is diagnosed, based on the following:
the amniotic sac of 1 baby has a DVP depth of less than 2 cm and
the amniotic sac of another baby has a DVP depth of:
-ver 8 cm before 20+0 weeks of pregnancy or
-ver 10 cm from 20+0 weeks.
Refer the woman to her named specialist obstetrician for multiple pregnancy in her second or third trimester for further assessment and monitoring if:
the amniotic sac of 1 baby has a DVP depth in the normal range and
the amniotic sac of another baby has a DVP depth of:
less than 2 cm or
cm or more.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on diagnostic monitoring for feto-fetal transfusion syndrome .
Full details of the evidence and the committee's discussion are in evidence review A: screening for feto-fetal transfusion syndrome.
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Do not use abdominal palpation or symphysis–fundal height measurements to monitor for fetal growth restriction in women with a monochorionic twin or triplet pregnancy.
At each ultrasound scan from 16 weeks, offer women with a monochorionic twin or triplet pregnancy diagnostic monitoring for fetal weight discordance using 2 or more biometric parameters (in addition to amniotic fluid level assessment). To assess amniotic fluid levels, measure the DVP on either side of the amniotic membrane.
Continue monitoring women with a monochorionic twin or triplet pregnancy for fetal weight discordance at intervals that should not exceed 14 days.
Calculate and document EFW discordance in monochorionic twins using the formula below : ( ÷ EFW larger fetus) × 100
The named specialist obstetrician should review the estimated fetal weights of dichorionic and monochorionic triplets and calculate EFW discordance based on their understanding of the implications of chorionicity.
Increase diagnostic monitoring in the second and third trimesters to at least weekly, and include doppler assessment of the umbilical artery flow for each baby, if:
there is an EFW discordance of 20% or more and/or
the EFW of any of the babies is below the 10th centile for gestational age.
Refer women with a monochorionic twin or triplet pregnancy to a tertiary level fetal medicine centre if there is an EFW discordance of 25% or more and the EFW of any of the babies is below the 10th centile for gestational age because this is a clinically important indicator of selective fetal growth restriction.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see rationale and impact section on diagnostic monitoring for fetal growth restriction in monochorionic pregnancy .
Full details of the evidence and the committee's discussion are in evidence review B: screening for fetal growth restriction.
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Offer weekly ultrasound monitoring for TAPS from 16 weeks of pregnancy using middle cerebral artery peak systolic velocity (MCA‑PSV) to women whose pregnancies are complicated by:
feto-fetal transfusion syndrome that has been treated by fetoscopic laser therapy or
selective fetal growth restriction (defined by an EFW discordance of 25% or more and an EFW of any of the babies below the 10th centile for gestational age).
For women with a monochorionic pregnancy showing any of the following:
cardiovascular compromise (such as fetal hydrops or cardiomegaly) or
unexplained isolated polyhydramnios or
abnormal umbilical artery perform ultrasound MCA‑PSV measurements to help detect advanced-stage TAPS, and seek management advice immediately from a tertiary level fetal medicine specialist.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on diagnostic monitoring for TAPS .
Full details of the evidence and the committee's discussion are in evidence review C: screening for TAPS.
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# Preventing preterm birth
The committee did not make any recommendations on vaginal progesterone for preventing preterm birth in twin pregnancies because of emerging evidence in this area. NICE will carry out an exceptional update based on the new evidence when it becomes available.
Do not offer intramuscular progesterone to prevent spontaneous preterm birth in women with a twin or triplet pregnancy.
Do not offer the following interventions (alone or in combination) routinely to prevent spontaneous preterm birth in women with a twin or triplet pregnancy:
arabin pessary
bed rest
cervical cerclage
-ral tocolytics.
For a short explanation of why the committee made the 2019 recommendations (and why they did not make a recommendation on vaginal progesterone) and how they might affect practice, see the rationale and impact section on preventing preterm birth .
Full details of the evidence and the committee's discussion are in evidence review E: interventions to prevent spontaneous preterm birth.
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## Corticosteroids
Inform women with a twin or triplet pregnancy of their increased risk of preterm birth (see the recommendation explaining screening for preterm birth to women and their family members in the section on screening for preterm birth) and about the benefits of targeted corticosteroids.
Do not use single or multiple untargeted (routine) courses of corticosteroids in twin or triplet pregnancy. Inform women that there is no benefit in using untargeted administration of corticosteroids.
# Maternal complications
## Hypertension
Measure blood pressure and test urine for proteinuria to screen for hypertensive disorders at each antenatal appointment in a twin and triplet pregnancy in line with NICE's guideline on antenatal care for uncomplicated pregnancies.
Advise women with a twin or triplet pregnancy to take low-dose aspirin daily from 12 weeks until the birth of the babies if they have 2 or more of the risk factors specified in NICE's guideline on hypertension in pregnancy. In September 2019, this was an off-label use of aspirin. See NICE's information on prescribing medicines.
# Indications for referral to a tertiary level fetal medicine centre
Seek a consultant opinion from a tertiary level fetal medicine centre for:
pregnancies with a shared amnion:
monochorionic monoamniotic twins
dichorionic diamniotic triplets
monochorionic diamniotic triplets
monochorionic monoamniotic triplets
pregnancies complicated by any of the following:
fetal weight discordance (of 25% or more) and an EFW of any of the babies below the 10th centile for gestational age
fetal anomaly (structural or chromosomal)
discordant fetal death
feto-fetal transfusion syndrome
twin reverse arterial perfusion sequence (TRAP)
conjoined twins or triplets
suspected TAPS (see the recommendations in the section on twin anaemia polycythaemia sequence).
# Planning birth: information and support
From 24 weeks in a twin or triplet pregnancy, discuss with the woman (and her family members or carers, as appropriate) her plans and wishes for the birth of her babies. Provide information that is tailored to each woman's pregnancy, taking into account her needs and preferences. Revisit these conversations whenever clinically indicated and whenever the woman wants to.
Ensure the following has been discussed by 28 weeks at the latest:
place of birth and the possible need to transfer in case of preterm birth
timing and possible modes of birth
analgesia during labour (or for caesarean birth)
intrapartum fetal heart monitoring
management of the third stage of labour.
Follow NICE's guideline on patient experience in adult NHS services for how to provide information and communicate with women and their families and carers.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on planning birth .
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# Timing of birth
## Antenatal information for women
Explain to women with a twin pregnancy that about 60 in 100 twin pregnancies result in spontaneous birth before 37 weeks.
Explain to women with a triplet pregnancy that about 75 in 100 triplet pregnancies result in spontaneous birth before 35 weeks.
Explain to women with a twin or triplet pregnancy that spontaneous preterm birth and planned preterm birth are associated with an increased risk of admission to a neonatal unit.
Explain to women with an uncomplicated dichorionic diamniotic twin pregnancy that:
planned birth from 37+0 weeks does not appear to be associated with an increased risk of serious neonatal adverse outcomes and
continuing the pregnancy beyond 37+6 weeks increases the risk of fetal death.
Explain to women with an uncomplicated monochorionic diamniotic twin pregnancy that:
planned birth from 36+0 weeks does not appear to be associated with an increased risk of serious neonatal adverse outcomes and
continuing the pregnancy beyond 36+6 weeks increases the risk of fetal death.
Explain to women with an uncomplicated monochorionic monoamniotic twin pregnancy that planned birth between 32+0 and 33+6 weeks does not appear to be associated with an increased risk of serious neonatal adverse outcomes. Also explain that:
these babies will usually need to be admitted to the neonatal unit and have an increased risk of respiratory problems
continuing the pregnancy beyond 33+6 weeks increases the risk of fetal death.
Explain to women with an uncomplicated trichorionic triamniotic or dichorionic triamniotic triplet pregnancy that continuing the pregnancy beyond 35+6 weeks increases the risk of fetal death.
Explain to women with a monochorionic triamniotic triplet pregnancy or a triplet pregnancy that involves a shared amnion that the timing of birth will be decided and discussed with each woman individually.
## When to offer planned birth
Offer planned birth at 37 weeks to women with an uncomplicated dichorionic diamniotic twin pregnancy.
Offer planned birth as follows, after a course of antenatal corticosteroids has been considered (see the section on maternal corticosteroids in NICE's guideline on preterm labour and birth):
at 36 weeks for women with an uncomplicated monochorionic diamniotic twin pregnancy
between 32+0 and 33+6 weeks for women with an uncomplicated monochorionic monoamniotic twin pregnancy
at 35 weeks for women with an uncomplicated trichorionic triamniotic or dichorionic triamniotic triplet pregnancy.
Offer an individual assessment to determine the timing of planned birth in women with any of the following:
a complicated twin or triplet pregnancy
a monochorionic triamniotic triplet pregnancy
a triplet pregnancy that involves a shared amnion.
For women who decline planned birth at the timing recommended in recommendations 1.9.9 and 1.9.10, offer weekly appointments with the specialist obstetrician. At each appointment, offer an ultrasound scan and perform assessments of amniotic fluid level and doppler of the umbilical artery flow for each baby in addition to fortnightly fetal growth scans.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on timing of birth .
Full details of the evidence and the committee's discussion are in evidence review J: timing of birth.
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# Mode of birth
## Twin pregnancy: dichorionic diamniotic or monochorionic diamniotic
Explain to women with an uncomplicated twin pregnancy planning their mode of birth that planned vaginal birth and planned caesarean section are both safe choices for them and their babies if all of the following apply:
the pregnancy remains uncomplicated and has progressed beyond 32 weeks
there are no obstetric contraindications to labour
the first baby is in a cephalic (head-first) presentation
there is no significant size discordance between the twins.
Explain to women with an uncomplicated twin pregnancy that for women giving birth after 32 weeks (see recommendation 1.10.1):
more than a third of women who plan a vaginal birth go on to have a caesarean section
almost all women who plan a caesarean section do have one, but a few women have a vaginal birth before caesarean section can be carried out
a small number of women who plan a vaginal birth will need an emergency caesarean section to deliver the second twin after vaginal birth of the first twin.
Offer caesarean section to women if the first twin is not cephalic at the time of planned birth.
Offer caesarean section to women in established preterm labour between 26 and 32 weeks if the first twin is not cephalic.
Offer an individualised assessment of mode of birth to women in suspected, diagnosed or established preterm labour before 26 weeks. Take into account the risks of caesarean section (see NICE's guideline on preterm labour and birth) and the chance of survival of the babies.
## Twin pregnancy: monochorionic monoamniotic
Offer a caesarean section to women with a monochorionic monoamniotic twin pregnancy:
at the time of planned birth (between 32+0 and 33+6 weeks) or
after any complication is diagnosed in her pregnancy requiring earlier delivery or
if she is in established preterm labour, and gestational age suggests there is a reasonable chance of survival of the babies (unless the first twin is close to vaginal birth and a senior obstetrician advises continuing to vaginal birth).
## Triplet pregnancy
Offer a caesarean section to women with a triplet pregnancy:
at the time of planned birth (35 weeks) or
after any complication is diagnosed in her pregnancy requiring earlier delivery or
if she is in established preterm labour, and gestational age suggests there is a reasonable chance of survival of the babies.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on mode of birth .
Full details of the evidence and the committee's discussion are in evidence review F: mode of birth.
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# Fetal monitoring during labour in twin pregnancy
## Antenatal information for women
By 28 weeks of pregnancy, discuss continuous cardiotocography with women with a twin pregnancy and their family members or carers (as appropriate) and address any concerns. Explain that the recommendations on cardiotocography are based on evidence from women with a singleton pregnancy because there is a lack of evidence specific to twin pregnancy or preterm babies.
Explain to the woman that continuous cardiotocography is used to monitor the babies' heartbeats and her labour contractions, and that:
it allows simultaneous monitoring of both babies
it might restrict her mobility
normal traces show the babies are coping well with labour; if traces are not normal, there will be less certainty about the babies' condition
it is normal to see changes to the fetal heart rate pattern during labour and this does not necessarily mean there is a problem
findings from the cardiotocograph are used to help make decisions during labour and birth, but these will also be based on her wishes, her condition and that of her babies.
## Intrapartum monitoring
Offer continuous cardiotocography to women with a twin pregnancy who are in established labour and are more than 26 weeks pregnant.
Perform a portable ultrasound scan when established labour starts, to confirm which twin is which, the presentation of each twin, and to locate the fetal hearts.
Do not offer intermittent auscultation to women with a twin pregnancy who are in established labour and are more than 26 weeks pregnant.
For women between 23+0 and 25+6 weeks of pregnancy who are in established labour, involve a senior obstetrician in discussions with the woman and her family members or carers about how to monitor the fetal heart rates.
When carrying out cardiotocography:
use dual channel cardiotocography monitors to allow simultaneous monitoring of both fetal hearts
document on the cardiotocograph and in the clinical records which cardiotocography trace belongs to which baby
monitor the maternal pulse electronically and display it simultaneously on the same cardiotocography trace.
Consider separating the fetal heart rates by 20 beats/minute if there is difficulty differentiating between them.
Classify and interpret cardiotocography in line with the section on the use of cardiotocography for monitoring during labour in the NICE guideline on fetal monitoring in labour, taking into account that:
twin pregnancy should be considered a fetal clinical risk factor when classifying a cardiotocography trace as 'abnormal' versus 'non-reassuring'
fetal scalp stimulation should not be performed in twin pregnancy to gain reassurance after a cardiotocography trace that is categorised as 'pathological'.
## Reviewing cardiotocography
Carry out systematic assessments of both cardiotocographs at least hourly, and more frequently if there are concerns.
At each systematic assessment, document which cardiotocography trace belongs to which baby.
Be aware of the possibility of monitoring the same baby twice. At each cardiotocography review, ensure that twin synchronicity is not occurring.
## Management based on cardiotocography
For definitions of 'suspicious' and 'pathological' cardiotocograph traces, see the table on management based on interpretation of cardiotocograph traces in NICE's guideline on intrapartum care for healthy women and babies.
If abdominal monitoring is unsuccessful or there are concerns about synchronicity of the fetal hearts:
involve a senior obstetrician and senior midwife
apply a fetal scalp electrode to the first baby (only after 34 weeks and if there are no contraindications) while continuing abdominal monitoring of the second baby
perform a bedside ultrasound scan to confirm both fetal heart rates
if monitoring remains unsatisfactory, consider a caesarean section.
If the cardiotocograph trace is categorised as 'suspicious' in the first baby during established labour:
involve the senior obstetrician and senior midwife
correct any reversible causes
apply a fetal scalp electrode to the first baby (only after 34 weeks and if there are no contraindications) while continuing abdominal monitoring of the second baby.
If the cardiotocograph trace is categorised as 'pathological' in the first baby during established labour:
involve the senior obstetrician and senior midwife
discuss with the woman and her family members or carers the possible use of fetal blood sampling of the first baby from 34 weeks if the benefits are likely to outweigh the potential risks.
When offering fetal blood sampling in twin pregnancy, discuss with the woman and her family members or carers that if a blood sample cannot be obtained then she is likely to need a caesarean section.
If the results of fetal blood sampling are not available within 20 minutes or fetal blood sampling is contraindicated, offer an immediate caesarean section to women with a twin pregnancy.
If the cardiotocograph trace is categorised as 'pathological' in the first baby during the second stage of labour:
involve the senior obstetrician and senior midwife
assess whether an assisted vaginal birth is an option
if vaginal birth is not an option or cannot be achieved within 20 minutes, offer an immediate caesarean section.
If the cardiotocograph trace of the second baby is categorised as 'suspicious' or 'pathological' during established labour before the first baby is born:
involve the senior obstetrician and senior midwife
if vaginal birth of the second baby cannot be achieved within 20 minutes, discuss performing a caesarean section with the woman and her family members or carers.
After the birth of the first baby:
continue to monitor the second baby using cardiotocography
if there is 'suspicious' or 'pathological' cardiotocography, and vaginal birth cannot be achieved within 20 minutes, discuss performing a caesarean section with the woman and her family members or carers.
After the birth of both babies, consider double clamping the cord to allow umbilical cord blood gases to be sampled. Ensure that the samples are correctly labelled for each baby.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on fetal monitoring during labour .
Full details of the evidence and the committee's discussion are in evidence review G: fetal monitoring.
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# Analgesia
Discuss options for analgesia and anaesthesia with women (and their family members or carers, as appropriate), whether they are planning a vaginal birth or caesarean section. Ensure this discussion takes place by 28 weeks at the latest.
Offer an epidural to women with a twin or triplet pregnancy who choose to have a vaginal birth. Explain that this is likely to:
improve the chance of success and optimal timing of assisted vaginal birth of all the babies
enable a quicker birth by emergency caesarean section if needed.
Offer regional anaesthesia to women with a twin or triplet pregnancy who are having a caesarean section.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on analgesia .
Full details of the evidence and the committee's discussion are in evidence review H: analgesia.
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# Managing the third stage of labour
## Assessing risk
Start assessing the risk of postpartum haemorrhage in women with a twin or triplet pregnancy in the antenatal period and continue throughout labour and the third stage (see the section on risk factors for postpartum haemorrhage in NICE's guideline on intrapartum care for healthy women and babies).
Offer each woman an individualised assessment of her risk of postpartum haemorrhage and explain that multiple pregnancy is a risk factor for increased blood loss at delivery.
## Management
By 28 weeks of pregnancy, discuss options for managing the third stage of labour with women with a twin or triplet pregnancy.
Do not offer physiological management of the third stage to women with a twin or triplet pregnancy.
Offer women with a twin or triplet pregnancy active management of the third stage. Explain that it is associated with a lower risk of postpartum haemorrhage and/or blood transfusion.
Consider active management of the third stage with additional uterotonics for women who have 1 or more risk factors (in addition to a twin or triplet pregnancy) for postpartum haemorrhage.
## Blood transfusion
By 28 weeks of pregnancy, discuss with women with a twin or triplet pregnancy the potential need for blood transfusion, including the need for intravenous access. Document this discussion in the woman's notes.
At the start of established labour in women with a twin or triplet pregnancy:
ensure that intravenous access is available so that prompt blood transfusion and intravenous fluids can be given if needed
take a maternal blood sample for a full blood count and group and save.
Ensure that the appropriate blood transfusion is available for urgent administration.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on managing the third stage of labour .
Full details of the evidence and the committee's discussion are in evidence review I: interventions to prevent postpartum haemorrhage in the third stage of labour.
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# Terms used in this guideline
## Active management of the third stage
In a vaginal birth, active management consists of 10 IU of oxytocin by intramuscular injection immediately after the birth of the last baby and before the cord is clamped and cut. In a caesarean section, it consists of 5 IU of oxytocin by intravenous injection immediately after the birth of the last baby and before the cord is clamped and cut.
## Amnionicity
The number of amnions (inner membranes) that surround babies in a multiple pregnancy. Pregnancies with 1 amnion (so that all babies share an amniotic sac) are described as monoamniotic; pregnancies with 2 amnions are diamniotic; and pregnancies with 3 amnions are triamniotic. Also see the box on chorionicity and amnionicity in twin and triplet pregnancy.
## Chorionicity
The number of chorionic (outer) membranes that surround babies in a multiple pregnancy. If there is only 1 membrane, the pregnancy is described as monochorionic; if there are 2, the pregnancy is dichorionic; and if there are 3, the pregnancy is trichorionic. Monochorionic twin pregnancies and monochorionic or dichorionic triplet pregnancies carry higher risks because babies share a placenta. Also see the box on chorionicity and amnionicity in twin and triplet pregnancy.
## Feto-fetal transfusion syndrome
Feto-fetal transfusion syndrome (FFTS) occurs when blood moves from one baby to another. The baby that loses the blood is called the donor and the baby receiving the blood is called the recipient. Feto-fetal transfusion syndrome is a complication of monochorionic multiple pregnancies arising from shared placental circulation. It is also referred to as twin-to-twin transfusion syndrome in twin pregnancies.
## Group and save
This is a blood sampling process. It consists of a blood group and an antibody screen to determine the woman's blood group and whether she has atypical red cell antibodies in her blood. If atypical antibodies are present, the laboratory will do additional work to identify them. This will allow blood to be issued in an emergency very quickly.
## Specialist obstetrician
An obstetrician with a special interest, experience and knowledge of managing multiple pregnancy, and who works regularly with women with a multiple pregnancy.
## Tertiary level fetal medicine centre
A specialist regional (or supra-regional) fetal medicine centre that has a multidisciplinary team with the expertise and infrastructure to assess and manage complicated twin and triplet pregnancies. This includes providing complex fetal interventions or therapies, for example, fetoscopic laser ablation for feto-fetal transfusion syndrome; and selective termination of pregnancy using techniques such as fetoscopic cord occlusion or radiofrequency ablation.
## Twin anaemia polycythaemia sequences
Twin anaemia polycythaemia sequences (TAPS) is a complication affecting monochorionic twin or triplet pregnancies. It is a rare, chronic form of feto-fetal transfusion caused by the joining of fine blood vessels connecting the fetal circulations on the placenta. It presents when there are unequal blood counts between the twins in the womb. When TAPS occurs, the recipient twin is at risk for successively increasing blood count, called polycythaemia, and the donor twin for progressive blood loss, or anaemia. TAPS occurs without the differences in levels of amniotic fluids between the fetuses (polyhydramnios-oligohydramnios) that is usually seen in FFTS.# Recommendations for research
The guideline committee has made the following recommendations for research.
As part of the 2019 update, the guideline committee made an additional recommendation for research on the identification on twin anaemia polycythaemia sequence (TAPS). The committee removed 6 of the 2011 recommendations on screening for chromosomal conditions, screening for feto-fetal transfusion syndrome, defining fetal growth restriction, predicting and preventing spontaneous preterm birth, and perinatal and neonatal morbidity and mortality in babies born by elective birth.
# Key recommendations for research
## Screening to detect twin anaemia polycythaemia sequence
What is the most accurate prenatal screening marker for TAPS, including middle cerebral artery peak systolic velocity (MCA‑PSV)?
For a short explanation of why the committee made the recommendation for research, see the rationale on diagnostic monitoring for twin anaemia polycythaemia sequence .
Full details of the evidence and the committee's discussion are in evidence review C: screening for TAPS.
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## Information and support
Does additional information and emotional support improve outcomes in twin and triplet pregnancies?
## Specialist care
Does specialist antenatal care for women with twin and triplet pregnancies improve outcomes for women and their babies?
## Indications for referral to a tertiary level fetal medicine centre
What is the incidence of monochorionic monoamniotic twin and triplet pregnancies, and what clinical management strategies are most effective in such pregnancies?
# Other recommendations for research
## Gestational age
How should gestational age be estimated in twin and triplet pregnancies?
## Chorionicity
What is the most accurate method of determining chorionicity in twin and triplet pregnancies at different gestational ages, and how does operator experience affect the accuracy of different methods?
## Nutritional supplements
Is dietary supplementation with vitamins or minerals, or dietary manipulation in terms of calorie intake, effective in twin and triplet pregnancies?
## Diet and lifestyle advice
Is dietary advice specific to twin and triplet pregnancies effective in improving maternal and fetal health and wellbeing?
## Screening for structural abnormalities
When and how should screening for structural abnormalities be conducted in twin and triplet pregnancies?
## Hypertension
Which clinical factors, laboratory screening tests, and ultrasound tests are predictive of hypertensive disorders in twin and triplet pregnancies?
## Untargeted corticosteroids
What is the clinical and cost effectiveness, and safety, of routine antenatal administration of a single course of corticosteroids for women with twin and triplet pregnancies who are not in labour and in whom labour and birth are not imminent?
## Indications for referral to a tertiary level fetal medicine centre
What is the clinical and cost effectiveness of referral to tertiary level fetal medicine centres for twin and triplet pregnancies complicated by discordant fetal growth, discordant fetal anomaly or discordant fetal death? # Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Intrapartum care
Recommendation 1.3.6
## Why the committee made the recommendation
The committee recognised that the core multidisciplinary team recommended by the previous guideline (see recommendation 1.3.1) provides care during the antenatal period and would not be the same team providing intrapartum care. Because intrapartum care was added to the guideline update, they made a recommendation to clarify that healthcare professionals supporting women when they are giving birth should also have knowledge and experience in multiple pregnancy.
## How the recommendation might affect practice
The recommendation reinforces current practice.
Return to recommendation
# Screening for chromosomal conditions
Recommendations 1.4.3 to 1.4.8
## Why the committee made the recommendations
Since the 2011 guideline, the National Screening Committee's recommendations on screening for fetal chromosomal conditions have been published and have been implemented by the NHS fetal anomaly screening programme (FASP). These apply to women with both singleton and twin pregnancies, so the 2011 recommendations were replaced by a cross reference to this screening programme. The committee recognised that no current guidance exists for triplets so they retained a recommendation on triplets from the 2011 guideline. However, based on their expertise they decided this existing recommendation would apply only to screening in trichorionic triplets so they made an additional recommendation about dichorionic and monochorionic triplet pregnancies. Because of the complexity of screening these types of triplet pregnancies, this screening should only be carried out after referral to a tertiary level fetal medicine centre.
## How the recommendations might affect practice
The recommendations reinforce current best practice.
Return to recommendations
# Screening for preterm birth
Recommendations 1.4.13 to 1.4.15
## Why the committee made the recommendations
The committee agreed, based on their experience and expertise, that women should be given information about the higher risk of preterm birth in twin and triplet pregnancy compared with singleton pregnancy.
The committee retained the existing 2011 recommendations that fetal fibronectin testing and home uterine activity monitoring should not be used to predict the risk of spontaneous preterm birth because there was still no evidence suggesting they were accurate.
## Why the committee did not make a recommendation on cervical length screening in twin pregnancy
The evidence suggested that cervical length is a moderate predictor of spontaneous preterm birth in twin pregnancy. Although there were some inconsistencies between studies, the committee agreed they still supported the use of cervical length measurements to predict preterm birth in twin pregnancy. Establishing that a woman is at risk of preterm birth allows an intervention to be offered, and there is some evidence that vaginal progesterone may reduce this risk in women with a twin pregnancy. However, the committee was also aware that new evidence would be emerging about the use of vaginal progesterone in subgroups of women with a short cervix that could change their conclusions about its effectiveness. This uncertainty meant the committee could not recommend vaginal progesterone to prevent preterm birth. Because of this, the committee also decided they could not recommend cervical length screening in the absence of an effective intervention to offer women with a higher risk of preterm birth.
## How the recommendations might affect practice
The recommendations reinforce current best practice.
Return to recommendations
# Screening for fetal growth restriction and feto-fetal transfusion syndrome in the first trimester
Recommendation 1.4.16
## Why the committee made the recommendation
There was evidence that discordance in either crown–rump length or nuchal translucency during the first trimester is not an accurate predictor of growth discordance in the second and third trimester. The committee discussed the evidence for other ultrasound screening measures in the first trimester and decided that because of its low quality they were not confident in recommending any screening tests in the first trimester.
The evidence showed that none of the first trimester screening tests were able to detect the risk of feto-fetal transfusion syndrome developing later in the pregnancy. Although there were uncertainties in this evidence, it was supported by the committee's clinical experience and current clinical practice.
## How the recommendation might affect practice
The recommendation reinforces current practice.
Return to recommendations
# Diagnostic monitoring for fetal growth restriction in dichorionic twin and trichorionic triplet pregnancies
Recommendations 1.4.17 to 1.4.23
## Why the committee made the recommendations
Based on evidence which showed that abdominal palpation and symphysis–fundal height were not accurate measurements to diagnose fetal growth restriction, the committee recommended that these should not be used.
Fetal growth restriction is associated with perinatal mortality, morbidity and preterm birth. The committee agreed that monitoring using ultrasound scanning is essential to identify women in this high-risk group.
The evidence was limited on the frequency of ultrasound scanning for women with dichorionic twin pregnancies but, based on their expertise, the committee agreed that women with a dichorionic twin pregnancy should have scans no more than 28 days apart.
They also recommended ultrasound monitoring at least every 14 days for women with all types of triplet pregnancy (recommendations 1.4.19 and 1.4.32) because they are at higher risk of fetal growth restriction.
Based on both the evidence and their expertise, the committee recommended using at least 2 different biometric parameters as well as amniotic fluid level assessment to provide greater accuracy in calculating estimated fetal weight (EFW).
The Royal College of Obstetricians and Gynaecologists' Green Top guideline on monochorionic twin pregnancy recommends referring women 'for assessment and management in fetal medicine units with recognised relevant expertise' if there is an EFW discordance of more than 20%. In the committee's experience, this level of discordance should cause concern in all types of twin and triplet pregnancy and should prompt increased monitoring. However, they recommended instead increasing to weekly monitoring and adding the extra parameter of a doppler assessment. This would be equivalent to the specialist assessment recommended by the Green Top guideline because it would need to be carried out by the specialist core team (in line with recommendation 1.3.1) who have experience and knowledge of managing twin and triplet pregnancies. The committee agreed that this would not be inconsistent with the Green Top guideline.
The committee also agreed that the EFWs themselves should be taken into account. Based on the evidence and their expertise they recommended the 10th centile for gestational age as a threshold for concern that should prompt increased monitoring.
The evidence was inconclusive about an exact threshold for referral to a tertiary level fetal medicine centre, so based on their own experience the committee decided that an EFW discordance of 25% or more (along with an EFW below the 10th centile for gestational age) should warrant referral. At this level of discordance, there would be an increased risk of perinatal morbidity and mortality that should prompt intervention rather than increased assessment. The tertiary level fetal medicine centre would have the expertise to weigh up the benefits and risks of conservative management, birth or invasive fetal therapy to improve the chance of a positive pregnancy outcome.
## How the recommendations might affect practice
These recommendations are largely reinforcing current practice in twin pregnancy and should have a minimal impact on local ultrasound resourcing. They are consistent with other national and international guidance.
The recommendations to monitor all women with a triplet pregnancy at no more than 14‑day intervals (irrespective of chorionicity) are a change in practice, particularly for women with a trichorionic triamniotic pregnancy. For these women, previous recommendations suggested 4‑weekly scans. However, the change is justified because all types of triplet pregnancy are at high risk of fetal growth restriction. The recommendation should not have a significant impact on clinical resources because of the low number of women with a triplet pregnancy.
Return to recommendations
# Diagnostic monitoring for feto-fetal transfusion syndrome
Recommendations 1.4.24 to 1.4.29
## Why the committee made the recommendations
The committee agreed that feto-fetal transfusion syndrome is difficult to detect using amniotic fluid discordance before 16 weeks of pregnancy. After this stage, amniotic fluid levels have increased and differences between them can be used to diagnose feto-fetal transfusion syndrome. Monitoring fortnightly from 16 weeks should ensure that feto-fetal transfusion syndrome is diagnosed as early as possible. The committee decided based on their expertise – and on limited evidence from studies that conducted diagnostic scans after 24 weeks – that continuing fortnightly monitoring until birth would improve outcomes for women who develop feto-fetal transfusion syndrome later in pregnancy (although it is less common after 26 weeks). The committee also agreed that offering women with a monochorionic pregnancy scans at 14-day intervals means that the woman can be monitored efficiently for all the complications in recommendation 1.4.24 at each scan.
To support this frequency of monitoring, the committee also increased the number of reviews by the specialist obstetrician from at least 2 (in the 2011 guideline) to at least 5 for dichorionic and monochorionic triamniotic triplet pregnancies (recommendation 1.3.10). Dichorionic triamniotic triplets have an increased risk of adverse outcomes compared with monochorionic diamniotic twins if feto-fetal transfusion occurs. The risk of complications of monochorionicity, and of adverse outcomes if complications occur, is higher in triplets than in twins. More frequent review by the specialist obstetrician would ensure optimal critical assessment of ultrasound findings (including findings related to feto-fetal transfusion syndrome) and any need for more frequent monitoring.
The committee agreed that making sure the amniotic membrane is visible in the scan reduces the chance of measuring the same sac twice in error and improves accuracy in identifying a difference between the babies' amniotic fluid levels.
Based on their knowledge and experience, the committee agreed that women should be referred immediately to a tertiary level fetal medicine centre when differences in amniotic fluid levels meet the criteria for diagnosing feto-fetal transfusion syndrome. The clinical course of feto-fetal transfusion syndrome can be unpredictable so this would allow prompt assessment and early intervention. They also agreed that when differences in amniotic fluid levels are measured that do not yet meet the threshold for feto-fetal transfusion syndrome, women should be seen by their named specialist obstetrician for multiple pregnancy and offered more frequent monitoring, using doppler assessment to help detect feto-fetal transfusion syndrome as early as possible.
## How the recommendations might affect practice
Monitoring for feto-fetal transfusion syndrome from 16 weeks of pregnancy until birth is a change to current practice, in which monitoring is only carried out until week 24. Early detection would enable prompt management, and this would outweigh the cost of additional ultrasound.
Return to recommendations
# Diagnostic monitoring for fetal growth restriction in monochorionic twin and triplet pregnancy
Recommendations 1.4.30 to 1.4.36
A monochorionic twin or triplet pregnancy is one in which any of the babies share a placenta and a chorionic (outer) membrane. This includes monochorionic twins and dichorionic and monochorionic triplets.
## Why the committee made the recommendations
Based on evidence which showed that abdominal palpation and symphysis–fundal height were not accurate measurements to diagnose fetal growth restriction, the committee recommended that these should not be used.
Fetal growth restriction is associated with perinatal mortality, morbidity and preterm birth. The committee agreed that monitoring using ultrasound scanning is essential to identify women in this high-risk group.
The evidence was limited on the frequency of ultrasound scanning for women with monochorionic pregnancies, so the committee used their expertise to make recommendations. They agreed that women with a monochorionic twin pregnancy need more frequent scans than women with a dichorionic twin pregnancy because they have a higher risk of severe growth discordance.
Scanning at no more than 14-day intervals would allow the woman to be referred promptly either to her specialist obstetrician for multiple pregnancy or to a tertiary level fetal medicine centre depending on the EFWs (see below). The committee also agreed that because women with a monochorionic pregnancy should be having scans at 14‑day intervals to monitor for feto-fetal transfusion syndrome, these timings mean they can be monitored for both of these complications at the same time (in line with recommendation 1.4.24).
The committee also recommended ultrasound monitoring at least every 14 days for women with all types of triplet pregnancy (recommendations 1.4.19 and 1.4.32) because they are at higher risk of fetal growth restriction.
Based on both the evidence and their expertise, the committee recommended using at least 2 different biometric parameters as well as amniotic fluid level assessment to provide greater accuracy in calculating EFW.
The Royal College of Obstetricians and Gynaecologists' Green Top guideline on monochorionic twin pregnancy recommends referring women 'for assessment and management in fetal medicine units with recognised relevant expertise' if there is an EFW discordance of more than 20%. The committee agreed with the Green Top guideline that this level should cause concern and prompt increased monitoring, but they recommended instead increasing to weekly monitoring and adding the extra parameter of a doppler assessment. This would be equivalent to the specialist assessment recommended by the Green Top guideline because it would need to be carried out by the specialist core team (in line with recommendation 1.3.1) who have experience and knowledge of managing twin and triplet pregnancies. The committee agreed that this would not be inconsistent with the Green Top guideline.
The committee also agreed that the estimated fetal weights themselves should be taken into account. Based on the evidence they recommended the 10th centile for gestational age as a threshold for concern that should prompt increased monitoring.
The evidence was inconclusive about an exact threshold for referral to a tertiary level fetal medicine centre, so based on their own experience the committee decided that an EFW discordance of 25% or more (along with an EFW below the 10th centile) should warrant referral. At this level of discordance, there would be an increased risk of perinatal morbidity and mortality that should prompt intervention rather than increased assessment. The tertiary level fetal medicine centre would have the expertise to weigh up the benefits and risks of conservative management, birth or invasive fetal therapy to try to improve the chance of a positive pregnancy outcome.
## How the recommendations might affect practice
These recommendations are largely reinforcing current practice in twin pregnancy and should have a minimal impact on local ultrasound resourcing. They are consistent with other national and international guidance.
The recommendation to monitor all women with a triplet pregnancy at no more than 14‑day intervals (irrespective of chorionicity) is a change in practice, particularly for women with a trichorionic triamniotic pregnancy. For these women, previous recommendations suggested 4‑weekly scans. However, the change is justified because all types of triplet pregnancy are at high risk of fetal growth restriction. The recommendation should not have a significant impact on clinical resources because of the low number of women with a triplet pregnancy.
Return to recommendations
# Diagnostic monitoring for twin anaemia polycythaemia sequence
Recommendations 1.4.37 and 1.4.38
## Why the committee made the recommendations
There was limited evidence for screening and diagnostic monitoring for twin anaemia polycythaemia sequence (TAPS). The committee discussed, based on their expertise, that there is also limited evidence on the natural history of spontaneous TAPS and effective interventions for it in uncomplicated monochorionic pregnancies. They agreed that its incidence is likely to be low, so they could not recommend screening for it in women whose monochorionic pregnancy is uncomplicated.
The committee agreed that monitoring would be beneficial for women with the complications in recommendations 1.4.37 and 1.4.38. They recommended screening for TAPS in this population for 2 reasons:
Complicated monochorionic pregnancies have an increased risk of fetal and neonatal death and morbidity. Diagnosing TAPS as a further complication is likely to influence how the woman's pregnancy is managed, including the timing of preterm birth.
Advanced TAPS (stages 3 and 4) is associated with abnormal fetal umbilical artery and ductus venosus doppler parameters, or signs of fetal cardiac failure in the anaemic baby. These can also occur in a number of other conditions, so the diagnosis of severe TAPS (either alone or as a comorbidity) may be missed if it is not specifically screened for.
The committee concluded that for women who have a pregnancy in which TAPS is a comorbid complication or is of advanced stage, the risk to the babies without diagnosis and intervention is likely to be greater than the potential harms of interventions. These include preterm birth or potential in‑utero therapies, such as in‑utero transfusion, in pre-viable or extremely premature pregnancies.
The committee agreed that when TAPS is suspected, women should be referred to a tertiary level fetal medicine centre. They felt that the benefits of managing complicated monochorionic pregnancies in this setting would outweigh the potential disadvantages of inconvenience of travel and transfer to units away from home. The committee decided not to specify diagnostic criteria because they wanted to emphasise the importance of referral to a tertiary level referral centre when TAPS is suspected, so that decisions about further assessment and management can be made with each individual woman.
Given the limited evidence on the diagnostic accuracy of middle cerebral artery peak systolic velocity (MCA‑PSV) for all types of monochorionic twins, regardless of complications, and uncertainties about the natural history of TAPS and its management, the committee decided to make a recommendation for research on screening to detect twin anaemia polycythaemia sequence to inform future guidance.
## How the recommendations might affect practice
The recommendation may increase the number of assessments of women with complicated monochorionic pregnancies and referral for appropriate management. However, the committee agreed that any increase in referrals would be offset by the benefits of better detection and management of complicated monochorionic pregnancies.
Return to recommendations
# Preventing preterm birth
Recommendations 1.5.1 and 1.5.2
## Why the committee made the recommendations
The evidence for intramuscular progesterone in the prevention of spontaneous preterm birth showed it had no clinical benefit and, in some instances, had negative or unpleasant side effects, so it was not recommended.
The committee retained the existing 2011 recommendation that arabin pessary, bed rest, cervical cerclage and oral tocolytics should not be used routinely to prevent spontaneous preterm birth because there was still no evidence to support their use.
## Why the committee did not make a recommendation on vaginal progesterone
The committee decided not to make recommendations on the use of vaginal progesterone to prevent preterm birth because they knew about evidence that would be emerging about the use of progesterone in subgroups of women with a short cervix that could change their conclusions about its effectiveness. This also meant the committee preferred not to recommend cervical length screening (see the rationale section on cervical length screening in twin pregnancy). NICE will carry out an exceptional update based on the new evidence when it becomes available.
## How the recommendations might affect practice
The recommendations reinforce current practice.
Return to recommendations
# Planning birth: information and support
Recommendations 1.8.1 to 1.8.3
## Why the committee made the recommendations
The committee discussed the importance of providing care that is woman-centred, in which shared decision-making between the woman and her healthcare professional is essential. The committee agreed on the topics that need to be discussed with women to explain the available options and find out their wishes. Information needs to be tailored to each woman's pregnancy because some twin and triplet pregnancies carry more risks than others.
The committee acknowledged equality considerations for women who may have additional needs (such as needing an interpreter) in the context of providing information and communication. They cross-referred to NICE's guideline on patient experience in adult NHS services, which describes general good practice on how to do this.
Return to recommendations
# Timing of birth
Recommendations 1.9.1 to 1.9.12
## Why the committee made the recommendations
The committee agreed that it was critical to give women the information they need to participate in shared decisions about when their babies are born. This includes explaining the known risk of spontaneous preterm birth in twin and triplet pregnancy and its possible consequences, such as admission to a neonatal unit. The committee retained this advice from the 2011 guideline because it was consistent with their experience and knowledge. They agreed that this information is important for planning the timing of birth.
Women also need to know why it is recommended for them to have a planned birth by a particular week of pregnancy (also see when to offer planned birth). There is a trade-off between clinical benefits and harms when women have not given birth spontaneously by a given gestational age. These include the risks of neonatal mortality and morbidity associated with planned birth compared with the risks of stillbirth from continued pregnancy. The committee agreed that both timing and mode of birth should be discussed with women in the context of these potential risks. Women can use this advice to make an informed choice.
There was not enough good evidence to conclusively identify the optimal timing of birth according to chorionicity and amnionicity, so the committee also used their expertise and experience to make recommendations.
Evidence suggests a consistently higher fetal death rate (at all gestational ages) in monochorionic twin pregnancies than in dichorionic twin pregnancies. The committee therefore recommended earlier planned birth, at 36 weeks, for women with a monochorionic diamniotic pregnancy to reflect the higher risk and complexity of this type of pregnancy. This was consistent with the 2011 guideline and therefore corresponds to current clinical practice.
The committee also clarified the timing of birth for monochorionic monoamniotic twins, which was not explicitly covered by the 2011 guideline – the previous guideline did not divide monochorionic twins into diamniotic or monoamniotic groups. Based on some evidence and their own knowledge and experience, the committee recommended offering planned birth between 32+0 and 33+6 weeks because this timing did not appear to be associated with an increased risk of serious neonatal adverse outcomes.
The committee clarified the recommendations from the 2011 guideline by considering triplet pregnancies by type rather than as a single group. No evidence was found on timing of birth in triplet pregnancy but the committee agreed based on their own clinical experience that continuing an uncomplicated trichorionic triamniotic or a dichorionic triamniotic triplet pregnancy beyond 35+6 weeks of pregnancy would lead to an increased risk of fetal death (recommendation 1.9.7). Planned birth should therefore be offered at 35 weeks (recommendation 1.9.10).
Because of significant risks for the babies in complicated twin and triplet pregnancies, and the rareness of monochorionic triamniotic triplet pregnancies and triplet pregnancies with a shared amnion, timing of birth should be assessed and discussed individually (recommendations 1.9.8 and 1.9.11).
The committee highlighted that women's choice needs to be respected and that if a woman declines planned birth at the recommended time, she should be offered weekly appointments to minimise risk, monitor progress and help to identify any complications as soon as possible.
## How the recommendations might affect practice
The recommendations clarify the timing of when women with a monochorionic monoamniotic pregnancy should be offered planned birth. Although this is a change from the 2011 guideline, it reinforces current practice.
Return to recommendations
# Mode of birth
## Why the committee made the recommendations
Recommendations 1.10.1 to 1.10.5
For women who are more than 32 weeks pregnant and have an uncomplicated pregnancy, the evidence showed there is no significant difference in risk between vaginal birth and caesarean section, both for the woman and her babies. The committee's experience supported this, so they agreed that healthcare professionals should explain this to the woman and support her choice as long as the conditions in recommendation 1.10.1 are met and the first baby is in a head-first position.
There was only limited evidence about mode of birth when the first baby is not head first. The committee agreed that in their clinical experience, this carries a higher risk of problems such as cord accidents during birth. Because of this, a caesarean section is the safest option to offer women after 32 weeks and for women in established preterm labour between 26 and 32 weeks.
According to the evidence, not all women give birth according to their birth plan. The committee decided it was important to explain this to women so that they are prepared for the possibility of not giving birth in the way they prefer.
Recommendations 1.10.6 and 1.10.7
Monochorionic monoamniotic twin pregnancies and triplet pregnancies are the least common and highest-risk types of pregnancy and evidence about mode of birth was limited for these women. However, the committee agreed from their experience that caesarean section should be the preferred option and should be offered at the time the birth is planned to happen or after the diagnosis of established labour. If the first twin is close to being born vaginally there can be risks for the babies, so the committee decided that senior obstetric assessment would be needed.
## How the recommendations might affect practice
The recommendations largely reflect current practice. Supporting the woman's preferred mode of birth might increase the number of planned vaginal births, which may reduce costs. This is likely to be partly offset by the fact that a proportion of these women would go on to give birth by caesarean section for one or both twins.
Return to recommendations
# Fetal monitoring during labour in twin pregnancy
Recommendations 1.11.1 to 1.11.21
## Why the committee made the recommendations
There was no evidence on the most effective method of fetal monitoring in labour for improving outcomes in women with a twin pregnancy and their babies, so the committee used their expertise and experience along with NICE guidance on fetal monitoring in singleton pregnancy (NICE's guideline on intrapartum care for healthy women and babies) to make recommendations. They agreed that clinically it is well recognised that twins are at increased risk of complications during labour, especially the second twin, so they recommended continuous fetal monitoring. Continuous cardiotocography monitoring is the only modality that can assess both twin fetal heart rates simultaneously during established labour.
The committee agreed on the importance of explaining to women the lack of evidence about monitoring with cardiotocography specifically in twins, and that recommendations are based on NICE guidance for singleton pregnancy (intrapartum care for healthy women and babies). Healthcare professionals should provide a detailed explanation of what cardiotocography involves and why it is used and give women a chance to discuss their wishes and concerns. Recommending this before 28 weeks gives women time to make an informed decision and takes into account the fact that many twins are born prematurely.
The committee recommended offering continuous cardiotocography to women in established labour with a twin pregnancy over 26 weeks because at this gestational age, neonatal survival rates improve and the risks of neonatal morbidity from preterm birth are falling. The advantages of using cardiotocography over intermittent auscultation monitoring include the ability to assess baseline variability and monitor continuously.
Performing a portable ultrasound (bedside) scan at the start of established labour not only helps to confirm which is the first and which the second twin and locate the fetal hearts but also confirms presentation – malpresentation is more common in twin pregnancy than singleton pregnancy and an emergency caesarean section may be indicated if the first twin presents in the breech position.
The committee recommended involving a senior obstetrician to decide how twins are monitored in established extreme premature labour (23+0 to 25+6 weeks of pregnancy) in line with NICE's guideline on premature labour and birth in singleton pregnancies.
The committee recommended dual channel monitors to make sure both fetal heart rates could be monitored and displayed accurately at the same time on the same record during labour. Maternal pulse monitoring should be displayed on the same continuous cardiotocography trace to ensure 2 fetal heart rates were being recorded (without mistaking the maternal heart rate for a fetal heart rate).
The committee recommended classifying and interpreting cardiotocography in a way that is broadly consistent with the NICE guideline on intrapartum care for healthy women and babies, but with additional considerations specific to twins. These include regarding twin pregnancy as a fetal clinical risk factor when classifying a cardiotocograph finding as 'abnormal' or 'non-reassuring'. This would result in a lower threshold for classifying a cardiotocograph as pathological.
Failing to successfully monitor one or both babies could lead to adverse perinatal outcomes so the committee recommended involving a senior healthcare professional. They also recommended applying a fetal scalp electrode to the first baby while continuing abdominal monitoring of the second baby if abdominal monitoring is unsuccessful or there are concerns about synchronicity of the fetal hearts. This should only be carried out after 34 weeks of pregnancy and if there are no contraindications such as HIV, hepatitis or maternal thrombocytopenia.
If there is 'suspicious' cardiotocography in the first baby during established labour, the committee recommended involving a senior healthcare professional to help manage reversible causes such as dehydration, infection or positional loss of contact, before applying a fetal scalp electrode to the first baby (in the absence of contraindications) while continuing abdominal monitoring of the second baby.
In case of 'pathological' cardiotocography in the first baby, a senior healthcare professional should discuss with the woman using fetal blood sampling in the first baby if the benefits are likely to outweigh the potential risks – these include avoiding a second-stage caesarean section, which increases maternal morbidity and mortality.
After the first baby is born, cardiotocographic monitoring of the second baby should continue to detect any 'suspicious' or 'pathological' cardiotocography that could lead to the need for a caesarean section.
The committee did not make recommendations for women with a triplet pregnancy because most of these women give birth by caesarean section. Monitoring in labour would therefore be rare and decisions would be made on an individual basis.
## How the recommendations might affect practice
The recommendations are consistent with the NICE guideline on intrapartum care for healthy women and babies taking into account the twin-specific measures. It is not anticipated that the recommendations will lead to major changes in current clinical practice.
Return to recommendations
# Analgesia
Recommendations 1.12.1 to 1.12.3
## Why the committee made the recommendations
There is limited evidence on analgesia in labour for women with a twin pregnancy, and no evidence for women with a triplet pregnancy, so the committee used their expertise and experience along with the very limited evidence to make recommendations. They agreed that there is variation in practice in relation to when healthcare professionals discuss analgesia and anaesthesia with women and what they should discuss, so they specified when this should happen during pregnancy and what to cover.
Women with a twin or triplet pregnancy have an increased risk of intervention in labour, including assisted birth or caesarean section for one or more of the babies, and additional internal manoeuvres. Having an epidural in place allows analgesia or anaesthesia to be given quickly when it is needed, reducing the potential need for emergency general anaesthesia.
The limited evidence suggested that having an epidural in place also reduces the need for emergency caesarean section for the second twin after vaginal birth of the first twin, possibly by allowing more effective internal manoeuvres to allow the second twin to be born vaginally.
## How the recommendations might affect practice
The recommendations reinforce current best practice.
Return to recommendations
# Managing the third stage of labour
Recommendations 1.13.1 to 1.13.9
## Why the committee made the recommendations
The evidence was very limited, so the committee used their clinical expertise and experience to make recommendations. Multiple pregnancy is a risk factor for postpartum haemorrhage (see NICE's guideline on intrapartum care for healthy women and babies) because of over-distension of the uterus and enlarged placenta(s). The committee agreed that healthcare professionals should explain this to women in the antenatal period and assess and re-evaluate each woman's individual risk as her pregnancy progresses.
Because of the risk of postpartum haemorrhage, the committee agreed that active management of the third stage of labour using uterotonics should be offered to all women, and physiological management should not be offered.
It is already well-established as current practice and is supported by the committee's experience that when women have more than 1 risk factor for postpartum haemorrhage, additional uterotonics can reduce this risk. There is no clear evidence on the comparative effectiveness of different uterotonics in twin or triplet pregnancy. Each uterotonic has risk factors and contraindications, so the committee did not recommend a specific one.
The committee agreed on the importance of having existing intravenous access and blood products readily available in case a postpartum haemorrhage does occur.
## How the recommendations might affect practice
The recommendations reinforce current best practice.
Return to recommendations# Context
Twins or triplets occur in approximately 1 in 60 pregnancies (16 in every 1,000 women giving birth in 2015 had a multiple birth), and 3% of live-born babies are from multiple gestations. The incidence of multiple births has risen in the past 30 years. This is due mainly to increasing use of assisted reproduction techniques, including in vitro fertilisation (IVF), and also to changing demographics as women defer pregnancy and twins are more common at later ages (102 in every 1,000 women giving birth in 2015 were aged 45 or over).
Women with a twin or triplet pregnancy are at higher risk compared with women with a singleton pregnancy. Adverse outcomes are more likely, both for the woman and her babies, during the prenatal and intrapartum periods. Because of this, women need increased monitoring and more contact with healthcare professionals during their pregnancy.
Assessment and planning start as soon as the twin or triplet pregnancy is detected and continue throughout pregnancy at each antenatal contact. Determining the chorionicity and amnionicity of the pregnancy allows the risk to be stratified and the number of antenatal visits and ultrasound examinations to be planned. It is important that ultrasound surveillance is carefully scheduled to monitor for complications including selective fetal growth restriction, feto-fetal transfusion syndrome and twin anaemia polycythaemia sequence (TAPS).
Identifying complications earlier means that decisions can be made promptly about referring the woman to a tertiary level fetal medicine centre. It also informs discussions with women in their second and third trimesters about their hopes and wishes in relation to timing and mode of birth, and the management of the intrapartum period (including fetal monitoring, analgesia and the third stage of labour).
This guideline replaces the previous NICE guideline on multiple pregnancy (CG129). The surveillance process found new evidence and identified a need to include intrapartum care, an area that was not included in the original guideline. In current practice, a significant proportion of multiple pregnancy losses occur intrapartum and the risk of adverse perinatal outcomes is greater in multiple than in singleton pregnancies.
The guideline updates recommendations on screening and monitoring for selective fetal growth restriction and feto-fetal transfusion syndrome, and makes new recommendations on screening and monitoring for TAPS; screening for and preventing preterm birth; and timing of birth. New recommendations on intrapartum care cover mode of birth, fetal monitoring, analgesia and managing the third stage of labour.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidance explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nType of pregnancy\n\nChorionicity and amnionicity\n\nDichorionic diamniotic twins\n\nBoth babies have a separate placenta and amniotic sac.\n\nMonochorionic diamniotic twins\n\nBoth babies share a placenta but have separate amniotic sacs.\n\nMonochorionic monoamniotic twins\n\nBoth babies share a placenta and amniotic sac.\n\nTrichorionic triamniotic triplets\n\nEach baby has a separate placenta and amniotic sac.\n\nDichorionic triamniotic triplets\n\nOne baby has a separate placenta and 2 of the babies share a placenta.\n\nAll 3 babies have separate amniotic sacs.\n\nDichorionic diamniotic triplets\n\nOne baby has a separate placenta and amniotic.\n\nTwo of the babies share a placenta and amniotic sac.\n\nMonochorionic triamniotic triplets\n\nAll 3 babies share 1 placenta.\n\nAll 3 babies have separate amniotic sacs.\n\nMonochorionic diamniotic triplets\n\nAll 3 babies share 1 placenta.\n\nOne baby has a separate amniotic sac and 2 babies share 1 sac.\n\nMonochorionic monoamniotic triplets\n\nAll 3 babies share a placenta and amniotic sac.\n\n# Determining gestational age and chorionicity\n\n## Gestational age\n\nOffer women with a twin or triplet pregnancy a first trimester ultrasound scan to estimate gestational age and determine chorionicity and amnionicity (ideally, these should all be performed at the same scan; see the recommendations on determining chorionicity and amnionicity and assigning nomenclature). See the recommendations on screening for chromosomal conditions. [2011, amended 2019]\n\nEstimate gestational age from the largest baby in a twin or triplet pregnancy to avoid the risk of estimating it from a baby with early growth pathology. \n\n## Chorionicity and amnionicity\n\nDetermine chorionicity and amnionicity at the time of detecting a twin or triplet pregnancy by ultrasound using:\n\nthe number of placental masses\n\nthe presence of amniotic membrane(s) and membrane thickness\n\nthe lambda or T‑sign. [2011, amended 2019]\n\nAssign nomenclature to babies (for example, upper and lower, or left and right) in a twin or triplet pregnancy, and document this clearly in the woman's notes to ensure consistency throughout pregnancy. \n\nIf a woman with a twin or triplet pregnancy presents after 14+0 weeks, determine chorionicity and amnionicity at the earliest opportunity by ultrasound using all of the following:\n\nthe number of placental masses\n\nthe presence of amniotic membrane(s) and membrane thickness\n\nthe lambda or T-sign\n\ndiscordant fetal sex. [2011, amended 2019]\n\nIf it is not possible to determine chorionicity or amnionicity by ultrasound at the time of detecting the twin or triplet pregnancy, seek a second opinion from a senior sonographer or refer the woman to a healthcare professional who is competent in determining chorionicity and amnionicity by ultrasound scan as soon as possible. [2011, amended 2019]\n\nIf it is difficult to determine chorionicity, even after referral (for example, because the woman has booked late in pregnancy), manage the pregnancy as a monochorionic pregnancy until proved otherwise. \n\nProvide regular training so that sonographers can identify the lambda or T-sign accurately and confidently. Less experienced sonographers should have support from senior colleagues. \n\nTraining should cover ultrasound scan measurements needed for women who book after 14+0 weeks and should emphasise that the risks associated with twin and triplet pregnancy are determined by chorionicity and not zygosity. \n\nConduct regular clinical audits to evaluate the accuracy of determining chorionicity and amnionicity. [2011, amended 2019]\n\nIf transabdominal ultrasound scan views are poor because of a retroverted uterus or a high BMI, use a transvaginal ultrasound scan to determine chorionicity and amnionicity. [2011, amended 2019]\n\nDo not use 3‑dimensional (3‑D) ultrasound scans to determine chorionicity and amnionicity. [2011, amended 2019]\n\nNetworks should agree care pathways for managing all twin and triplet pregnancies to ensure that each woman has a care plan in place that is appropriate for the chorionicity and amnionicity of her pregnancy. [2011, amended 2019]\n\n# General care\n\n## Information and emotional support\n\nExplain sensitively the aims and possible outcomes of all screening and diagnostic tests to women with a twin or triplet pregnancy to minimise their anxiety. \n\n## Diet, lifestyle and nutritional supplements\n\nGive women with a twin or triplet pregnancy the same advice about diet, lifestyle and nutritional supplements as in routine antenatal care (see NICE's guideline on antenatal care for uncomplicated pregnancies). \n\nBe aware of the higher incidence of anaemia in women with a twin or triplet pregnancy compared with women with a singleton pregnancy. \n\nPerform a full blood count at 20 to 24\xa0weeks to identify women with a twin or triplet pregnancy who need early supplementation with iron or folic acid (this is in addition to the test for anaemia at the routine booking appointment recommended in NICE's guideline on antenatal care for uncomplicated pregnancies). Repeat at 28\xa0weeks as in routine antenatal care. \n\n# Delivery of antenatal and intrapartum care\n\n## Antenatal care\n\nAntenatal clinical care for women with a twin or triplet pregnancy should be provided by a nominated multidisciplinary team consisting of:\n\na core team of named specialist obstetricians, specialist midwives and sonographers, all of whom have experience and knowledge of managing twin and triplet pregnancies\n\nan enhanced team for referrals, which should include:\n\n\n\na perinatal mental health professional\n\na women's health physiotherapist\n\nan infant feeding specialist\n\na dietitian. [2011, amended 2019]\n\n\n\nMembers of the enhanced team should have experience and knowledge relevant to twin and triplet pregnancies. \n\nDo not routinely refer all women with a twin or triplet pregnancy to the enhanced team but base the decision to refer on each woman's needs. \n\nCoordinate clinical care for women with a twin or triplet pregnancy to:\n\nminimise the number of hospital visits\n\nprovide care as close to the woman's home as possible\n\nprovide continuity of care within and between hospitals and the community. \n\nThe core team should offer information and emotional support specific to twin and triplet pregnancies at their first contact with the woman and provide ongoing opportunities for further discussion and advice including:\n\nantenatal and postnatal mental health and wellbeing\n\nantenatal nutrition (see the recommendation on giving advice in the section on diet, lifestyle and nutritional supplements)\n\nthe risks, symptoms and signs of preterm labour and the potential need for corticosteroids for fetal lung maturation\n\nlikely timing of birth (see the section on timing of birth) and possible modes of birth (see the section on mode of birth)\n\nbreastfeeding\n\nparenting. \n\n## Intrapartum care\n\nIntrapartum care for women with a twin or triplet pregnancy should be provided by a multidisciplinary team of obstetricians and midwives who have experience and knowledge of managing twin and triplet pregnancies in the intrapartum period. \n\nFor a short explanation of why the committee made the 2019 recommendation and how it might affect practice, see the rationale and impact on intrapartum care\xa0.\n\nLoading. Please wait.\n\n## Schedule of specialist antenatal appointments\n\nThe schedule of specialist appointments is also shown as part of a multiple pregnancy antenatal care resource produced by Twins Trust and endorsed by NICE.\n\nOffer women with an uncomplicated dichorionic diamniotic twin pregnancy at least 8\xa0antenatal appointments with a healthcare professional from the core team. At least 2\xa0of these appointments should be with the specialist obstetrician.\n\nCombine appointments with scans when crown–rump length measures from 45.0\xa0mm to 84.0\xa0mm (at approximately 11+2 weeks to 14+1 weeks) and then at estimated gestations of 20, 24, 28, 32 and 36\xa0weeks.\n\nOffer additional appointments without scans at 16\xa0and 34\xa0weeks. [2011, amended 2019]\n\nOffer women with an uncomplicated monochorionic diamniotic twin pregnancy at least 11\xa0antenatal appointments with a healthcare professional from the core team. At least 2\xa0of these appointments should be with the specialist obstetrician.\n\nCombine appointments with scans when crown–rump length measures from 45.0\xa0mm to 84.0\xa0mm (at approximately 11+2 weeks to 14+1 weeks) and then at estimated gestations of 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34\xa0weeks. [2011, amended 2019]\n\nOffer women with an uncomplicated trichorionic triamniotic triplet pregnancy at least 9\xa0antenatal appointments with a healthcare professional from the core team. At least 2\xa0of these appointments should be with the specialist obstetrician.\n\nCombine appointments with scans when crown–rump length measures from 45.0\xa0mm to 84.0\xa0mm (at approximately 11+2 weeks to 14+1 weeks) and then at estimated gestations of 20, 24, 26, 28, 30, 32 and 34\xa0weeks.\n\nOffer an additional appointment without a scan at 16\xa0weeks. [2011, amended 2019]\n\nOffer women with a dichorionic triamniotic or monochorionic triamniotic triplet pregnancy at least 11\xa0antenatal appointments with a healthcare professional from the core team. At least 5\xa0of these appointments should be with the specialist obstetrician.\n\nCombine appointments with scans when crown–rump length measures from 45.0\xa0mm to 84.0\xa0mm (at approximately 11+2 weeks to 14+1 weeks) and then at estimated gestations of 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34\xa0weeks. [2011, amended 2019]\n\nOffer women with a twin or triplet pregnancy involving a shared amnion individualised care from a consultant in a tertiary level fetal medicine centre (see the recommendation on indications for referral to a tertiary level fetal medicine centre). \n\n# Fetal complications\n\n## Information about screening\n\nA healthcare professional with experience of caring for women with twin and triplet pregnancies should offer information and counselling to women before and after every screening test. \n\nInform women with a twin or triplet pregnancy about the complexity of decisions they may need to make depending on the outcomes of screening, including different options according to the chorionicity and amnionicity of the pregnancy. [2011, amended 2019]\n\n## Screening for chromosomal conditions\n\nOffer women with a twin pregnancy information on and screening for Down's syndrome, Edwards' syndrome and Patau's syndrome as outlined in the NHS fetal anomaly screening programme (FASP). \n\nBefore offering screening for Down's syndrome, Edwards' syndrome and Patau's syndrome, give women with a triplet pregnancy information about:\n\nthe greater likelihood of Down's syndrome, Edwards' syndrome and Patau's syndrome in triplet pregnancy\n\nthe different options for screening\n\nthe increased false positive rate of screening tests in triplet pregnancy\n\ntheir greater likelihood of being offered invasive testing\n\ntheir greater likelihood of complications of invasive testing\n\nthe physical risks and psychological implications in the short and long term relating to selective fetal reduction. [2011, amended 2019]\n\nHealthcare professionals who screen for Down's syndrome, Edwards' syndrome and Patau's syndrome in trichorionic triplet pregnancy should:\n\nmap the fetal positions\n\nuse nuchal translucency and maternal age to screen for Down's syndrome, Edwards' syndrome and Patau's syndrome when crown–rump length measures from 45.0\xa0mm to 84.0\xa0mm (at approximately 11+2\xa0weeks to 14+1\xa0weeks)\n\ncalculate the chance of Down's syndrome, Edwards' syndrome and Patau's syndrome for each fetus. [2011, amended 2019]\n\nRefer women with a dichorionic and monochorionic triplet pregnancy who want to have screening for Down's syndrome, Edwards' syndrome and Patau's syndrome to a tertiary level fetal medicine centre. \n\nDo not use second trimester serum screening for Down's syndrome in triplet pregnancies. [2011, amended 2019]\n\nRefer women with any type of triplet pregnancy who have a higher chance of Down's syndrome, Edwards' syndrome or Patau's syndrome (use a threshold of 1 in 150 at term) to a fetal medicine specialist in a tertiary-level fetal medicine centre. [2011, amended 2019]\n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on screening for chromosomal conditions\xa0.\n\nLoading. Please wait.\n\n## Screening for structural abnormalities\n\nOffer screening for structural abnormalities (such as cardiac abnormalities) in twin and triplet pregnancies as in routine antenatal care; see NICE's guideline on antenatal care for uncomplicated pregnancies and the NHS fetal anomaly screening programme. \n\nConsider scheduling ultrasound scans in twin and triplet pregnancies at a slightly later gestational age than in singleton pregnancies and be aware that the scans will take longer to perform. \n\nAllow 45\xa0minutes for the anomaly scan in twin and triplet pregnancies (as recommended by FASP). \n\nAllow 30\xa0minutes for growth scans in twin and triplet pregnancies. \n\n## Screening for preterm birth\n\nAlso see the section on preventing preterm birth.\n\nExplain to women and their family members or carers (as appropriate) that:\n\nthey have a higher risk of spontaneous preterm birth (see the section on timing of birth) than women with a singleton pregnancy and\n\nthis risk is further increased if they have other risk factors, such as a spontaneous preterm birth in a previous pregnancy. \n\nDo not use fetal fibronectin testing alone to predict the risk of spontaneous preterm birth in twin and triplet pregnancy. \n\nDo not use home uterine activity monitoring to predict the risk of spontaneous preterm birth in twin and triplet pregnancy. \n\nFor a short explanation of why the committee made the 2019 recommendations (and why they did not make a recommendation on cervical length screening) and how they might affect practice, see the rationale and impact section on screening for preterm birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: screening for spontaneous preterm birth.\n\nLoading. Please wait.\n\n## Screening for fetal growth restriction and feto-fetal transfusion syndrome in the first trimester\n\nDo not offer women with a twin or triplet pregnancy screening for fetal growth restriction or feto-fetal transfusion syndrome in the first trimester. \n\nFor a short explanation of why the committee made this 2019 recommendation and how it might affect practice, see the rationale and impact section on screening for fetal growth restriction and feto-fetal transfusion syndrome in the first trimester\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: screening for feto-fetal transfusion syndrome and evidence review B: screening for fetal growth restriction.\n\nLoading. Please wait.\n\n## Diagnostic monitoring for fetal growth restriction in dichorionic twin and trichorionic triplet pregnancies\n\nDo not use abdominal palpation or symphysis–fundal height measurements to monitor for fetal growth restriction in a dichorionic twin or trichorionic triplet pregnancy. \n\nAt each ultrasound scan from 24\xa0weeks, offer women with a dichorionic twin or trichorionic triplet pregnancy diagnostic monitoring for fetal weight discordance using 2\xa0or more biometric parameters and amniotic fluid levels. To assess amniotic fluid levels, measure the deepest vertical pocket (DVP) on either side of the amniotic membrane. \n\nContinue monitoring for fetal weight discordance at intervals that do not exceed:\n\ndays for women with a dichorionic twin pregnancy\n\ndays for women with a trichorionic triplet pregnancy. \n\nCalculate and document estimated fetal weight (EFW) discordance for dichorionic twins using the formula below : ([EFW larger fetus − EFW smaller fetus] ÷ EFW larger fetus) ×\xa0100\n\nCalculate and document EFW discordance for trichorionic triplets using the formula below :([EFW largest fetus − EFW smallest fetus] ÷ EFW largest fetus) ×\xa0100and([EFW largest fetus − EFW middle fetus] ÷ EFW largest fetus) ×\xa0100\n\nIncrease diagnostic monitoring in the second and third trimesters to at least weekly, and include doppler assessment of the umbilical artery flow for each baby, if:\n\nthere is an EFW discordance of 20% or more and/or\n\nthe EFW of any of the babies is below the 10th centile for gestational age. \n\nRefer women with a dichorionic twin or trichorionic triplet pregnancy to a tertiary level fetal medicine centre if there is an EFW discordance of 25% or more and the EFW of any of the babies is below the 10th centile for gestational age because this is a clinically important indicator of selective fetal growth restriction. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on diagnostic monitoring for fetal growth restriction in dichorionic twin and trichorionic triplet pregnancies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: screening for fetal growth restriction.\n\nLoading. Please wait.\n\n## Diagnostic monitoring for complications of monochorionicity in twin and triplet pregnancy\n\nA monochorionic twin or triplet pregnancy is one in which any of the babies share a placenta and a chorionic (outer) membrane. This includes monochorionic twins and dichorionic and monochorionic triplets.\n\nOffer women simultaneous monitoring for feto-fetal transfusion syndrome, fetal growth restriction and advanced-stage twin anaemia polycythaemia sequence (TAPS) at every ultrasound assessment to monitor effectively for all complications of monochorionicity. Explain that the relative likelihood of each complication changes with advancing gestation but that they can all occur at any gestational age. \n\nOffer diagnostic monitoring for feto-fetal transfusion syndrome to women with a monochorionic twin or triplet pregnancy. Monitor with ultrasound every 14\xa0days from 16\xa0weeks until birth. \n\nUse ultrasound assessment, with a visible amniotic membrane within the measurement image, to monitor for feto-fetal transfusion syndrome. Measure the DVP depths of amniotic fluid on either side of the amniotic membrane. \n\nIncrease the frequency of diagnostic monitoring for feto-fetal transfusion syndrome in the woman's second and third trimester to at least weekly if there are concerns about differences between the babies' amniotic fluid level (a difference in DVP depth of 4\xa0cm or more). Include doppler assessment of the umbilical artery flow for each baby. \n\nRefer the woman to a tertiary level fetal medicine centre if feto-fetal transfusion syndrome is diagnosed, based on the following:\n\nthe amniotic sac of 1 baby has a DVP depth of less than 2\xa0cm and\n\nthe amniotic sac of another baby has a DVP depth of:\n\n\n\nover 8\xa0cm before 20+0\xa0weeks of pregnancy or\n\nover 10\xa0cm from 20+0\xa0weeks. \n\n\n\nRefer the woman to her named specialist obstetrician for multiple pregnancy in her second or third trimester for further assessment and monitoring if:\n\nthe amniotic sac of 1\xa0baby has a DVP depth in the normal range and\n\nthe amniotic sac of another baby has a DVP depth of:\n\n\n\nless than 2\xa0cm or\n\ncm or more. \n\n\n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on diagnostic monitoring for feto-fetal transfusion syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: screening for feto-fetal transfusion syndrome.\n\nLoading. Please wait.\n\nDo not use abdominal palpation or symphysis–fundal height measurements to monitor for fetal growth restriction in women with a monochorionic twin or triplet pregnancy. \n\nAt each ultrasound scan from 16\xa0weeks, offer women with a monochorionic twin or triplet pregnancy diagnostic monitoring for fetal weight discordance using 2\xa0or more biometric parameters (in addition to amniotic fluid level assessment). To assess amniotic fluid levels, measure the DVP on either side of the amniotic membrane. \n\nContinue monitoring women with a monochorionic twin or triplet pregnancy for fetal weight discordance at intervals that should not exceed 14\xa0days. \n\nCalculate and document EFW discordance in monochorionic twins using the formula below : ([EFW larger fetus − EFW smaller fetus] ÷ EFW larger fetus) ×\xa0100\n\nThe named specialist obstetrician should review the estimated fetal weights of dichorionic and monochorionic triplets and calculate EFW discordance based on their understanding of the implications of chorionicity. \n\nIncrease diagnostic monitoring in the second and third trimesters to at least weekly, and include doppler assessment of the umbilical artery flow for each baby, if:\n\nthere is an EFW discordance of 20% or more and/or\n\nthe EFW of any of the babies is below the 10th centile for gestational age. \n\nRefer women with a monochorionic twin or triplet pregnancy to a tertiary level fetal medicine centre if there is an EFW discordance of 25% or more and the EFW of any of the babies is below the 10th centile for gestational age because this is a clinically important indicator of selective fetal growth restriction. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see rationale and impact section on diagnostic monitoring for fetal growth restriction in monochorionic pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: screening for fetal growth restriction.\n\nLoading. Please wait.\n\nOffer weekly ultrasound monitoring for TAPS from 16\xa0weeks of pregnancy using middle cerebral artery peak systolic velocity (MCA‑PSV) to women whose pregnancies are complicated by:\n\nfeto-fetal transfusion syndrome that has been treated by fetoscopic laser therapy or\n\nselective fetal growth restriction (defined by an EFW discordance of 25% or more and an EFW of any of the babies below the 10th centile for gestational age). \n\nFor women with a monochorionic pregnancy showing any of the following:\n\ncardiovascular compromise (such as fetal hydrops or cardiomegaly) or\n\nunexplained isolated polyhydramnios or\n\nabnormal umbilical artery perform ultrasound MCA‑PSV measurements to help detect advanced-stage TAPS, and seek management advice immediately from a tertiary level fetal medicine specialist. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on diagnostic monitoring for TAPS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: screening for TAPS.\n\nLoading. Please wait.\n\n# Preventing preterm birth\n\nThe committee did not make any recommendations on vaginal progesterone for preventing preterm birth in twin pregnancies because of emerging evidence in this area. NICE will carry out an exceptional update based on the new evidence when it becomes available.\n\nDo not offer intramuscular progesterone to prevent spontaneous preterm birth in women with a twin or triplet pregnancy. \n\nDo not offer the following interventions (alone or in combination) routinely to prevent spontaneous preterm birth in women with a twin or triplet pregnancy:\n\narabin pessary\n\nbed rest\n\ncervical cerclage\n\noral tocolytics. \n\nFor a short explanation of why the committee made the 2019 recommendations (and why they did not make a recommendation on vaginal progesterone) and how they might affect practice, see the rationale and impact section on preventing preterm birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: interventions to prevent spontaneous preterm birth.\n\nLoading. Please wait.\n\n## Corticosteroids\n\nInform women with a twin or triplet pregnancy of their increased risk of preterm birth (see the recommendation explaining screening for preterm birth to women and their family members in the section on screening for preterm birth) and about the benefits of targeted corticosteroids. \n\nDo not use single or multiple untargeted (routine) courses of corticosteroids in twin or triplet pregnancy. Inform women that there is no benefit in using untargeted administration of corticosteroids. \n\n# Maternal complications\n\n## Hypertension\n\nMeasure blood pressure and test urine for proteinuria to screen for hypertensive disorders at each antenatal appointment in a twin and triplet pregnancy in line with NICE's guideline on antenatal care for uncomplicated pregnancies. \n\nAdvise women with a twin or triplet pregnancy to take low-dose aspirin daily from 12\xa0weeks until the birth of the babies if they have 2\xa0or more of the risk factors specified in NICE's guideline on hypertension in pregnancy. [2011, amended 2019]In September 2019, this was an off-label use of aspirin. See NICE's information on prescribing medicines.\n\n# Indications for referral to a tertiary level fetal medicine centre\n\nSeek a consultant opinion from a tertiary level fetal medicine centre for:\n\npregnancies with a shared amnion:\n\n\n\nmonochorionic monoamniotic twins\n\ndichorionic diamniotic triplets\n\nmonochorionic diamniotic triplets\n\nmonochorionic monoamniotic triplets\n\n\n\npregnancies complicated by any of the following:\n\n\n\nfetal weight discordance (of 25% or more) and an EFW of any of the babies below the 10th centile for gestational age\n\nfetal anomaly (structural or chromosomal)\n\ndiscordant fetal death\n\nfeto-fetal transfusion syndrome\n\ntwin reverse arterial perfusion sequence (TRAP)\n\nconjoined twins or triplets\n\nsuspected TAPS (see the recommendations in the section on twin anaemia polycythaemia sequence). [2011, amended 2019]\n\n\n\n# Planning birth: information and support\n\nFrom 24 weeks in a twin or triplet pregnancy, discuss with the woman (and her family members or carers, as appropriate) her plans and wishes for the birth of her babies. Provide information that is tailored to each woman's pregnancy, taking into account her needs and preferences. Revisit these conversations whenever clinically indicated and whenever the woman wants to. \n\nEnsure the following has been discussed by 28\xa0weeks at the latest:\n\nplace of birth and the possible need to transfer in case of preterm birth\n\ntiming and possible modes of birth\n\nanalgesia during labour (or for caesarean birth)\n\nintrapartum fetal heart monitoring\n\nmanagement of the third stage of labour. \n\nFollow NICE's guideline on patient experience in adult NHS services for how to provide information and communicate with women and their families and carers. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on planning birth\xa0.\n\nLoading. Please wait.\n\n# Timing of birth\n\n## Antenatal information for women\n\nExplain to women with a twin pregnancy that about 60 in 100 twin pregnancies result in spontaneous birth before 37\xa0weeks. \n\nExplain to women with a triplet pregnancy that about 75 in 100 triplet pregnancies result in spontaneous birth before 35\xa0weeks. \n\nExplain to women with a twin or triplet pregnancy that spontaneous preterm birth and planned preterm birth are associated with an increased risk of admission to a neonatal unit. \n\nExplain to women with an uncomplicated dichorionic diamniotic twin pregnancy that:\n\nplanned birth from 37+0\xa0weeks does not appear to be associated with an increased risk of serious neonatal adverse outcomes and\n\ncontinuing the pregnancy beyond 37+6\xa0weeks increases the risk of fetal death. \n\nExplain to women with an uncomplicated monochorionic diamniotic twin pregnancy that:\n\nplanned birth from 36+0 weeks does not appear to be associated with an increased risk of serious neonatal adverse outcomes and\n\ncontinuing the pregnancy beyond 36+6 weeks increases the risk of fetal death. \n\nExplain to women with an uncomplicated monochorionic monoamniotic twin pregnancy that planned birth between 32+0 and 33+6\xa0weeks does not appear to be associated with an increased risk of serious neonatal adverse outcomes. Also explain that:\n\nthese babies will usually need to be admitted to the neonatal unit and have an increased risk of respiratory problems\n\ncontinuing the pregnancy beyond 33+6\xa0weeks increases the risk of fetal death. \n\nExplain to women with an uncomplicated trichorionic triamniotic or dichorionic triamniotic triplet pregnancy that continuing the pregnancy beyond 35+6\xa0weeks increases the risk of fetal death. \n\nExplain to women with a monochorionic triamniotic triplet pregnancy or a triplet pregnancy that involves a shared amnion that the timing of birth will be decided and discussed with each woman individually. \n\n## When to offer planned birth\n\nOffer planned birth at 37\xa0weeks to women with an uncomplicated dichorionic diamniotic twin pregnancy. \n\nOffer planned birth as follows, after a course of antenatal corticosteroids has been considered (see the section on maternal corticosteroids in NICE's guideline on preterm labour and birth):\n\nat 36\xa0weeks for women with an uncomplicated monochorionic diamniotic twin pregnancy\n\nbetween 32+0 and 33+6\xa0weeks for women with an uncomplicated monochorionic monoamniotic twin pregnancy\n\nat 35\xa0weeks for women with an uncomplicated trichorionic triamniotic or dichorionic triamniotic triplet pregnancy. \n\nOffer an individual assessment to determine the timing of planned birth in women with any of the following:\n\na complicated twin or triplet pregnancy\n\na monochorionic triamniotic triplet pregnancy\n\na triplet pregnancy that involves a shared amnion. \n\nFor women who decline planned birth at the timing recommended in recommendations 1.9.9 and 1.9.10, offer weekly appointments with the specialist obstetrician. At each appointment, offer an ultrasound scan and perform assessments of amniotic fluid level and doppler of the umbilical artery flow for each baby in addition to fortnightly fetal growth scans. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on timing of birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: timing of birth.\n\nLoading. Please wait.\n\n# Mode of birth\n\n## Twin pregnancy: dichorionic diamniotic or monochorionic diamniotic\n\nExplain to women with an uncomplicated twin pregnancy planning their mode of birth that planned vaginal birth and planned caesarean section are both safe choices for them and their babies if all of the following apply:\n\nthe pregnancy remains uncomplicated and has progressed beyond 32\xa0weeks\n\nthere are no obstetric contraindications to labour\n\nthe first baby is in a cephalic (head-first) presentation\n\nthere is no significant size discordance between the twins. \n\nExplain to women with an uncomplicated twin pregnancy that for women giving birth after 32\xa0weeks (see recommendation 1.10.1):\n\nmore than a third of women who plan a vaginal birth go on to have a caesarean section\n\nalmost all women who plan a caesarean section do have one, but a few women have a vaginal birth before caesarean section can be carried out\n\na small number of women who plan a vaginal birth will need an emergency caesarean section to deliver the second twin after vaginal birth of the first twin. \n\nOffer caesarean section to women if the first twin is not cephalic at the time of planned birth. \n\nOffer caesarean section to women in established preterm labour between 26\xa0and 32\xa0weeks if the first twin is not cephalic. \n\nOffer an individualised assessment of mode of birth to women in suspected, diagnosed or established preterm labour before 26\xa0weeks. Take into account the risks of caesarean section (see NICE's guideline on preterm labour and birth) and the chance of survival of the babies. \n\n## Twin pregnancy: monochorionic monoamniotic\n\nOffer a caesarean section to women with a monochorionic monoamniotic twin pregnancy:\n\nat the time of planned birth (between 32+0 and 33+6\xa0weeks) or\n\nafter any complication is diagnosed in her pregnancy requiring earlier delivery or\n\nif she is in established preterm labour, and gestational age suggests there is a reasonable chance of survival of the babies (unless the first twin is close to vaginal birth and a senior obstetrician advises continuing to vaginal birth). \n\n## Triplet pregnancy\n\nOffer a caesarean section to women with a triplet pregnancy:\n\nat the time of planned birth (35\xa0weeks) or\n\nafter any complication is diagnosed in her pregnancy requiring earlier delivery or\n\nif she is in established preterm labour, and gestational age suggests there is a reasonable chance of survival of the babies. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on mode of birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: mode of birth.\n\nLoading. Please wait.\n\n# Fetal monitoring during labour in twin pregnancy\n\n## Antenatal information for women\n\nBy 28\xa0weeks of pregnancy, discuss continuous cardiotocography with women with a twin pregnancy and their family members or carers (as appropriate) and address any concerns. Explain that the recommendations on cardiotocography are based on evidence from women with a singleton pregnancy because there is a lack of evidence specific to twin pregnancy or preterm babies. \n\nExplain to the woman that continuous cardiotocography is used to monitor the babies' heartbeats and her labour contractions, and that:\n\nit allows simultaneous monitoring of both babies\n\nit might restrict her mobility\n\nnormal traces show the babies are coping well with labour; if traces are not normal, there will be less certainty about the babies' condition\n\nit is normal to see changes to the fetal heart rate pattern during labour and this does not necessarily mean there is a problem\n\nfindings from the cardiotocograph are used to help make decisions during labour and birth, but these will also be based on her wishes, her condition and that of her babies. \n\n## Intrapartum monitoring\n\nOffer continuous cardiotocography to women with a twin pregnancy who are in established labour and are more than 26\xa0weeks pregnant. \n\nPerform a portable ultrasound scan when established labour starts, to confirm which twin is which, the presentation of each twin, and to locate the fetal hearts. \n\nDo not offer intermittent auscultation to women with a twin pregnancy who are in established labour and are more than 26\xa0weeks pregnant. \n\nFor women between 23+0 and 25+6 weeks of pregnancy who are in established labour, involve a senior obstetrician in discussions with the woman and her family members or carers about how to monitor the fetal heart rates. \n\nWhen carrying out cardiotocography:\n\nuse dual channel cardiotocography monitors to allow simultaneous monitoring of both fetal hearts\n\ndocument on the cardiotocograph and in the clinical records which cardiotocography trace belongs to which baby\n\nmonitor the maternal pulse electronically and display it simultaneously on the same cardiotocography trace. \n\nConsider separating the fetal heart rates by 20\xa0beats/minute if there is difficulty differentiating between them. \n\nClassify and interpret cardiotocography in line with the section on the use of cardiotocography for monitoring during labour in the NICE guideline on fetal monitoring in labour, taking into account that:\n\ntwin pregnancy should be considered a fetal clinical risk factor when classifying a cardiotocography trace as 'abnormal' versus 'non-reassuring'\n\nfetal scalp stimulation should not be performed in twin pregnancy to gain reassurance after a cardiotocography trace that is categorised as 'pathological'. \n\n## Reviewing cardiotocography\n\nCarry out systematic assessments of both cardiotocographs at least hourly, and more frequently if there are concerns. \n\nAt each systematic assessment, document which cardiotocography trace belongs to which baby. \n\nBe aware of the possibility of monitoring the same baby twice. At each cardiotocography review, ensure that twin synchronicity is not occurring. \n\n## Management based on cardiotocography\n\nFor definitions of 'suspicious' and 'pathological' cardiotocograph traces, see the table on management based on interpretation of cardiotocograph traces in NICE's guideline on intrapartum care for healthy women and babies.\n\nIf abdominal monitoring is unsuccessful or there are concerns about synchronicity of the fetal hearts:\n\ninvolve a senior obstetrician and senior midwife\n\napply a fetal scalp electrode to the first baby (only after 34\xa0weeks and if there are no contraindications) while continuing abdominal monitoring of the second baby\n\nperform a bedside ultrasound scan to confirm both fetal heart rates\n\nif monitoring remains unsatisfactory, consider a caesarean section. \n\nIf the cardiotocograph trace is categorised as 'suspicious' in the first baby during established labour:\n\ninvolve the senior obstetrician and senior midwife\n\ncorrect any reversible causes\n\napply a fetal scalp electrode to the first baby (only after 34\xa0weeks and if there are no contraindications) while continuing abdominal monitoring of the second baby. \n\nIf the cardiotocograph trace is categorised as 'pathological' in the first baby during established labour:\n\ninvolve the senior obstetrician and senior midwife\n\ndiscuss with the woman and her family members or carers the possible use of fetal blood sampling of the first baby from 34\xa0weeks if the benefits are likely to outweigh the potential risks. \n\nWhen offering fetal blood sampling in twin pregnancy, discuss with the woman and her family members or carers that if a blood sample cannot be obtained then she is likely to need a caesarean section. \n\nIf the results of fetal blood sampling are not available within 20\xa0minutes or fetal blood sampling is contraindicated, offer an immediate caesarean section to women with a twin pregnancy. \n\nIf the cardiotocograph trace is categorised as 'pathological' in the first baby during the second stage of labour:\n\ninvolve the senior obstetrician and senior midwife\n\nassess whether an assisted vaginal birth is an option\n\nif vaginal birth is not an option or cannot be achieved within 20\xa0minutes, offer an immediate caesarean section. \n\nIf the cardiotocograph trace of the second baby is categorised as 'suspicious' or 'pathological' during established labour before the first baby is born:\n\ninvolve the senior obstetrician and senior midwife\n\nif vaginal birth of the second baby cannot be achieved within 20\xa0minutes, discuss performing a caesarean section with the woman and her family members or carers. \n\nAfter the birth of the first baby:\n\ncontinue to monitor the second baby using cardiotocography\n\nif there is 'suspicious' or 'pathological' cardiotocography, and vaginal birth cannot be achieved within 20\xa0minutes, discuss performing a caesarean section with the woman and her family members or carers. \n\nAfter the birth of both babies, consider double clamping the cord to allow umbilical cord blood gases to be sampled. Ensure that the samples are correctly labelled for each baby. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on fetal monitoring during labour\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: fetal monitoring.\n\nLoading. Please wait.\n\n# Analgesia\n\nDiscuss options for analgesia and anaesthesia with women (and their family members or carers, as appropriate), whether they are planning a vaginal birth or caesarean section. Ensure this discussion takes place by 28 weeks at the latest. \n\nOffer an epidural to women with a twin or triplet pregnancy who choose to have a vaginal birth. Explain that this is likely to:\n\nimprove the chance of success and optimal timing of assisted vaginal birth of all the babies\n\nenable a quicker birth by emergency caesarean section if needed. \n\nOffer regional anaesthesia to women with a twin or triplet pregnancy who are having a caesarean section. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on analgesia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: analgesia.\n\nLoading. Please wait.\n\n# Managing the third stage of labour\n\n## Assessing risk\n\nStart assessing the risk of postpartum haemorrhage in women with a twin or triplet pregnancy in the antenatal period and continue throughout labour and the third stage (see the section on risk factors for postpartum haemorrhage in NICE's guideline on intrapartum care for healthy women and babies). \n\nOffer each woman an individualised assessment of her risk of postpartum haemorrhage and explain that multiple pregnancy is a risk factor for increased blood loss at delivery. \n\n## Management\n\nBy 28\xa0weeks of pregnancy, discuss options for managing the third stage of labour with women with a twin or triplet pregnancy. \n\nDo not offer physiological management of the third stage to women with a twin or triplet pregnancy. \n\nOffer women with a twin or triplet pregnancy active management of the third stage. Explain that it is associated with a lower risk of postpartum haemorrhage and/or blood transfusion. \n\nConsider active management of the third stage with additional uterotonics for women who have 1\xa0or more risk factors (in addition to a twin or triplet pregnancy) for postpartum haemorrhage. \n\n## Blood transfusion\n\nBy 28\xa0weeks of pregnancy, discuss with women with a twin or triplet pregnancy the potential need for blood transfusion, including the need for intravenous access. Document this discussion in the woman's notes. \n\nAt the start of established labour in women with a twin or triplet pregnancy:\n\nensure that intravenous access is available so that prompt blood transfusion and intravenous fluids can be given if needed\n\ntake a maternal blood sample for a full blood count and group and save. \n\nEnsure that the appropriate blood transfusion is available for urgent administration. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on managing the third stage of labour\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: interventions to prevent postpartum haemorrhage in the third stage of labour.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Active management of the third stage\n\nIn a vaginal birth, active management consists of 10\xa0IU of oxytocin by intramuscular injection immediately after the birth of the last baby and before the cord is clamped and cut. In a caesarean section, it consists of 5\xa0IU of oxytocin by intravenous injection immediately after the birth of the last baby and before the cord is clamped and cut.\n\n## Amnionicity\n\nThe number of amnions (inner membranes) that surround babies in a multiple pregnancy. Pregnancies with 1\xa0amnion (so that all babies share an amniotic sac) are described as monoamniotic; pregnancies with 2\xa0amnions are diamniotic; and pregnancies with 3\xa0amnions are triamniotic. Also see the box on chorionicity and amnionicity in twin and triplet pregnancy.\n\n## Chorionicity\n\nThe number of chorionic (outer) membranes that surround babies in a multiple pregnancy. If there is only 1\xa0membrane, the pregnancy is described as monochorionic; if there are\xa02, the pregnancy is dichorionic; and if there are\xa03, the pregnancy is trichorionic. Monochorionic twin pregnancies and monochorionic or dichorionic triplet pregnancies carry higher risks because babies share a placenta. Also see the box on chorionicity and amnionicity in twin and triplet pregnancy.\n\n## Feto-fetal transfusion syndrome\n\nFeto-fetal transfusion syndrome (FFTS) occurs when blood moves from one baby to another. The baby that loses the blood is called the donor and the baby receiving the blood is called the recipient. Feto-fetal transfusion syndrome is a complication of monochorionic multiple pregnancies arising from shared placental circulation. It is also referred to as twin-to-twin transfusion syndrome in twin pregnancies.\n\n## Group and save\n\nThis is a blood sampling process. It consists of a blood group and an antibody screen to determine the woman's blood group and whether she has atypical red cell antibodies in her blood. If atypical antibodies are present, the laboratory will do additional work to identify them. This will allow blood to be issued in an emergency very quickly.\n\n## Specialist obstetrician\n\nAn obstetrician with a special interest, experience and knowledge of managing multiple pregnancy, and who works regularly with women with a multiple pregnancy.\n\n## Tertiary level fetal medicine centre\n\nA specialist regional (or supra-regional) fetal medicine centre that has a multidisciplinary team with the expertise and infrastructure to assess and manage complicated twin and triplet pregnancies. This includes providing complex fetal interventions or therapies, for example, fetoscopic laser ablation for feto-fetal transfusion syndrome; and selective termination of pregnancy using techniques such as fetoscopic cord occlusion or radiofrequency ablation.\n\n## Twin anaemia polycythaemia sequences\n\nTwin anaemia polycythaemia sequences (TAPS) is a complication affecting monochorionic twin or triplet pregnancies. It is a rare, chronic form of feto-fetal transfusion caused by the joining of fine blood vessels connecting the fetal circulations on the placenta. It presents when there are unequal blood counts between the twins in the womb. When TAPS occurs, the recipient twin is at risk for successively increasing blood count, called polycythaemia, and the donor twin for progressive blood loss, or anaemia. TAPS occurs without the differences in levels of amniotic fluids between the fetuses (polyhydramnios-oligohydramnios) that is usually seen in FFTS.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\nAs part of the 2019 update, the guideline committee made an additional recommendation for research on the identification on twin anaemia polycythaemia sequence (TAPS). The committee removed 6\xa0of the 2011 recommendations on screening for chromosomal conditions, screening for feto-fetal transfusion syndrome, defining fetal growth restriction, predicting and preventing spontaneous preterm birth, and perinatal and neonatal morbidity and mortality in babies born by elective birth.\n\n# Key recommendations for research\n\n## Screening to detect twin anaemia polycythaemia sequence\n\nWhat is the most accurate prenatal screening marker for TAPS, including middle cerebral artery peak systolic velocity (MCA‑PSV)? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on diagnostic monitoring for twin anaemia polycythaemia sequence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: screening for TAPS.\n\nLoading. Please wait.\n\n## Information and support\n\nDoes additional information and emotional support improve outcomes in twin and triplet pregnancies? \n\n## Specialist care\n\nDoes specialist antenatal care for women with twin and triplet pregnancies improve outcomes for women and their babies? \n\n## Indications for referral to a tertiary level fetal medicine centre\n\nWhat is the incidence of monochorionic monoamniotic twin and triplet pregnancies, and what clinical management strategies are most effective in such pregnancies? \n\n# Other recommendations for research\n\n## Gestational age\n\nHow should gestational age be estimated in twin and triplet pregnancies? \n\n## Chorionicity\n\nWhat is the most accurate method of determining chorionicity in twin and triplet pregnancies at different gestational ages, and how does operator experience affect the accuracy of different methods? \n\n## Nutritional supplements\n\nIs dietary supplementation with vitamins or minerals, or dietary manipulation in terms of calorie intake, effective in twin and triplet pregnancies? \n\n## Diet and lifestyle advice\n\nIs dietary advice specific to twin and triplet pregnancies effective in improving maternal and fetal health and wellbeing? \n\n## Screening for structural abnormalities\n\nWhen and how should screening for structural abnormalities be conducted in twin and triplet pregnancies? \n\n## Hypertension\n\nWhich clinical factors, laboratory screening tests, and ultrasound tests are predictive of hypertensive disorders in twin and triplet pregnancies? \n\n## Untargeted corticosteroids\n\nWhat is the clinical and cost effectiveness, and safety, of routine antenatal administration of a single course of corticosteroids for women with twin and triplet pregnancies who are not in labour and in whom labour and birth are not imminent? \n\n## Indications for referral to a tertiary level fetal medicine centre\n\nWhat is the clinical and cost effectiveness of referral to tertiary level fetal medicine centres for twin and triplet pregnancies complicated by discordant fetal growth, discordant fetal anomaly or discordant fetal death? ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Intrapartum care\n\nRecommendation 1.3.6\n\n## Why the committee made the recommendation\n\nThe committee recognised that the core multidisciplinary team recommended by the previous guideline (see recommendation 1.3.1) provides care during the antenatal period and would not be the same team providing intrapartum care. Because intrapartum care was added to the guideline update, they made a recommendation to clarify that healthcare professionals supporting women when they are giving birth should also have knowledge and experience in multiple pregnancy.\n\n## How the recommendation might affect practice\n\nThe recommendation reinforces current practice.\n\nReturn to recommendation\n\n# Screening for chromosomal conditions\n\nRecommendations 1.4.3 to 1.4.8\n\n## Why the committee made the recommendations\n\nSince the 2011 guideline, the National Screening Committee's recommendations on screening for fetal chromosomal conditions have been published and have been implemented by the NHS fetal anomaly screening programme (FASP). These apply to women with both singleton and twin pregnancies, so the 2011 recommendations were replaced by a cross reference to this screening programme. The committee recognised that no current guidance exists for triplets so they retained a recommendation on triplets from the 2011 guideline. However, based on their expertise they decided this existing recommendation would apply only to screening in trichorionic triplets so they made an additional recommendation about dichorionic and monochorionic triplet pregnancies. Because of the complexity of screening these types of triplet pregnancies, this screening should only be carried out after referral to a tertiary level fetal medicine centre.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice.\n\nReturn to recommendations\n\n# Screening for preterm birth\n\nRecommendations 1.4.13 to 1.4.15\n\n## Why the committee made the recommendations\n\nThe committee agreed, based on their experience and expertise, that women should be given information about the higher risk of preterm birth in twin and triplet pregnancy compared with singleton pregnancy.\n\nThe committee retained the existing 2011 recommendations that fetal fibronectin testing and home uterine activity monitoring should not be used to predict the risk of spontaneous preterm birth because there was still no evidence suggesting they were accurate.\n\n## Why the committee did not make a recommendation on cervical length screening in twin pregnancy\n\nThe evidence suggested that cervical length is a moderate predictor of spontaneous preterm birth in twin pregnancy. Although there were some inconsistencies between studies, the committee agreed they still supported the use of cervical length measurements to predict preterm birth in twin pregnancy. Establishing that a woman is at risk of preterm birth allows an intervention to be offered, and there is some evidence that vaginal progesterone may reduce this risk in women with a twin pregnancy. However, the committee was also aware that new evidence would be emerging about the use of vaginal progesterone in subgroups of women with a short cervix that could change their conclusions about its effectiveness. This uncertainty meant the committee could not recommend vaginal progesterone to prevent preterm birth. Because of this, the committee also decided they could not recommend cervical length screening in the absence of an effective intervention to offer women with a higher risk of preterm birth.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice.\n\nReturn to recommendations\n\n# Screening for fetal growth restriction and feto-fetal transfusion syndrome in the first trimester\n\nRecommendation 1.4.16\n\n## Why the committee made the recommendation\n\nThere was evidence that discordance in either crown–rump length or nuchal translucency during the first trimester is not an accurate predictor of growth discordance in the second and third trimester. The committee discussed the evidence for other ultrasound screening measures in the first trimester and decided that because of its low quality they were not confident in recommending any screening tests in the first trimester.\n\nThe evidence showed that none of the first trimester screening tests were able to detect the risk of feto-fetal transfusion syndrome developing later in the pregnancy. Although there were uncertainties in this evidence, it was supported by the committee's clinical experience and current clinical practice.\n\n## How the recommendation might affect practice\n\nThe recommendation reinforces current practice.\n\nReturn to recommendations\n\n# Diagnostic monitoring for fetal growth restriction in dichorionic twin and trichorionic triplet pregnancies\n\nRecommendations 1.4.17 to 1.4.23\n\n## Why the committee made the recommendations\n\nBased on evidence which showed that abdominal palpation and symphysis–fundal height were not accurate measurements to diagnose fetal growth restriction, the committee recommended that these should not be used.\n\nFetal growth restriction is associated with perinatal mortality, morbidity and preterm birth. The committee agreed that monitoring using ultrasound scanning is essential to identify women in this high-risk group.\n\nThe evidence was limited on the frequency of ultrasound scanning for women with dichorionic twin pregnancies but, based on their expertise, the committee agreed that women with a dichorionic twin pregnancy should have scans no more than 28\xa0days apart.\n\nThey also recommended ultrasound monitoring at least every 14\xa0days for women with all types of triplet pregnancy (recommendations 1.4.19 and 1.4.32) because they are at higher risk of fetal growth restriction.\n\nBased on both the evidence and their expertise, the committee recommended using at least 2\xa0different biometric parameters as well as amniotic fluid level assessment to provide greater accuracy in calculating estimated fetal weight (EFW).\n\nThe Royal College of Obstetricians and Gynaecologists' Green Top guideline on monochorionic twin pregnancy recommends referring women 'for assessment and management in fetal medicine units with recognised relevant expertise' if there is an EFW discordance of more than 20%. In the committee's experience, this level of discordance should cause concern in all types of twin and triplet pregnancy and should prompt increased monitoring. However, they recommended instead increasing to weekly monitoring and adding the extra parameter of a doppler assessment. This would be equivalent to the specialist assessment recommended by the Green Top guideline because it would need to be carried out by the specialist core team (in line with recommendation 1.3.1) who have experience and knowledge of managing twin and triplet pregnancies. The committee agreed that this would not be inconsistent with the Green Top guideline.\n\nThe committee also agreed that the EFWs themselves should be taken into account. Based on the evidence and their expertise they recommended the 10th centile for gestational age as a threshold for concern that should prompt increased monitoring.\n\nThe evidence was inconclusive about an exact threshold for referral to a tertiary level fetal medicine centre, so based on their own experience the committee decided that an EFW discordance of 25% or more (along with an EFW below the 10th centile for gestational age) should warrant referral. At this level of discordance, there would be an increased risk of perinatal morbidity and mortality that should prompt intervention rather than increased assessment. The tertiary level fetal medicine centre would have the expertise to weigh up the benefits and risks of conservative management, birth or invasive fetal therapy to improve the chance of a positive pregnancy outcome.\n\n## How the recommendations might affect practice\n\nThese recommendations are largely reinforcing current practice in twin pregnancy and should have a minimal impact on local ultrasound resourcing. They are consistent with other national and international guidance.\n\nThe recommendations to monitor all women with a triplet pregnancy at no more than 14‑day intervals (irrespective of chorionicity) are a change in practice, particularly for women with a trichorionic triamniotic pregnancy. For these women, previous recommendations suggested 4‑weekly scans. However, the change is justified because all types of triplet pregnancy are at high risk of fetal growth restriction. The recommendation should not have a significant impact on clinical resources because of the low number of women with a triplet pregnancy.\n\nReturn to recommendations\n\n# Diagnostic monitoring for feto-fetal transfusion syndrome\n\nRecommendations 1.4.24 to 1.4.29\n\n## Why the committee made the recommendations\n\nThe committee agreed that feto-fetal transfusion syndrome is difficult to detect using amniotic fluid discordance before 16\xa0weeks of pregnancy. After this stage, amniotic fluid levels have increased and differences between them can be used to diagnose feto-fetal transfusion syndrome. Monitoring fortnightly from 16\xa0weeks should ensure that feto-fetal transfusion syndrome is diagnosed as early as possible. The committee decided based on their expertise – and on limited evidence from studies that conducted diagnostic scans after 24\xa0weeks – that continuing fortnightly monitoring until birth would improve outcomes for women who develop feto-fetal transfusion syndrome later in pregnancy (although it is less common after 26\xa0weeks). The committee also agreed that offering women with a monochorionic pregnancy scans at 14-day intervals means that the woman can be monitored efficiently for all the complications in recommendation 1.4.24 at each scan.\n\nTo support this frequency of monitoring, the committee also increased the number of reviews by the specialist obstetrician from at least\xa02 (in the 2011 guideline) to at least\xa05 for dichorionic and monochorionic triamniotic triplet pregnancies (recommendation 1.3.10). Dichorionic triamniotic triplets have an increased risk of adverse outcomes compared with monochorionic diamniotic twins if feto-fetal transfusion occurs. The risk of complications of monochorionicity, and of adverse outcomes if complications occur, is higher in triplets than in twins. More frequent review by the specialist obstetrician would ensure optimal critical assessment of ultrasound findings (including findings related to feto-fetal transfusion syndrome) and any need for more frequent monitoring.\n\nThe committee agreed that making sure the amniotic membrane is visible in the scan reduces the chance of measuring the same sac twice in error and improves accuracy in identifying a difference between the babies' amniotic fluid levels.\n\nBased on their knowledge and experience, the committee agreed that women should be referred immediately to a tertiary level fetal medicine centre when differences in amniotic fluid levels meet the criteria for diagnosing feto-fetal transfusion syndrome. The clinical course of feto-fetal transfusion syndrome can be unpredictable so this would allow prompt assessment and early intervention. They also agreed that when differences in amniotic fluid levels are measured that do not yet meet the threshold for feto-fetal transfusion syndrome, women should be seen by their named specialist obstetrician for multiple pregnancy and offered more frequent monitoring, using doppler assessment to help detect feto-fetal transfusion syndrome as early as possible.\n\n## How the recommendations might affect practice\n\nMonitoring for feto-fetal transfusion syndrome from 16\xa0weeks of pregnancy until birth is a change to current practice, in which monitoring is only carried out until week\xa024. Early detection would enable prompt management, and this would outweigh the cost of additional ultrasound.\n\nReturn to recommendations\n\n# Diagnostic monitoring for fetal growth restriction in monochorionic twin and triplet pregnancy\n\nRecommendations 1.4.30 to 1.4.36\n\nA monochorionic twin or triplet pregnancy is one in which any of the babies share a placenta and a chorionic (outer) membrane. This includes monochorionic twins and dichorionic and monochorionic triplets.\n\n## Why the committee made the recommendations\n\nBased on evidence which showed that abdominal palpation and symphysis–fundal height were not accurate measurements to diagnose fetal growth restriction, the committee recommended that these should not be used.\n\nFetal growth restriction is associated with perinatal mortality, morbidity and preterm birth. The committee agreed that monitoring using ultrasound scanning is essential to identify women in this high-risk group.\n\nThe evidence was limited on the frequency of ultrasound scanning for women with monochorionic pregnancies, so the committee used their expertise to make recommendations. They agreed that women with a monochorionic twin pregnancy need more frequent scans than women with a dichorionic twin pregnancy because they have a higher risk of severe growth discordance.\n\nScanning at no more than 14-day intervals would allow the woman to be referred promptly either to her specialist obstetrician for multiple pregnancy or to a tertiary level fetal medicine centre depending on the EFWs (see below). The committee also agreed that because women with a monochorionic pregnancy should be having scans at 14‑day intervals to monitor for feto-fetal transfusion syndrome, these timings mean they can be monitored for both of these complications at the same time (in line with recommendation 1.4.24).\n\nThe committee also recommended ultrasound monitoring at least every 14\xa0days for women with all types of triplet pregnancy (recommendations 1.4.19 and 1.4.32) because they are at higher risk of fetal growth restriction.\n\nBased on both the evidence and their expertise, the committee recommended using at least 2\xa0different biometric parameters as well as amniotic fluid level assessment to provide greater accuracy in calculating EFW.\n\nThe Royal College of Obstetricians and Gynaecologists' Green Top guideline on monochorionic twin pregnancy recommends referring women 'for assessment and management in fetal medicine units with recognised relevant expertise' if there is an EFW discordance of more than 20%. The committee agreed with the Green Top guideline that this level should cause concern and prompt increased monitoring, but they recommended instead increasing to weekly monitoring and adding the extra parameter of a doppler assessment. This would be equivalent to the specialist assessment recommended by the Green Top guideline because it would need to be carried out by the specialist core team (in line with recommendation 1.3.1) who have experience and knowledge of managing twin and triplet pregnancies. The committee agreed that this would not be inconsistent with the Green Top guideline.\n\nThe committee also agreed that the estimated fetal weights themselves should be taken into account. Based on the evidence they recommended the 10th centile for gestational age as a threshold for concern that should prompt increased monitoring.\n\nThe evidence was inconclusive about an exact threshold for referral to a tertiary level fetal medicine centre, so based on their own experience the committee decided that an EFW discordance of 25% or more (along with an EFW below the 10th centile) should warrant referral. At this level of discordance, there would be an increased risk of perinatal morbidity and mortality that should prompt intervention rather than increased assessment. The tertiary level fetal medicine centre would have the expertise to weigh up the benefits and risks of conservative management, birth or invasive fetal therapy to try to improve the chance of a positive pregnancy outcome.\n\n## How the recommendations might affect practice\n\nThese recommendations are largely reinforcing current practice in twin pregnancy and should have a minimal impact on local ultrasound resourcing. They are consistent with other national and international guidance.\n\nThe recommendation to monitor all women with a triplet pregnancy at no more than 14‑day intervals (irrespective of chorionicity) is a change in practice, particularly for women with a trichorionic triamniotic pregnancy. For these women, previous recommendations suggested 4‑weekly scans. However, the change is justified because all types of triplet pregnancy are at high risk of fetal growth restriction. The recommendation should not have a significant impact on clinical resources because of the low number of women with a triplet pregnancy.\n\nReturn to recommendations\n\n# Diagnostic monitoring for twin anaemia polycythaemia sequence\n\nRecommendations 1.4.37 and 1.4.38\n\n## Why the committee made the recommendations\n\nThere was limited evidence for screening and diagnostic monitoring for twin anaemia polycythaemia sequence (TAPS). The committee discussed, based on their expertise, that there is also limited evidence on the natural history of spontaneous TAPS and effective interventions for it in uncomplicated monochorionic pregnancies. They agreed that its incidence is likely to be low, so they could not recommend screening for it in women whose monochorionic pregnancy is uncomplicated.\n\nThe committee agreed that monitoring would be beneficial for women with the complications in recommendations 1.4.37 and 1.4.38. They recommended screening for TAPS in this population for 2 reasons:\n\nComplicated monochorionic pregnancies have an increased risk of fetal and neonatal death and morbidity. Diagnosing TAPS as a further complication is likely to influence how the woman's pregnancy is managed, including the timing of preterm birth.\n\nAdvanced TAPS (stages 3 and 4) is associated with abnormal fetal umbilical artery and ductus venosus doppler parameters, or signs of fetal cardiac failure in the anaemic baby. These can also occur in a number of other conditions, so the diagnosis of severe TAPS (either alone or as a comorbidity) may be missed if it is not specifically screened for.\n\nThe committee concluded that for women who have a pregnancy in which TAPS is a comorbid complication or is of advanced stage, the risk to the babies without diagnosis and intervention is likely to be greater than the potential harms of interventions. These include preterm birth or potential in‑utero therapies, such as in‑utero transfusion, in pre-viable or extremely premature pregnancies.\n\nThe committee agreed that when TAPS is suspected, women should be referred to a tertiary level fetal medicine centre. They felt that the benefits of managing complicated monochorionic pregnancies in this setting would outweigh the potential disadvantages of inconvenience of travel and transfer to units away from home. The committee decided not to specify diagnostic criteria because they wanted to emphasise the importance of referral to a tertiary level referral centre when TAPS is suspected, so that decisions about further assessment and management can be made with each individual woman.\n\nGiven the limited evidence on the diagnostic accuracy of middle cerebral artery peak systolic velocity (MCA‑PSV) for all types of monochorionic twins, regardless of complications, and uncertainties about the natural history of TAPS and its management, the committee decided to make a recommendation for research on screening to detect twin anaemia polycythaemia sequence to inform future guidance.\n\n## How the recommendations might affect practice\n\nThe recommendation may increase the number of assessments of women with complicated monochorionic pregnancies and referral for appropriate management. However, the committee agreed that any increase in referrals would be offset by the benefits of better detection and management of complicated monochorionic pregnancies.\n\nReturn to recommendations\n\n# Preventing preterm birth\n\nRecommendations 1.5.1 and 1.5.2\n\n## Why the committee made the recommendations\n\nThe evidence for intramuscular progesterone in the prevention of spontaneous preterm birth showed it had no clinical benefit and, in some instances, had negative or unpleasant side effects, so it was not recommended.\n\nThe committee retained the existing 2011 recommendation that arabin pessary, bed rest, cervical cerclage and oral tocolytics should not be used routinely to prevent spontaneous preterm birth because there was still no evidence to support their use.\n\n## Why the committee did not make a recommendation on vaginal progesterone\n\nThe committee decided not to make recommendations on the use of vaginal progesterone to prevent preterm birth because they knew about evidence that would be emerging about the use of progesterone in subgroups of women with a short cervix that could change their conclusions about its effectiveness. This also meant the committee preferred not to recommend cervical length screening (see the rationale section on cervical length screening in twin pregnancy). NICE will carry out an exceptional update based on the new evidence when it becomes available.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current practice.\n\nReturn to recommendations\n\n# Planning birth: information and support\n\nRecommendations 1.8.1 to 1.8.3\n\n## Why the committee made the recommendations\n\nThe committee discussed the importance of providing care that is woman-centred, in which shared decision-making between the woman and her healthcare professional is essential. The committee agreed on the topics that need to be discussed with women to explain the available options and find out their wishes. Information needs to be tailored to each woman's pregnancy because some twin and triplet pregnancies carry more risks than others.\n\nThe committee acknowledged equality considerations for women who may have additional needs (such as needing an interpreter) in the context of providing information and communication. They cross-referred to NICE's guideline on patient experience in adult NHS services, which describes general good practice on how to do this.\n\nReturn to recommendations\n\n# Timing of birth\n\nRecommendations 1.9.1 to 1.9.12\n\n## Why the committee made the recommendations\n\nThe committee agreed that it was critical to give women the information they need to participate in shared decisions about when their babies are born. This includes explaining the known risk of spontaneous preterm birth in twin and triplet pregnancy and its possible consequences, such as admission to a neonatal unit. The committee retained this advice from the 2011 guideline because it was consistent with their experience and knowledge. They agreed that this information is important for planning the timing of birth.\n\nWomen also need to know why it is recommended for them to have a planned birth by a particular week of pregnancy (also see when to offer planned birth). There is a trade-off between clinical benefits and harms when women have not given birth spontaneously by a given gestational age. These include the risks of neonatal mortality and morbidity associated with planned birth compared with the risks of stillbirth from continued pregnancy. The committee agreed that both timing and mode of birth should be discussed with women in the context of these potential risks. Women can use this advice to make an informed choice.\n\nThere was not enough good evidence to conclusively identify the optimal timing of birth according to chorionicity and amnionicity, so the committee also used their expertise and experience to make recommendations.\n\nEvidence suggests a consistently higher fetal death rate (at all gestational ages) in monochorionic twin pregnancies than in dichorionic twin pregnancies. The committee therefore recommended earlier planned birth, at 36\xa0weeks, for women with a monochorionic diamniotic pregnancy to reflect the higher risk and complexity of this type of pregnancy. This was consistent with the 2011 guideline and therefore corresponds to current clinical practice.\n\nThe committee also clarified the timing of birth for monochorionic monoamniotic twins, which was not explicitly covered by the 2011 guideline – the previous guideline did not divide monochorionic twins into diamniotic or monoamniotic groups. Based on some evidence and their own knowledge and experience, the committee recommended offering planned birth between 32+0 and 33+6\xa0weeks because this timing did not appear to be associated with an increased risk of serious neonatal adverse outcomes.\n\nThe committee clarified the recommendations from the 2011 guideline by considering triplet pregnancies by type rather than as a single group. No evidence was found on timing of birth in triplet pregnancy but the committee agreed based on their own clinical experience that continuing an uncomplicated trichorionic triamniotic or a dichorionic triamniotic triplet pregnancy beyond 35+6\xa0weeks of pregnancy would lead to an increased risk of fetal death (recommendation 1.9.7). Planned birth should therefore be offered at 35\xa0weeks (recommendation 1.9.10).\n\nBecause of significant risks for the babies in complicated twin and triplet pregnancies, and the rareness of monochorionic triamniotic triplet pregnancies and triplet pregnancies with a shared amnion, timing of birth should be assessed and discussed individually (recommendations 1.9.8 and 1.9.11).\n\nThe committee highlighted that women's choice needs to be respected and that if a woman declines planned birth at the recommended time, she should be offered weekly appointments to minimise risk, monitor progress and help to identify any complications as soon as possible.\n\n## How the recommendations might affect practice\n\nThe recommendations clarify the timing of when women with a monochorionic monoamniotic pregnancy should be offered planned birth. Although this is a change from the 2011 guideline, it reinforces current practice.\n\nReturn to recommendations\n\n# Mode of birth\n\n## Why the committee made the recommendations\n\nRecommendations 1.10.1 to 1.10.5\n\nFor women who are more than 32\xa0weeks pregnant and have an uncomplicated pregnancy, the evidence showed there is no significant difference in risk between vaginal birth and caesarean section, both for the woman and her babies. The committee's experience supported this, so they agreed that healthcare professionals should explain this to the woman and support her choice as long as the conditions in recommendation 1.10.1 are met and the first baby is in a head-first position.\n\nThere was only limited evidence about mode of birth when the first baby is not head first. The committee agreed that in their clinical experience, this carries a higher risk of problems such as cord accidents during birth. Because of this, a caesarean section is the safest option to offer women after 32\xa0weeks and for women in established preterm labour between 26 and 32\xa0weeks.\n\nAccording to the evidence, not all women give birth according to their birth plan. The committee decided it was important to explain this to women so that they are prepared for the possibility of not giving birth in the way they prefer.\n\nRecommendations 1.10.6 and 1.10.7\n\nMonochorionic monoamniotic twin pregnancies and triplet pregnancies are the least common and highest-risk types of pregnancy and evidence about mode of birth was limited for these women. However, the committee agreed from their experience that caesarean section should be the preferred option and should be offered at the time the birth is planned to happen or after the diagnosis of established labour. If the first twin is close to being born vaginally there can be risks for the babies, so the committee decided that senior obstetric assessment would be needed.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current practice. Supporting the woman's preferred mode of birth might increase the number of planned vaginal births, which may reduce costs. This is likely to be partly offset by the fact that a proportion of these women would go on to give birth by caesarean section for one or both twins.\n\nReturn to recommendations\n\n# Fetal monitoring during labour in twin pregnancy\n\nRecommendations 1.11.1 to 1.11.21\n\n## Why the committee made the recommendations\n\nThere was no evidence on the most effective method of fetal monitoring in labour for improving outcomes in women with a twin pregnancy and their babies, so the committee used their expertise and experience along with NICE guidance on fetal monitoring in singleton pregnancy (NICE's guideline on intrapartum care for healthy women and babies) to make recommendations. They agreed that clinically it is well recognised that twins are at increased risk of complications during labour, especially the second twin, so they recommended continuous fetal monitoring. Continuous cardiotocography monitoring is the only modality that can assess both twin fetal heart rates simultaneously during established labour.\n\nThe committee agreed on the importance of explaining to women the lack of evidence about monitoring with cardiotocography specifically in twins, and that recommendations are based on NICE guidance for singleton pregnancy (intrapartum care for healthy women and babies). Healthcare professionals should provide a detailed explanation of what cardiotocography involves and why it is used and give women a chance to discuss their wishes and concerns. Recommending this before 28\xa0weeks gives women time to make an informed decision and takes into account the fact that many twins are born prematurely.\n\nThe committee recommended offering continuous cardiotocography to women in established labour with a twin pregnancy over 26\xa0weeks because at this gestational age, neonatal survival rates improve and the risks of neonatal morbidity from preterm birth are falling. The advantages of using cardiotocography over intermittent auscultation monitoring include the ability to assess baseline variability and monitor continuously.\n\nPerforming a portable ultrasound (bedside) scan at the start of established labour not only helps to confirm which is the first and which the second twin and locate the fetal hearts but also confirms presentation – malpresentation is more common in twin pregnancy than singleton pregnancy and an emergency caesarean section may be indicated if the first twin presents in the breech position.\n\nThe committee recommended involving a senior obstetrician to decide how twins are monitored in established extreme premature labour (23+0 to 25+6 weeks of pregnancy) in line with NICE's guideline on premature labour and birth in singleton pregnancies.\n\nThe committee recommended dual channel monitors to make sure both fetal heart rates could be monitored and displayed accurately at the same time on the same record during labour. Maternal pulse monitoring should be displayed on the same continuous cardiotocography trace to ensure 2\xa0fetal heart rates were being recorded (without mistaking the maternal heart rate for a fetal heart rate).\n\nThe committee recommended classifying and interpreting cardiotocography in a way that is broadly consistent with the NICE guideline on intrapartum care for healthy women and babies, but with additional considerations specific to twins. These include regarding twin pregnancy as a fetal clinical risk factor when classifying a cardiotocograph finding as 'abnormal' or 'non-reassuring'. This would result in a lower threshold for classifying a cardiotocograph as pathological.\n\nFailing to successfully monitor one or both babies could lead to adverse perinatal outcomes so the committee recommended involving a senior healthcare professional. They also recommended applying a fetal scalp electrode to the first baby while continuing abdominal monitoring of the second baby if abdominal monitoring is unsuccessful or there are concerns about synchronicity of the fetal hearts. This should only be carried out after 34\xa0weeks of pregnancy and if there are no contraindications such as HIV, hepatitis or maternal thrombocytopenia.\n\nIf there is 'suspicious' cardiotocography in the first baby during established labour, the committee recommended involving a senior healthcare professional to help manage reversible causes such as dehydration, infection or positional loss of contact, before applying a fetal scalp electrode to the first baby (in the absence of contraindications) while continuing abdominal monitoring of the second baby.\n\nIn case of 'pathological' cardiotocography in the first baby, a senior healthcare professional should discuss with the woman using fetal blood sampling in the first baby if the benefits are likely to outweigh the potential risks – these include avoiding a second-stage caesarean section, which increases maternal morbidity and mortality.\n\nAfter the first baby is born, cardiotocographic monitoring of the second baby should continue to detect any 'suspicious' or 'pathological' cardiotocography that could lead to the need for a caesarean section.\n\nThe committee did not make recommendations for women with a triplet pregnancy because most of these women give birth by caesarean section. Monitoring in labour would therefore be rare and decisions would be made on an individual basis.\n\n## How the recommendations might affect practice\n\nThe recommendations are consistent with the NICE guideline on intrapartum care for healthy women and babies taking into account the twin-specific measures. It is not anticipated that the recommendations will lead to major changes in current clinical practice.\n\nReturn to recommendations\n\n# Analgesia\n\nRecommendations 1.12.1 to 1.12.3\n\n## Why the committee made the recommendations\n\nThere is limited evidence on analgesia in labour for women with a twin pregnancy, and no evidence for women with a triplet pregnancy, so the committee used their expertise and experience along with the very limited evidence to make recommendations. They agreed that there is variation in practice in relation to when healthcare professionals discuss analgesia and anaesthesia with women and what they should discuss, so they specified when this should happen during pregnancy and what to cover.\n\nWomen with a twin or triplet pregnancy have an increased risk of intervention in labour, including assisted birth or caesarean section for one or more of the babies, and additional internal manoeuvres. Having an epidural in place allows analgesia or anaesthesia to be given quickly when it is needed, reducing the potential need for emergency general anaesthesia.\n\nThe limited evidence suggested that having an epidural in place also reduces the need for emergency caesarean section for the second twin after vaginal birth of the first twin, possibly by allowing more effective internal manoeuvres to allow the second twin to be born vaginally.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice.\n\nReturn to recommendations\n\n# Managing the third stage of labour\n\nRecommendations 1.13.1 to 1.13.9\n\n## Why the committee made the recommendations\n\nThe evidence was very limited, so the committee used their clinical expertise and experience to make recommendations. Multiple pregnancy is a risk factor for postpartum haemorrhage (see NICE's guideline on intrapartum care for healthy women and babies) because of over-distension of the uterus and enlarged placenta(s). The committee agreed that healthcare professionals should explain this to women in the antenatal period and assess and re-evaluate each woman's individual risk as her pregnancy progresses.\n\nBecause of the risk of postpartum haemorrhage, the committee agreed that active management of the third stage of labour using uterotonics should be offered to all women, and physiological management should not be offered.\n\nIt is already well-established as current practice and is supported by the committee's experience that when women have more than 1\xa0risk factor for postpartum haemorrhage, additional uterotonics can reduce this risk. There is no clear evidence on the comparative effectiveness of different uterotonics in twin or triplet pregnancy. Each uterotonic has risk factors and contraindications, so the committee did not recommend a specific one.\n\nThe committee agreed on the importance of having existing intravenous access and blood products readily available in case a postpartum haemorrhage does occur.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice.\n\nReturn to recommendations", 'Context': 'Twins or triplets occur in approximately 1 in 60 pregnancies (16 in every 1,000 women giving birth in 2015 had a multiple birth), and 3% of live-born babies are from multiple gestations. The incidence of multiple births has risen in the past 30\xa0years. This is due mainly to increasing use of assisted reproduction techniques, including in\xa0vitro fertilisation (IVF), and also to changing demographics as women defer pregnancy and twins are more common at later ages (102 in every 1,000 women giving birth in 2015 were aged 45\xa0or over).\n\nWomen with a twin or triplet pregnancy are at higher risk compared with women with a singleton pregnancy. Adverse outcomes are more likely, both for the woman and her babies, during the prenatal and intrapartum periods. Because of this, women need increased monitoring and more contact with healthcare professionals during their pregnancy.\n\nAssessment and planning start as soon as the twin or triplet pregnancy is detected and continue throughout pregnancy at each antenatal contact. Determining the chorionicity and amnionicity of the pregnancy allows the risk to be stratified and the number of antenatal visits and ultrasound examinations to be planned. It is important that ultrasound surveillance is carefully scheduled to monitor for complications including selective fetal growth restriction, feto-fetal transfusion syndrome and twin anaemia polycythaemia sequence (TAPS).\n\nIdentifying complications earlier means that decisions can be made promptly about referring the woman to a tertiary level fetal medicine centre. It also informs discussions with women in their second and third trimesters about their hopes and wishes in relation to timing and mode of birth, and the management of the intrapartum period (including fetal monitoring, analgesia and the third stage of labour).\n\nThis guideline replaces the previous NICE guideline on multiple pregnancy (CG129). The surveillance process found new evidence and identified a need to include intrapartum care, an area that was not included in the original guideline. In current practice, a significant proportion of multiple pregnancy losses occur intrapartum and the risk of adverse perinatal outcomes is greater in multiple than in singleton pregnancies.\n\nThe guideline updates recommendations on screening and monitoring for selective fetal growth restriction and feto-fetal transfusion syndrome, and makes new recommendations on screening and monitoring for TAPS; screening for and preventing preterm birth; and timing of birth. New recommendations on intrapartum care cover mode of birth, fetal monitoring, analgesia and managing the third stage of labour.'}
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https://www.nice.org.uk/guidance/ng137
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This guideline covers the care that should be offered to women with a twin or triplet pregnancy in addition to the routine care that is offered to all women during pregnancy. It aims to reduce the risk of complications and improve outcomes for women and their babies.
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6a27f91803ec4e09682fda028ec7e7349c9a3980
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nice
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Benralizumab for treating severe eosinophilic asthma
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Benralizumab for treating severe eosinophilic asthma
Evidence-based recommendations on benralizumab (Fasenra) for treating severe eosinophilic asthma in adults.
# Recommendations
Benralizumab, as an add-on therapy, is recommended as an option for treating severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids and long-acting beta-agonists, only if:
the person has agreed to and followed the optimised standard treatment plan and
the blood eosinophil count has been recorded as 300 cells per microlitre or more and the person has had 4 or more exacerbations needing systemic corticosteroids in the previous 12 months, or has had continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months (that is, the person is eligible for mepolizumab) or
the blood eosinophil count has been recorded as 400 cells per microlitre or more with 3 or more exacerbations needing systemic corticosteroids in the past 12 months (that is, the person is eligible for reslizumab).Benralizumab is recommended only if the company provides it according to the commercial arrangement.
If benralizumab, mepolizumab or reslizumab are equally suitable, start treatment with the least expensive option (taking into account drug and administration costs).
At 12 months:
stop benralizumab if the asthma has not responded adequately or
continue benralizumab if the asthma has responded adequately and assess response each year.An adequate response is defined as:
a clinically meaningful reduction in the number of severe exacerbations needing systemic corticosteroids or
a clinically significant reduction in continuous oral-corticosteroid use while maintaining or improving asthma control.
These recommendations are not intended to affect treatment with benralizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Severe asthma is usually treated with inhaled corticosteroids plus another drug, such as a long-acting beta-agonist. These may not work well enough for eosinophilic asthma, which is a type of severe asthma that can be difficult to control. Continuous oral corticosteroids may be needed to prevent exacerbations (asthma attacks) but they can cause long-term side effects. Some people are able to have mepolizumab or reslizumab, which are recommended for slightly different populations. They are biological treatments, as is benralizumab. Biological treatments help to control the asthma, and may allow the oral corticosteroids to be reduced.
Clinical trial results show that taking benralizumab plus standard treatment reduces exacerbations and the use of oral corticosteroids, compared with placebo. There are no trials directly comparing benralizumab, mepolizumab and reslizumab, and the relative clinical effectiveness of these treatments is not known. In an indirect comparison of benralizumab with mepolizumab, there is no significant difference in asthma exacerbations.
The company's mixed population is not suitable for considering the cost effectiveness of benralizumab compared with standard care. This is because it is a population of people with a blood eosinophil count of 300 cells per microlitre or more, who have had 3 or more exacerbations in the previous year, and includes some people who are taking maintenance oral corticosteroids. This combines people who are eligible for mepolizumab or reslizumab with other people with less severe disease who are not eligible for biological treatments and can only be offered standard care. The absolute treatment benefit and cost effectiveness of benralizumab varies depending on whether patients are eligible for mepolizumab and reslizumab and what their individual treatment options are.
For people who cannot have mepolizumab or reslizumab and standard care is the only option (that is, with an eosinophil count of less than 400 cells per microlitre, who have had 3 or fewer exacerbations in the last 12 months and are not taking oral corticosteroids), the clinical effectiveness of benralizumab is uncertain. This is because these people comprised a small percentage of the trial population and the cost-effectiveness estimates are higher than can be considered cost effective.
Benralizumab is clinically and cost effective compared with mepolizumab for people with an eosinophil count of 300 cells per microlitre, who have had 4 or more exacerbations or are taking maintenance oral corticosteroids, or both. It is also cost effective compared with reslizumab for people with a blood eosinophil count of 400 cells per microlitre or more, who have had 3 or more exacerbations in the past 12 months. Therefore, it can be recommended for people who could have mepolizumab or reslizumab.# Information about benralizumab
# Marketing authorisation indication
Benralizumab (Fasenra, AstraZeneca) is indicated as 'add-on maintenance treatment in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists'.
# Dosage in the marketing authorisation
The recommended dosage is 30 mg every 4 weeks for the first 3 doses then every 8 weeks, given by subcutaneous injection using a pre-filled syringe.
# Price
The list price is £1,955 per 30‑mg pre-filled syringe (company submission). The company has a commercial arrangement. This makes benralizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with severe eosinophilic asthma will welcome an additional treatment option that may reduce the need for oral corticosteroids
Severe eosinophilic asthma that is inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists is a debilitating condition, with many distressing symptoms. Exacerbations can happen without warning, be life-threatening, cause fear, and result in hospitalisation and intubation. People are often unable to work and may need help with day-to-day activities because of the symptoms. The patient expert explained that, for many people with severe eosinophilic asthma, it does not respond to standard treatment, and more intensive treatments are needed to control symptoms and prevent exacerbations. The clinical experts explained that inadequately controlled severe eosinophilic asthma is frequently treated with oral corticosteroids. NICE guidance recommends biological treatments such as mepolizumab and reslizumab for some people with inadequately controlled eosinophilic asthma (see the NICE technology appraisal guidance on mepolizumab and reslizumab for treating severe eosinophilic asthma). The patient expert explained that these have been life-transforming for some people. However, there are specific eligibility criteria for these drugs and not all patients are eligible to have them. The patient expert noted that inhaled or oral corticosteroids are the main treatment for preventing exacerbations in uncontrolled asthma. When taken frequently or long-term, these can cause major side effects including diabetes, glaucoma, weight gain, bone-density loss, raised blood pressure and mood swings. This has a significant impact on the lives of patients and their families, including the need for numerous additional drugs and hospital visits to monitor and treat the side effects. The patient expert noted that the potential to reduce or avoid oral corticosteroids, over and above improved control of asthma symptoms, is particularly important to patients. The committee concluded that people with severe eosinophilic asthma that is uncontrolled on standard treatment would welcome a new treatment option, particularly if it reduces or avoids the use of oral corticosteroids.
## Benralizumab could offer an easier method of administration than reslizumab, and a more convenient dosing schedule than existing biological treatments
The clinical experts explained that benralizumab is given by subcutaneous injection using a pre-filled syringe (mepolizumab is also given by subcutaneous injection). This is an easier method of administration compared with reslizumab, which is given by intravenous injection. The dosing schedule for benralizumab is more convenient and needs fewer hospital visits than reslizumab and mepolizumab, which are both given every 4 weeks. The first 3 doses of benralizumab are given once every 4 weeks, and then every 8 weeks. The clinical experts considered this convenience in administration to be potentially very beneficial for patients. The patient expert highlighted that benralizumab would be preferred by many patients because its mode of administration and dosing schedule need less travel and fewer visits to specialist centres. The patient expert and the clinical experts confirmed that reduction in oral-corticosteroid use and its associated complications would be valuable to patients and significantly improve their quality of life. The committee concluded that benralizumab potentially offers benefits compared with existing biological treatments, by reducing visits to hospital, which could be important for people with severe eosinophilic asthma.
# Clinical management and comparators
## Benralizumab is a biological agent, and mepolizumab and reslizumab are relevant comparators
The clinical experts explained that treatment for asthma in clinical practice follows the NICE guideline on diagnosis, monitoring and chronic asthma management and the Global Initiative for Asthma 2017 guideline (which includes the use of mepolizumab, reslizumab and omalizumab). Management of uncontrolled asthma uses a step-up approach in which the dose of inhaled corticosteroids is continuously increased, while another drug is also taken for maintenance treatment. If the asthma is still uncontrolled, then oral corticosteroids are added. Because long-term use of corticosteroids is associated with side effects, the guidelines state that inhaled and oral corticosteroids should be used at the lowest doses at which asthma control is maintained, and other treatments should be considered to minimise the use of oral corticosteroids. Eosinophilic asthma is a subtype of asthma, with inflammatory cellular infiltration in the airway. It can be associated with allergy, higher risk of exacerbations, hospitalisation, dependency on oral corticosteroids and increased risk of dying. Biological treatments for people with severe eosinophilic asthma that is inadequately controlled, despite taking high-dose inhaled corticosteroids and long-acting beta-agonists, aim to both reduce the number and severity of exacerbations and reduce or avoid the use of oral corticosteroids. The committee concluded that benralizumab, although having a different mechanism of action to mepolizumab and reslizumab, also acts by reducing eosinophils, and these are therefore appropriate comparators for benralizumab.
## There is insufficient evidence to recommend benralizumab for people who would not currently be offered biological treatments
The clinical experts explained that patients with uncontrolled asthma who have a blood eosinophil count of at least 300 cells per microlitre, and have had at least 3 exacerbations needing systemic corticosteroids in the past 12 months, are referred to specialist asthma centres. These are commissioned by NHS England to be prescribers of the existing biological treatments for eosinophilic asthma (reslizumab and mepolizumab). At the specialist centre, the patient's asthma control is optimised on standard treatment, which may bring the symptoms under control. This is done before the need and eligibility for biological treatment is assessed. This in part explains why uptake of mepolizumab and reslizumab is seemingly low, because patients having optimised care at specialist centres may not need a biological treatment. Also, patients may choose not to have the existing biologicals because the dosing schedules can be difficult to maintain, the treatment is potentially life-long, and there is limited long-term evidence on their use. The clinical experts explained that the system for commissioning existing biologicals is working efficiently and represents established clinical practice in the NHS (in line with NICE's methods guide: sections 6.2.2 and 6.2.3). They did not consider it appropriate at present to use a lower eligibility threshold for treatment with benralizumab than for the existing biologicals. The committee concluded that controlled access to biologicals is working efficiently in the NHS and it is appropriate to consider benralizumab alongside the existing biologicals, and that there is insufficient evidence at present for widening access to include people with less severe asthma (that is, people with lower blood eosinophil counts and fewer exacerbations than are specified in the current NICE recommendations for mepolizumab or reslizumab, and who are not taking maintenance oral corticosteroids).
## The choice of comparator depends on oral-corticosteroid use, eosinophil count and the number of exacerbations
The committee noted that the clinical trials (CALIMA and SIROCCO) recruited people with 2 or more exacerbations in the previous year. It noted that the company proposed a sub-population of people with a blood eosinophil count of 300 cells per microlitre or more, who have had 3 or more exacerbations in the previous year or are taking maintenance oral corticosteroids. The company considered that this represents people with more severe eosinophilic asthma, who it considers will get the most benefit from benralizumab. The committee agreed to consider this population but noted that it includes people with differing severity of asthma (defined by eosinophil level, baseline oral-corticosteroid use and the number of exacerbations in the previous year). It therefore includes people who would be offered different treatment options in the NHS:
people with a blood eosinophil count of 300 cells per microlitre or more, who have had at least 4 exacerbations in the previous 12 months or who are taking oral corticosteroids, can have mepolizumab
people with a blood eosinophil count of 400 cells per microlitre or more, who have had at least 3 exacerbations in the previous 12 months, can have reslizumab
people with a blood eosinophil count of 300 to 399 cells per microlitre, who have had exactly 3 exacerbations in the previous 12 months and are not taking oral corticosteroids, would be offered standard care because they are not eligible for a biological treatment.
# Clinical effectiveness
## Benralizumab is more clinically effective than standard care in the clinical trial populations
The company's clinical evidence comes from 3 randomised-controlled trials: SIROCCO, CALIMA and ZONDA. These compared benralizumab with placebo in people with uncontrolled asthma, taking high-dose inhaled corticosteroids and a long-acting beta-agonist, who had not already had treatment with any biological. SIROCCO and CALIMA included people who had 2 or more exacerbations in the previous year and a blood eosinophil count of 300 cells per microlitre or more (for the primary end point). ZONDA included people who had 1 or more exacerbations in the previous year and a blood eosinophil count of 150 cells per microlitre or more. The primary outcome in SIROCCO and CALIMA was annual asthma exacerbation rate, and in ZONDA it was the percentage reduction in oral-corticosteroid dose from baseline. The committee noted that the pooled results of SIROCCO and CALIMA show that benralizumab reduces the annual rate of exacerbations by 43% compared with placebo (risk ratio 0.57, 95% confidence interval 0.47 to 0.69; p<0.0001) in the intention-to-treat population. The results also suggest that benralizumab is more clinically effective in people with a blood eosinophil count of 300 cells per microlitre or more, or in people who had 3 or more exacerbations. In a pooled subgroup analysis of people with a blood eosinophil count of at least 300 cells per microlitre who had 3 or more exacerbations, benralizumab significantly reduced the annual asthma exacerbation rate by 53% compared with placebo (RR 0.47, 95% CI 0.32 to 0.67; p<0.001). Results from the intention-to-treat analysis from ZONDA showed that benralizumab reduced the median final oral-corticosteroid dose by 75% from baseline, compared with a reduction of 25% for placebo (median treatment difference 37.5%, 95% CI 20.8 to 50.0; p<0.001). Although the pooled SIROCCO and CALIMA data showed that benralizumab reduced the annual exacerbation rate, the committee noted that the absolute reduction depends on the baseline rate, which is related to the severity of the asthma before treatment began. For example, for the same relative reduction, people who have had 4 exacerbations will experience a greater numerical reduction in exacerbations than people who have had 2 exacerbations. The clinical experts also explained that treatment will be more effective in people who have a higher blood eosinophil count than those with a lower blood eosinophil count. The committee concluded that benralizumab is clinically effective as an addition to standard care in people with a blood eosinophil count of at least 300 cells per microlitre, who have had 3 or more exacerbations or are taking maintenance oral corticosteroids, but the size of the benefit will be greater for patients who have had more exacerbations with higher eosinophil counts.
## The comparison of the mixed population with standard care is not appropriate for the purposes of decision making
The committee considered the population of patients proposed by the company (that is, people with a blood eosinophil count of 300 cells per microlitre or more, who have had 3 or more exacerbations in the previous year or are taking maintenance oral corticosteroids). The committee noted that the CALIMA and SIROCCO trials included people with 2 or more previous exacerbations, and that the company's submission had excluded people with 2 exacerbations and only included people with more severe eosinophilic asthma (3 or more exacerbations) on the basis that people with more severe asthma would benefit most from benralizumab treatment. The committee noted that the absolute effectiveness of benralizumab will be greater in people with more severe disease (that is, those who have had more exacerbations and/or with a higher eosinophil count). It noted that the range of asthma severity in the company's proposed population, which it based on the populations in the clinical trials, may not be generalisable to people who have benralizumab in clinical practice in England. It considered this to be a key area of uncertainty, which will have a large impact on the clinical and cost effectiveness of benralizumab in any 'mixed' population. The committee was particularly interested in the proportion of patients included in the mixed population who had exactly 3 exacerbations (including those with an eosinophil count between 300 and 399 cells per microlitre and not taking maintenance oral corticosteroids, who are not eligible for treatment with a biological), because this represents a widening of the population that would be eligible for biologicals. It noted that the company provided a range-estimate for the proportion of people in this population in response to the second appraisal consultation document (which is academic in confidence), and noted that this represents a small proportion of the overall mixed population. The company used the lowest proportion in the range to model the cost-effectiveness estimates for benralizumab. The committee concluded that the company's mixed population is based entirely on the patient populations included in the trials, and is not appropriate for decision making. Standard care alone would be a comparator only for people who have had exactly 3 exacerbations, who have an eosinophil count of between 300 to 399 cells per microlitre and are not taking maintenance oral corticosteroids. This represents a very small group of people with less severe disease, who would not currently be eligible for biological treatment. The remaining patients in the mixed population would be eligible for the existing biologicals, but some may choose to have standard care. The committee concluded that the mixed population is not suitable for the purposes of decision making, and that standard care alone is not an appropriate comparator for all patients. It is more appropriate to consider the clinical and cost effectiveness of benralizumab in relation to the eligibility of patients for other treatments available in the NHS (based on the severity of disease defined by oral-corticosteroid use, eosinophil count and the number of exacerbations), rather than considering standard care alone as an appropriate comparator for all patients.
## The clinical-effectiveness estimates for benralizumab are uncertain in the subgroup of people who are not currently eligible for biologicals
The committee considered the clinical effectiveness of benralizumab for people who would not currently be eligible for a biological. It noted that the rate ratio for marginal annual exacerbations from a pooled SIROCCO and CALIMA subgroup analysis was 0.39 for this population. It concluded that this analysis was based on small patient numbers and that it is too soon to consider widening the population eligible for benralizumab, based on a small subgroup analysis and limited efficacy data.
## The clinical effectiveness of benralizumab compared with reslizumab and mepolizumab is uncertain
The committee noted that the company did not do a network meta-analysis (NMA) to compare the clinical effectiveness of benralizumab with reslizumab and mepolizumab, because of the significant differences in the patient populations in the trials for these 3 drugs. The company argued that it is more appropriate to adjust for differences in patient characteristics between the trials using an anchored matched-adjusted indirect comparison (MAIC), rather than an NMA. However, this was only feasible for the comparison with mepolizumab because differences in the baseline characteristics of the people in the reslizumab trial prevented a MAIC being done. Instead, the company made the simple assumption that benralizumab and reslizumab have the same clinical efficacy. The ERG agreed that a MAIC comparing benralizumab with reslizumab is not feasible, but it noted that there is no evidence to support the assumption of clinical equivalence. The committee agreed that no evidence had been provided to support this assumption and it concluded that the relative efficacy of benralizumab and reslizumab could not be determined. The committee noted that the MAIC with mepolizumab showed no significant differences between benralizumab and mepolizumab. However, a non-significant advantage of one over the other was shown, depending on whether data from the MUSCA trial were included in the analysis. MUSCA was a 24‑week trial that was not included in the MAIC by the company because the primary outcome was health-related quality of life. Without the MUSCA data, the results favour benralizumab but the reverse is the case if MUSCA data are included. The committee noted that the MAIC comparing benralizumab with mepolizumab was done in the full trial populations, because relevant subgroup data were not available for mepolizumab. The relative effect was assumed to apply to the subgroup of people with a blood eosinophil count of 300 cells per microlitre or more, who had 4 or more exacerbations or were taking maintenance oral corticosteroids. The company explained that the MAIC matched people having benralizumab to people in the mepolizumab trial, and it assumed that the relative difference in efficacy between the 2 treatments is the same in the most severe subgroup as in the intention-to-treat population. The committee considered that despite the rationale provided by the company during consultation, the use of the MAIC instead of an NMA had not been adequately justified. It also considered that the rationale is inconsistent with the company's use of the clinical-effectiveness estimates from the MAIC, which were applied to a population with different characteristics. The committee noted that an NMA of mepolizumab and reslizumab could have been done, and this might have been useful for its decision making. However, it noted that an NMA may be affected by heterogeneity in the characteristics of the trial populations. The committee therefore concluded that there remains uncertainty about the clinical effectiveness of benralizumab compared with mepolizumab and reslizumab because the method used for the comparison with mepolizumab is not considered robust, and a simple assumption of equivalence, with no underpinning evidence, was used for reslizumab.
# The company's economic model
## The model structure is appropriate for decision making
The company submitted a 4‑state Markov model comparing benralizumab with mepolizumab, reslizumab and standard care in people with a blood eosinophil count of at least 300 cells per microlitre, who had had 3 or more exacerbations or were taking maintenance oral corticosteroids. The committee noted that assessment of response was modelled at 52 weeks, when 'responders' continued taking the biological treatments and 'non-responders' started standard care. The committee noted that the model included a stopping rule but it was unclear if response was reassessed every year. It considered that treatment continuation based on annual reassessment is appropriate, because people have their asthma reassessed every year in clinical practice and this is consistent with NICE's guidance on reslizumab. The efficacy and clinical parameters in the model were derived from pooled SIROCCO and CALIMA data, ZONDA data, the MAIC results for the comparison of benralizumab with mepolizumab, published literature and previous NICE appraisals. The committee noted that the clinical effectiveness of benralizumab compared with mepolizumab was based on a MAIC, which it had considerable reservations about (see section 3.9). However, the committee considered it commendable that the model attempted to incorporate some of the long-term complications of oral-corticosteroid use in the model, even though some effects cannot be reversed so some steroid-sparing benefits may not be realised. Taking everything into account, the committee accepted that the model structure is appropriate for decision making.
# Clinical inputs to the model
## The proportion of people taking maintenance oral corticosteroids at baseline in the comparison with mepolizumab and standard care is uncertain
In response to consultation the company provided an updated model, which included an updated confidential discount to the list price of benralizumab and used many of the model inputs preferred by the committee. Different proportions of maintenance oral-corticosteroid use at baseline were used, depending on the comparator (54.1% for standard care and 60% for mepolizumab). The ERG preferred a value of 41.7% sourced from a UK registry of patients with severe asthma (Heaney 2010) for the standard care comparison, and a value of 60% for the mepolizumab comparison. The clinical experts confirmed that in clinical practice in the UK, about 66% to 80% of people starting to take mepolizumab will be taking maintenance oral corticosteroids. The committee noted that it is difficult to determine the proportion of people taking maintenance oral corticosteroids in the company's mixed population (see section 3.7). This is a key area of uncertainty in the model, which has a substantial impact on the cost effectiveness of benralizumab.
## The amended asthma-related mortality estimates are appropriate
The committee noted that asthma-related mortality is often a key driver of cost effectiveness in asthma models. It heard from the clinical experts that the National Review of Asthma Deaths (NRAD) report indicated that asthma-related deaths have decreased substantially in all age categories, except in people over 75. The clinical experts explained that asthma-related deaths are rare, with about 300 to 400 deaths annually in the UK. They commented that some deaths originally recorded as asthma-related in the NRAD report were later found not to have been caused by asthma. The committee noted that in the model provided by the company in response to the first appraisal consultation document, asthma-related mortality was updated to include an average probability of death of 0.0078 per hospital admission (sourced from the British Thoracic Society asthma audit for people aged 45 to 54 years and 55 to 64 years). This was preferred by the committee. The committee concluded that the asthma-related mortality estimates in the company's revised model are appropriate.
# The company's updated base-case economic analysis
## The company's mixed population is not suitable for making decisions about the cost effectiveness of benralizumab relative to standard care
The committee considered the mixed population proposed by the company of people with a blood eosinophil count of at least 300 cells per microlitre, who had had 3 or more exacerbations or were taking maintenance oral corticosteroids. The modelled population requires assumptions to be made about the proportion of patients who would be considered for benralizumab in clinical practice depending on use of maintenance oral corticosteroids, number of prior exacerbations, and blood eosinophil count. The committee noted that within this population some people would be eligible for treatment with other biologicals, and it was therefore only interested in the incremental cost-effectiveness ratio (ICER) compared with standard care in people who were not eligible for biologicals (see section 3.16). The committee concluded that the base-case deterministic ICER in the mixed population for benralizumab compared with standard care provided by the company in response to consultation (£25,192 per quality-adjusted life year gained) and the ERG exploratory analysis (£25,587 per QALY gained) are not relevant to decision making. For these reasons, the committee did not consider it appropriate to base its decision making on the ICER from a mixed population that is based solely on proportions from the trials.
## When mepolizumab is a treatment option, benralizumab is a cost-effective use of NHS resources
The committee considered people who are eligible for treatment with mepolizumab (that is, people who are taking oral corticosteroids or have had 4 or more exacerbations, with an eosinophil count of 300 cells per microlitre or more). It noted that when the updated patient access scheme (PAS) price of benralizumab and the PAS price for mepolizumab are used in the model, the ICER is below £20,000 per QALY gained. However, the QALY gain for benralizumab compared with mepolizumab in the company's model is small and is based on an assumption of superior clinical benefit for benralizumab from the MAIC, which the committee did not accept as robust (see section 3.9). The committee considered benralizumab to have similar overall health benefits to mepolizumab although it acknowledged that there is some benefit for benralizumab, particularly in the method and frequency of administration. It was reassured that benralizumab and mepolizumab were shown to have similar long-term costs in a cost-comparison done by the ERG, which assumed equal efficacy and used PAS prices and estimated administration costs. The committee therefore concluded that benralizumab is cost effective in people who are eligible for mepolizumab. Given the lack of clear evidence of superiority of one over the other, the committee concluded that if both are equally suitable for the patient, the least expensive option should be chosen (taking into account drug and administration costs).
## When reslizumab is a treatment option, benralizumab is a cost-effective use of NHS resources
The committee considered people who are eligible for treatment with reslizumab (that is, people who have an eosinophil count of 400 cells per microlitre or more and have had at least 3 exacerbations). It noted that when the PAS prices for benralizumab and reslizumab were used in the ERG analysis, benralizumab is clearly cost effective compared with reslizumab. Although the simple assumption of clinical equivalence between the 2 treatments is questionable, it is reasonable to assume that they are not very different. The committee concluded that benralizumab can be considered cost effective for people who are eligible for reslizumab. It acknowledged the potential benefit of benralizumab, particularly in the method and frequency of administration compared with the intravenous administration of reslizumab, and concluded that if both are equally suitable for the patient, the least expensive should be chosen (taking into account drug and administration costs).
## When standard care is the only treatment option, benralizumab is not a cost-effective use of NHS resources
The committee considered the population for whom standard care is the only treatment option (that is, people with an eosinophil count between 300 to 399 cells per microlitre, who have had exactly 3 exacerbations and are not taking oral corticosteroids). The clinical experts explained that many people with inadequately controlled eosinophilic asthma who are not eligible for treatment with biologicals would have oral corticosteroids, rather than continuing on inhaled medication alone. The committee noted that the company proposed the use of benralizumab earlier in the treatment pathway than existing biologicals are currently used, and it would therefore need to be convinced of the clinical and cost effectiveness of benralizumab in this specific population. It recalled that the clinical experts consider it is too soon to widen the benralizumab-eligible population to include a new population of patients with less severe disease (see section 3.7) and noted the uncertainty about the clinical effectiveness of benralizumab in these patients (see section 3.8). Therefore, the cost-effectiveness estimates for this population in the company's model are highly uncertain. The committee noted that the company's ICER for benralizumab compared with standard care in people who are not eligible for biologicals (£38,304 per QALY gained) is above the range considered a cost-effective use of NHS resources. It also heard from the ERG that this ICER is associated with significant uncertainty because a very small patient sample was used to obtain the updated transition probabilities and utility values. The committee noted that when the same transition probabilities as those used in the base-case population are used, the ICER increases to £45,406 per QALY gained. It concluded that the most plausible ICER is uncertain for the population that is not eligible for biologicals, but it would be above the level that is considered a cost-effective use of NHS resources.
Having concluded that benralizumab was cost effective in the population for whom mepolizumab or reslizumab were currently recommended, the committee noted that the guidance on these drugs included a recommendation to review the need for continued treatment at 12 months. It further noted that the summary of product characteristics for benralizumab says that a decision to continue the therapy should be made at least annually based on disease severity, level of exacerbation control and blood eosinophil counts. The committee agreed that the recommendation for reviewing treatment every 12 months that applies to the other biologicals is equally appropriate for benralizumab.
# Innovation
The committee acknowledged the advantages to patients of an 8‑weekly dosing regimen. It noted that reduced administration costs were included in the economic modelling, which it considered reasonable.
The committee noted that benralizumab results in near-complete depletion of blood eosinophils within 24 hours of the first dose, and this depletion is maintained throughout the treatment period. Mepolizumab and reslizumab indirectly reduce the activation, proliferation and survival of eosinophils, resulting in eosinophil reduction but not near-complete depletion. Complete loss of eosinophils could be beneficial; however, it could theoretically carry some risks. The clinical experts commented that benralizumab is the only biological treatment available as a pre-filled syringe, and that is has a more convenient 8‑week dosing schedule. People are not currently able to self-administer benralizumab at home, but this might become possible in future. The clinical experts expressed the opinion that the differences in mode of action for benralizumab compared with mepolizumab and reslizumab are not of themselves innovative, but the convenience of administration of benralizumab would ease some of the burden of living with severe eosinophilic asthma. The committee concluded that benralizumab would be beneficial for patients, but it had not been presented with evidence that there are additional benefits that had not been captured in the cost-effectiveness analyses.
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{'Recommendations': "Benralizumab, as an add-on therapy, is recommended as an option for treating severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids and long-acting beta-agonists, only if:\n\nthe person has agreed to and followed the optimised standard treatment plan and\n\nthe blood eosinophil count has been recorded as 300\xa0cells per microlitre or more and the person has had 4\xa0or more exacerbations needing systemic corticosteroids in the previous 12\xa0months, or has had continuous oral corticosteroids of at least the equivalent of prednisolone 5\xa0mg per day over the previous 6\xa0months (that is, the person is eligible for mepolizumab) or\n\nthe blood eosinophil count has been recorded as 400\xa0cells per microlitre or more with 3\xa0or more exacerbations needing systemic corticosteroids in the past 12\xa0months (that is, the person is eligible for reslizumab).Benralizumab is recommended only if the company provides it according to the commercial arrangement.\n\nIf benralizumab, mepolizumab or reslizumab are equally suitable, start treatment with the least expensive option (taking into account drug and administration costs).\n\nAt 12\xa0months:\n\nstop benralizumab if the asthma has not responded adequately or\n\ncontinue benralizumab if the asthma has responded adequately and assess response each year.An adequate response is defined as:\n\n\n\na clinically meaningful reduction in the number of severe exacerbations needing systemic corticosteroids or\n\na clinically significant reduction in continuous oral-corticosteroid use while maintaining or improving asthma control.\n\n\n\nThese recommendations are not intended to affect treatment with benralizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nSevere asthma is usually treated with inhaled corticosteroids plus another drug, such as a long-acting beta-agonist. These may not work well enough for eosinophilic asthma, which is a type of severe asthma that can be difficult to control. Continuous oral corticosteroids may be needed to prevent exacerbations (asthma attacks) but they can cause long-term side effects. Some people are able to have mepolizumab or reslizumab, which are recommended for slightly different populations. They are biological treatments, as is benralizumab. Biological treatments help to control the asthma, and may allow the oral corticosteroids to be reduced.\n\nClinical trial results show that taking benralizumab plus standard treatment reduces exacerbations and the use of oral corticosteroids, compared with placebo. There are no trials directly comparing benralizumab, mepolizumab and reslizumab, and the relative clinical effectiveness of these treatments is not known. In an indirect comparison of benralizumab with mepolizumab, there is no significant difference in asthma exacerbations.\n\nThe company's mixed population is not suitable for considering the cost effectiveness of benralizumab compared with standard care. This is because it is a population of people with a blood eosinophil count of 300\xa0cells per microlitre or more, who have had 3\xa0or more exacerbations in the previous year, and includes some people who are taking maintenance oral corticosteroids. This combines people who are eligible for mepolizumab or reslizumab with other people with less severe disease who are not eligible for biological treatments and can only be offered standard care. The absolute treatment benefit and cost effectiveness of benralizumab varies depending on whether patients are eligible for mepolizumab and reslizumab and what their individual treatment options are.\n\nFor people who cannot have mepolizumab or reslizumab and standard care is the only option (that is, with an eosinophil count of less than 400\xa0cells per microlitre, who have had 3\xa0or fewer exacerbations in the last 12\xa0months and are not taking oral corticosteroids), the clinical effectiveness of benralizumab is uncertain. This is because these people comprised a small percentage of the trial population and the cost-effectiveness estimates are higher than can be considered cost effective.\n\nBenralizumab is clinically and cost effective compared with mepolizumab for people with an eosinophil count of 300\xa0cells per microlitre, who have had 4\xa0or more exacerbations or are taking maintenance oral corticosteroids, or both. It is also cost effective compared with reslizumab for people with a blood eosinophil count of 400\xa0cells per microlitre or more, who have had 3\xa0or more exacerbations in the past 12\xa0months. Therefore, it can be recommended for people who could have mepolizumab or reslizumab.", 'Information about benralizumab': "# Marketing authorisation indication\n\nBenralizumab (Fasenra, AstraZeneca) is indicated as 'add-on maintenance treatment in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists'.\n\n# Dosage in the marketing authorisation\n\nThe recommended dosage is 30\xa0mg every 4\xa0weeks for the first 3\xa0doses then every 8\xa0weeks, given by subcutaneous injection using a pre-filled syringe.\n\n# Price\n\nThe list price is £1,955 per 30‑mg pre-filled syringe (company submission). The company has a commercial arrangement. This makes benralizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with severe eosinophilic asthma will welcome an additional treatment option that may reduce the need for oral corticosteroids\n\nSevere eosinophilic asthma that is inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists is a debilitating condition, with many distressing symptoms. Exacerbations can happen without warning, be life-threatening, cause fear, and result in hospitalisation and intubation. People are often unable to work and may need help with day-to-day activities because of the symptoms. The patient expert explained that, for many people with severe eosinophilic asthma, it does not respond to standard treatment, and more intensive treatments are needed to control symptoms and prevent exacerbations. The clinical experts explained that inadequately controlled severe eosinophilic asthma is frequently treated with oral corticosteroids. NICE guidance recommends biological treatments such as mepolizumab and reslizumab for some people with inadequately controlled eosinophilic asthma (see the NICE technology appraisal guidance on mepolizumab and reslizumab for treating severe eosinophilic asthma). The patient expert explained that these have been life-transforming for some people. However, there are specific eligibility criteria for these drugs and not all patients are eligible to have them. The patient expert noted that inhaled or oral corticosteroids are the main treatment for preventing exacerbations in uncontrolled asthma. When taken frequently or long-term, these can cause major side effects including diabetes, glaucoma, weight gain, bone-density loss, raised blood pressure and mood swings. This has a significant impact on the lives of patients and their families, including the need for numerous additional drugs and hospital visits to monitor and treat the side effects. The patient expert noted that the potential to reduce or avoid oral corticosteroids, over and above improved control of asthma symptoms, is particularly important to patients. The committee concluded that people with severe eosinophilic asthma that is uncontrolled on standard treatment would welcome a new treatment option, particularly if it reduces or avoids the use of oral corticosteroids.\n\n## Benralizumab could offer an easier method of administration than reslizumab, and a more convenient dosing schedule than existing biological treatments\n\nThe clinical experts explained that benralizumab is given by subcutaneous injection using a pre-filled syringe (mepolizumab is also given by subcutaneous injection). This is an easier method of administration compared with reslizumab, which is given by intravenous injection. The dosing schedule for benralizumab is more convenient and needs fewer hospital visits than reslizumab and mepolizumab, which are both given every 4\xa0weeks. The first 3\xa0doses of benralizumab are given once every 4\xa0weeks, and then every 8\xa0weeks. The clinical experts considered this convenience in administration to be potentially very beneficial for patients. The patient expert highlighted that benralizumab would be preferred by many patients because its mode of administration and dosing schedule need less travel and fewer visits to specialist centres. The patient expert and the clinical experts confirmed that reduction in oral-corticosteroid use and its associated complications would be valuable to patients and significantly improve their quality of life. The committee concluded that benralizumab potentially offers benefits compared with existing biological treatments, by reducing visits to hospital, which could be important for people with severe eosinophilic asthma.\n\n# Clinical management and comparators\n\n## Benralizumab is a biological agent, and mepolizumab and reslizumab are relevant comparators\n\nThe clinical experts explained that treatment for asthma in clinical practice follows the NICE guideline on diagnosis, monitoring and chronic asthma management and the Global Initiative for Asthma 2017 guideline (which includes the use of mepolizumab, reslizumab and omalizumab). Management of uncontrolled asthma uses a step-up approach in which the dose of inhaled corticosteroids is continuously increased, while another drug is also taken for maintenance treatment. If the asthma is still uncontrolled, then oral corticosteroids are added. Because long-term use of corticosteroids is associated with side effects, the guidelines state that inhaled and oral corticosteroids should be used at the lowest doses at which asthma control is maintained, and other treatments should be considered to minimise the use of oral corticosteroids. Eosinophilic asthma is a subtype of asthma, with inflammatory cellular infiltration in the airway. It can be associated with allergy, higher risk of exacerbations, hospitalisation, dependency on oral corticosteroids and increased risk of dying. Biological treatments for people with severe eosinophilic asthma that is inadequately controlled, despite taking high-dose inhaled corticosteroids and long-acting beta-agonists, aim to both reduce the number and severity of exacerbations and reduce or avoid the use of oral corticosteroids. The committee concluded that benralizumab, although having a different mechanism of action to mepolizumab and reslizumab, also acts by reducing eosinophils, and these are therefore appropriate comparators for benralizumab.\n\n## There is insufficient evidence to recommend benralizumab for people who would not currently be offered biological treatments\n\nThe clinical experts explained that patients with uncontrolled asthma who have a blood eosinophil count of at least 300\xa0cells per microlitre, and have had at least 3\xa0exacerbations needing systemic corticosteroids in the past 12\xa0months, are referred to specialist asthma centres. These are commissioned by NHS England to be prescribers of the existing biological treatments for eosinophilic asthma (reslizumab and mepolizumab). At the specialist centre, the patient's asthma control is optimised on standard treatment, which may bring the symptoms under control. This is done before the need and eligibility for biological treatment is assessed. This in part explains why uptake of mepolizumab and reslizumab is seemingly low, because patients having optimised care at specialist centres may not need a biological treatment. Also, patients may choose not to have the existing biologicals because the dosing schedules can be difficult to maintain, the treatment is potentially life-long, and there is limited long-term evidence on their use. The clinical experts explained that the system for commissioning existing biologicals is working efficiently and represents established clinical practice in the NHS (in line with NICE's methods guide: sections 6.2.2 and 6.2.3). They did not consider it appropriate at present to use a lower eligibility threshold for treatment with benralizumab than for the existing biologicals. The committee concluded that controlled access to biologicals is working efficiently in the NHS and it is appropriate to consider benralizumab alongside the existing biologicals, and that there is insufficient evidence at present for widening access to include people with less severe asthma (that is, people with lower blood eosinophil counts and fewer exacerbations than are specified in the current NICE recommendations for mepolizumab or reslizumab, and who are not taking maintenance oral corticosteroids).\n\n## The choice of comparator depends on oral-corticosteroid use, eosinophil count and the number of exacerbations\n\nThe committee noted that the clinical trials (CALIMA and SIROCCO) recruited people with 2\xa0or more exacerbations in the previous year. It noted that the company proposed a sub-population of people with a blood eosinophil count of 300\xa0cells per microlitre or more, who have had 3\xa0or more exacerbations in the previous year or are taking maintenance oral corticosteroids. The company considered that this represents people with more severe eosinophilic asthma, who it considers will get the most benefit from benralizumab. The committee agreed to consider this population but noted that it includes people with differing severity of asthma (defined by eosinophil level, baseline oral-corticosteroid use and the number of exacerbations in the previous year). It therefore includes people who would be offered different treatment options in the NHS:\n\npeople with a blood eosinophil count of 300\xa0cells per microlitre or more, who have had at least 4\xa0exacerbations in the previous 12\xa0months or who are taking oral corticosteroids, can have mepolizumab\n\npeople with a blood eosinophil count of 400\xa0cells per microlitre or more, who have had at least 3\xa0exacerbations in the previous 12\xa0months, can have reslizumab\n\npeople with a blood eosinophil count of 300\xa0to 399\xa0cells per microlitre, who have had exactly 3\xa0exacerbations in the previous 12\xa0months and are not taking oral corticosteroids, would be offered standard care because they are not eligible for a biological treatment.\n\n# Clinical effectiveness\n\n## Benralizumab is more clinically effective than standard care in the clinical trial populations\n\nThe company's clinical evidence comes from 3\xa0randomised-controlled trials: SIROCCO, CALIMA and ZONDA. These compared benralizumab with placebo in people with uncontrolled asthma, taking high-dose inhaled corticosteroids and a long-acting beta-agonist, who had not already had treatment with any biological. SIROCCO and CALIMA included people who had 2\xa0or more exacerbations in the previous year and a blood eosinophil count of 300\xa0cells per microlitre or more (for the primary end point). ZONDA included people who had 1\xa0or more exacerbations in the previous year and a blood eosinophil count of 150\xa0cells per microlitre or more. The primary outcome in SIROCCO and CALIMA was annual asthma exacerbation rate, and in ZONDA it was the percentage reduction in oral-corticosteroid dose from baseline. The committee noted that the pooled results of SIROCCO and CALIMA show that benralizumab reduces the annual rate of exacerbations by 43% compared with placebo (risk ratio [RR] 0.57, 95% confidence interval [CI] 0.47 to 0.69; p<0.0001) in the intention-to-treat population. The results also suggest that benralizumab is more clinically effective in people with a blood eosinophil count of 300\xa0cells per microlitre or more, or in people who had 3\xa0or more exacerbations. In a pooled subgroup analysis of people with a blood eosinophil count of at least 300\xa0cells per microlitre who had 3\xa0or more exacerbations, benralizumab significantly reduced the annual asthma exacerbation rate by 53% compared with placebo (RR 0.47, 95% CI 0.32 to 0.67; p<0.001). Results from the intention-to-treat analysis from ZONDA showed that benralizumab reduced the median final oral-corticosteroid dose by 75% from baseline, compared with a reduction of 25% for placebo (median treatment difference 37.5%, 95% CI 20.8 to 50.0; p<0.001). Although the pooled SIROCCO and CALIMA data showed that benralizumab reduced the annual exacerbation rate, the committee noted that the absolute reduction depends on the baseline rate, which is related to the severity of the asthma before treatment began. For example, for the same relative reduction, people who have had 4\xa0exacerbations will experience a greater numerical reduction in exacerbations than people who have had 2\xa0exacerbations. The clinical experts also explained that treatment will be more effective in people who have a higher blood eosinophil count than those with a lower blood eosinophil count. The committee concluded that benralizumab is clinically effective as an addition to standard care in people with a blood eosinophil count of at least 300\xa0cells per microlitre, who have had 3\xa0or more exacerbations or are taking maintenance oral corticosteroids, but the size of the benefit will be greater for patients who have had more exacerbations with higher eosinophil counts.\n\n## The comparison of the mixed population with standard care is not appropriate for the purposes of decision making\n\nThe committee considered the population of patients proposed by the company (that is, people with a blood eosinophil count of 300\xa0cells per microlitre or more, who have had 3\xa0or more exacerbations in the previous year or are taking maintenance oral corticosteroids). The committee noted that the CALIMA and SIROCCO trials included people with 2\xa0or more previous exacerbations, and that the company's submission had excluded people with 2\xa0exacerbations and only included people with more severe eosinophilic asthma (3\xa0or more exacerbations) on the basis that people with more severe asthma would benefit most from benralizumab treatment. The committee noted that the absolute effectiveness of benralizumab will be greater in people with more severe disease (that is, those who have had more exacerbations and/or with a higher eosinophil count). It noted that the range of asthma severity in the company's proposed population, which it based on the populations in the clinical trials, may not be generalisable to people who have benralizumab in clinical practice in England. It considered this to be a key area of uncertainty, which will have a large impact on the clinical and cost effectiveness of benralizumab in any 'mixed' population. The committee was particularly interested in the proportion of patients included in the mixed population who had exactly 3\xa0exacerbations (including those with an eosinophil count between 300\xa0and 399\xa0cells per microlitre and not taking maintenance oral corticosteroids, who are not eligible for treatment with a biological), because this represents a widening of the population that would be eligible for biologicals. It noted that the company provided a range-estimate for the proportion of people in this population in response to the second appraisal consultation document (which is academic in confidence), and noted that this represents a small proportion of the overall mixed population. The company used the lowest proportion in the range to model the cost-effectiveness estimates for benralizumab. The committee concluded that the company's mixed population is based entirely on the patient populations included in the trials, and is not appropriate for decision making. Standard care alone would be a comparator only for people who have had exactly 3\xa0exacerbations, who have an eosinophil count of between 300\xa0to 399\xa0cells per microlitre and are not taking maintenance oral corticosteroids. This represents a very small group of people with less severe disease, who would not currently be eligible for biological treatment. The remaining patients in the mixed population would be eligible for the existing biologicals, but some may choose to have standard care. The committee concluded that the mixed population is not suitable for the purposes of decision making, and that standard care alone is not an appropriate comparator for all patients. It is more appropriate to consider the clinical and cost effectiveness of benralizumab in relation to the eligibility of patients for other treatments available in the NHS (based on the severity of disease defined by oral-corticosteroid use, eosinophil count and the number of exacerbations), rather than considering standard care alone as an appropriate comparator for all patients.\n\n## The clinical-effectiveness estimates for benralizumab are uncertain in the subgroup of people who are not currently eligible for biologicals\n\nThe committee considered the clinical effectiveness of benralizumab for people who would not currently be eligible for a biological. It noted that the rate ratio for marginal annual exacerbations from a pooled SIROCCO and CALIMA subgroup analysis was 0.39 for this population. It concluded that this analysis was based on small patient numbers and that it is too soon to consider widening the population eligible for benralizumab, based on a small subgroup analysis and limited efficacy data.\n\n## The clinical effectiveness of benralizumab compared with reslizumab and mepolizumab is uncertain\n\nThe committee noted that the company did not do a network meta-analysis (NMA) to compare the clinical effectiveness of benralizumab with reslizumab and mepolizumab, because of the significant differences in the patient populations in the trials for these 3\xa0drugs. The company argued that it is more appropriate to adjust for differences in patient characteristics between the trials using an anchored matched-adjusted indirect comparison (MAIC), rather than an NMA. However, this was only feasible for the comparison with mepolizumab because differences in the baseline characteristics of the people in the reslizumab trial prevented a MAIC being done. Instead, the company made the simple assumption that benralizumab and reslizumab have the same clinical efficacy. The ERG agreed that a MAIC comparing benralizumab with reslizumab is not feasible, but it noted that there is no evidence to support the assumption of clinical equivalence. The committee agreed that no evidence had been provided to support this assumption and it concluded that the relative efficacy of benralizumab and reslizumab could not be determined. The committee noted that the MAIC with mepolizumab showed no significant differences between benralizumab and mepolizumab. However, a non-significant advantage of one over the other was shown, depending on whether data from the MUSCA trial were included in the analysis. MUSCA was a 24‑week trial that was not included in the MAIC by the company because the primary outcome was health-related quality of life. Without the MUSCA data, the results favour benralizumab but the reverse is the case if MUSCA data are included. The committee noted that the MAIC comparing benralizumab with mepolizumab was done in the full trial populations, because relevant subgroup data were not available for mepolizumab. The relative effect was assumed to apply to the subgroup of people with a blood eosinophil count of 300\xa0cells per microlitre or more, who had 4\xa0or more exacerbations or were taking maintenance oral corticosteroids. The company explained that the MAIC matched people having benralizumab to people in the mepolizumab trial, and it assumed that the relative difference in efficacy between the 2\xa0treatments is the same in the most severe subgroup as in the intention-to-treat population. The committee considered that despite the rationale provided by the company during consultation, the use of the MAIC instead of an NMA had not been adequately justified. It also considered that the rationale is inconsistent with the company's use of the clinical-effectiveness estimates from the MAIC, which were applied to a population with different characteristics. The committee noted that an NMA of mepolizumab and reslizumab could have been done, and this might have been useful for its decision making. However, it noted that an NMA may be affected by heterogeneity in the characteristics of the trial populations. The committee therefore concluded that there remains uncertainty about the clinical effectiveness of benralizumab compared with mepolizumab and reslizumab because the method used for the comparison with mepolizumab is not considered robust, and a simple assumption of equivalence, with no underpinning evidence, was used for reslizumab.\n\n# The company's economic model\n\n## The model structure is appropriate for decision making\n\nThe company submitted a 4‑state Markov model comparing benralizumab with mepolizumab, reslizumab and standard care in people with a blood eosinophil count of at least 300\xa0cells per microlitre, who had had 3\xa0or more exacerbations or were taking maintenance oral corticosteroids. The committee noted that assessment of response was modelled at 52\xa0weeks, when 'responders' continued taking the biological treatments and 'non-responders' started standard care. The committee noted that the model included a stopping rule but it was unclear if response was reassessed every year. It considered that treatment continuation based on annual reassessment is appropriate, because people have their asthma reassessed every year in clinical practice and this is consistent with NICE's guidance on reslizumab. The efficacy and clinical parameters in the model were derived from pooled SIROCCO and CALIMA data, ZONDA data, the MAIC results for the comparison of benralizumab with mepolizumab, published literature and previous NICE appraisals. The committee noted that the clinical effectiveness of benralizumab compared with mepolizumab was based on a MAIC, which it had considerable reservations about (see section\xa03.9). However, the committee considered it commendable that the model attempted to incorporate some of the long-term complications of oral-corticosteroid use in the model, even though some effects cannot be reversed so some steroid-sparing benefits may not be realised. Taking everything into account, the committee accepted that the model structure is appropriate for decision making.\n\n# Clinical inputs to the model\n\n## The proportion of people taking maintenance oral corticosteroids at baseline in the comparison with mepolizumab and standard care is uncertain\n\nIn response to consultation the company provided an updated model, which included an updated confidential discount to the list price of benralizumab and used many of the model inputs preferred by the committee. Different proportions of maintenance oral-corticosteroid use at baseline were used, depending on the comparator (54.1% for standard care and 60% for mepolizumab). The ERG preferred a value of 41.7% sourced from a UK registry of patients with severe asthma (Heaney\xa02010) for the standard care comparison, and a value of 60% for the mepolizumab comparison. The clinical experts confirmed that in clinical practice in the UK, about 66% to 80% of people starting to take mepolizumab will be taking maintenance oral corticosteroids. The committee noted that it is difficult to determine the proportion of people taking maintenance oral corticosteroids in the company's mixed population (see section\xa03.7). This is a key area of uncertainty in the model, which has a substantial impact on the cost effectiveness of benralizumab.\n\n## The amended asthma-related mortality estimates are appropriate\n\nThe committee noted that asthma-related mortality is often a key driver of cost effectiveness in asthma models. It heard from the clinical experts that the National Review of Asthma Deaths (NRAD) report indicated that asthma-related deaths have decreased substantially in all age categories, except in people over\xa075. The clinical experts explained that asthma-related deaths are rare, with about 300\xa0to 400\xa0deaths annually in the UK. They commented that some deaths originally recorded as asthma-related in the NRAD report were later found not to have been caused by asthma. The committee noted that in the model provided by the company in response to the first appraisal consultation document, asthma-related mortality was updated to include an average probability of death of 0.0078\xa0per hospital admission (sourced from the British Thoracic Society asthma audit for people aged 45\xa0to\xa054\xa0years and 55\xa0to\xa064\xa0years). This was preferred by the committee. The committee concluded that the asthma-related mortality estimates in the company's revised model are appropriate.\n\n# The company's updated base-case economic analysis\n\n## The company's mixed population is not suitable for making decisions about the cost effectiveness of benralizumab relative to standard care\n\nThe committee considered the mixed population proposed by the company of people with a blood eosinophil count of at least 300\xa0cells per microlitre, who had had 3\xa0or more exacerbations or were taking maintenance oral corticosteroids. The modelled population requires assumptions to be made about the proportion of patients who would be considered for benralizumab in clinical practice depending on use of maintenance oral corticosteroids, number of prior exacerbations, and blood eosinophil count. The committee noted that within this population some people would be eligible for treatment with other biologicals, and it was therefore only interested in the incremental cost-effectiveness ratio (ICER) compared with standard care in people who were not eligible for biologicals (see section\xa03.16). The committee concluded that the base-case deterministic ICER in the mixed population for benralizumab compared with standard care provided by the company in response to consultation (£25,192 per quality-adjusted life year [QALY] gained) and the ERG exploratory analysis (£25,587 per QALY gained) are not relevant to decision making. For these reasons, the committee did not consider it appropriate to base its decision making on the ICER from a mixed population that is based solely on proportions from the trials.\n\n## When mepolizumab is a treatment option, benralizumab is a cost-effective use of NHS resources\n\nThe committee considered people who are eligible for treatment with mepolizumab (that is, people who are taking oral corticosteroids or have had 4\xa0or more exacerbations, with an eosinophil count of 300\xa0cells per microlitre or more). It noted that when the updated patient access scheme (PAS) price of benralizumab and the PAS price for mepolizumab are used in the model, the ICER is below £20,000 per QALY gained. However, the QALY gain for benralizumab compared with mepolizumab in the company's model is small and is based on an assumption of superior clinical benefit for benralizumab from the MAIC, which the committee did not accept as robust (see section\xa03.9). The committee considered benralizumab to have similar overall health benefits to mepolizumab although it acknowledged that there is some benefit for benralizumab, particularly in the method and frequency of administration. It was reassured that benralizumab and mepolizumab were shown to have similar long-term costs in a cost-comparison done by the ERG, which assumed equal efficacy and used PAS prices and estimated administration costs. The committee therefore concluded that benralizumab is cost effective in people who are eligible for mepolizumab. Given the lack of clear evidence of superiority of one over the other, the committee concluded that if both are equally suitable for the patient, the least expensive option should be chosen (taking into account drug and administration costs).\n\n## When reslizumab is a treatment option, benralizumab is a cost-effective use of NHS resources\n\nThe committee considered people who are eligible for treatment with reslizumab (that is, people who have an eosinophil count of 400\xa0cells per microlitre or more and have had at least 3\xa0exacerbations). It noted that when the PAS prices for benralizumab and reslizumab were used in the ERG analysis, benralizumab is clearly cost effective compared with reslizumab. Although the simple assumption of clinical equivalence between the 2\xa0treatments is questionable, it is reasonable to assume that they are not very different. The committee concluded that benralizumab can be considered cost effective for people who are eligible for reslizumab. It acknowledged the potential benefit of benralizumab, particularly in the method and frequency of administration compared with the intravenous administration of reslizumab, and concluded that if both are equally suitable for the patient, the least expensive should be chosen (taking into account drug and administration costs).\n\n## When standard care is the only treatment option, benralizumab is not a cost-effective use of NHS resources\n\nThe committee considered the population for whom standard care is the only treatment option (that is, people with an eosinophil count between 300\xa0to\xa0399 cells per microlitre, who have had exactly 3\xa0exacerbations and are not taking oral corticosteroids). The clinical experts explained that many people with inadequately controlled eosinophilic asthma who are not eligible for treatment with biologicals would have oral corticosteroids, rather than continuing on inhaled medication alone. The committee noted that the company proposed the use of benralizumab earlier in the treatment pathway than existing biologicals are currently used, and it would therefore need to be convinced of the clinical and cost effectiveness of benralizumab in this specific population. It recalled that the clinical experts consider it is too soon to widen the benralizumab-eligible population to include a new population of patients with less severe disease (see section\xa03.7) and noted the uncertainty about the clinical effectiveness of benralizumab in these patients (see section\xa03.8). Therefore, the cost-effectiveness estimates for this population in the company's model are highly uncertain. The committee noted that the company's ICER for benralizumab compared with standard care in people who are not eligible for biologicals (£38,304 per QALY gained) is above the range considered a cost-effective use of NHS resources. It also heard from the ERG that this ICER is associated with significant uncertainty because a very small patient sample was used to obtain the updated transition probabilities and utility values. The committee noted that when the same transition probabilities as those used in the base-case population are used, the ICER increases to £45,406 per QALY gained. It concluded that the most plausible ICER is uncertain for the population that is not eligible for biologicals, but it would be above the level that is considered a cost-effective use of NHS resources.\n\nHaving concluded that benralizumab was cost effective in the population for whom mepolizumab or reslizumab were currently recommended, the committee noted that the guidance on these drugs included a recommendation to review the need for continued treatment at 12\xa0months. It further noted that the summary of product characteristics for benralizumab says that a decision to continue the therapy should be made at least annually based on disease severity, level of exacerbation control and blood eosinophil counts. The committee agreed that the recommendation for reviewing treatment every 12\xa0months that applies to the other biologicals is equally appropriate for benralizumab.\n\n# Innovation\n\nThe committee acknowledged the advantages to patients of an 8‑weekly dosing regimen. It noted that reduced administration costs were included in the economic modelling, which it considered reasonable.\n\nThe committee noted that benralizumab results in near-complete depletion of blood eosinophils within 24\xa0hours of the first dose, and this depletion is maintained throughout the treatment period. Mepolizumab and reslizumab indirectly reduce the activation, proliferation and survival of eosinophils, resulting in eosinophil reduction but not near-complete depletion. Complete loss of eosinophils could be beneficial; however, it could theoretically carry some risks. The clinical experts commented that benralizumab is the only biological treatment available as a pre-filled syringe, and that is has a more convenient 8‑week dosing schedule. People are not currently able to self-administer benralizumab at home, but this might become possible in future. The clinical experts expressed the opinion that the differences in mode of action for benralizumab compared with mepolizumab and reslizumab are not of themselves innovative, but the convenience of administration of benralizumab would ease some of the burden of living with severe eosinophilic asthma. The committee concluded that benralizumab would be beneficial for patients, but it had not been presented with evidence that there are additional benefits that had not been captured in the cost-effectiveness analyses."}
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https://www.nice.org.uk/guidance/ta565
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Evidence-based recommendations on benralizumab (Fasenra) for treating severe eosinophilic asthma in adults.
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8a3e3348b980c4b1fd47c5d7a2d5d9ad6a648f8d
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nice
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Olaparib for maintenance treatment of BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after response to first-line platinum-based chemotherapy
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Olaparib for maintenance treatment of BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after response to first-line platinum-based chemotherapy
Evidence-based recommendations on olaparib (Lynparza) for treating BRCA mutation‑positive, advanced ovarian, fallopian tube or primary peritoneal cancer that has responded to first-line platinum-based chemotherapy in adults.
# Recommendations
Olaparib is recommended for use within the Cancer Drugs Fund as an option for the maintenance treatment of BRCA mutation‑positive, advanced (FIGO stages 3 and 4), high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to first-line platinum-based chemotherapy in adults. It is recommended only if the conditions in the managed access agreement for olaparib are followed.
This recommendation is not intended to affect treatment with olaparib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
There are currently no maintenance treatments for BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after a positive response to first-line platinum-based chemotherapy. Olaparib is currently recommended after 3 or more lines of platinum-based chemotherapy. Using olaparib earlier in the treatment pathway would be an important development because earlier use can achieve the greatest benefit and may have the potential to cure the disease.
An ongoing clinical trial shows that olaparib delays disease progression. But it is not known whether people having olaparib live longer because people in the trial have not been followed up for long enough. The currently available clinical trial evidence does not show a significant difference in overall survival between olaparib and placebo. This makes the estimates of cost effectiveness very uncertain. Therefore, olaparib is not recommended for routine use in the NHS.
If olaparib increases the length of time people live it has the potential to be cost effective, but more evidence from the ongoing trial is needed to address the uncertainties. Therefore, it is recommended for use in the Cancer Drugs Fund, while further data are collected.# Information about olaparib
Marketing authorisation indication
Olaparib (Lynparza, AstraZeneca) as tablets is indicated as 'monotherapy for the maintenance treatment of adult patients with advanced (FIGO stages 3 and 4) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy'.
Dosage in the marketing authorisation
Olaparib is taken orally. It is currently available both in a tablet and a capsule formulation. However, the capsule formulation is only licensed for people with relapsed BRCA mutation-positive platinum-sensitive ovarian cancer and will be phased out when no longer needed by patients. The marketing authorisation relevant to the current appraisal is for olaparib tablets. Therefore, only olaparib tablets are covered by this appraisal.
The dosage of olaparib as tablets is 300 mg (2 × 150 mg tablets) taken twice daily (600 mg per day). A 100-mg tablet is available for dose reductions.
For first-line maintenance treatment, it is recommended that olaparib is continued until radiological disease progression, unacceptable toxicity, or for up to 2 years if there is no radiological evidence of disease. Patients with evidence of disease at 2 years, who in the opinion of the treating physician can derive further benefit from continuous treatment, can have treatment beyond 2 years.
Price
The list price for tablets is £2,317.50 per 14-day pack; £4,635.00 per 28-day cycle (excluding VAT; BNF online, accessed May 2019). The company has a commercial arrangement.# Committee discussion
The appraisal committee (section 6) considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
Olaparib has a marketing authorisation for FIGO stage 3 or 4 BRCA mutation-positive advanced ovarian, fallopian tube and primary peritoneal cancer. Therefore FIGO stage 2 disease is not considered in this appraisal.
Olaparib for maintenance treatment after response to first-line platinum-based chemotherapy does not meet the criteria for using a 1.5% discount rate for costs and benefits. Therefore, the reference case 3.5% discount rate should be applied in the cost-effectiveness analyses.The price per tablet of olaparib is the same regardless of dose, so the cost of treatment per day for a reduced dose is the same as a full dose. Therefore, the economic modelling should use the cost of whole tablets rather than the average cost per milligram.The committee recognised that there are remaining areas of uncertainty with the analyses presented (see the technical report) and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage.
# Clinical need and treatment pathway
## Advanced ovarian, fallopian tube and peritoneal cancer have a high disease burden
The patient experts explained that advanced ovarian cancer is a devastating condition and people living with this condition have a high unmet clinical need. The disease has a poor prognosis and patients live with the fear of relapse with no prospect of cure. The clinical experts explained that survival rates for ovarian cancer are worse in the UK than in other developed countries. Reasons for this may include more advanced surgical techniques and better access to drug treatments in other countries. The committee concluded that patients with ovarian cancer have a high unmet clinical need.
## The availability of olaparib earlier in the treatment pathway is an important development in managing BRCA mutation-positive advanced ovarian cancer
Currently, there are no first-line maintenance treatment options for newly diagnosed BRCA mutation-positive advanced ovarian cancer. It is usually treated with surgery and platinum-based chemotherapy after which there is no active treatment. Unfortunately, the disease recurs in most people. Olaparib is a poly-ADP-ribose (PARP) inhibitor. Maintenance treatment with PARP inhibitors is available at later lines in the treatment pathway. The availability of olaparib as a first-line maintenance treatment is an important development in the management of BRCA mutation-positive advanced ovarian cancer because it is expected to have the greatest benefit when used early, and is considered to have the potential to cure the disease in some people if given before the first recurrence. The committee heard from a patient expert who started taking olaparib for advanced ovarian cancer after surgery and 4 lines of chemotherapy. She explained that olaparib has been transformative for her, extending her life. It has allowed her to live a normal life with manageable side effects, especially compared with the side effects of chemotherapy. The committee heard that olaparib would be most beneficial after initial chemotherapy, when people still feel relatively well, their body is stronger to cope with any side effects and there is greater potential to cure the disease. The committee concluded that the availability of olaparib after first-line platinum-based chemotherapy represents an important development in the management of BRCA mutation-positive advanced disease and would be highly valued by patients and clinicians.
## The place of PARP inhibitors in the treatment pathway is not yet fully established
PARP inhibitors are not routinely commissioned as maintenance treatment after second-line platinum-based chemotherapy, although niraparib is currently available through the Cancer Drugs Fund and there is an ongoing NICE appraisal for olaparib as a second-line treatment. Therefore, it is not yet known whether second-line use of PARP inhibitors will become standard care. NICE's technology guidance recommends olaparib capsules for BRCA mutation-positive advanced ovarian cancer after 3 or more lines of platinum-based chemotherapy. The committee noted that, in SOLO‑1, the main clinical trial of olaparib tablets as a maintenance treatment after first-line platinum-based chemotherapy (see section 3.6), people in the routine surveillance arm could have a PARP inhibitor after disease progression if their disease responded to subsequent platinum-based chemotherapy. The clinical experts explained that the proportion of people who had a subsequent PARP inhibitor in the trial is a reasonable reflection of current clinical practice. However, it is uncertain how clinical practice will change with further NICE recommendations for second-line use and the potential introduction of olaparib as a first-line treatment. The committee concluded that there is uncertainty around future use of PARP inhibitors because of the evolving pathway of care.
## There is no evidence for retreatment with a PARP inhibitor
The committee considered whether retreatment with a PARP inhibitor would happen in clinical practice, noting that a very small proportion of people in the olaparib arm of SOLO‑1 had retreatment later in the pathway. The clinical experts explained that, for relapsed disease, treatment with a PARP inhibitor is normally continued until disease progression or unacceptable toxicity. However, the marketing authorisation stipulates that first-line olaparib treatment should be stopped after 2 years, unless there is evidence of residual disease and the patient is likely to derive further benefit. Therefore, it is possible that tumour sensitivity to PARP inhibitors might be retained after subsequent chemotherapy. The clinical experts explained that there is currently no evidence on retreatment with a PARP inhibitor and there is a need for this to be tested in a clinical trial. The committee concluded that it is unknown whether tumour sensitivity to PARP inhibitors would be retained after subsequent chemotherapy and that there is currently no evidence for retreatment.
# Stopping treatment after 2 years
## Around 15% of patients are likely to continue taking olaparib after 2 years because of residual disease
In SOLO‑1, 82% of patients were in complete response to platinum-based chemotherapy and 18% were in partial response. After 2 years of treatment, 10% of patients continued olaparib because they had residual disease. This is in line with the marketing authorisation (see section 3.4). The committee considered whether these proportions are generalisable to UK clinical practice. It heard from the clinical experts that despite recent developments in surgical techniques, the outcomes of ovarian cancer in the UK are worse than in other developed countries (see section 3.1). The clinical exerts explained that because BRCA mutation-positive ovarian cancer is very responsive to platinum-based chemotherapy, the proportion of people in the UK eligible for olaparib who would have a partial, rather than complete, response is unlikely to be higher than 30%, according to the clinical experts. Also, because olaparib reduces tumour burden while maintaining response to platinum-based chemotherapy, the percentage who would have residual disease by the end of the 2‑year treatment period is likely to be halved to around 15%. The committee recognised that uncertainty in the percentage of patients with residual disease could have a substantial effect on treatment costs and introduces financial uncertainty for the NHS. The committee concluded that it is reasonable to expect that approximately 15% of patients would continue treatment with olaparib beyond 2 years, however this estimate is uncertain and may be optimistic considering the current outcomes of patients with ovarian cancer in the UK.
# Clinical trial evidence from the SOLO‑1 trial
## Olaparib improves progression-free survival
SOLO‑1 is a double-blind randomised clinical trial of olaparib compared with placebo in people with newly diagnosed FIGO stage 3 or 4, BRCA mutation-positive advanced ovarian cancer after first-line platinum-based chemotherapy. The primary end point of the trial is progression-free survival and a statistically significant improvement was reached at 50.6% data maturity. The median progression-free survival is 13.8 months in the placebo arm and has not been reached in the olaparib arm, but the company estimates it to be at least 3 years longer than placebo (hazard ratio 0.30, 95% confidence interval 0.23 to 0.41). The clinical experts explained that these results are extremely promising, and it is exceptional that so many people are disease free after 4 years because this has not been seen previously in ovarian cancer trials. They also explained that maintaining progression-free survival after first-line chemotherapy for a long period is vital and the longer it is maintained the higher the potential for cure from the disease. The committee concluded that olaparib showed an impressive improvement in progression-free survival.
## Overall survival data are immature but olaparib is expected to extend life
Overall survival was a secondary end point in SOLO‑1. There was a small non-statistically significant benefit for olaparib compared with placebo, but at 21% maturity the median was not reached in either arm (HR 0.95, 95% CI 0.60 to 1.53). The clinical experts explained that they expect to see similarly positive overall survival benefits as for progression-free survival, but currently the data are too immature to predict the size of the benefit. The committee noted that the overall survival Kaplan–Meier curves from SOLO‑1 converged during the initial follow-up period, which could suggest no further overall survival benefit. However, it heard from the company that study 19, a trial of olaparib for relapsed ovarian cancer, showed a similar pattern of convergence after 37 months of follow up. After 78 months of follow up an overall survival benefit was observed for olaparib compared with placebo. The committee considered that it is unknown to what extent the results of SOLO‑1 will mirror those from study 19. The clinical experts explained that the latest data cut from study 19 shows that 10% of patients are disease free after 10 years, indicating cure. These 'super responders' are more likely to be people who had a complete response to platinum-based chemotherapy and, because a complete response is more likely at an earlier stage of the disease, the results from SOLO‑1 are expected to be very favourable. The company also presented evidence from other ovarian cancer trials showing that a progression-free survival benefit can translate into an overall survival benefit. A systematic review by Sundar et al. (2012) of 37 trials of advanced primary or recurrent ovarian cancer indicates that the relationship between progression-free survival and overall survival benefit is 1 to 1. The results of 2 trials of first-line treatment of advanced ovarian cancer (GOG‑172 and JGOG-3016) suggest that the relationship could be 1 to 2 or more. The committee concluded that the extent to which the progression-free survival benefit will translate into overall survival benefit is uncertain, but it is expected that treatment with olaparib will extend life.
## The relationship between second progression-free survival and overall survival is not established
Second progression-free survival (that is, time from randomisation to second progression ) is a secondary outcome in SOLO‑1. At the latest data cut, 26.5% of patients in the olaparib arm and 39.7% of patients in the placebo arm had progressed after second-line therapy. The median PFS‑2 has not been reached in the olaparib arm and is 41.9 months in the placebo arm (HR 0.50, 95% CI 0.35 to 0.72). The committee heard from the clinical experts and the company that overall survival results may lag behind progression-free survival by several years and that PFS-2 is a reasonable surrogate. However, the committee concluded that while a longer PFS‑2 could be considered to be an indicator of continued treatment benefit, in the absence of mature evidence on the effect of olaparib on overall survival, a clear relationship between PFS‑2 and overall survival has not been established.
# Evidence from the Edinburgh Ovarian Cancer Database
## The Edinburgh Ovarian Cancer Database provides real-world survival data
The Edinburgh Ovarian Cancer Database collects data on people with ovarian cancer in Scotland since the mid-1980s. The company did an analysis of data from people with BRCA mutation-positive disease diagnosed between 2000 and 2009 (n=129) to indicate long-term survival trends, and to externally validate the survival outputs of its economic model. The committee heard from the clinical experts and the company that the characteristics of people in this analysis are similar to those in SOLO‑1 in terms of median age and subsequent PARP inhibitor use, and that most had high-grade serous stage 3 or 4 ovarian cancer. However, there was no information on the number of people with complete or partial response to platinum-based chemotherapy. Therefore, it is not clear how comparable the population of the Edinburgh Ovarian Cancer Database is with the population of SOLO-1. The committee accepted that the Edinburgh Ovarian Cancer Database provides some real-world data on survival outcomes, but it has limitations. In the absence of mature overall survival data from SOLO‑1, the data does provide at least an indication of expected survival outcomes in current practice.
# Model structure
## The 4‑state health model has limitations but is acceptable for decision making
To estimate the cost effectiveness of olaparib compared with routine surveillance the company presented a partitioned survival model with 3 states (progression-free, progressed disease and death). The ERG considered that this model oversimplifies the treatment pathway, because people can have multiple progressions with ovarian cancer. In response to technical engagement, the company submitted an updated partitioned survival model with 4 health states. It includes a PFS‑2 health state using data from SOLO‑1. Clinical-effectiveness evidence comes from SOLO‑1, where subsequent PARP inhibitor use occurred in both arms (see section 3.3 and section 3.4). The ERG found it problematic that the model does not allow testing for different assumptions about subsequent PARP inhibitor use, and it was concerned that the trial might not reflect UK clinical practice. The committee recalled the clinical experts' view that subsequent PARP inhibitor use in SOLO‑1 is a reasonable reflection of clinical practice but there is uncertainty around use of PARP inhibitors after second-line platinum-based chemotherapy (see section 3.3 and section 3.4). The ERG suggested that a sequenced model would have been more appropriate for decision making. The committee understood that this type of model needs data from multiple studies to populate the parameters at each available therapy line. It noted that the company had considered this approach but could not develop it because of lack of data to populate each health state. The committee agreed that the model structure proposed by the ERG has some merit, but acknowledged that implementing it would be a complex undertaking. It noted that the main driver of the model is overall survival and, whichever approach is used, the immaturity of the clinical evidence and the complexity of the clinical pathway are limiting factors in the modelling of long-term outcomes. It understood the ERG's concern that the company's model uses extrapolation of PFS‑2 to predict survival, not overall survival data from the trial, which is a significant limitation of the company's approach. However, the committee was concerned that a different model structure would not resolve the uncertainties associated with the overall survival modelling. It therefore concluded that the 4‑state model is acceptable for decision making.
# Modelling overall survival
## The modelling of overall survival is very uncertain
The key driver of the results of the model is the way in which overall survival is modelled. The company did not estimate an overall survival curve for the routine surveillance arm using the immature SOLO‑1 overall survival data, because it considered that any extrapolation method using this immature data would result in unrealistic survival estimates in the routine surveillance arm. Instead, it used PFS‑2 as a surrogate for overall survival. The committee acknowledged that PFS‑2 is generally accepted as an indicator of prolonged benefit in clinical trials of maintenance treatments (see section 3.8). However, it was concerned that the model outputs do not reflect the SOLO‑1 interim results, which show convergence of the curves after about 40 months of follow up (see section 3.7). By contrast, the model predicts that at 20 years about 20% more people are alive in the olaparib arm compared with the routine surveillance arm (38% compared with 18%). The clinical experts considered that in the absence of more mature clinical data this is a reasonable prediction and in line with expectations given the overall survival results from study 19. The committee noted that the survival curves in study 19 also converged at early data cuts, but survival gains were observed after several years. It is unknown whether the results of SOLO‑1 will mirror this pattern with longer follow up (see section 3.7). The committee also noted that the modelling results for the routine surveillance arm are broadly consistent with the survival rates from the Edinburgh Ovarian Cancer Database, which it had concluded provides some real-world data on survival outcomes (see section 3.9). The committee acknowledged this but reiterated that not using the available overall survival data from the trial is a major weakness of the modelling. It considered that the modelling of overall survival is associated with considerable uncertainty and may overestimate the survival gain for olaparib, based on the data available from the trial so far. It concluded that it is not possible to resolve this uncertainty until more mature overall survival data are available from SOLO‑1.
# Cost-effectiveness estimate
## Olaparib has not been shown to be cost effective compared with routine surveillance
The company's base-case incremental cost-effectiveness ratio (ICER) for olaparib compared with routine surveillance using the 4‑state model is £17,480 per quality-adjusted life year (QALY) gained. However, the committee considered that this ICER is highly uncertain for the following reasons:
The modelling of overall survival is extremely uncertain and may overestimate the survival gain for olaparib based on the data currently available from SOLO‑1 (see section 3.9).
The percentage of patients eligible for olaparib in the NHS who have a complete response to platinum-based chemotherapy could be less than in the trial. The clinical experts estimate it to be about 70% of all responders, whereas it was 82% in SOLO‑1. It is expected that people in complete response are more likely to have long-term benefit than those with residual disease. A lower percentage of people with complete response in the NHS could result in worse outcomes than seen in the trial.
There is uncertainty about the percentage of people who would have residual disease and be eligible to continue olaparib treatment beyond 2 years, and this could have a large impact on treatment costs. The committee concluded that about 15% of patients in UK clinical practice could be eligible to continue treatment beyond 2 years, compared with 10% in the company's model. However, the estimate of 15% may be optimistic because of the worse outcomes of people with ovarian cancer in the UK (see section 3.5).
There is uncertainty about use of PARP inhibitors after second-line platinum-based chemotherapy and about retreatment with a PARP inhibitor (see section 3.3 and section 3.4).
The price per tablet of olaparib is the same regardless of dose, so the cost of treatment per day for a reduced dose is the same as a full dose. Using the cost of olaparib at full dose increases the ICER, and it was concluded after technical engagement that the modelling should use the cost of whole tablets rather than the average cost per milligram.Because of these uncertainties the committee considered that the ICER could be substantially higher than the company's estimate, and the committee was not convinced that the ICER had been shown to be within the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained). Therefore, it concluded that it could not recommend olaparib for routine use in the NHS as first-line maintenance treatment for BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer.
# Cancer Drugs Fund
## Mature overall survival data would resolve the uncertainties in the clinical and cost-effectiveness evidence
Having concluded that olaparib could not be recommended for routine use, the committee then considered if it could be recommended within the Cancer Drugs Fund for maintenance treatment of BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after response to first-line platinum-based chemotherapy. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It recognised that olaparib is an innovative treatment for advanced disease after first-line platinum-based chemotherapy. It therefore considered whether clinical uncertainty associated with olaparib could be addressed through collection of additional data from SOLO‑1. The committee heard from the company that an interim overall survival analysis is expected within the next 2 years. It agreed that more mature overall survival data would be a valuable addition to the clinical evidence base and are likely to resolve the major uncertainties. The committee concluded that overall survival data from SOLO‑1 should be directly used in the company's future modelling of overall survival.
## Olaparib meets the criteria for inclusion in the Cancer Drugs Fund for treating BRCA mutation-positive advanced ovarian, fallopian tube or primary peritoneal cancer
The committee recalled that the company's base-case ICER for olaparib compared with routine surveillance is £17,480 per QALY gained. It is based on the assumptions that 82% of people have complete response to platinum-based chemotherapy before starting olaparib, and no more than 10% of people will continue treatment beyond 2 years. The committee recalled that these assumptions are uncertain and may not reflect clinical practice in the NHS (see section 3.5 and section 3.12). Importantly, the company's analysis also assumes that about 20% of people will be cured from ovarian cancer. Although the clinical experts had explained that cure is possible and the 20% estimate is plausible, the committee noted that no overall survival benefit has yet been demonstrated in SOLO‑1 (see section 3.7). Therefore, the committee considered that the company's base-case ICER may be an optimistic estimate of the cost effectiveness of olaparib (see section 3.12) and that it is plausible that the ICER could be much higher, exceeding the range that is usually considered an efficient use of NHS resources. However, while accepting that the upper bound of the range of plausible ICERs is highly uncertain, the committee considered that there is plausible potential for olaparib to be cost effective in routine use, pending the results from SOLO‑1. Therefore, olaparib meets the criteria for inclusion in the Cancer Drugs Fund for treating BRCA mutation-positive advanced ovarian, fallopian tube or primary peritoneal cancer after response to first-line platinum-based chemotherapy.
# Conclusion
## Olaparib has the plausible potential to be cost effective and is recommended for use within the Cancer Drugs Fund
Results from SOLO‑1 show an impressive improvement in progression-free survival for olaparib compared with placebo. However, mature overall survival data are not available yet and the extent to which the progression-free survival benefit will translate into an overall survival benefit is unknown. Because of the uncertainty about the overall survival benefit, the estimates of cost effectiveness are very uncertain and olaparib cannot be recommended for routine use in the NHS. If olaparib increases overall survival it has the potential to be cost effective. Mature overall survival data from SOLO‑1 are needed to address the uncertainties in the clinical and cost effectiveness. Olaparib is therefore recommended for use within the Cancer Drugs Fund as an option for treating BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer while further overall survival data are collected.# Recommendations for data collection
As a condition of the positive recommendation and the managed access agreement, the company is required to collect efficacy data from the SOLO‑1 trial.
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{'Recommendations': 'Olaparib is recommended for use within the Cancer Drugs Fund as an option for the maintenance treatment of BRCA mutation‑positive, advanced (FIGO stages\xa03 and\xa04), high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to first-line platinum-based chemotherapy in adults. It is recommended only if the conditions in the managed access agreement for olaparib are followed.\n\nThis recommendation is not intended to affect treatment with olaparib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere are currently no maintenance treatments for BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after a positive response to first-line platinum-based chemotherapy. Olaparib is currently recommended after 3\xa0or more lines of platinum-based chemotherapy. Using olaparib earlier in the treatment pathway would be an important development because earlier use can achieve the greatest benefit and may have the potential to cure the disease.\n\nAn ongoing clinical trial shows that olaparib delays disease progression. But it is not known whether people having olaparib live longer because people in the trial have not been followed up for long enough. The currently available clinical trial evidence does not show a significant difference in overall survival between olaparib and placebo. This makes the estimates of cost effectiveness very uncertain. Therefore, olaparib is not recommended for routine use in the NHS.\n\nIf olaparib increases the length of time people live it has the potential to be cost effective, but more evidence from the ongoing trial is needed to address the uncertainties. Therefore, it is recommended for use in the Cancer Drugs Fund, while further data are collected.', 'Information about olaparib': "Marketing authorisation indication\n\nOlaparib (Lynparza, AstraZeneca) as tablets is indicated as 'monotherapy for the maintenance treatment of adult patients with advanced (FIGO stages\xa03 and\xa04) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy'.\n\nDosage in the marketing authorisation\n\nOlaparib is taken orally. It is currently available both in a tablet and a capsule formulation. However, the capsule formulation is only licensed for people with relapsed BRCA mutation-positive platinum-sensitive ovarian cancer and will be phased out when no longer needed by patients. The marketing authorisation relevant to the current appraisal is for olaparib tablets. Therefore, only olaparib tablets are covered by this appraisal.\n\nThe dosage of olaparib as tablets is 300\xa0mg (2\xa0×\xa0150\xa0mg tablets) taken twice daily (600\xa0mg per day). A 100-mg tablet is available for dose reductions.\n\nFor first-line maintenance treatment, it is recommended that olaparib is continued until radiological disease progression, unacceptable toxicity, or for up to 2\xa0years if there is no radiological evidence of disease. Patients with evidence of disease at 2\xa0years, who in the opinion of the treating physician can derive further benefit from continuous treatment, can have treatment beyond 2\xa0years.\n\nPrice\n\nThe list price for tablets is £2,317.50 per 14-day pack; £4,635.00 per 28-day cycle (excluding VAT; BNF online, accessed May 2019). The company has a commercial arrangement.", 'Committee discussion': "The appraisal committee (section\xa06) considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nOlaparib has a marketing authorisation for FIGO stage\xa03 or\xa04 BRCA mutation-positive advanced ovarian, fallopian tube and primary peritoneal cancer. Therefore FIGO stage\xa02 disease is not considered in this appraisal.\n\nOlaparib for maintenance treatment after response to first-line platinum-based chemotherapy does not meet the criteria for using a 1.5%\xa0discount rate for costs and benefits. Therefore, the reference case 3.5%\xa0discount rate should be applied in the cost-effectiveness analyses.The price per tablet of olaparib is the same regardless of dose, so the cost of treatment per day for a reduced dose is the same as a full dose. Therefore, the economic modelling should use the cost of whole tablets rather than the average cost per milligram.The committee recognised that there are remaining areas of uncertainty with the analyses presented (see the technical report) and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage.\n\n# Clinical need and treatment pathway\n\n## Advanced ovarian, fallopian tube and peritoneal cancer have a high disease burden\n\nThe patient experts explained that advanced ovarian cancer is a devastating condition and people living with this condition have a high unmet clinical need. The disease has a poor prognosis and patients live with the fear of relapse with no prospect of cure. The clinical experts explained that survival rates for ovarian cancer are worse in the UK than in other developed countries. Reasons for this may include more advanced surgical techniques and better access to drug treatments in other countries. The committee concluded that patients with ovarian cancer have a high unmet clinical need.\n\n## The availability of olaparib earlier in the treatment pathway is an important development in managing BRCA mutation-positive advanced ovarian cancer\n\nCurrently, there are no first-line maintenance treatment options for newly diagnosed BRCA mutation-positive advanced ovarian cancer. It is usually treated with surgery and platinum-based chemotherapy after which there is no active treatment. Unfortunately, the disease recurs in most people. Olaparib is a poly-ADP-ribose (PARP) inhibitor. Maintenance treatment with PARP inhibitors is available at later lines in the treatment pathway. The availability of olaparib as a first-line maintenance treatment is an important development in the management of BRCA mutation-positive advanced ovarian cancer because it is expected to have the greatest benefit when used early, and is considered to have the potential to cure the disease in some people if given before the first recurrence. The committee heard from a patient expert who started taking olaparib for advanced ovarian cancer after surgery and 4\xa0lines of chemotherapy. She explained that olaparib has been transformative for her, extending her life. It has allowed her to live a normal life with manageable side effects, especially compared with the side effects of chemotherapy. The committee heard that olaparib would be most beneficial after initial chemotherapy, when people still feel relatively well, their body is stronger to cope with any side effects and there is greater potential to cure the disease. The committee concluded that the availability of olaparib after first-line platinum-based chemotherapy represents an important development in the management of BRCA mutation-positive advanced disease and would be highly valued by patients and clinicians.\n\n## The place of PARP inhibitors in the treatment pathway is not yet fully established\n\nPARP inhibitors are not routinely commissioned as maintenance treatment after second-line platinum-based chemotherapy, although niraparib is currently available through the Cancer Drugs Fund and there is an ongoing NICE appraisal for olaparib as a second-line treatment. Therefore, it is not yet known whether second-line use of PARP inhibitors will become standard care. NICE's technology guidance recommends olaparib capsules for BRCA mutation-positive advanced ovarian cancer after 3\xa0or\xa0more lines of platinum-based chemotherapy. The committee noted that, in SOLO‑1, the main clinical trial of olaparib tablets as a maintenance treatment after first-line platinum-based chemotherapy (see section\xa03.6), people in the routine surveillance arm could have a PARP inhibitor after disease progression if their disease responded to subsequent platinum-based chemotherapy. The clinical experts explained that the proportion of people who had a subsequent PARP inhibitor in the trial is a reasonable reflection of current clinical practice. However, it is uncertain how clinical practice will change with further NICE recommendations for second-line use and the potential introduction of olaparib as a first-line treatment. The committee concluded that there is uncertainty around future use of PARP inhibitors because of the evolving pathway of care.\n\n## There is no evidence for retreatment with a PARP inhibitor\n\nThe committee considered whether retreatment with a PARP inhibitor would happen in clinical practice, noting that a very small proportion of people in the olaparib arm of SOLO‑1 had retreatment later in the pathway. The clinical experts explained that, for relapsed disease, treatment with a PARP inhibitor is normally continued until disease progression or unacceptable toxicity. However, the marketing authorisation stipulates that first-line olaparib treatment should be stopped after 2\xa0years, unless there is evidence of residual disease and the patient is likely to derive further benefit. Therefore, it is possible that tumour sensitivity to PARP inhibitors might be retained after subsequent chemotherapy. The clinical experts explained that there is currently no evidence on retreatment with a PARP inhibitor and there is a need for this to be tested in a clinical trial. The committee concluded that it is unknown whether tumour sensitivity to PARP inhibitors would be retained after subsequent chemotherapy and that there is currently no evidence for retreatment.\n\n# Stopping treatment after 2\xa0years\n\n## Around 15% of patients are likely to continue taking olaparib after 2\xa0years because of residual disease\n\nIn SOLO‑1, 82% of patients were in complete response to platinum-based chemotherapy and 18% were in partial response. After 2\xa0years of treatment, 10% of patients continued olaparib because they had residual disease. This is in line with the marketing authorisation (see section\xa03.4). The committee considered whether these proportions are generalisable to UK clinical practice. It heard from the clinical experts that despite recent developments in surgical techniques, the outcomes of ovarian cancer in the UK are worse than in other developed countries (see section\xa03.1). The clinical exerts explained that because BRCA mutation-positive ovarian cancer is very responsive to platinum-based chemotherapy, the proportion of people in the UK eligible for olaparib who would have a partial, rather than complete, response is unlikely to be higher than 30%, according to the clinical experts. Also, because olaparib reduces tumour burden while maintaining response to platinum-based chemotherapy, the percentage who would have residual disease by the end of the 2‑year treatment period is likely to be halved to around 15%. The committee recognised that uncertainty in the percentage of patients with residual disease could have a substantial effect on treatment costs and introduces financial uncertainty for the NHS. The committee concluded that it is reasonable to expect that approximately 15% of patients would continue treatment with olaparib beyond 2\xa0years, however this estimate is uncertain and may be optimistic considering the current outcomes of patients with ovarian cancer in the UK.\n\n# Clinical trial evidence from the SOLO‑1 trial\n\n## Olaparib improves progression-free survival\n\nSOLO‑1 is a double-blind randomised clinical trial of olaparib compared with placebo in people with newly diagnosed FIGO stage\xa03 or\xa04, BRCA mutation-positive advanced ovarian cancer after first-line platinum-based chemotherapy. The primary end point of the trial is progression-free survival and a statistically significant improvement was reached at 50.6%\xa0data maturity. The median progression-free survival is 13.8\xa0months in the placebo arm and has not been reached in the olaparib arm, but the company estimates it to be at least 3\xa0years longer than placebo (hazard ratio [HR]\xa00.30, 95% confidence interval [CI] 0.23 to 0.41). The clinical experts explained that these results are extremely promising, and it is exceptional that so many people are disease free after 4\xa0years because this has not been seen previously in ovarian cancer trials. They also explained that maintaining progression-free survival after first-line chemotherapy for a long period is vital and the longer it is maintained the higher the potential for cure from the disease. The committee concluded that olaparib showed an impressive improvement in progression-free survival.\n\n## Overall survival data are immature but olaparib is expected to extend life\n\nOverall survival was a secondary end point in SOLO‑1. There was a small non-statistically significant benefit for olaparib compared with placebo, but at 21%\xa0maturity the median was not reached in either arm (HR 0.95, 95% CI 0.60 to 1.53). The clinical experts explained that they expect to see similarly positive overall survival benefits as for progression-free survival, but currently the data are too immature to predict the size of the benefit. The committee noted that the overall survival Kaplan–Meier curves from SOLO‑1 converged during the initial follow-up period, which could suggest no further overall survival benefit. However, it heard from the company that study\xa019, a trial of olaparib for relapsed ovarian cancer, showed a similar pattern of convergence after 37\xa0months of follow up. After 78\xa0months of follow up an overall survival benefit was observed for olaparib compared with placebo. The committee considered that it is unknown to what extent the results of SOLO‑1 will mirror those from study\xa019. The clinical experts explained that the latest data cut from study\xa019 shows that 10% of patients are disease free after 10\xa0years, indicating cure. These 'super responders' are more likely to be people who had a complete response to platinum-based chemotherapy and, because a complete response is more likely at an earlier stage of the disease, the results from SOLO‑1 are expected to be very favourable. The company also presented evidence from other ovarian cancer trials showing that a progression-free survival benefit can translate into an overall survival benefit. A systematic review by Sundar et al. (2012) of 37\xa0trials of advanced primary or recurrent ovarian cancer indicates that the relationship between progression-free survival and overall survival benefit is 1\xa0to\xa01. The results of 2\xa0trials of first-line treatment of advanced ovarian cancer (GOG‑172 and JGOG-3016) suggest that the relationship could be 1\xa0to\xa02 or more. The committee concluded that the extent to which the progression-free survival benefit will translate into overall survival benefit is uncertain, but it is expected that treatment with olaparib will extend life.\n\n## The relationship between second progression-free survival and overall survival is not established\n\nSecond progression-free survival (that is, time from randomisation to second progression [PFS‑2]) is a secondary outcome in SOLO‑1. At the latest data cut, 26.5% of patients in the olaparib arm and 39.7% of patients in the placebo arm had progressed after second-line therapy. The median PFS‑2 has not been reached in the olaparib arm and is 41.9\xa0months in the placebo arm (HR 0.50, 95% CI 0.35 to 0.72). The committee heard from the clinical experts and the company that overall survival results may lag behind progression-free survival by several years and that PFS-2 is a reasonable surrogate. However, the committee concluded that while a longer PFS‑2 could be considered to be an indicator of continued treatment benefit, in the absence of mature evidence on the effect of olaparib on overall survival, a clear relationship between PFS‑2 and overall survival has not been established.\n\n# Evidence from the Edinburgh Ovarian Cancer Database\n\n## The Edinburgh Ovarian Cancer Database provides real-world survival data\n\nThe Edinburgh Ovarian Cancer Database collects data on people with ovarian cancer in Scotland since the mid-1980s. The company did an analysis of data from people with BRCA mutation-positive disease diagnosed between 2000 and 2009 (n=129) to indicate long-term survival trends, and to externally validate the survival outputs of its economic model. The committee heard from the clinical experts and the company that the characteristics of people in this analysis are similar to those in SOLO‑1 in terms of median age and subsequent PARP inhibitor use, and that most had high-grade serous stage\xa03 or\xa04 ovarian cancer. However, there was no information on the number of people with complete or partial response to platinum-based chemotherapy. Therefore, it is not clear how comparable the population of the Edinburgh Ovarian Cancer Database is with the population of SOLO-1. The committee accepted that the Edinburgh Ovarian Cancer Database provides some real-world data on survival outcomes, but it has limitations. In the absence of mature overall survival data from SOLO‑1, the data does provide at least an indication of expected survival outcomes in current practice.\n\n# Model structure\n\n## The 4‑state health model has limitations but is acceptable for decision making\n\nTo estimate the cost effectiveness of olaparib compared with routine surveillance the company presented a partitioned survival model with 3\xa0states (progression-free, progressed disease and death). The ERG considered that this model oversimplifies the treatment pathway, because people can have multiple progressions with ovarian cancer. In response to technical engagement, the company submitted an updated partitioned survival model with 4\xa0health states. It includes a PFS‑2 health state using data from SOLO‑1. Clinical-effectiveness evidence comes from SOLO‑1, where subsequent PARP inhibitor use occurred in both arms (see section\xa03.3 and section\xa03.4). The ERG found it problematic that the model does not allow testing for different assumptions about subsequent PARP inhibitor use, and it was concerned that the trial might not reflect UK clinical practice. The committee recalled the clinical experts' view that subsequent PARP inhibitor use in SOLO‑1 is a reasonable reflection of clinical practice but there is uncertainty around use of PARP inhibitors after second-line platinum-based chemotherapy (see section\xa03.3 and section\xa03.4). The ERG suggested that a sequenced model would have been more appropriate for decision making. The committee understood that this type of model needs data from multiple studies to populate the parameters at each available therapy line. It noted that the company had considered this approach but could not develop it because of lack of data to populate each health state. The committee agreed that the model structure proposed by the ERG has some merit, but acknowledged that implementing it would be a complex undertaking. It noted that the main driver of the model is overall survival and, whichever approach is used, the immaturity of the clinical evidence and the complexity of the clinical pathway are limiting factors in the modelling of long-term outcomes. It understood the ERG's concern that the company's model uses extrapolation of PFS‑2 to predict survival, not overall survival data from the trial, which is a significant limitation of the company's approach. However, the committee was concerned that a different model structure would not resolve the uncertainties associated with the overall survival modelling. It therefore concluded that the 4‑state model is acceptable for decision making.\n\n# Modelling overall survival\n\n## The modelling of overall survival is very uncertain\n\nThe key driver of the results of the model is the way in which overall survival is modelled. The company did not estimate an overall survival curve for the routine surveillance arm using the immature SOLO‑1 overall survival data, because it considered that any extrapolation method using this immature data would result in unrealistic survival estimates in the routine surveillance arm. Instead, it used PFS‑2 as a surrogate for overall survival. The committee acknowledged that PFS‑2 is generally accepted as an indicator of prolonged benefit in clinical trials of maintenance treatments (see section\xa03.8). However, it was concerned that the model outputs do not reflect the SOLO‑1 interim results, which show convergence of the curves after about 40\xa0months of follow up (see section\xa03.7). By contrast, the model predicts that at 20\xa0years about 20% more people are alive in the olaparib arm compared with the routine surveillance arm (38% compared with 18%). The clinical experts considered that in the absence of more mature clinical data this is a reasonable prediction and in line with expectations given the overall survival results from study\xa019. The committee noted that the survival curves in study\xa019 also converged at early data cuts, but survival gains were observed after several years. It is unknown whether the results of SOLO‑1 will mirror this pattern with longer follow up (see section\xa03.7). The committee also noted that the modelling results for the routine surveillance arm are broadly consistent with the survival rates from the Edinburgh Ovarian Cancer Database, which it had concluded provides some real-world data on survival outcomes (see section\xa03.9). The committee acknowledged this but reiterated that not using the available overall survival data from the trial is a major weakness of the modelling. It considered that the modelling of overall survival is associated with considerable uncertainty and may overestimate the survival gain for olaparib, based on the data available from the trial so far. It concluded that it is not possible to resolve this uncertainty until more mature overall survival data are available from SOLO‑1.\n\n# Cost-effectiveness estimate\n\n## Olaparib has not been shown to be cost effective compared with routine surveillance\n\nThe company's base-case incremental cost-effectiveness ratio (ICER) for olaparib compared with routine surveillance using the 4‑state model is £17,480 per quality-adjusted life year (QALY) gained. However, the committee considered that this ICER is highly uncertain for the following reasons:\n\nThe modelling of overall survival is extremely uncertain and may overestimate the survival gain for olaparib based on the data currently available from SOLO‑1 (see section\xa03.9).\n\nThe percentage of patients eligible for olaparib in the NHS who have a complete response to platinum-based chemotherapy could be less than in the trial. The clinical experts estimate it to be about 70% of all responders, whereas it was 82% in SOLO‑1. It is expected that people in complete response are more likely to have long-term benefit than those with residual disease. A lower percentage of people with complete response in the NHS could result in worse outcomes than seen in the trial.\n\nThere is uncertainty about the percentage of people who would have residual disease and be eligible to continue olaparib treatment beyond 2\xa0years, and this could have a large impact on treatment costs. The committee concluded that about 15% of patients in UK clinical practice could be eligible to continue treatment beyond 2\xa0years, compared with 10% in the company's model. However, the estimate of 15% may be optimistic because of the worse outcomes of people with ovarian cancer in the UK (see section\xa03.5).\n\nThere is uncertainty about use of PARP inhibitors after second-line platinum-based chemotherapy and about retreatment with a PARP inhibitor (see section\xa03.3 and section\xa03.4).\n\nThe price per tablet of olaparib is the same regardless of dose, so the cost of treatment per day for a reduced dose is the same as a full dose. Using the cost of olaparib at full dose increases the ICER, and it was concluded after technical engagement that the modelling should use the cost of whole tablets rather than the average cost per milligram.Because of these uncertainties the committee considered that the ICER could be substantially higher than the company's estimate, and the committee was not convinced that the ICER had been shown to be within the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained). Therefore, it concluded that it could not recommend olaparib for routine use in the NHS as first-line maintenance treatment for BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer.\n\n# Cancer Drugs Fund\n\n## Mature overall survival data would resolve the uncertainties in the clinical and cost-effectiveness evidence\n\nHaving concluded that olaparib could not be recommended for routine use, the committee then considered if it could be recommended within the Cancer Drugs Fund for maintenance treatment of BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after response to first-line platinum-based chemotherapy. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It recognised that olaparib is an innovative treatment for advanced disease after first-line platinum-based chemotherapy. It therefore considered whether clinical uncertainty associated with olaparib could be addressed through collection of additional data from SOLO‑1. The committee heard from the company that an interim overall survival analysis is expected within the next 2\xa0years. It agreed that more mature overall survival data would be a valuable addition to the clinical evidence base and are likely to resolve the major uncertainties. The committee concluded that overall survival data from SOLO‑1 should be directly used in the company's future modelling of overall survival.\n\n## Olaparib meets the criteria for inclusion in the Cancer Drugs Fund for treating BRCA mutation-positive advanced ovarian, fallopian tube or primary peritoneal cancer\n\nThe committee recalled that the company's base-case ICER for olaparib compared with routine surveillance is £17,480 per QALY gained. It is based on the assumptions that 82% of people have complete response to platinum-based chemotherapy before starting olaparib, and no more than 10% of people will continue treatment beyond 2\xa0years. The committee recalled that these assumptions are uncertain and may not reflect clinical practice in the NHS (see section\xa03.5 and section\xa03.12). Importantly, the company's analysis also assumes that about 20% of people will be cured from ovarian cancer. Although the clinical experts had explained that cure is possible and the 20% estimate is plausible, the committee noted that no overall survival benefit has yet been demonstrated in SOLO‑1 (see section\xa03.7). Therefore, the committee considered that the company's base-case ICER may be an optimistic estimate of the cost effectiveness of olaparib (see section\xa03.12) and that it is plausible that the ICER could be much higher, exceeding the range that is usually considered an efficient use of NHS resources. However, while accepting that the upper bound of the range of plausible ICERs is highly uncertain, the committee considered that there is plausible potential for olaparib to be cost effective in routine use, pending the results from SOLO‑1. Therefore, olaparib meets the criteria for inclusion in the Cancer Drugs Fund for treating BRCA mutation-positive advanced ovarian, fallopian tube or primary peritoneal cancer after response to first-line platinum-based chemotherapy.\n\n# Conclusion\n\n## Olaparib has the plausible potential to be cost effective and is recommended for use within the Cancer Drugs Fund\n\nResults from SOLO‑1 show an impressive improvement in progression-free survival for olaparib compared with placebo. However, mature overall survival data are not available yet and the extent to which the progression-free survival benefit will translate into an overall survival benefit is unknown. Because of the uncertainty about the overall survival benefit, the estimates of cost effectiveness are very uncertain and olaparib cannot be recommended for routine use in the NHS. If olaparib increases overall survival it has the potential to be cost effective. Mature overall survival data from SOLO‑1 are needed to address the uncertainties in the clinical and cost effectiveness. Olaparib is therefore recommended for use within the Cancer Drugs Fund as an option for treating BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer while further overall survival data are collected.", 'Recommendations for data collection': 'As a condition of the positive recommendation and the managed access agreement, the company is required to collect efficacy data from the SOLO‑1 trial.'}
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https://www.nice.org.uk/guidance/ta598
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Evidence-based recommendations on olaparib (Lynparza) for treating BRCA mutation‑positive, advanced ovarian, fallopian tube or primary peritoneal cancer that has responded to first-line platinum-based chemotherapy in adults.
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5a8efaf97e0d1b84b9d0c7ffb7eb637972f0f164
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nice
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Risankizumab for treating moderate to severe plaque psoriasis
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Risankizumab for treating moderate to severe plaque psoriasis
Evidence-based recommendations on risankizumab (Skyrizi) for treating moderate to severe plaque psoriasis in adults.
# Recommendations
Risankizumab is recommended as an option for treating plaque psoriasis in adults, only if:
the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 and
the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and
the company provides the drug according to the commercial arrangement.
Stop risankizumab treatment at 16 weeks if the psoriasis has not responded adequately. An adequate response is defined as:
a 75% reduction in the PASI score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from when treatment started.
If patients and their clinicians consider risankizumab to be one of a range of suitable treatments, including guselkumab, secukinumab and ixekizumab, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).
When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with risankizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Risankizumab is proposed as an alternative to other biological therapies already recommended by NICE for treating severe plaque psoriasis in adults. Evidence from clinical trials shows that risankizumab is more effective than adalimumab and ustekinumab. Indirect comparisons suggest that risankizumab is likely to provide similar health benefits compared with guselkumab, and better PASI response rates compared with many other biologicals.
For the cost comparison, it is appropriate to compare risankizumab with guselkumab. The total costs associated with risankizumab are similar to or lower than those associated with guselkumab. Therefore, risankizumab is recommended as an option for use in the NHS for severe plaque psoriasis that has not responded to systemic non-biological treatments, or if these are contraindicated or not tolerated.# Information about Risankizumab
Marketing authorisation indication
Risankizumab (Skyrizi, AbbVie) has a marketing authorisation 'for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.
Dosage in the marketing authorisation
Risankizumab is administered by subcutaneous injection at a dose of 150 mg at weeks 0 and 4, and then every 12 weeks.
Consideration should be given to stopping treatment in people whose condition has shown no response after 16 weeks of treatment.
Price
The list price of risankizumab is £3,326.09 per 150 mg dose (excluding VAT; price as quoted in company's submission).
The company has a commercial arrangement. This makes risankizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by AbbVie and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Decision problem
## The company's decision problem is relevant to clinical practice
The company proposed that risankizumab should be considered in adults as an alternative to other biological therapies for psoriasis that has not responded adequately to non-biological systemic treatment or phototherapy, or if these are contraindicated or not tolerated. The company's proposed decision problem was narrower than risankizumab's marketing authorisation because it excluded people who had not had systemic non-biological therapy or phototherapy. However, the committee agreed that the proposed population was consistent with previous NICE recommendations for biological treatments for psoriasis, and with their use in clinical practice. The company presented a comparison with a NICE-recommended biological treatment (NICE technology appraisal guidance on guselkumab for treating moderate to severe plaque psoriasis). The committee agreed that this was consistent with the criteria for a cost-comparison appraisal (see section 3.6). The committee recalled that NICE's technology appraisal guidance on guselkumab recommends that treatment should stop if there is an inadequate response at 16 weeks. An adequate response is defined as:
a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in Dermatology Life Quality Index (DLQI) from when treatment started.The committee considered that it would be reasonable to consider the same approach for this appraisal and concluded that the company's decision problem was relevant to clinical practice.
# Clinical effectiveness
## Risankizumab is more effective than adalimumab and ustekinumab
Risankizumab has been studied in 4 randomised controlled trials including a total of about 2,200 adults with plaque psoriasis. It was directly compared with ustekinumab in 2 trials (UltIMMa‑1 and UltIMMa‑2), and to adalimumab in the IMMvent trial. In these trials, risankizumab was associated with statistically significant improvements compared with ustekinumab and adalimumab in primary and secondary outcomes, including PASI response rates. The committee noted that an improvement in PASI 90 response, a primary endpoint of the trials, is particularly important to patients. Risankizumab was associated with a higher PASI 90 response at week 16 than ustekinumab (UltIMMa‑1: PASI 90 response rates 75.3% and 42.0% respectively, p<0.001) or adalimumab (IMMvent: PASI 90 response rates 72.4% and 47.4% respectively, p<0.001). The committee accepted that the results of these trials showed that risankizumab was more effective than adalimumab and ustekinumab.
## The company's network meta-analyses are suitable for decision making
The company did a series of network meta-analyses on PASI response rates, health-related quality of life (using DLQI) and safety outcomes. These compared risankizumab with guselkumab and with all other NICE-recommended biological agents (using data from 57 randomised controlled trials). The ERG was satisfied with the search strategy, the methodological quality of the included trials and the methodology used for the network meta-analyses. The committee accepted the ERG's view, concluding that the network meta-analyses provided by the company was suitable for decision making.
## Risankizumab provides similar PASI response rates to guselkumab, and similar or better rates than other biologicals
The committee acknowledged that PASI 75 is a key outcome when deciding whether to continue treatment. It noted that the results of the network meta-analysis suggested that risankizumab was similarly effective to guselkumab in terms of PASI 75 response. The committee appreciated that the company analyses also covered a range of outcomes, and that the results for PASI 100 were broadly consistent with those for PASI 75. It noted the safety and tolerability outcomes in the company's network meta-analysis and considered that risankizumab had a similar safety profile to other biologicals for psoriasis. The committee concluded that risankizumab provides similar benefits to guselkumab, and clinical benefits either similar to or greater than other biological agents.
# Cost comparison
## The total costs associated with risankizumab are similar to or lower than those associated with guselkumab
The company presented a cost-comparison analysis that modelled the total costs of risankizumab and the comparator guselkumab over 10 years. It took into account stopping treatment based on PASI 75 response rates, which was consistent with the stopping rules specified in NICE's technology appraisal guidance for guselkumab. The base-case analysis used the same PASI 75 response rates and applied the same rate of long-term stopping of treatment during maintenance therapy for both risankizumab and guselkumab. The committee accepted the company's base-case model. Taking into account the confidential patient access schemes for risankizumab and guselkumab, the committee concluded that the total costs associated with risankizumab were similar to or lower than those associated with guselkumab (the exact results cannot be reported here because the discounts are confidential).
## Risankizumab is recommended as an option for treating severe plaque psoriasis in adults
The committee concluded that the criteria for a positive cost comparison were met because:
risankizumab provided similar overall health benefits to guselkumab and
the total costs associated with risankizumab were similar to or lower than the total costs associated with guselkumab.The committee therefore recommended risankizumab as an option for treating plaque psoriasis in adults. It concluded that the recommendations for risankizumab should be consistent with the company's proposal and NICE's technology appraisal guidance recommendations for guselkumab, that is:
if the disease is severe (that is, a PASI of 10 or more and a DLQI of more than 10) and
when the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and
when treatment is stopped at 16 weeks if the psoriasis has not responded adequately.
## The PASI and DLQI may not be appropriate for all people with psoriasis
The committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:
the PASI might underestimate disease severity in people with darker skin
the DLQI has limited validity in some people, and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI, and make any adjustments they consider appropriate.
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{'Recommendations': 'Risankizumab is recommended as an option for treating plaque psoriasis in adults, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of\xa010 or more and a Dermatology Life Quality Index (DLQI) of more than\xa010 and\n\nthe disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and\n\nthe company provides the drug according to the commercial arrangement.\n\nStop risankizumab treatment at 16\xa0weeks if the psoriasis has not responded adequately. An adequate response is defined as:\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from when treatment started.\n\nIf patients and their clinicians consider risankizumab to be one of a range of suitable treatments, including guselkumab, secukinumab and ixekizumab, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with risankizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nRisankizumab is proposed as an alternative to other biological therapies already recommended by NICE for treating severe plaque psoriasis in adults. Evidence from clinical trials shows that risankizumab is more effective than adalimumab and ustekinumab. Indirect comparisons suggest that risankizumab is likely to provide similar health benefits compared with guselkumab, and better PASI response rates compared with many other biologicals.\n\nFor the cost comparison, it is appropriate to compare risankizumab with guselkumab. The total costs associated with risankizumab are similar to or lower than those associated with guselkumab. Therefore, risankizumab is recommended as an option for use in the NHS for severe plaque psoriasis that has not responded to systemic non-biological treatments, or if these are contraindicated or not tolerated.', 'Information about Risankizumab': "Marketing authorisation indication\n\nRisankizumab (Skyrizi, AbbVie) has a marketing authorisation 'for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.\n\nDosage in the marketing authorisation\n\nRisankizumab is administered by subcutaneous injection at a dose of 150\xa0mg at weeks\xa00 and\xa04, and then every 12\xa0weeks.\n\nConsideration should be given to stopping treatment in people whose condition has shown no response after 16\xa0weeks of treatment.\n\nPrice\n\nThe list price of risankizumab is £3,326.09 per 150\xa0mg dose (excluding VAT; price as quoted in company's submission).\n\nThe company has a commercial arrangement. This makes risankizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by AbbVie and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Decision problem\n\n## The company's decision problem is relevant to clinical practice\n\nThe company proposed that risankizumab should be considered in adults as an alternative to other biological therapies for psoriasis that has not responded adequately to non-biological systemic treatment or phototherapy, or if these are contraindicated or not tolerated. The company's proposed decision problem was narrower than risankizumab's marketing authorisation because it excluded people who had not had systemic non-biological therapy or phototherapy. However, the committee agreed that the proposed population was consistent with previous NICE recommendations for biological treatments for psoriasis, and with their use in clinical practice. The company presented a comparison with a NICE-recommended biological treatment (NICE technology appraisal guidance on guselkumab for treating moderate to severe plaque psoriasis). The committee agreed that this was consistent with the criteria for a cost-comparison appraisal (see section\xa03.6). The committee recalled that NICE's technology appraisal guidance on guselkumab recommends that treatment should stop if there is an inadequate response at 16\xa0weeks. An adequate response is defined as:\n\na 75% reduction in the Psoriasis Area and Severity Index score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in Dermatology Life Quality Index (DLQI) from when treatment started.The committee considered that it would be reasonable to consider the same approach for this appraisal and concluded that the company's decision problem was relevant to clinical practice.\n\n# Clinical effectiveness\n\n## Risankizumab is more effective than adalimumab and ustekinumab\n\nRisankizumab has been studied in 4\xa0randomised controlled trials including a total of about 2,200\xa0adults with plaque psoriasis. It was directly compared with ustekinumab in 2\xa0trials (UltIMMa‑1 and UltIMMa‑2), and to adalimumab in the IMMvent trial. In these trials, risankizumab was associated with statistically significant improvements compared with ustekinumab and adalimumab in primary and secondary outcomes, including PASI response rates. The committee noted that an improvement in PASI\xa090 response, a primary endpoint of the trials, is particularly important to patients. Risankizumab was associated with a higher PASI\xa090 response at week\xa016 than ustekinumab (UltIMMa‑1: PASI\xa090 response rates 75.3% and 42.0% respectively, p<0.001) or adalimumab (IMMvent: PASI\xa090 response rates 72.4% and 47.4% respectively, p<0.001). The committee accepted that the results of these trials showed that risankizumab was more effective than adalimumab and ustekinumab.\n\n## The company's network meta-analyses are suitable for decision making\n\nThe company did a series of network meta-analyses on PASI response rates, health-related quality of life (using DLQI) and safety outcomes. These compared risankizumab with guselkumab and with all other NICE-recommended biological agents (using data from 57\xa0randomised controlled trials). The ERG was satisfied with the search strategy, the methodological quality of the included trials and the methodology used for the network meta-analyses. The committee accepted the ERG's view, concluding that the network meta-analyses provided by the company was suitable for decision making.\n\n## Risankizumab provides similar PASI response rates to guselkumab, and similar or better rates than other biologicals\n\nThe committee acknowledged that PASI\xa075 is a key outcome when deciding whether to continue treatment. It noted that the results of the network meta-analysis suggested that risankizumab was similarly effective to guselkumab in terms of PASI\xa075 response. The committee appreciated that the company analyses also covered a range of outcomes, and that the results for PASI\xa0100 were broadly consistent with those for PASI\xa075. It noted the safety and tolerability outcomes in the company's network meta-analysis and considered that risankizumab had a similar safety profile to other biologicals for psoriasis. The committee concluded that risankizumab provides similar benefits to guselkumab, and clinical benefits either similar to or greater than other biological agents.\n\n# Cost comparison\n\n## The total costs associated with risankizumab are similar to or lower than those associated with guselkumab\n\nThe company presented a cost-comparison analysis that modelled the total costs of risankizumab and the comparator guselkumab over 10\xa0years. It took into account stopping treatment based on PASI\xa075 response rates, which was consistent with the stopping rules specified in NICE's technology appraisal guidance for guselkumab. The base-case analysis used the same PASI\xa075 response rates and applied the same rate of long-term stopping of treatment during maintenance therapy for both risankizumab and guselkumab. The committee accepted the company's base-case model. Taking into account the confidential patient access schemes for risankizumab and guselkumab, the committee concluded that the total costs associated with risankizumab were similar to or lower than those associated with guselkumab (the exact results cannot be reported here because the discounts are confidential).\n\n## Risankizumab is recommended as an option for treating severe plaque psoriasis in adults\n\nThe committee concluded that the criteria for a positive cost comparison were met because:\n\nrisankizumab provided similar overall health benefits to guselkumab and\n\nthe total costs associated with risankizumab were similar to or lower than the total costs associated with guselkumab.The committee therefore recommended risankizumab as an option for treating plaque psoriasis in adults. It concluded that the recommendations for risankizumab should be consistent with the company's proposal and NICE's technology appraisal guidance recommendations for guselkumab, that is:\n\nif the disease is severe (that is, a PASI of 10\xa0or more and a DLQI of more than\xa010) and\n\nwhen the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and\n\nwhen treatment is stopped at 16\xa0weeks if the psoriasis has not responded adequately.\n\n## The PASI and DLQI may not be appropriate for all people with psoriasis\n\nThe committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:\n\nthe PASI might underestimate disease severity in people with darker skin\n\nthe DLQI has limited validity in some people, and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI, and make any adjustments they consider appropriate."}
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https://www.nice.org.uk/guidance/ta596
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Evidence-based recommendations on risankizumab (Skyrizi) for treating moderate to severe plaque psoriasis in adults.
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7ebbf32eabd7278aae767b24a7ac7e7c969ae1b9
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nice
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Low-energy contact X-ray brachytherapy (the Papillon technique) for locally advanced rectal cancer
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Low-energy contact X-ray brachytherapy (the Papillon technique) for locally advanced rectal cancer
Evidence-based recommendations on low-energy contact X‑ray brachytherapy (the Papillon technique) for locally advanced rectal cancer in adults. This involves using an X‑ray tube inserted into the rectum to destroy the cancer cells.
# Recommendations
Current evidence on the safety and efficacy of low-energy contact X‑ray brachytherapy (the Papillon technique) for locally advanced rectal cancer is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should include randomised controlled trials comparing this procedure with standard care and report details of patient selection (including tumour type and suitability for surgery), patient-reported outcomes, quality of life and long-term outcomes.# The condition, current treatments and procedure
# The condition
Rectal cancer is a common form of bowel cancer. The risk of developing it rises with age. Symptoms include rectal bleeding, obstruction, perforation, pain and discharge. Symptoms may result from the tumour invading organs near the rectum (such as the bladder). Early stages of rectal cancer may be asymptomatic and some patients present with locally advanced rectal cancer, commonly defined as T3 or T4 primary tumours or nodal metastases, or stage 2 (T3 to T4, node negative) or stage 3 (T1 to T4, node positive).
# Current treatments
There is variation in the clinical management and treatments offered for locally advanced rectal cancer. Radical surgery in the form of total mesorectal excision (TME) offers the best chance for cure in some patients. Patients who choose not to have surgery, or are not fit enough to have it, may have neoadjuvant chemoradiotherapy (such as external beam radiotherapy, with or without brachytherapy). The aim is to reduce the tumour size, alleviate symptoms, and improve survival and quality of life.
# The procedure
Low-energy contact X‑ray brachytherapy (CXB) is also known as the Papillion technique. It may be given with external beam radiotherapy or chemotherapy, or both. It is usually delivered in a day-patient setting. The patient is given an enema before treatment to empty the rectum. With the patient in a knee-to-chest, prone jack-knife or supine position, local anaesthesia and glyceryl trinitrate are applied to the anal sphincter to numb the area and relax the sphincter muscles. A sigmoidoscope is inserted through the anal sphincter to ascertain the size and position of the tumour. Then a rigid endorectal treatment applicator is inserted and placed in contact with the tumour. A contact X‑ray tube is introduced into the applicator. It emits low-energy X‑rays that penetrate tissue by only a few millimetres, minimising damage to deeper tissues.
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{'Recommendations': 'Current evidence on the safety and efficacy of low-energy contact X‑ray brachytherapy (the Papillon technique) for locally advanced rectal cancer is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include randomised controlled trials comparing this procedure with standard care and report details of patient selection (including tumour type and suitability for surgery), patient-reported outcomes, quality of life and long-term outcomes.', 'The condition, current treatments and procedure': '# The condition\n\nRectal cancer is a common form of bowel cancer. The risk of developing it rises with age. Symptoms include rectal bleeding, obstruction, perforation, pain and discharge. Symptoms may result from the tumour invading organs near the rectum (such as the bladder). Early stages of rectal cancer may be asymptomatic and some patients present with locally advanced rectal cancer, commonly defined as T3\xa0or\xa0T4 primary tumours or nodal metastases, or stage\xa02 (T3 to T4, node negative) or stage\xa03 (T1 to T4, node positive).\n\n# Current treatments\n\nThere is variation in the clinical management and treatments offered for locally advanced rectal cancer. Radical surgery in the form of total mesorectal excision (TME) offers the best chance for cure in some patients. Patients who choose not to have surgery, or are not fit enough to have it, may have neoadjuvant chemoradiotherapy (such as external beam radiotherapy, with or without brachytherapy). The aim is to reduce the tumour size, alleviate symptoms, and improve survival and quality of life.\n\n# The procedure\n\nLow-energy contact X‑ray brachytherapy (CXB) is also known as the Papillion technique. It may be given with external beam radiotherapy or chemotherapy, or both. It is usually delivered in a day-patient setting. The patient is given an enema before treatment to empty the rectum. With the patient in a knee-to-chest, prone jack-knife or supine position, local anaesthesia and glyceryl trinitrate are applied to the anal sphincter to numb the area and relax the sphincter muscles. A sigmoidoscope is inserted through the anal sphincter to ascertain the size and position of the tumour. Then a rigid endorectal treatment applicator is inserted and placed in contact with the tumour. A contact X‑ray tube is introduced into the applicator. It emits low-energy X‑rays that penetrate tissue by only a few millimetres, minimising damage to deeper tissues.'}
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https://www.nice.org.uk/guidance/ipg659
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Evidence-based recommendations on low-energy contact X‑ray brachytherapy (the Papillon technique) for locally advanced rectal cancer in adults. This involves using an X‑ray tube inserted into the rectum to destroy the cancer cells.
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6e6fd1fab9d877c5d668668ea5b6c15a48dbdd7c
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nice
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Endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms
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Endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms
Evidence-based recommendations on endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms in adults. This involves inserting a wire-mesh device into the aneurysm to act as a plug when a blood clot forms inside it.
# Recommendations
Current evidence on the safety and efficacy of endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Patient selection should be done by a multidisciplinary team, except for in emergency situations, when this may be replaced by a discussion between an interventional neuroradiologist and neurosurgeon.
The procedure should only be done in specialised centres with expertise in the use of this technology and access to neurosurgical facilities.# The condition, current treatments and procedure
# The condition
An intracranial aneurysm is a bulge in a blood vessel in the brain caused by a weakness in the blood vessel wall, usually where it branches. Most brain aneurysms only cause noticeable symptoms if they rupture. However, large aneurysms may cause local compression symptoms before they rupture, such as headache. Rupture of intracranial aneurysms causes subarachnoid haemorrhage and is associated with a very poor prognosis. About 10% of people die before reaching hospital and a further 50% die within 4 weeks. About 50% of people who survive a subarachnoid haemorrhage have a persistent neurological deficit.
If an intracranial aneurysm is detected before it ruptures, treatment may be recommended to prevent it rupturing in the future. This is typically only done if the risk of a rupture is particularly high.
# Current treatments
Current options for managing intracranial aneurysms include coiling, often with stent placement (stent-assisted coiling), neurosurgical clipping through a craniotomy (with or without bypass procedures), parent vessel occlusion (by open neurosurgery or by endovascular means) and conservative management. Flow diverter embolisation devices, which are placed in the parent blood vessel to divert blood flow away from the aneurysm itself, may be an option for some people with intracranial aneurysms.
# The procedure
Endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms is used for the embolisation of ruptured and unruptured intracranial aneurysms. It may be particularly suitable for people with wide-necked aneurysms. The procedure is usually done under general anaesthesia. A catheter is inserted into the femoral artery and advanced into the cerebral circulation under X‑ray guidance. A second, smaller catheter is put inside the first and is inserted into the aneurysm. A basket-like device made of fine wire mesh is then pushed through the second catheter and placed into the aneurysm sac. The mesh device covers the aneurysm neck and obstructs blood flow into the aneurysm sac, creating blood stasis and promoting endothelial growth across the neck of the aneurysm. The appropriate device size is selected according to the aneurysm width and height.
The aim is to prevent the aneurysm from rupturing or to stop further bleeding from an aneurysm that has already ruptured.
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{'Recommendations': 'Current evidence on the safety and efficacy of endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a multidisciplinary team, except for in emergency situations, when this may be replaced by a discussion between an interventional neuroradiologist and neurosurgeon.\n\nThe procedure should only be done in specialised centres with expertise in the use of this technology and access to neurosurgical facilities.', 'The condition, current treatments and procedure': '# The condition\n\nAn intracranial aneurysm is a bulge in a blood vessel in the brain caused by a weakness in the blood vessel wall, usually where it branches. Most brain aneurysms only cause noticeable symptoms if they rupture. However, large aneurysms may cause local compression symptoms before they rupture, such as headache. Rupture of intracranial aneurysms causes subarachnoid haemorrhage and is associated with a very poor prognosis. About 10% of people die before reaching hospital and a further 50% die within 4\xa0weeks. About 50% of people who survive a subarachnoid haemorrhage have a persistent neurological deficit.\n\nIf an intracranial aneurysm is detected before it ruptures, treatment may be recommended to prevent it rupturing in the future. This is typically only done if the risk of a rupture is particularly high.\n\n# Current treatments\n\nCurrent options for managing intracranial aneurysms include coiling, often with stent placement (stent-assisted coiling), neurosurgical clipping through a craniotomy (with or without bypass procedures), parent vessel occlusion (by open neurosurgery or by endovascular means) and conservative management. Flow diverter embolisation devices, which are placed in the parent blood vessel to divert blood flow away from the aneurysm itself, may be an option for some people with intracranial aneurysms.\n\n# The procedure\n\nEndovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms is used for the embolisation of ruptured and unruptured intracranial aneurysms. It may be particularly suitable for people with wide-necked aneurysms. The procedure is usually done under general anaesthesia. A catheter is inserted into the femoral artery and advanced into the cerebral circulation under X‑ray guidance. A second, smaller catheter is put inside the first and is inserted into the aneurysm. A basket-like device made of fine wire mesh is then pushed through the second catheter and placed into the aneurysm sac. The mesh device covers the aneurysm neck and obstructs blood flow into the aneurysm sac, creating blood stasis and promoting endothelial growth across the neck of the aneurysm. The appropriate device size is selected according to the aneurysm width and height.\n\nThe aim is to prevent the aneurysm from rupturing or to stop further bleeding from an aneurysm that has already ruptured.'}
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https://www.nice.org.uk/guidance/ipg658
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Evidence-based recommendations on endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms in adults. This involves inserting a wire-mesh device into the aneurysm to act as a plug when a blood clot forms inside it.
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461907a557eba1da79e6193a6a903e183cc2e85b
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nice
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Dacomitinib for untreated EGFR mutation-positive non-small-cell lung cancer
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Dacomitinib for untreated EGFR mutation-positive non-small-cell lung cancer
Evidence-based recommendations on dacomitinib (Vizimpro) for untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer in adults.
# Recommendations
Dacomitinib is recommended, within its marketing authorisation, as an option for untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in adults. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Locally advanced or metastatic EGFR mutation-positive NSCLC is usually first treated with afatinib, erlotinib or gefitinib.
Evidence from a randomised controlled trial shows that people who take dacomitinib live longer than people who take gefitinib. They also live longer before their disease gets worse. An indirect comparison suggests there is no difference between dacomitinib and afatinib in terms of how long people live or how long it is before their disease gets worse.
There is some uncertainty about the assumptions used in the cost-effectiveness modelling. But the most plausible cost-effectiveness estimate is within what NICE normally considers an acceptable use of NHS resources. So dacomitinib is recommended.# Information about dacomitinib
Marketing authorisation indication
Dacomitinib (Vizimpro, Pfizer), as monotherapy, is intended for 'the first-line treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer with epidermal growth factor receptor-activating mutations'.
Dosage in the marketing authorisation
Based on the company submission, dacomitinib is given orally at a dosage of 45 mg until disease progression or unacceptable toxicity. Dacomitinib is available in 3 dose strengths: 45 mg, 30 mg and 15 mg.
Price
Indicative list price: £2,703 for 30×15 mg, 30×30 mg or 30×45 mg capsules.
The company has a commercial arrangement. This makes dacomitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need
## People would welcome a new treatment option
The patient experts highlighted that epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) tends to present late, so people have more advanced disease at diagnosis compared with the wider NSCLC population. The patient experts also noted that dacomitinib may improve overall survival, which is especially important to patients and their families. The committee agreed that people with EGFR mutation-positive NSCLC would welcome additional treatment options that improve overall survival.
# Clinical management
## Erlotinib, gefitinib and afatinib are appropriate comparators
The clinical experts explained that in line with NICE guidance, locally advanced or metastatic EGFR mutation-positive NSCLC is usually first treated with a tyrosine kinase inhibitor such as erlotinib, gefitinib or afatinib (see NICE technology appraisal guidance on erlotinib, gefitinib and afatinib). The committee understood that afatinib is more common in NHS clinical practice in England because as a second-generation tyrosine kinase inhibitor it is better than both erlotinib and gefitinib (first-generation tyrosine kinase inhibitors) in terms of prolonging progression-free survival. The committee also understood that afatinib is associated with more adverse events than erlotinib and gefitinib, so it is generally only offered to people with good Eastern Cooperative Oncology Group (ECOG) performance status. The clinical experts explained that this would also be the case for dacomitinib. The committee agreed that although afatinib is the most commonly used tyrosine kinase inhibitor and has a similar adverse-event profile to dacomitinib, gefitinib and erlotinib were also used in established NHS practice in England. So gefitinib and erlotinib were also listed as comparators in NICE's final scope.
# Clinical evidence
## Evidence from an open-label randomised controlled trial is relevant and high quality
The main clinical evidence came from ARCHER 1050, a multicentre, open-label, phase III randomised controlled trial. It compared the efficacy and safety of dacomitinib (n=227) with gefitinib (n=225) in adults with untreated locally advanced or metastatic EGFR mutation-positive NSCLC. Patients had either the exon 19 deletion (del19) or exon 21 (L858R) EGFR mutation. The trial included 71 study sites in 7 countries (China, Hong Kong, Japan, Republic of Korea, Italy, Poland and Spain). The primary outcome was progression-free survival, determined by blinded independent review committee. Secondary outcomes included overall survival, objective response rate, length of response, adverse events, time to treatment failure and health-related quality of life. After disease progression, patients could have subsequent treatment with a different drug (see section 3.6). The committee noted that in the trials used to inform NICE technology appraisal guidance on erlotinib, gefitinib and afatinib, the comparator was chemotherapy. But in ARCHER 1050 the comparator was gefitinib (the trial compared a second-generation tyrosine kinase inhibitor with a first-generation tyrosine kinase inhibitor ). The committee concluded that ARCHER 1050 was a well-conducted trial providing high-quality evidence relevant to the appraisal.
## The treatment arms in ARCHER 1050 are well balanced
The ERG noted that in the trial, 64.3% of patients having dacomitinib were women compared with only 55.6% of patients having gefitinib. The committee was aware that there was some evidence to suggest that tyrosine kinase inhibitors tend to be more effective at treating EGFR mutation-positive NSCLC in women than in men, and so the trial could be biased in favour of dacomitinib. But the clinical experts did not consider sex to be an important factor. The committee concluded that the treatment arms in ARCHER 1050 were generally well balanced.
## Dacomitinib improves progression-free and overall survival compared with gefitinib
The results of ARCHER 1050 showed that dacomitinib statistically significantly improved progression-free survival compared with gefitinib (14.7 months for dacomitinib compared with 9.2 months for gefitinib; hazard ratio 0.589, 95% confidence interval 0.47 to 0.74). Exploratory analyses also showed that dacomitinib improved overall survival compared with gefitinib (34.1 months for dacomitinib compared with 26.8 months for gefitinib; HR 0.760, 95% CI 0.58 to 0.99). During consultation, the company manufacturing gefitinib highlighted that the overall survival Kaplan–Meier curves for dacomitinib and gefitinib crossed at around 11 months (and possibly at around 36 months too). The company suggested that this shows that a specific subgroup (or subgroups) derives more benefit from gefitinib than dacomitinib. Although the committee acknowledged that the Kaplan–Meier curves did cross, it concluded that overall dacomitinib is associated with improved progression-free and overall survival compared with gefitinib.
## It is unclear how subsequent treatments may affect overall survival in ARCHER 1050
In ARCHER 1050, patients who stopped taking the study drug (dacomitinib or gefitinib) could then have subsequent treatment with a different drug (the company considered the subsequent treatments to be confidential so they cannot be reported here). But the committee noted that these subsequent treatments did not reflect the type and proportion of those used in clinical practice in the NHS in England. The committee agreed that there was uncertainty about how subsequent treatments may have affected the overall survival estimates in ARCHER 1050, and that it would consider this in its decision making.
## The results of ARCHER 1050 are generalisable to NHS clinical practice in England
The committee considered whether the baseline characteristics of patients in ARCHER 1050 reflected those seen in NHS clinical practice in England. It noted that the patients in the trial had only the exon 19 deletion (del19) or exon 21 (L858R) EGFR mutations. The clinical experts explained that these 2 mutations account for around 90% of all EGFR mutations. Also, most trials only include people with these mutations, including the trials that were carried out with other tyrosine kinase inhibitors. The committee acknowledged that although other mutations may not respond as well to dacomitinib, the Committee for Medicinal Products for Human Use (CHMP) did not restrict its positive opinion for dacomitinib to these 2 mutations (see section 2). The committee therefore agreed that the EGFR mutation status of patients in ARCHER 1050 generally reflected that seen in NHS clinical practice in England. It also noted that the trial included a large proportion of patients of Asian family origin (74.9% in the dacomitinib treatment arm and 78.2% in the gefitinib treatment arm) because many of the trial centres were in East Asia. It recalled that ethnicity was a prespecified subgroup in ARCHER 1050, and that the company had provided analyses in response to clarification, but the results were underpowered (overall survival: Asian family origin subgroup HR 0.81, 95% CI 0.6 to 1.11; non-Asian family origin subgroup HR 0.72, 95% CI 0.43 to 1.20. The results for progression-free survival are considered academic in confidence by the company and so cannot be reported here). During consultation, the company manufacturing gefitinib highlighted evidence suggesting that Asian ethnicity has been identified as a favourable independent prognostic factor for overall survival in NSCLC, irrespective of smoking status. The committee noted that in the company's overall survival analyses for ethnicity, dacomitinib showed a survival benefit compared with gefitinib in both the non-Asian and Asian family origin subgroups. Although ARCHER 1050 was not powered for subgroup analyses, the results were all aligned and were in favour of dacomitinib (except for the subgroup with ECOG performance status 0). The committee noted that there appeared to be much better progression-free survival for the Asian family origin subgroup, which was not reflected in overall survival for the same population. The committee agreed that there was no conclusive evidence that ethnicity has a significant effect on overall survival. Because the trial was not powered for subgroup analyses, the committee considered that the results from the whole trial population would be generalisable to the population seen in clinical practice in England. The committee noted that ARCHER 1050 excluded people with brain metastases: these are associated with a poor prognosis and often occur in people with EGFR mutation-positive NSCLC. This was an important difference between ARCHER 1050 and the LUX-Lung 7 trial (used in the comparison of afatinib with gefitinib; see section 3.9), in which 16% of patients had brain metastases. The committee concluded that overall, the trial results from ARCHER 1050 were generalisable to NHS clinical practice in England.
## Dacomitinib is associated with more adverse events and may need more dose reductions than gefitinib
The committee noted that dacomitinib had a higher incidence of common adverse events than gefitinib, and that there were more dose reductions in the dacomitinib treatment arm than in the gefitinib treatment arm (66.1% and 8.0% respectively). The committee was also aware that second-generation tyrosine kinase inhibitors such as afatinib are associated with more adverse events, whereas first-generation tyrosine kinase inhibitors are generally better tolerated (see section 3.2). The clinical experts agreed that the differences in the drugs' adverse-event profiles are well known and this is reflected in how they are used in clinical practice. That is, they are used according to whether a person is well enough for treatment, which is typically categorised by ECOG performance status. Although the clinical experts acknowledged that adverse events associated with second-generation tyrosine kinase inhibitors could be effectively managed in clinical practice, they highlighted that the adverse events were detrimental to people's quality of life. The Cancer Drugs Fund clinical lead also highlighted NHS England's concerns about the toxicity of dacomitinib and the high rates of adverse events that are likely to be seen in practice. The committee agreed that dacomitinib had a higher incidence of adverse events and needed more dose reductions than gefitinib. It concluded that how this affected health-related quality of life and resource costs for managing adverse events should be fully captured in the cost-effectiveness analysis.
## The results from the company's fractional polynomial network meta-analysis are uncertain
The company did a network meta-analysis to compare dacomitinib with the other comparators in the scope, afatinib and erlotinib. It did a fractional polynomial network meta-analysis as described by Janssen et al. (2011), because it considered that the proportional hazards assumption may have been violated in ARCHER 1050 (that is, the hazard ratios were not constant over time). The committee understood that fractional polynomial network meta-analysis differs from a traditional network meta-analysis in that it fits hazard ratios that can vary over time rather than being constant. Based on the evidence from clinical experts, other phase III randomised controlled trials and previous NICE appraisals, the company assumed equivalence between gefitinib and erlotinib. The committee agreed that this assumption was appropriate. The company obtained the relative effect estimates of progression-free and overall survival for afatinib and dacomitinib compared with gefitinib from the LUX-Lung 7 trial (which compared afatinib with gefitinib). In its submission, the company presented the projected means for progression-free and overall survival along with the medians compared with the observed data from ARCHER 1050, to provide face validity for the model (the company considered the results to be commercial in confidence and so they cannot be reported here). The committee recalled the ERG's concerns about differences in patients' baseline characteristics in ARCHER 1050 and LUX-Lung 7, specifically the proportion of patients of Asian family origin and the presence of brain metastases (see section 3.7). The committee agreed that these differences, in particular the exclusion of people with brain metastases from ARCHER 1050, added uncertainty to any estimates from the analysis. The ERG also expressed concerns about extrapolating progression-free and overall survival outcomes from fractional polynomial models: they tend to over-fit to the tail of the data, often resulting in implausible survival extrapolations. The committee noted that these concerns were supported by the large number of models that the company had to reject because of the clinically implausible extrapolations of survival outcomes. The committee concluded that the results from the company's fractional polynomial network meta-analysis were uncertain.
## There is no statistically significant difference between dacomitinib and afatinib in terms of progression-free and overall survival
The ERG did its own indirect treatment comparison to address these uncertainties, and because the company's model did not report hazard ratios for progression-free or overall survival between dacomitinib and afatinib. The ERG did a fixed-effects network meta-analysis using data from ARCHER 1050 for dacomitinib and from LUX-Lung 7 for afatinib. The company agreed with the ERG's approach to estimating the hazard ratios. The results suggested that dacomitinib might be better than afatinib in terms of extending progression-free and overall survival, but there was no significant difference between the 2 treatments (progression-free survival HR 0.80, 95% CI 0.57 to 1.12; overall survival HR 0.88, 95% CI 0.61 to 1.29). The committee recalled that there was uncertainty around any estimates from a network meta-analysis that used data from ARCHER 1050 and LUX-Lung 7, because of the differences between the trials in terms of baseline patient characteristics (and because the proportional hazards assumption may have been violated in ARCHER 1050). It concluded that any estimates were uncertain and based on the evidence available there was no statistically significant difference between dacomitinib and afatinib in terms of extending progression-free and overall survival.
# The company's economic model
## The company's model is appropriate for decision making
The company used a partitioned-survival economic model that included 3 health states: pre-progression, post-progression and death. The model included either dacomitinib, afatinib, gefitinib or erlotinib as first-line treatment, followed by osimertinib (if T790M mutation-positive) or chemotherapy. The committee was concerned that the model captured only the costs and not the clinical benefits of subsequent treatments. However, the committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for NSCLC.
# Survival extrapolation
## There are uncertainties in how the company modelled progression-free survival
In its original base case, the company modelled progression-free survival for gefitinib using a generalised gamma curve fitted to the gefitinib treatment arm of ARCHER 1050. It modelled progression-free survival for erlotinib by assuming equivalent efficacy with gefitinib. It then used the fractional polynomial network meta-analysis (model P1=0.5, P2=1.5) to obtain time-varying hazard ratios for afatinib and dacomitinib relative to gefitinib (see section 3.10), before applying these to the gefitinib extrapolation. The committee had concerns about the company's modelling of progression-free survival:
The progression-free survival for gefitinib after 2 years potentially underestimated the quality-adjusted life years (QALYs) and costs for the comparators.
The extrapolation of dacomitinib and afatinib relied on results from the fractional polynomial network meta-analysis, which were themselves uncertain (see section 3.9).
The progression-free survival curves suggested that dacomitinib had the highest progression-free survival up to 38 months, after which afatinib had the highest progression-free survival. The committee agreed that there was no clinical rationale for dacomitinib to be less effective than the comparators in terms of progression-free survival after 38 months.The committee agreed that there was uncertainty around the company's modelling of progression-free survival because of the implausibility of the results. This made the company's incremental cost-effectiveness ratios (ICERs) highly uncertain.
## The ERG's modelling of progression-free survival is appropriate
In its original base case, the ERG used the log-normal parametric curve for gefitinib and the fractional polynomial network meta-analysis for the other comparators (P1=0.5, P2=1). The afatinib extrapolation remained implausible so the ERG assumed the progression-free survival of afatinib to be equal to the mean progression-free survival of dacomitinib and gefitinib after 36 months. It also did a scenario analysis in which it assumed the progression-free survival of afatinib to be equal to the mean progression-free survival of dacomitinib and gefitinib after 55 months. Although it recognised the uncertainties, the committee preferred this approach because it produced more plausible results than the company's base case. It therefore agreed that the ERG's modelling of progression-free survival was appropriate and its decision making should be based on this.
## The company's modelling of overall survival produces some implausible results
In its original base case, the company modelled overall survival in the same way it modelled progression-free survival (see section 3.12). The committee had concerns about the company's modelling of overall survival:
The generalised gamma curve may underestimate overall survival with gefitinib.
The modelling suggested that the efficacy of afatinib relative to gefitinib decreased over time while the efficacy of dacomitinib improved over time; clinical expert advice to the ERG questioned the plausibility of this. The clinical experts acknowledged that effective treatments may provide some benefit for a limited time after stopping treatment, but the committee recalled that there was no evidence to suggest that afatinib and dacomitinib provided different benefits after stopping treatment.
Dacomitinib appears to provide benefits both before and after disease progression. This is unlikely to be plausible, because it is uncommon for progression-free survival to mirror post-progression survival, and even less common for progression-free survival to be extended into post-progression survival.The committee therefore agreed that the company's modelling of overall survival produced some implausible results.
## The ERG's modelling of overall survival is the most appropriate for decision making
In its original base case, the ERG used the log-logistic curve for gefitinib and the fractional polynomial network meta-analysis for the other comparators (P1=−0.5). It assumed equal efficacy for overall survival between all treatments after 36 months. The ERG acknowledged that assuming equal efficacy from 48 or 60 months could also be considered plausible and explored these in scenario analyses. The ERG also did a scenario analysis in which it assumed equivalent post-progression survival for all treatments after 71 months. The committee agreed that there was uncertainty around the company's modelling of overall survival because of the implausibility of the results (see section 3.14) and that all the ERG's scenario analyses were clinically plausible. The committee concluded that its decision making should be based on the ERG's modelling of overall survival.
## The extrapolation of overall survival data after 36 months is highly uncertain
During consultation the company highlighted that the committee had accepted that all of the ERG's overall survival analyses (see section 3.15) were clinically plausible. It commented that the committee should further consider the ERG's scenario analysis in which equivalent post-progression survival for all treatments after 71 months was assumed. The committee noted the company's rationale for assuming equivalent post-progression survival for all treatments after 71 months. The company asserted that the ERG's base-case assumption of equal efficacy for overall survival modelling after 36 months cannot be considered plausible given the proportion of patients having treatment at 36 months who would be expected to get clinical benefit from ongoing treatment. The company also asserted that a scenario assuming equal post-progression survival after 71 months was the most clinically plausible scenario given the results of its 3 post-hoc analyses of post-progression survival from ARCHER 1050:
For the intention-to-treat population, the company calculated post-progression survival from the date of progression-free survival (independent review committee) to the date of overall survival event or censored date as applicable. It considered that the results (considered academic in confidence by the company, and therefore cannot be reported here) suggested that there was an improvement in post-progression survival in the dacomitinib arm compared with the gefitinib arm (hazard ratio less than 1). Therefore the company considered that equivalent post-progression survival should be a worst-case scenario.
The company did a second post-progression survival analysis which only included patients with an observed progression-free survival event. It considered the results (considered academic in confidence by the company, and therefore cannot be reported here) to be conservative because patients whose disease progresses early have a longer follow up post progression and a higher chance of death before censoring. The company further commented that for these patients it was more likely that the true (uncensored) post-progression survival was reached compared with patients who were on therapy for longer.
The company did a third analysis to determine the extent to which longer progression-free survival is associated with longer post-progression survival. It calculated post-progression survival for 3 equally sized groups in ARCHER 1050 based on progression-free survival duration. The company commented that for the intention-to-treat population (including both dacomitinib and gefitinib patients), there was a significant difference between the post-progression survival curves based on progression-free duration (results considered academic in confidence by the company, and therefore cannot be reported here) for both the dacomitinib and the gefitinib arms.The committee acknowledged that clinical expert opinion had suggested that similar post-progression survival between comparator treatments would be expected. However, the committee understood that neither the ERG's original scenario analysis in which equivalent post-progression survival for all treatments after 71 months was assumed (see section 3.15) nor the company's post-hoc analyses accounted for treatment discontinuations or subsequent treatments. The ERG reiterated at the second committee meeting that the company's fractional polynomial analysis of the observed data from ARCHER 1050 and the ERG's restricted cubic spline analysis of the reconstructed data both showed the loss of the initial overall survival benefit of dacomitinib compared with gefitinib and afatinib before 36 months. The committee was aware that with the company's best-fitting second-order fractional polynomial model (P1=1, P2=1.5) the hazard ratio between dacomitinib and gefitinib crossed 1 at roughly 27 months, and then increased sharply, with similar patterns reported for all other second-order models. Similarly, in the ERG's analysis, the hazard ratio crossed 1 at roughly 24 months before also increasing sharply. The committee was also aware that the ERG did a sensitivity analysis in which it censored the survival times of the 10 most recent overall survival events in the dacomitinib arm of ARCHER 1050. The ERG commented that it was clear that dacomitinib's efficacy on overall survival in the trial reduced before 31 months. Therefore implementing the hazard ratio from 36 months may not be conservative, but in line with the observed data. The ERG again explained that it preferred to use the hazard ratio for overall survival equal to 1 at 36 months because the fractional polynomial extrapolations for overall survival all provided implausible results. The committee recognised that extrapolating overall survival after 36 months was highly uncertain because of the lack of trial data. It concluded that it should consider the overall survival data extrapolation after 36 months further when determining the most plausible ICER (see section 3.23).
# Health-related quality of life
## The model should include age-related disutilities
In its original base case the company used utility values from ARCHER 1050 for dacomitinib and gefitinib for progression-free disease (the company considers the values to be academic in confidence and therefore cannot be reported here). The company assumed that the utility value for afatinib would be the same as that of dacomitinib, and that the value for erlotinib would be the same as that of gefitinib, based on the similarity of their respective adverse-event profiles. The committee considered that this was appropriate. However, the company did not include any age-related disutilities. The committee accepted that these should have been included in the model given the starting age of the population modelled and the length of the time horizon.
## Using utility values for progressed disease from ARCHER 1050 or Labbé is not appropriate
In its original base case the company used a utility value of 0.64 from Labbé (2017) for progressed disease. The ERG considered it more appropriate to use utility values from ARCHER 1050 for progressed disease (the values are academic in confidence and cannot be reported here). This was because there were limitations with the data from Labbé (including differences in patient baseline characteristics between ARCHER 1050 and Labbé, in particular the exclusion of people with brain metastases from ARCHER 1050). However, the clinical experts commented that the difference between the ARCHER 1050 and Labbé utility values would be unlikely to translate into a clinically meaningful difference. During consultation, the company reiterated its view that the Labbé utility value was the most appropriate to use. It highlighted that the ARCHER 1050 utility value for progressed disease only represented a single time point very close to disease progression. Therefore, it cannot be considered robust enough to capture the gradual decline in quality of life during additional lines of therapy, disease progression and time before death. The ERG considered the ARCHER 1050 population to be most relevant to this appraisal in terms of disease stage and the interventions people had. The committee agreed that neither the ARCHER 1050 nor the Labbé utility value was ideal, but each had their merits. The committee also recalled that a utility value of 0.678 was used in NICE's technology appraisal guidance for osimertinib for treating locally advanced or metastatic EGFR T790M mutation-positive non-small-cell lung cancer. It was also considered appropriate in the ongoing appraisal of osimertinib for untreated EGFR‑positive non-small-cell lung cancer. The committee acknowledged that the utility value for progressed disease was not a significant factor in the cost-effectiveness analysis but agreed that it was appropriate to use the utility value of 0.678 for progressed disease.
## The analyses should include disutilities associated with adverse events
In its original base case, the company did not include any disutilities for adverse events but incorporated a one-off treatment-specific disutility in a scenario analysis. The company's rationale for not including these disutilities was that the utility values from ARCHER 1050 would already incorporate the effect of adverse events through EQ-5D-3L data collected during the trial. To include treatment-specific utility decrements for adverse events would effectively double count the effect of adverse events. However, the ERG considered that the base-case analysis should include treatment-specific disutilities for adverse events. Many of the most common adverse events are limited in duration, and the EQ-5D-3L only captures how people feel on the day they complete it. The clinical experts also explained how the EQ-5D-3L does not capture the full impact of certain adverse events, such as diarrhoea, on health-related quality of life. The committee concluded that it was more appropriate to include disutilities associated with adverse events in the base-case analyses.
# Resource use and costs
## The company's assumptions about health benefits and costs of subsequent therapies are implausible
In its original base case, the company assumed that 71% of people having tyrosine kinase inhibitors would also have disease progression and second-line treatment. Of these, 56% would develop the T790M mutation and have osimertinib and the other 44% would have chemotherapy. The model also assumed that 48% of the original cohort would have third-line treatment; of these, 56% would have chemotherapy (the same people who had second-line osimertinib) and 44% would have docetaxel (the same people who had second-line chemotherapy). The committee was aware of NICE's statement on handling comparators and treatment sequences on the Cancer Drugs Fund. This states that 'products recommended for use in the Cancer Drugs Fund after 1 April 2016 should not be considered as comparators, or appropriately included in a treatment sequence, in subsequent relevant appraisals'. The committee accepted that it was appropriate for osimertinib to be included in the treatment sequence in the model for dacomitinib, because this appraisal started before the position statement came into effect. The committee noted that the proportions and subsequent treatments used in the model did not reflect those used in ARCHER 1050 (see section 3.6). The Cancer Drugs Fund clinical lead explained that the proportions of people having second- and third-line treatments were higher than those seen in NHS clinical practice (50% to 60% for second line and 25% to 30% for third line). Also, osimertinib has been used less than would be expected in NHS clinical practice in England (8% to 13%), so the model overestimates its use. The clinical experts agreed that the proportions of people having subsequent treatments in the model were too high. The committee understood that the company had used the same proportions for second- and third-line treatments for all 4 tyrosine kinase inhibitors; so, although the exact proportions were inaccurate, the costs applied to the dacomitinib and comparator treatment arms were the same. But the committee recalled that the model did not capture the clinical benefits of subsequent treatment. It concluded that the company's assumptions about treatment costs and benefits in the model did not reflect the type and proportion of subsequent treatments taken by patients in the trial.
# Results of the cost-effectiveness analyses
## The company's updated deterministic base-case ICER for dacomitinib was below £30,000 per QALY gained
The company's 2 updated base-case analyses provided in response to consultation both included:
an increased discount in dacomitinib's commercial arrangement
the committee's preferred modelling of progression-free survival (see section 3.13)
age-related disutilities (see section 3.17)
disutilities for adverse events (see section 3.19).Updated base case 1 included:
equivalent post-progression survival (hazard ratio=1) from 71 months (see section 3.16)
the Labbé post-progression utility value (0.64; see section 3.18).Updated base case 2 included:
no additional survival benefit (hazard ratio=1) after 60 months (see section 3.15)
the Labbé post-progression utility value (0.64; see section 3.18).When the updated final commercial arrangement was included, both base cases resulted in ICERs below £30,000 per QALY gained. Because the dacomitinib commercial arrangement is confidential, the exact ICERs cannot be reported here.
## The ERG's updated base-case ICER for dacomitinib is over £30,000 per QALY gained
The ERG provided its updated preferred base case. This included the comparator commercial arrangements and the dacomitinib commercial arrangement that was submitted in response to consultation, assuming:
no additional survival benefit after 36 months (see section 3.16)
the post-progression utility value from ARCHER 1050 (see section 3.18).The committee noted that the ERG's updated base case was above £30,000 per QALY gained. The ERG also provided scenario analyses with ICERs for:
no additional survival benefit after 48 months
no additional survival benefit after 60 months and
equivalent post-progression survival (hazard ratio=1 from 71 months).The committee noted that the ICERs for no additional survival benefit after 60 months and for equivalent post-progression survival were both below £30,000 per QALY gained. The ICER for no additional survival benefit after 48 months was above £30,000 per QALY gained. Because dacomitinib and the comparators have confidential commercial arrangements, the exact ICERs cannot be reported here. However, these ICERs did not include the company's final commercial arrangement (see section 3.23).
## The most plausible ICER for dacomitinib is within the range normally considered to be a cost-effective use of NHS resources
The committee was aware that the differences among the company's and ERG's base cases and the alternative scenario ICERs were driven by the different assumptions about overall survival for all treatments. It recalled that the ERG's updated base case assumed equal efficacy for all treatments after 36 months (see section 3.22). But the company's updated base cases submitted in response to consultation assumed either equivalent post-progression survival from 71 months (updated base case 1, see section 3.21) or no additional survival benefit after 60 months (updated base case 2, see section 3.21). The committee noted the range of ICERs produced by the ERG's updated base case and scenario analyses and the company's 2 updated base-case analyses. The committee recognised that there were no clinical data from ARCHER 1050 after 36 months and that all the economic modelling predicted a hazard ratio for overall survival equal to 1 from 36 months. The committee accepted the company's position that the ERG's original base-case analysis, which assumed no additional survival after 36 months, resulted in a proportion of patients having treatment with dacomitinib at 36 months who would be expected to have clinical benefit from this ongoing treatment (see section 3.16). The committee also recognised clinical opinion that post-progression survival could be similar between treatments because of ongoing tyrosine kinase inhibitor treatment. After considering the trial data, the economic modelling and clinical opinion, the committee felt that on balance the cost-effectiveness estimates for dacomitinib would lie between the ERG's updated base-case analysis (hazard ratio for overall survival equal to 1 at 36 months) and the company's updated base case 1 (equal post-progression survival from 71 months). The committee decided that the most plausible ICER for dacomitinib would approximate to the ICER associated with the ERG's scenario analysis for assuming equal efficacy from 48 months (because dacomitinib and the comparators have confidential commercial arrangements, the exact ICERs cannot be reported here). When the company submitted analyses incorporating the final commercial arrangement, it included the assumption that there was no survival gain after 48 months and a utility value of 0.678 (see section 3.18). The ICER for this analysis was below £30,000 per QALY gained (dacomitinib has a confidential commercial arrangement so the exact ICER cannot be reported here). The committee therefore concluded that the most plausible ICER for dacomitinib was within the range normally considered to be a cost-effective use of NHS resources (dacomitinib and the comparators have confidential commercial arrangements so the exact ICERs cannot be reported here).
# End of life
## Dacomitinib does not meet the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company submission stated that dacomitinib does not meet the end-of-life criteria. The committee considered the clinical evidence and agreed that life expectancy for people with untreated locally advanced or metastatic EGFR mutation-positive NSCLC having standard care is more than 2 years: in ARCHER 1050, the median overall survival with gefitinib was 26.8 months (95% CI 23.7 to 32.1). The committee therefore concluded that dacomitinib did not meet the end-of-life criteria for this indication.
# Innovation
## The model adequately captures the benefits of dacomitinib
The company considered dacomitinib to be innovative, highlighting that it improves survival compared with gefitinib, erlotinib and afatinib. The clinical experts agreed that dacomitinib is an effective second-generation tyrosine kinase inhibitor and that people would welcome additional treatment options. However, they also highlighted that there is no evidence to support dacomitinib's use for patients with brain metastases because they were excluded from ARCHER 1050. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.
# Conclusion
## Dacomitinib is recommended for routine use in the NHS
Having considered all the available evidence for dacomitinib, the committee concluded that dacomitinib was a cost-effective use of NHS resources for untreated locally advanced or metastatic EGFR mutation-positive NSCLC.
# Other factors
No equality or social value judgement issues were identified.
|
{'Recommendations': 'Dacomitinib is recommended, within its marketing authorisation, as an option for untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in adults. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nLocally advanced or metastatic EGFR mutation-positive NSCLC is usually first treated with afatinib, erlotinib or gefitinib.\n\nEvidence from a randomised controlled trial shows that people who take dacomitinib live longer than people who take gefitinib. They also live longer before their disease gets worse. An indirect comparison suggests there is no difference between dacomitinib and afatinib in terms of how long people live or how long it is before their disease gets worse.\n\nThere is some uncertainty about the assumptions used in the cost-effectiveness modelling. But the most plausible cost-effectiveness estimate is within what NICE normally considers an acceptable use of NHS resources. So dacomitinib is recommended.', 'Information about dacomitinib': "Marketing authorisation indication\n\nDacomitinib (Vizimpro, Pfizer), as monotherapy, is intended for 'the first-line treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer with epidermal growth factor receptor-activating mutations'.\n\nDosage in the marketing authorisation\n\nBased on the company submission, dacomitinib is given orally at a dosage of 45\xa0mg until disease progression or unacceptable toxicity. Dacomitinib is available in 3\xa0dose strengths: 45\xa0mg, 30\xa0mg and 15\xa0mg.\n\nPrice\n\nIndicative list price: £2,703 for 30×15\xa0mg, 30×30\xa0mg or 30×45\xa0mg capsules.\n\nThe company has a commercial arrangement. This makes dacomitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## People would welcome a new treatment option\n\nThe patient experts highlighted that epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) tends to present late, so people have more advanced disease at diagnosis compared with the wider NSCLC population. The patient experts also noted that dacomitinib may improve overall survival, which is especially important to patients and their families. The committee agreed that people with EGFR mutation-positive NSCLC would welcome additional treatment options that improve overall survival.\n\n# Clinical management\n\n## Erlotinib, gefitinib and afatinib are appropriate comparators\n\nThe clinical experts explained that in line with NICE guidance, locally advanced or metastatic EGFR mutation-positive NSCLC is usually first treated with a tyrosine kinase inhibitor such as erlotinib, gefitinib or afatinib (see NICE technology appraisal guidance on erlotinib, gefitinib and afatinib). The committee understood that afatinib is more common in NHS clinical practice in England because as a second-generation tyrosine kinase inhibitor it is better than both erlotinib and gefitinib (first-generation tyrosine kinase inhibitors) in terms of prolonging progression-free survival. The committee also understood that afatinib is associated with more adverse events than erlotinib and gefitinib, so it is generally only offered to people with good Eastern Cooperative Oncology Group (ECOG) performance status. The clinical experts explained that this would also be the case for dacomitinib. The committee agreed that although afatinib is the most commonly used tyrosine kinase inhibitor and has a similar adverse-event profile to dacomitinib, gefitinib and erlotinib were also used in established NHS practice in England. So gefitinib and erlotinib were also listed as comparators in NICE's final scope.\n\n# Clinical evidence\n\n## Evidence from an open-label randomised controlled trial is relevant and high quality\n\nThe main clinical evidence came from ARCHER\xa01050, a multicentre, open-label, phase\xa0III randomised controlled trial. It compared the efficacy and safety of dacomitinib (n=227) with gefitinib (n=225) in adults with untreated locally advanced or metastatic EGFR mutation-positive NSCLC. Patients had either the exon\xa019 deletion (del19) or exon\xa021 (L858R) EGFR mutation. The trial included 71\xa0study sites in 7\xa0countries (China, Hong Kong, Japan, Republic of Korea, Italy, Poland and Spain). The primary outcome was progression-free survival, determined by blinded independent review committee. Secondary outcomes included overall survival, objective response rate, length of response, adverse events, time to treatment failure and health-related quality of life. After disease progression, patients could have subsequent treatment with a different drug (see section\xa03.6). The committee noted that in the trials used to inform NICE technology appraisal guidance on erlotinib, gefitinib and afatinib, the comparator was chemotherapy. But in ARCHER\xa01050 the comparator was gefitinib (the trial compared a second-generation tyrosine kinase inhibitor [dacomitinib] with a first-generation tyrosine kinase inhibitor [gefitinib]). The committee concluded that ARCHER\xa01050 was a well-conducted trial providing high-quality evidence relevant to the appraisal.\n\n## The treatment arms in ARCHER\xa01050 are well balanced\n\nThe ERG noted that in the trial, 64.3% of patients having dacomitinib were women compared with only 55.6% of patients having gefitinib. The committee was aware that there was some evidence to suggest that tyrosine kinase inhibitors tend to be more effective at treating EGFR mutation-positive NSCLC in women than in men, and so the trial could be biased in favour of dacomitinib. But the clinical experts did not consider sex to be an important factor. The committee concluded that the treatment arms in ARCHER\xa01050 were generally well balanced.\n\n## Dacomitinib improves progression-free and overall survival compared with gefitinib\n\nThe results of ARCHER\xa01050 showed that dacomitinib statistically significantly improved progression-free survival compared with gefitinib (14.7\xa0months for dacomitinib compared with 9.2\xa0months for gefitinib; hazard ratio [HR] 0.589, 95% confidence interval [CI] 0.47 to 0.74). Exploratory analyses also showed that dacomitinib improved overall survival compared with gefitinib (34.1\xa0months for dacomitinib compared with 26.8\xa0months for gefitinib; HR 0.760, 95% CI 0.58 to 0.99). During consultation, the company manufacturing gefitinib highlighted that the overall survival Kaplan–Meier curves for dacomitinib and gefitinib crossed at around 11\xa0months (and possibly at around 36\xa0months too). The company suggested that this shows that a specific subgroup (or subgroups) derives more benefit from gefitinib than dacomitinib. Although the committee acknowledged that the Kaplan–Meier curves did cross, it concluded that overall dacomitinib is associated with improved progression-free and overall survival compared with gefitinib.\n\n## It is unclear how subsequent treatments may affect overall survival in ARCHER\xa01050\n\nIn ARCHER\xa01050, patients who stopped taking the study drug (dacomitinib or gefitinib) could then have subsequent treatment with a different drug (the company considered the subsequent treatments to be confidential so they cannot be reported here). But the committee noted that these subsequent treatments did not reflect the type and proportion of those used in clinical practice in the NHS in England. The committee agreed that there was uncertainty about how subsequent treatments may have affected the overall survival estimates in ARCHER\xa01050, and that it would consider this in its decision making.\n\n## The results of ARCHER\xa01050 are generalisable to NHS clinical practice in England\n\nThe committee considered whether the baseline characteristics of patients in ARCHER\xa01050 reflected those seen in NHS clinical practice in England. It noted that the patients in the trial had only the exon\xa019 deletion (del19) or exon\xa021 (L858R) EGFR mutations. The clinical experts explained that these 2\xa0mutations account for around 90% of all EGFR mutations. Also, most trials only include people with these mutations, including the trials that were carried out with other tyrosine kinase inhibitors. The committee acknowledged that although other mutations may not respond as well to dacomitinib, the Committee for Medicinal Products for Human Use (CHMP) did not restrict its positive opinion for dacomitinib to these 2\xa0mutations (see section 2). The committee therefore agreed that the EGFR mutation status of patients in ARCHER\xa01050 generally reflected that seen in NHS clinical practice in England. It also noted that the trial included a large proportion of patients of Asian family origin (74.9% in the dacomitinib treatment arm and 78.2% in the gefitinib treatment arm) because many of the trial centres were in East Asia. It recalled that ethnicity was a prespecified subgroup in ARCHER\xa01050, and that the company had provided analyses in response to clarification, but the results were underpowered (overall survival: Asian family origin subgroup HR 0.81, 95% CI 0.6 to 1.11; non-Asian family origin subgroup HR 0.72, 95% CI 0.43 to 1.20. The results for progression-free survival are considered academic in confidence by the company and so cannot be reported here). During consultation, the company manufacturing gefitinib highlighted evidence suggesting that Asian ethnicity has been identified as a favourable independent prognostic factor for overall survival in NSCLC, irrespective of smoking status. The committee noted that in the company's overall survival analyses for ethnicity, dacomitinib showed a survival benefit compared with gefitinib in both the non-Asian and Asian family origin subgroups. Although ARCHER\xa01050 was not powered for subgroup analyses, the results were all aligned and were in favour of dacomitinib (except for the subgroup with ECOG performance status\xa00). The committee noted that there appeared to be much better progression-free survival for the Asian family origin subgroup, which was not reflected in overall survival for the same population. The committee agreed that there was no conclusive evidence that ethnicity has a significant effect on overall survival. Because the trial was not powered for subgroup analyses, the committee considered that the results from the whole trial population would be generalisable to the population seen in clinical practice in England. The committee noted that ARCHER\xa01050 excluded people with brain metastases: these are associated with a poor prognosis and often occur in people with EGFR mutation-positive NSCLC. This was an important difference between ARCHER\xa01050 and the LUX-Lung\xa07 trial (used in the comparison of afatinib with gefitinib; see section 3.9), in which 16% of patients had brain metastases. The committee concluded that overall, the trial results from ARCHER\xa01050 were generalisable to NHS clinical practice in England.\n\n## Dacomitinib is associated with more adverse events and may need more dose reductions than gefitinib\n\nThe committee noted that dacomitinib had a higher incidence of common adverse events than gefitinib, and that there were more dose reductions in the dacomitinib treatment arm than in the gefitinib treatment arm (66.1% and 8.0% respectively). The committee was also aware that second-generation tyrosine kinase inhibitors such as afatinib are associated with more adverse events, whereas first-generation tyrosine kinase inhibitors are generally better tolerated (see section 3.2). The clinical experts agreed that the differences in the drugs' adverse-event profiles are well known and this is reflected in how they are used in clinical practice. That is, they are used according to whether a person is well enough for treatment, which is typically categorised by ECOG performance status. Although the clinical experts acknowledged that adverse events associated with second-generation tyrosine kinase inhibitors could be effectively managed in clinical practice, they highlighted that the adverse events were detrimental to people's quality of life. The Cancer Drugs Fund clinical lead also highlighted NHS England's concerns about the toxicity of dacomitinib and the high rates of adverse events that are likely to be seen in practice. The committee agreed that dacomitinib had a higher incidence of adverse events and needed more dose reductions than gefitinib. It concluded that how this affected health-related quality of life and resource costs for managing adverse events should be fully captured in the cost-effectiveness analysis.\n\n## The results from the company's fractional polynomial network meta-analysis are uncertain\n\nThe company did a network meta-analysis to compare dacomitinib with the other comparators in the scope, afatinib and erlotinib. It did a fractional polynomial network meta-analysis as described by Janssen et al. (2011), because it considered that the proportional hazards assumption may have been violated in ARCHER\xa01050 (that is, the hazard ratios were not constant over time). The committee understood that fractional polynomial network meta-analysis differs from a traditional network meta-analysis in that it fits hazard ratios that can vary over time rather than being constant. Based on the evidence from clinical experts, other phase\xa0III randomised controlled trials and previous NICE appraisals, the company assumed equivalence between gefitinib and erlotinib. The committee agreed that this assumption was appropriate. The company obtained the relative effect estimates of progression-free and overall survival for afatinib and dacomitinib compared with gefitinib from the LUX-Lung\xa07 trial (which compared afatinib with gefitinib). In its submission, the company presented the projected means for progression-free and overall survival along with the medians compared with the observed data from ARCHER\xa01050, to provide face validity for the model (the company considered the results to be commercial in confidence and so they cannot be reported here). The committee recalled the ERG's concerns about differences in patients' baseline characteristics in ARCHER\xa01050 and LUX-Lung\xa07, specifically the proportion of patients of Asian family origin and the presence of brain metastases (see section 3.7). The committee agreed that these differences, in particular the exclusion of people with brain metastases from ARCHER\xa01050, added uncertainty to any estimates from the analysis. The ERG also expressed concerns about extrapolating progression-free and overall survival outcomes from fractional polynomial models: they tend to over-fit to the tail of the data, often resulting in implausible survival extrapolations. The committee noted that these concerns were supported by the large number of models that the company had to reject because of the clinically implausible extrapolations of survival outcomes. The committee concluded that the results from the company's fractional polynomial network meta-analysis were uncertain.\n\n## There is no statistically significant difference between dacomitinib and afatinib in terms of progression-free and overall survival\n\nThe ERG did its own indirect treatment comparison to address these uncertainties, and because the company's model did not report hazard ratios for progression-free or overall survival between dacomitinib and afatinib. The ERG did a fixed-effects network meta-analysis using data from ARCHER\xa01050 for dacomitinib and from LUX-Lung\xa07 for afatinib. The company agreed with the ERG's approach to estimating the hazard ratios. The results suggested that dacomitinib might be better than afatinib in terms of extending progression-free and overall survival, but there was no significant difference between the 2\xa0treatments (progression-free survival HR 0.80, 95% CI 0.57 to 1.12; overall survival HR 0.88, 95% CI 0.61 to 1.29). The committee recalled that there was uncertainty around any estimates from a network meta-analysis that used data from ARCHER\xa01050 and LUX-Lung\xa07, because of the differences between the trials in terms of baseline patient characteristics (and because the proportional hazards assumption may have been violated in ARCHER\xa01050). It concluded that any estimates were uncertain and based on the evidence available there was no statistically significant difference between dacomitinib and afatinib in terms of extending progression-free and overall survival.\n\n# The company's economic model\n\n## The company's model is appropriate for decision making\n\nThe company used a partitioned-survival economic model that included 3\xa0health states: pre-progression, post-progression and death. The model included either dacomitinib, afatinib, gefitinib or erlotinib as first-line treatment, followed by osimertinib (if T790M mutation-positive) or chemotherapy. The committee was concerned that the model captured only the costs and not the clinical benefits of subsequent treatments. However, the committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for NSCLC.\n\n# Survival extrapolation\n\n## There are uncertainties in how the company modelled progression-free survival\n\nIn its original base case, the company modelled progression-free survival for gefitinib using a generalised gamma curve fitted to the gefitinib treatment arm of ARCHER\xa01050. It modelled progression-free survival for erlotinib by assuming equivalent efficacy with gefitinib. It then used the fractional polynomial network meta-analysis (model P1=0.5, P2=1.5) to obtain time-varying hazard ratios for afatinib and dacomitinib relative to gefitinib (see section\xa03.10), before applying these to the gefitinib extrapolation. The committee had concerns about the company's modelling of progression-free survival:\n\nThe progression-free survival for gefitinib after 2\xa0years potentially underestimated the quality-adjusted life years (QALYs) and costs for the comparators.\n\nThe extrapolation of dacomitinib and afatinib relied on results from the fractional polynomial network meta-analysis, which were themselves uncertain (see section\xa03.9).\n\nThe progression-free survival curves suggested that dacomitinib had the highest progression-free survival up to 38\xa0months, after which afatinib had the highest progression-free survival. The committee agreed that there was no clinical rationale for dacomitinib to be less effective than the comparators in terms of progression-free survival after 38\xa0months.The committee agreed that there was uncertainty around the company's modelling of progression-free survival because of the implausibility of the results. This made the company's incremental cost-effectiveness ratios (ICERs) highly uncertain.\n\n## The ERG's modelling of progression-free survival is appropriate\n\nIn its original base case, the ERG used the log-normal parametric curve for gefitinib and the fractional polynomial network meta-analysis for the other comparators (P1=0.5, P2=1). The afatinib extrapolation remained implausible so the ERG assumed the progression-free survival of afatinib to be equal to the mean progression-free survival of dacomitinib and gefitinib after 36\xa0months. It also did a scenario analysis in which it assumed the progression-free survival of afatinib to be equal to the mean progression-free survival of dacomitinib and gefitinib after 55\xa0months. Although it recognised the uncertainties, the committee preferred this approach because it produced more plausible results than the company's base case. It therefore agreed that the ERG's modelling of progression-free survival was appropriate and its decision making should be based on this.\n\n## The company's modelling of overall survival produces some implausible results\n\nIn its original base case, the company modelled overall survival in the same way it modelled progression-free survival (see section 3.12). The committee had concerns about the company's modelling of overall survival:\n\nThe generalised gamma curve may underestimate overall survival with gefitinib.\n\nThe modelling suggested that the efficacy of afatinib relative to gefitinib decreased over time while the efficacy of dacomitinib improved over time; clinical expert advice to the ERG questioned the plausibility of this. The clinical experts acknowledged that effective treatments may provide some benefit for a limited time after stopping treatment, but the committee recalled that there was no evidence to suggest that afatinib and dacomitinib provided different benefits after stopping treatment.\n\nDacomitinib appears to provide benefits both before and after disease progression. This is unlikely to be plausible, because it is uncommon for progression-free survival to mirror post-progression survival, and even less common for progression-free survival to be extended into post-progression survival.The committee therefore agreed that the company's modelling of overall survival produced some implausible results.\n\n## The ERG's modelling of overall survival is the most appropriate for decision making\n\nIn its original base case, the ERG used the log-logistic curve for gefitinib and the fractional polynomial network meta-analysis for the other comparators (P1=−0.5). It assumed equal efficacy for overall survival between all treatments after 36\xa0months. The ERG acknowledged that assuming equal efficacy from 48\xa0or 60\xa0months could also be considered plausible and explored these in scenario analyses. The ERG also did a scenario analysis in which it assumed equivalent post-progression survival for all treatments after 71\xa0months. The committee agreed that there was uncertainty around the company's modelling of overall survival because of the implausibility of the results (see section 3.14) and that all the ERG's scenario analyses were clinically plausible. The committee concluded that its decision making should be based on the ERG's modelling of overall survival.\n\n## The extrapolation of overall survival data after 36\xa0months is highly uncertain\n\nDuring consultation the company highlighted that the committee had accepted that all of the ERG's overall survival analyses (see section 3.15) were clinically plausible. It commented that the committee should further consider the ERG's scenario analysis in which equivalent post-progression survival for all treatments after 71\xa0months was assumed. The committee noted the company's rationale for assuming equivalent post-progression survival for all treatments after 71\xa0months. The company asserted that the ERG's base-case assumption of equal efficacy for overall survival modelling after 36\xa0months cannot be considered plausible given the proportion of patients having treatment at 36\xa0months who would be expected to get clinical benefit from ongoing treatment. The company also asserted that a scenario assuming equal post-progression survival after 71\xa0months was the most clinically plausible scenario given the results of its 3\xa0post-hoc analyses of post-progression survival from ARCHER\xa01050:\n\nFor the intention-to-treat population, the company calculated post-progression survival from the date of progression-free survival (independent review committee) to the date of overall survival event or censored date as applicable. It considered that the results (considered academic in confidence by the company, and therefore cannot be reported here) suggested that there was an improvement in post-progression survival in the dacomitinib arm compared with the gefitinib arm (hazard ratio less than\xa01). Therefore the company considered that equivalent post-progression survival should be a worst-case scenario.\n\nThe company did a second post-progression survival analysis which only included patients with an observed progression-free survival event. It considered the results (considered academic in confidence by the company, and therefore cannot be reported here) to be conservative because patients whose disease progresses early have a longer follow up post progression and a higher chance of death before censoring. The company further commented that for these patients it was more likely that the true (uncensored) post-progression survival was reached compared with patients who were on therapy for longer.\n\nThe company did a third analysis to determine the extent to which longer progression-free survival is associated with longer post-progression survival. It calculated post-progression survival for 3\xa0equally sized groups in ARCHER\xa01050 based on progression-free survival duration. The company commented that for the intention-to-treat population (including both dacomitinib and gefitinib patients), there was a significant difference between the post-progression survival curves based on progression-free duration (results considered academic in confidence by the company, and therefore cannot be reported here) for both the dacomitinib and the gefitinib arms.The committee acknowledged that clinical expert opinion had suggested that similar post-progression survival between comparator treatments would be expected. However, the committee understood that neither the ERG's original scenario analysis in which equivalent post-progression survival for all treatments after 71\xa0months was assumed (see section 3.15) nor the company's post-hoc analyses accounted for treatment discontinuations or subsequent treatments. The ERG reiterated at the second committee meeting that the company's fractional polynomial analysis of the observed data from ARCHER\xa01050 and the ERG's restricted cubic spline analysis of the reconstructed data both showed the loss of the initial overall survival benefit of dacomitinib compared with gefitinib and afatinib before 36\xa0months. The committee was aware that with the company's best-fitting second-order fractional polynomial model (P1=1, P2=1.5) the hazard ratio between dacomitinib and gefitinib crossed\xa01 at roughly 27\xa0months, and then increased sharply, with similar patterns reported for all other second-order models. Similarly, in the ERG's analysis, the hazard ratio crossed\xa01 at roughly 24\xa0months before also increasing sharply. The committee was also aware that the ERG did a sensitivity analysis in which it censored the survival times of the 10\xa0most recent overall survival events in the dacomitinib arm of ARCHER\xa01050. The ERG commented that it was clear that dacomitinib's efficacy on overall survival in the trial reduced before 31\xa0months. Therefore implementing the hazard ratio from 36\xa0months may not be conservative, but in line with the observed data. The ERG again explained that it preferred to use the hazard ratio for overall survival equal to 1 at 36\xa0months because the fractional polynomial extrapolations for overall survival all provided implausible results. The committee recognised that extrapolating overall survival after 36\xa0months was highly uncertain because of the lack of trial data. It concluded that it should consider the overall survival data extrapolation after 36\xa0months further when determining the most plausible ICER (see section 3.23).\n\n# Health-related quality of life\n\n## The model should include age-related disutilities\n\nIn its original base case the company used utility values from ARCHER\xa01050 for dacomitinib and gefitinib for progression-free disease (the company considers the values to be academic in confidence and therefore cannot be reported here). The company assumed that the utility value for afatinib would be the same as that of dacomitinib, and that the value for erlotinib would be the same as that of gefitinib, based on the similarity of their respective adverse-event profiles. The committee considered that this was appropriate. However, the company did not include any age-related disutilities. The committee accepted that these should have been included in the model given the starting age of the population modelled and the length of the time horizon.\n\n## Using utility values for progressed disease from ARCHER\xa01050 or Labbé is not appropriate\n\nIn its original base case the company used a utility value of 0.64 from Labbé (2017) for progressed disease. The ERG considered it more appropriate to use utility values from ARCHER\xa01050 for progressed disease (the values are academic in confidence and cannot be reported here). This was because there were limitations with the data from Labbé (including differences in patient baseline characteristics between ARCHER\xa01050 and Labbé, in particular the exclusion of people with brain metastases from ARCHER\xa01050). However, the clinical experts commented that the difference between the ARCHER\xa01050 and Labbé utility values would be unlikely to translate into a clinically meaningful difference. During consultation, the company reiterated its view that the Labbé utility value was the most appropriate to use. It highlighted that the ARCHER\xa01050 utility value for progressed disease only represented a single time point very close to disease progression. Therefore, it cannot be considered robust enough to capture the gradual decline in quality of life during additional lines of therapy, disease progression and time before death. The ERG considered the ARCHER\xa01050 population to be most relevant to this appraisal in terms of disease stage and the interventions people had. The committee agreed that neither the ARCHER\xa01050 nor the Labbé utility value was ideal, but each had their merits. The committee also recalled that a utility value of 0.678 was used in NICE's technology appraisal guidance for osimertinib for treating locally advanced or metastatic EGFR T790M mutation-positive non-small-cell lung cancer. It was also considered appropriate in the ongoing appraisal of osimertinib for untreated EGFR‑positive non-small-cell lung cancer. The committee acknowledged that the utility value for progressed disease was not a significant factor in the cost-effectiveness analysis but agreed that it was appropriate to use the utility value of 0.678 for progressed disease.\n\n## The analyses should include disutilities associated with adverse events\n\nIn its original base case, the company did not include any disutilities for adverse events but incorporated a one-off treatment-specific disutility in a scenario analysis. The company's rationale for not including these disutilities was that the utility values from ARCHER\xa01050 would already incorporate the effect of adverse events through EQ-5D-3L data collected during the trial. To include treatment-specific utility decrements for adverse events would effectively double count the effect of adverse events. However, the ERG considered that the base-case analysis should include treatment-specific disutilities for adverse events. Many of the most common adverse events are limited in duration, and the EQ-5D-3L only captures how people feel on the day they complete it. The clinical experts also explained how the EQ-5D-3L does not capture the full impact of certain adverse events, such as diarrhoea, on health-related quality of life. The committee concluded that it was more appropriate to include disutilities associated with adverse events in the base-case analyses.\n\n# Resource use and costs\n\n## The company's assumptions about health benefits and costs of subsequent therapies are implausible\n\nIn its original base case, the company assumed that 71% of people having tyrosine kinase inhibitors would also have disease progression and second-line treatment. Of these, 56% would develop the T790M mutation and have osimertinib and the other 44% would have chemotherapy. The model also assumed that 48% of the original cohort would have third-line treatment; of these, 56% would have chemotherapy (the same people who had second-line osimertinib) and 44% would have docetaxel (the same people who had second-line chemotherapy). The committee was aware of NICE's statement on handling comparators and treatment sequences on the Cancer Drugs Fund. This states that 'products recommended for use in the Cancer Drugs Fund after 1\xa0April\xa02016 should not be considered as comparators, or appropriately included in a treatment sequence, in subsequent relevant appraisals'. The committee accepted that it was appropriate for osimertinib to be included in the treatment sequence in the model for dacomitinib, because this appraisal started before the position statement came into effect. The committee noted that the proportions and subsequent treatments used in the model did not reflect those used in ARCHER\xa01050 (see section 3.6). The Cancer Drugs Fund clinical lead explained that the proportions of people having second- and third-line treatments were higher than those seen in NHS clinical practice (50% to 60% for second line and 25% to 30% for third line). Also, osimertinib has been used less than would be expected in NHS clinical practice in England (8% to 13%), so the model overestimates its use. The clinical experts agreed that the proportions of people having subsequent treatments in the model were too high. The committee understood that the company had used the same proportions for second- and third-line treatments for all 4\xa0tyrosine kinase inhibitors; so, although the exact proportions were inaccurate, the costs applied to the dacomitinib and comparator treatment arms were the same. But the committee recalled that the model did not capture the clinical benefits of subsequent treatment. It concluded that the company's assumptions about treatment costs and benefits in the model did not reflect the type and proportion of subsequent treatments taken by patients in the trial.\n\n# Results of the cost-effectiveness analyses\n\n## The company's updated deterministic base-case ICER for dacomitinib was below £30,000 per QALY gained\n\nThe company's 2\xa0updated base-case analyses provided in response to consultation both included:\n\nan increased discount in dacomitinib's commercial arrangement\n\nthe committee's preferred modelling of progression-free survival (see section 3.13)\n\nage-related disutilities (see section 3.17)\n\ndisutilities for adverse events (see section 3.19).Updated base case\xa01 included:\n\nequivalent post-progression survival (hazard ratio=1) from 71\xa0months (see section 3.16)\n\nthe Labbé post-progression utility value (0.64; see section 3.18).Updated base case\xa02 included:\n\nno additional survival benefit (hazard ratio=1) after 60\xa0months (see section 3.15)\n\nthe Labbé post-progression utility value (0.64; see section 3.18).When the updated final commercial arrangement was included, both base cases resulted in ICERs below £30,000 per QALY gained. Because the dacomitinib commercial arrangement is confidential, the exact ICERs cannot be reported here.\n\n## The ERG's updated base-case ICER for dacomitinib is over £30,000 per QALY gained\n\nThe ERG provided its updated preferred base case. This included the comparator commercial arrangements and the dacomitinib commercial arrangement that was submitted in response to consultation, assuming:\n\nno additional survival benefit after 36\xa0months (see section 3.16)\n\nthe post-progression utility value from ARCHER\xa01050 (see section 3.18).The committee noted that the ERG's updated base case was above £30,000 per QALY gained. The ERG also provided scenario analyses with ICERs for:\n\nno additional survival benefit after 48\xa0months\n\nno additional survival benefit after 60\xa0months and\n\nequivalent post-progression survival (hazard ratio=1 from 71\xa0months).The committee noted that the ICERs for no additional survival benefit after 60\xa0months and for equivalent post-progression survival were both below £30,000 per QALY gained. The ICER for no additional survival benefit after 48\xa0months was above £30,000 per QALY gained. Because dacomitinib and the comparators have confidential commercial arrangements, the exact ICERs cannot be reported here. However, these ICERs did not include the company's final commercial arrangement (see section\xa03.23).\n\n## The most plausible ICER for dacomitinib is within the range normally considered to be a cost-effective use of NHS resources\n\nThe committee was aware that the differences among the company's and ERG's base cases and the alternative scenario ICERs were driven by the different assumptions about overall survival for all treatments. It recalled that the ERG's updated base case assumed equal efficacy for all treatments after 36\xa0months (see section 3.22). But the company's updated base cases submitted in response to consultation assumed either equivalent post-progression survival from 71\xa0months (updated base case\xa01, see section 3.21) or no additional survival benefit after 60\xa0months (updated base case\xa02, see section\xa03.21). The committee noted the range of ICERs produced by the ERG's updated base case and scenario analyses and the company's 2\xa0updated base-case analyses. The committee recognised that there were no clinical data from ARCHER\xa01050 after 36\xa0months and that all the economic modelling predicted a hazard ratio for overall survival equal to 1 from 36\xa0months. The committee accepted the company's position that the ERG's original base-case analysis, which assumed no additional survival after 36\xa0months, resulted in a proportion of patients having treatment with dacomitinib at 36\xa0months who would be expected to have clinical benefit from this ongoing treatment (see section 3.16). The committee also recognised clinical opinion that post-progression survival could be similar between treatments because of ongoing tyrosine kinase inhibitor treatment. After considering the trial data, the economic modelling and clinical opinion, the committee felt that on balance the cost-effectiveness estimates for dacomitinib would lie between the ERG's updated base-case analysis (hazard ratio for overall survival equal to 1 at 36\xa0months) and the company's updated base case\xa01 (equal post-progression survival from 71\xa0months). The committee decided that the most plausible ICER for dacomitinib would approximate to the ICER associated with the ERG's scenario analysis for assuming equal efficacy from 48\xa0months (because dacomitinib and the comparators have confidential commercial arrangements, the exact ICERs cannot be reported here). When the company submitted analyses incorporating the final commercial arrangement, it included the assumption that there was no survival gain after 48\xa0months and a utility value of 0.678 (see section 3.18). The ICER for this analysis was below £30,000 per QALY gained (dacomitinib has a confidential commercial arrangement so the exact ICER cannot be reported here). The committee therefore concluded that the most plausible ICER for dacomitinib was within the range normally considered to be a cost-effective use of NHS resources (dacomitinib and the comparators have confidential commercial arrangements so the exact ICERs cannot be reported here).\n\n# End of life\n\n## Dacomitinib does not meet the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company submission stated that dacomitinib does not meet the end-of-life criteria. The committee considered the clinical evidence and agreed that life expectancy for people with untreated locally advanced or metastatic EGFR mutation-positive NSCLC having standard care is more than 2\xa0years: in ARCHER\xa01050, the median overall survival with gefitinib was 26.8\xa0months (95% CI 23.7 to 32.1). The committee therefore concluded that dacomitinib did not meet the end-of-life criteria for this indication.\n\n# Innovation\n\n## The model adequately captures the benefits of dacomitinib\n\nThe company considered dacomitinib to be innovative, highlighting that it improves survival compared with gefitinib, erlotinib and afatinib. The clinical experts agreed that dacomitinib is an effective second-generation tyrosine kinase inhibitor and that people would welcome additional treatment options. However, they also highlighted that there is no evidence to support dacomitinib's use for patients with brain metastases because they were excluded from ARCHER\xa01050. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.\n\n# Conclusion\n\n## Dacomitinib is recommended for routine use in the NHS\n\nHaving considered all the available evidence for dacomitinib, the committee concluded that dacomitinib was a cost-effective use of NHS resources for untreated locally advanced or metastatic EGFR mutation-positive NSCLC.\n\n# Other factors\n\nNo equality or social value judgement issues were identified."}
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https://www.nice.org.uk/guidance/ta595
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Evidence-based recommendations on dacomitinib (Vizimpro) for untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer in adults.
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2aa01a23ba03b5e322eff0259eb5e74b1e28007c
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nice
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Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism
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Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism
This guideline covers assessing and reducing the risk of venous thromboembolism (VTE or blood clots, including deep vein thrombosis and pulmonary embolism) in people aged 16 and over in hospital. It aims to help healthcare professionals identify people most at risk and describes interventions that can be used to reduce the risk of VTE.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Risk assessment
## All patients
Assess all patients to identify the risk of venous thromboembolism (VTE) and bleeding (see the recommendation for all medical patients, for all surgical patients, for all pregnant women and all women who gave birth or had a miscarriage or termination of pregnancy in the past 6 weeks, for all people admitted to the critical care unit and for all acute psychiatric patients).
## People admitted to hospital
Assess all medical patients to identify the risk of VTE and bleeding:
as soon as possible after admission to hospital or by the time of the first consultant review
using a tool published by a national UK body, professional network or peer-reviewed journal.A tool commonly used to develop a treatment plan for medical patients is the Department of Health VTE risk assessment tool. (Reproduced with the permission of the Department of Health and Social Care under the Open Government Licence.)
Balance the person's individual risk of VTE against their risk of bleeding when deciding whether to offer pharmacological thromboprophylaxis to medical patients.
If using pharmacological VTE prophylaxis for medical patients, start it as soon as possible and within 14 hours of admission, unless otherwise stated in the population-specific recommendations (see the sections on interventions for people with acute coronary syndromes or acute stroke or for acutely ill patients, interventions for people with renal impairment, interventions for people with cancer, interventions for people having palliative care, interventions for people admitted to critical care, and interventions for people with psychiatric illness).
Assess all surgical and trauma patients to identify the risk of VTE and bleeding:
as soon as possible after admission to hospital or by the time of the first consultant review
using a tool published by a national UK body, professional network or peer-reviewed journal.A tool commonly used to develop a treatment plan for surgical patients is the Department of Health VTE risk assessment tool. (Reproduced with the permission of the Department of Health and Social Care under the Open Government Licence.)
Balance the person's individual risk of VTE against their risk of bleeding when deciding whether to offer pharmacological thromboprophylaxis to surgical and trauma patients.
If using pharmacological VTE prophylaxis for surgical and trauma patients, start it as soon as possible and within 14 hours of admission, unless otherwise stated in the population-specific recommendations (see the sections on interventions when using anaesthesia, interventions for people having orthopaedic surgery, interventions for people having elective spinal surgery or cranial surgery people with spinal injury, interventions for people with major trauma, interventions for people having abdominal, thoracic or head and neck surgery, and interventions for people having cardiac or vascular surgery).
Reassess all medical, surgical and trauma patients for risk of VTE and bleeding at the point of consultant review or if their clinical condition changes.
## Pregnant women and women who gave birth or had a miscarriage or termination of pregnancy in the past 6 weeks
Assess all women on admission to hospital or a midwife-led unit if they are pregnant or gave birth, had a miscarriage or had a termination of pregnancy in the past 6 weeks, to identify their risk of VTE and bleeding. Use a tool published by a national UK body, professional network or peer-reviewed journal. The most commonly used tool is the Royal College of Obstetricians and Gynaecologists risk assessment tool. (Reproduced from: Royal College of Obstetricians and Gynaecologists. Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green-top Guideline No. 37a. London: RCOG, 2015, with the permission of the Royal College of Obstetricians and Gynaecologists.)
Reassess risk of VTE and bleeding, and assess the need for thromboprophylaxis for all women:
within 6 hours of giving birth, having a miscarriage or having a termination of pregnancy or
if their clinical condition changes and they:
are pregnant or
gave birth, had a miscarriage or had a termination of pregnancy within the past 6 weeks.
# Giving information and planning for discharge
On admission ensure that people understand the reason for having a risk assessment for VTE and bleeding.
For people admitted to hospital who are at increased risk of VTE, give them and their family members or carers (as appropriate) verbal and written information on the following before offering VTE prophylaxis:
the person's risks and possible consequences of VTE
the importance of VTE prophylaxis and its possible side effects – for example, pharmacological prophylaxis can increase bleeding risk
the correct use of VTE prophylaxis – for example, anti-embolism stockings, intermittent pneumatic compression
how people can reduce their risk of VTE (such as keeping well hydrated and, if possible, exercising and becoming more mobile).
Be aware that heparins are of animal origin and this may be of concern to some people (See Religion or belief: a practical guide for the NHS). Discuss the alternatives with people who have concerns about using animal products, after discussing their suitability, advantages and disadvantages with the person.
As part of the discharge plan, give patients and their family members or carers (as appropriate) verbal and written information on:
the signs and symptoms of deep vein thrombosis (DVT) and pulmonary embolism
how people can reduce their risk of VTE (such as keeping well hydrated and, if possible, exercising and becoming more mobile)
the importance of seeking help if DVT, pulmonary embolism or other adverse events are suspected.
Give people discharged with VTE prophylaxis and their family members or carers (as appropriate) verbal and written information on:
the importance of using VTE prophylaxis correctly (including the correct administration and disposal of pharmacological prophylaxis)
the importance of continuing treatment for the recommended duration
the signs and symptoms of adverse events related to VTE prophylaxis
the importance of seeking help and who to contact if people have problems using VTE prophylaxis.
Ensure that people who are discharged with anti-embolism stockings:
understand the benefits of wearing them
understand the importance of wearing them correctly
understand the need to remove them daily for hygiene purposes
are able to remove and replace them, or have someone available who will be able to do this for them
know what to look for if there is a problem – for example, skin marking, blistering or discolouration, particularly over the heels and bony prominences
know who to contact if there is a problem
know when to stop wearing them.
Ensure that people who are discharged with pharmacological and/or mechanical VTE prophylaxis are able to use it correctly, or have arrangements made for someone to be available who will be able to help them.
Notify the person's GP if the person has been discharged with pharmacological and/or mechanical VTE prophylaxis to be used at home.
# All patients
## Mechanical prophylaxis
Do not offer anti-embolism stockings to people who have:
suspected or proven peripheral arterial disease
peripheral arterial bypass grafting
peripheral neuropathy or other causes of sensory impairment
any local conditions in which anti-embolism stockings may cause damage – for example, fragile 'tissue paper' skin, dermatitis, gangrene or recent skin graft
known allergy to material of manufacture
severe leg oedema
major limb deformity or unusual leg size or shape preventing correct fit.Use caution and clinical judgement when applying anti-embolism stockings over venous ulcers or wounds.
Ensure that people who need anti-embolism stockings have their legs measured and that they are provided with the correct size of stocking. Anti-embolism stockings should be fitted and patients shown how to use them by staff trained in their use.
Ensure that people who develop oedema or postoperative swelling have their legs re‑measured and anti-embolism stockings refitted.
If arterial disease is suspected, seek expert opinion before fitting anti-embolism stockings.
Use anti-embolism stockings that provide graduated compression and produce a calf pressure of 14 mmHg to 15 mmHg. (This relates to a pressure of 14 mmHg to18 mmHg at the ankle and is in line with the British Standard Institution's BS 661210:2018 Specification for graduated compression hosiery, anti-embolism hosiery and graduated support hosiery.)
Encourage people to wear their anti-embolism stockings day and night until they no longer have significantly reduced mobility.
Remove anti-embolism stockings daily for hygiene purposes and to inspect skin condition. In people with a significant reduction in mobility, poor skin integrity or any sensory loss, inspect the skin 2 or 3 times a day, particularly over the heels and bony prominences.
Monitor the use of anti-embolism stockings and offer assistance if they are not being worn correctly.
Stop the use of anti-embolism stockings if there is marking, blistering or discolouration of the skin, particularly over the heels and bony prominences, or if the person experiences pain or discomfort. If suitable, offer intermittent pneumatic compression as an alternative.
Do not offer intermittent pneumatic compression to people with a known allergy to the material of manufacture.
Advise the person to wear their device for as much time as possible.
## Pharmacological prophylaxis
For pharmacological VTE prophylaxis in people under 18, follow the recommendations on apixaban, aspirin, dabigatran etexilate, fondaparinux sodium, low-molecular-weight heparin (LMWH) and rivaroxaban in this guideline. In March 2018, the use of these drugs in young people under 18 was off label. See NICE's information on prescribing medicines.
## All surgery
Advise people to consider stopping oestrogen-containing oral contraceptives or hormone replacement therapy 4 weeks before elective surgery. If stopped, provide advice on alternative contraceptive methods.
## Nursing care: early mobilisation and hydration
Encourage people to mobilise as soon as possible.
Do not allow people to become dehydrated unless clinically indicated.
## People using antiplatelet agents
Consider VTE prophylaxis for people who are having antiplatelet agents for other conditions and whose risk of VTE outweighs their risk of bleeding. Take into account the risk of bleeding and of comorbidities such as arterial thrombosis.
If the risk of VTE outweighs the risk of bleeding, consider pharmacological VTE prophylaxis based on their condition or procedure.
If the risk of bleeding outweighs the risk of VTE, consider mechanical VTE prophylaxis.
## People using anticoagulation therapy
Consider VTE prophylaxis for people at increased risk of VTE who are interrupting anticoagulant therapy.
# Interventions for people with acute coronary syndromes or acute stroke or for acutely ill patients
## Acute coronary syndromes
Be aware that people receiving anticoagulant drugs as part of their treatment for an acute coronary syndrome do not usually need VTE prophylaxis. See also the recommendation in the section on people using anticoagulation therapy.
## Acute stroke patients
Do not offer anti-embolism stockings for VTE prophylaxis to people who are admitted for acute stroke.
Consider intermittent pneumatic compression for VTE prophylaxis for people who are immobile and admitted with acute stroke. If using, start it within 3 days of acute stroke.
Explain to the person admitted with acute stroke and their family members or carers (as appropriate) that intermittent pneumatic compression:
reduces the risk of DVT and may increase their chances of survival
will not help them recover from stroke, and there may be an associated increased risk of surviving with severe disability.
When using intermittent pneumatic compression for people who are admitted with acute stroke, provide it for 30 days or until the person is mobile or discharged, whichever is sooner.
## Acutely ill medical patients
For guidance on pharmacological VTE prophylaxis for people with COVID-19 pneumonia who are being treated in a hospital or community setting, see our COVID-19 rapid guideline on managing COVID-19.
Offer pharmacological VTE prophylaxis for a minimum of 7 days to acutely ill medical patients whose risk of VTE outweighs their risk of bleeding:
Use LMWH as first-line treatment.
If LMWH is contraindicated, use fondaparinux sodium. In March 2018, the use of LMWH and fondaparinux sodium in young people under 18 was off label. See NICE's information on prescribing medicines.
# Interventions for people with renal impairment
In March 2018, the use of LMWH in young people under 18 was off label. See NICE's information on prescribing medicines.
If using pharmacological VTE prophylaxis for people with renal impairment, choose either LMWH or unfractionated heparin (UFH).
If needed, reduce the dose of LMWH and UFH for people with renal impairment. Base the decision on multidisciplinary or senior opinion, or locally agreed protocols.
# Interventions for people with cancer
In March 2018:
the use of LMWH in young people under 18 in recommendations 1.6.2 and 1.6.3 was off label
the use of aspirin in recommendation 1.6.2 was off label.
See NICE's information on prescribing medicines.
Do not offer VTE prophylaxis to people with cancer who are receiving cancer-modifying treatments such as radiotherapy, chemotherapy or immunotherapy and who are mobile, except as outlined in recommendations 1.6.2 and 1.6.3, unless they are also at increased risk of VTE because of something other than the cancer.
Consider pharmacological VTE prophylaxis for people with myeloma who are receiving chemotherapy with thalidomide, pomalidomide or lenalidomide with steroids. Choose either:
aspirin (75 mg or 150 mg) or
LMWH.
Consider pharmacological VTE prophylaxis with LMWH for people with pancreatic cancer who are receiving chemotherapy.
If giving VTE prophylaxis to people with cancer (see recommendations 1.6.2 and 1.6.3), continue for as long as they are receiving chemotherapy.
# Interventions for people having palliative care
Consider pharmacological VTE prophylaxis for people who are having palliative care. Take into account temporary increases in thrombotic risk factors, risk of bleeding, likely life expectancy and the views of the person and their family members or carers (as appropriate):
Use LMWH as first-line treatment.
If LMWH is contraindicated, use fondaparinux sodium. In March 2018, the use of LMWH and fondaparinux sodium in young people under 18 was off label. See NICE's information on prescribing medicines.
Do not offer VTE prophylaxis to people in the last days of life.
For recommendations on shared decision-making in the last days of life, see the NICE guideline on care of dying adults in the last days of life.
Review VTE prophylaxis daily for people who are having palliative care, taking into account the views of the person, their family members or carers (as appropriate) and the multidisciplinary team.
# Interventions for people admitted to critical care
For guidance on pharmacological VTE prophylaxis for people with COVID-19 pneumonia who are being treated in a hospital or community setting, see our COVID-19 rapid guideline on managing COVID-19.
Assess all people admitted to the critical care unit for risk of VTE and bleeding.
Provide LMWH to people admitted to the critical care unit if pharmacological VTE prophylaxis is not contraindicated. For people with renal impairment, see the recommendations on interventions for people with renal impairment. In March 2018, the use of LMWH in young people under 18 was off label. See NICE's information on prescribing medicines.
Consider mechanical VTE prophylaxis for people admitted to the critical care unit if pharmacological prophylaxis is contraindicated based on their condition or procedure.
If using mechanical VTE prophylaxis for people admitted to the critical care unit, start it on admission and continue until the person no longer has reduced mobility relative to their normal or anticipated mobility.
Reassess VTE and bleeding risk daily for people in critical care units.
Assess VTE and bleeding risk more than once a day in people admitted to the critical care unit if the person's condition is changing rapidly.
# Interventions for people with psychiatric illness
In March 2018:
the use of LMWH in young people under 18 in recommendations 1.9.3 and 1.9.4 was off label
the use of fondaparinux sodium in young people under 18 in recommendation 1.9.4 was off label.
See NICE's information on prescribing medicines.
Assess all acute psychiatric patients to identify their risk of VTE and bleeding:
as soon as possible after admission to hospital or by the time of the first consultant review
using a tool published by a national UK body, professional network or peer-reviewed journal.A tool commonly used to develop a treatment plan for surgical patients is the Department of Health VTE risk assessment tool. (Reproduced with the permission of the Department of Health and Social Care under the Open Government Licence.)
Reassess all people admitted to an acute psychiatric ward for risk of VTE and bleeding at the point of consultant review or if their clinical condition changes.
Consider pharmacological VTE prophylaxis with LMWH for people admitted to an acute psychiatric ward whose risk of VTE outweighs their risk of bleeding.
Consider pharmacological VTE prophylaxis with fondaparinux sodium if LMWH is contraindicated for people admitted to an acute psychiatric ward whose risk of VTE outweighs their risk of bleeding.
Continue pharmacological VTE prophylaxis for people admitted to an acute psychiatric ward until the person is no longer at increased risk of VTE.
# Interventions when using anaesthesia
Consider regional anaesthesia for individual patients, in addition to other methods of VTE prophylaxis, as it carries a lower risk of VTE than general anaesthesia. Take into account the person's preferences, their suitability for regional anaesthesia and any other planned method of VTE prophylaxis.
If regional anaesthesia is used, plan the timing of pharmacological VTE prophylaxis to minimise the risk of epidural haematoma. If antiplatelet or anticoagulant agents are being used, or their use is planned, refer to the summary of product characteristics for guidance about the safety and timing of these in relation to the use of regional anaesthesia.
Do not routinely offer pharmacological or mechanical VTE prophylaxis to people undergoing a surgical procedure with local anaesthesia by local infiltration with no limitation of mobility.
# Interventions for people having orthopaedic surgery
## Lower limb immobilisation
Consider pharmacological VTE prophylaxis with LMWH or fondaparinux sodium for people with lower limb immobilisation whose risk of VTE outweighs their risk of bleeding. Consider stopping prophylaxis if lower limb immobilisation continues beyond 42 days. In March 2018, the use of LMWH and fondaparinux sodium in young people under 18 was off label. See NICE's information on prescribing medicines.
## Fragility fractures of the pelvis, hip and proximal femur
In March 2018, the use of LMWH and fondaparinux sodium in young people under 18 in recommendations 1.11.2 and 1.11.3 was off label. See NICE's information on prescribing medicines.
Offer VTE prophylaxis for a month to people with fragility fractures of the pelvis, hip or proximal femur if the risk of VTE outweighs the risk of bleeding. Choose either:
LMWH, starting 6 to12 hours after surgery or
fondaparinux sodium, starting 6 hours after surgery, providing there is low risk of bleeding.
Consider pre‑operative VTE prophylaxis for people with fragility fractures of the pelvis, hip or proximal femur if surgery is delayed beyond the day after admission. Give the last dose no less than 12 hours before surgery for LMWH or 24 hours before surgery for fondaparinux sodium.
Consider intermittent pneumatic compression for people with fragility fractures of the pelvis, hip or proximal femur at the time of admission if pharmacological prophylaxis is contraindicated. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
## Elective hip replacement
In March 2018:
the use of LMWH and rivaroxaban in young people under 18 in recommendation 1.11.5 was off label
the use of aspirin in recommendation 1.11.5 was off label
the use of apixaban and dabigatran etexilate in young people under 18 in recommendation 1.11.6 was off label.
See NICE's information on prescribing medicines.
Offer VTE prophylaxis to people undergoing elective hip replacement surgery whose risk of VTE outweighs their risk of bleeding. Choose any one of:
LMWH for 10 days followed by aspirin (75 mg or 150 mg) for a further 28 days.
LMWH for 28 days combined with anti-embolism stockings (until discharge).
Rivaroxaban, within its marketing authorisation, is recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery. (This text is from NICE technology appraisal guidance on rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults .)
Consider one of the following if none of the options in recommendation 1.11.5 can be used:
Apixaban is recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery. (This text is from NICE technology appraisal guidance on apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults .)
Dabigatran etexilate, within its marketing authorisation, is recommended as an option for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or elective total knee replacement surgery. (This text is from NICE technology appraisal guidance on dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults .)
Consider anti-embolism stockings until discharge from hospital if pharmacological interventions are contraindicated in people undergoing elective hip replacement surgery.
## Elective knee replacement
In March 2018:
the use of LMWH and rivaroxaban in young people under 18 in recommendation 1.11.8 was off label
the use of aspirin in recommendation 1.11.8 was off label
the use of apixaban and dabigatran etexilate in young people under 18 in recommendation 1.11.9 was off label.
See NICE's information on prescribing medicines.
Offer VTE prophylaxis to people undergoing elective knee replacement surgery whose VTE risk outweighs their risk of bleeding. Choose any one of:
Aspirin (75 mg or 150 mg) for 14 days.
LMWH for 14 days combined with anti-embolism stockings until discharge.
Rivaroxaban, within its marketing authorisation, is recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery. (This text is from NICE technology appraisal guidance on rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults .)
Consider one of the following if none of the options in recommendation 1.11.8 can be used:
Apixaban is recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery. (This text is from NICE technology appraisal guidance on apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults .)
Dabigatran etexilate, within its marketing authorisation, is recommended as an option for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or elective total knee replacement surgery. (This text is from NICE technology appraisal guidance on dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults .)
Consider intermittent pneumatic compression if pharmacological prophylaxis is contraindicated in people undergoing elective knee replacement surgery. Continue until the person is mobile.
## Non-arthroplasty orthopaedic knee surgery
Be aware that VTE prophylaxis is generally not needed for people undergoing arthroscopic knee surgery where:
total anaesthesia time is less than 90 minutes and
the person is at low risk of VTE.
Consider LMWH 6 to12 hours after surgery for 14 days for people undergoing arthroscopic knee surgery if:
total anaesthesia time is more than 90 minutes or the person's risk of VTE outweighs their risk of bleeding. In March 2018, the use of LMWH in young people under 18 was off label. See NICE's information on prescribing medicines.
Consider VTE prophylaxis for people undergoing other knee surgery (for example, osteotomy or fracture surgery) whose risk of VTE outweighs their risk of bleeding.
## Foot and ankle orthopaedic surgery
Consider pharmacological VTE prophylaxis for people undergoing foot or ankle surgery:
that requires immobilisation (for example, arthrodesis or arthroplasty); consider stopping prophylaxis if immobilisation continues beyond 42 days (see the recommendation on lower limb immobilisation) or
when total anaesthesia time is more than 90 minutes or
the person's risk of VTE outweighs their risk of bleeding.
## Upper limb orthopaedic surgery
Be aware that VTE prophylaxis is generally not needed if giving local or regional anaesthetic for upper limb surgery.
Consider VTE prophylaxis for people undergoing upper limb surgery if the person's total time under general anaesthetic is over 90 minutes or where their operation is likely to make it difficult for them to mobilise.
# Interventions for people having elective spinal surgery or cranial surgery or people with spinal injury
## Elective spinal surgery
In March 2018, the use of LMWH in young people under 18 in recommendations 1.12.2, 1.12.3 and 1.12.4 was off label. See NICE's information on prescribing medicines.
Offer mechanical VTE prophylaxis on admission to people undergoing elective spinal surgery. Choose either:
anti-embolism stockings or
intermittent pneumatic compression. Continue for 30 days or until the person is mobile or discharged, whichever is sooner.
Consider adding pharmacological VTE prophylaxis with LMWH for people undergoing elective spinal surgery whose risk of VTE outweighs their risk of bleeding, taking into account individual patient and surgical factors (major or complex surgery) and according to clinical judgement.
If using LMWH for people undergoing elective spinal surgery, start giving it 24 to 48 hours postoperatively according to clinical judgement, taking into account patient characteristics and surgical procedure. Continue for 30 days or until the person is mobile or discharged, whichever is sooner.
If needed, start LMWH earlier than 24 hours after the operation for people undergoing elective spinal surgery. Base the decision on multidisciplinary or senior opinion, or a locally agreed protocol.
## Cranial surgery
In March 2018, the use of LMWH in young people under 18 in recommendations 1.12.7, 1.12.8 and 1.12.9 was off label. See NICE's information on prescribing medicines.
Consider mechanical VTE prophylaxis for people undergoing cranial surgery.
If using mechanical VTE prophylaxis for people undergoing cranial surgery, start it on admission. Choose either:
anti-embolism stockings or
intermittent pneumatic compression. Continue for 30 days or until the person is mobile or discharged, whichever is sooner.
Consider adding pre‑operative pharmacological VTE prophylaxis with LMWH. Give the last dose no less than 24 hours before surgery for people undergoing cranial surgery whose risk of VTE outweighs their risk of bleeding.
Consider adding pharmacological VTE prophylaxis with LMWH, starting 24 to 48 hours after surgery for people undergoing cranial surgery whose risk of VTE outweighs their risk of bleeding. Continue for a minimum of 7 days.
If needed, start LMWH earlier than 24 hours after the operation for people undergoing cranial surgery. Base the decision on multidisciplinary or senior opinion, or a locally agreed protocol.
Do not offer pharmacological VTE prophylaxis to people with ruptured cranial vascular malformations (for example, brain aneurysms) or people with intracranial haemorrhage (spontaneous or traumatic) until the lesion has been secured or the condition has stabilised.
## Spinal injury
Consider mechanical VTE prophylaxis on admission for people with spinal injury. Choose either:
anti-embolism stockings (only in a specialist spinal injury unit and after multidisciplinary team discussion) or
intermittent pneumatic compression.
Reassess risk of bleeding 24 hours after initial admission in people with spinal injury.
Consider adding pharmacological VTE prophylaxis with LMWH 24 hours after initial admission for people with spinal injury who are not having surgery in the next 24 to 48 hours, if the benefit of reducing the risk of VTE outweighs the risk of bleeding. In March 2018, the use of LMWH in young people under 18 was off label. See NICE's information on prescribing medicines.
Continue VTE prophylaxis in people with spinal injury for 30 days or until the person is mobile or discharged, whichever is sooner.
# Interventions for people with major trauma
Offer mechanical VTE prophylaxis with intermittent pneumatic compression on admission to people with serious or major trauma. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
Reassess risk of VTE and bleeding in people with serious or major trauma whenever their clinical condition changes and at least daily.
Consider pharmacological VTE prophylaxis for people with serious or major trauma as soon as possible after the risk assessment when the risk of VTE outweighs the risk of bleeding. Continue for a minimum of 7 days.
# Interventions for people having abdominal, thoracic or head and neck surgery
## Abdominal surgery
Offer VTE prophylaxis to people undergoing abdominal (gastrointestinal, gynaecological, urological) surgery who are at increased risk of VTE. For people undergoing bariatric surgery, follow the recommendations in the section on bariatric surgery.
Start mechanical VTE prophylaxis on admission for people undergoing abdominal surgery. Choose either:
anti-embolism stockings or
intermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
Add pharmacological VTE prophylaxis for a minimum of 7 days for people undergoing abdominal surgery whose risk of VTE outweighs their risk of bleeding, taking into account individual patient factors and according to clinical judgement. Choose either:
LMWH or
fondaparinux sodium. In March 2018, the use of LMWH and fondaparinux sodium in young people under 18 was off label. See NICE's information on prescribing medicines.
Consider extending pharmacological VTE prophylaxis to 28 days postoperatively for people who have had major cancer surgery in the abdomen.
## Bariatric surgery
Offer VTE prophylaxis to people undergoing bariatric surgery.
Start mechanical VTE prophylaxis on admission for people undergoing bariatric surgery. Choose either:
anti-embolism stockings or
intermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
Add pharmacological VTE prophylaxis for people undergoing bariatric surgery for a minimum of 7 days for people whose risk of VTE outweighs their risk of bleeding. Choose either:
LMWH or
fondaparinux sodium. In March 2018, the use of LMWH and fondaparinux sodium in young people under 18 was off label. See NICE's information on prescribing medicines.
## Thoracic surgery
Consider VTE prophylaxis for people undergoing thoracic surgery who are at increased risk of VTE.
Start mechanical VTE prophylaxis on admission for people undergoing thoracic surgery. Choose either:
anti-embolism stockings or
intermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
Consider adding pharmacological VTE prophylaxis for people undergoing thoracic surgery for a minimum of 7 days to people whose risk of VTE outweighs their risk of bleeding:
Use LMWH as first-line treatment.
If LMWH is contraindicated, use fondaparinux sodium. In March 2018, the use of LMWH and fondaparinux sodium in young people under 18 was off label. See NICE's information on prescribing medicines.
## Head and neck surgery
Consider pharmacological VTE prophylaxis with LMWH for a minimum of 7 days for people undergoing oral or maxillofacial surgery whose risk of VTE outweighs their risk of bleeding. In March 2018, the use of LMWH in young people under 18 was off label. See NICE's information on prescribing medicines.
Consider mechanical VTE prophylaxis on admission for people undergoing oral or maxillofacial surgery who are at increased risk of VTE and high risk of bleeding. Choose either:
anti-embolism stockings or
intermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
Consider pharmacological VTE prophylaxis with LMWH for a minimum of 7 days for people undergoing ears, nose or throat (ENT) surgery whose risk of VTE outweighs their risk of bleeding. In March 2018, the use of LMWH in young people under 18 was off label. See NICE's information on prescribing medicines.
Consider mechanical VTE prophylaxis on admission for people undergoing ENT surgery who are at increased risk of VTE and high risk of bleeding. Choose either:
anti-embolism stockings or
intermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
# Interventions for people having cardiac or vascular surgery
## Cardiac surgery
Consider mechanical VTE prophylaxis on admission for people who are undergoing cardiac surgery who are at increased risk of VTE. Choose either:
anti-embolism stockings or
intermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
Consider adding pharmacological VTE prophylaxis for a minimum of 7 days for people who are undergoing cardiac surgery and are not having other anticoagulation therapy:
Use LMWH as first-line treatment.
If LMWH is contraindicated, use fondaparinux sodium. In March 2018, the use of LMWH and fondaparinux sodium in young people under 18 was off label. See NICE's information on prescribing medicines.
## Vascular surgery
Consider pharmacological VTE prophylaxis with LMWH for a minimum of 7 days for people who are undergoing open vascular surgery or major endovascular procedures, including endovascular aneurysm repair whose risk of VTE outweighs their risk of bleeding. In March 2018, the use of LMWH in young people under 18 was off label. See NICE's information on prescribing medicines.
Consider mechanical VTE prophylaxis on admission for people who are undergoing open vascular surgery or major endovascular procedures, including endovascular aneurysm repair, if pharmacological prophylaxis is contraindicated. Choose either:
anti-embolism stockings or
intermittent pneumatic compression.Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
Consider pharmacological VTE prophylaxis with LMWH for a minimum of 7 days for people who are undergoing lower limb amputation whose risk of VTE outweighs their risk of bleeding. In March 2018, the use of LMWH in young people under 18 was off label. See NICE's information on prescribing medicines.
Consider mechanical VTE prophylaxis with intermittent pneumatic compression on the contralateral leg, on admission, for people who are undergoing lower limb amputation and if pharmacological prophylaxis is contraindicated.
For people undergoing lower limb amputation, continue mechanical VTE prophylaxis until the person no longer has significantly reduced mobility relative to their anticipated mobility.
Be aware that VTE prophylaxis is generally not needed for people undergoing varicose vein surgery where:
total anaesthesia time is less than 90 minutes and
the person is at low risk of VTE.
Consider pharmacological VTE prophylaxis with LMWH, starting 6 to 12 hours after surgery and continuing for 7 days for people undergoing varicose vein surgery if:
total anaesthesia time is more than 90 minutes or
the person's risk of VTE outweighs their risk of bleeding. In March 2018, the use of LMWH in young people under 18 was off label. See NICE's information on prescribing medicines.
Consider mechanical VTE prophylaxis with anti-embolism stockings, on admission, for people undergoing varicose vein surgery:
who are at increased risk of VTE and
if pharmacological prophylaxis is contraindicated.
If using anti-embolism stockings for people undergoing varicose vein surgery, continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.
# Interventions for pregnant women and women who gave birth or had a miscarriage or termination of pregnancy in the past 6 weeks
In March 2018, the use of LMWH in young people under 18 in recommendations 1.16.1, 1.16.4, 1.16.5 and 1.16.6 was off label. See NICE's information on prescribing medicines.
Consider LMWH for all women who are admitted to hospital or a midwife-led unit if they are pregnant or gave birth, had a miscarriage or had a termination of pregnancy in the past 6 weeks, and whose risk of VTE outweighs their risk of bleeding.
Do not offer VTE prophylaxis to women admitted to hospital or a midwife-led unit who are in active labour.
Stop pharmacological VTE prophylaxis when women are in labour.
If using LMWH in pregnant women, start it as soon as possible and within 14 hours of the risk assessment being completed and continue until the woman is no longer at increased risk of VTE or until discharge from hospital or the midwife-led unit.
If using LMWH in women who gave birth or had a miscarriage or termination of pregnancy, start 4 to 8 hours after the event unless contraindicated and continue for a minimum of 7 days.
Consider combined prophylaxis with LMWH plus mechanical prophylaxis for pregnant women or women who gave birth or had a miscarriage or termination of pregnancy in the past 6 weeks and who are likely to be immobilised, or have significantly reduced mobility relative to their normal or anticipated mobility for 3 or more days after surgery, including caesarean section:
Use intermittent pneumatic compression as first-line treatment.
If intermittent pneumatic compression is contraindicated, use anti-embolism stockings.Continue until the woman no longer has significantly reduced mobility relative to her normal or anticipated mobility or until discharge from hospital.
# Terms used in this guideline
## Admission
Admission in the context of this guideline refers to admission as an inpatient, where a bed is provided for 1 or more nights, or admission as a day patient, where a bed is provided for a procedure including surgery or chemotherapy but not for an overnight stay.
## Discharge
Discharge in the context of this guideline refers to discharge from hospital as an inpatient or after a day procedure.
## Intermittent pneumatic compression
A method of prophylaxis that includes an air pump and inflatable garments in a system designed to improve venous circulation in the lower limbs of people at risk of DVT or pulmonary embolism. The inflation–deflation cycle of intermittent pneumatic compression therapy simulates the thigh, calf and foot's normal ambulatory pump action increasing both the volume and rate of blood flow, eliminating venous stasis and replicating the effects of the natural muscle pump. Intermittent pneumatic compression devices can be thigh- or knee-length sleeves that are wrapped around the leg, or a garment that can be wrapped around or worn on the foot that is designed to mimic the actions of walking.
## Lower limb immobilisation
Any clinical decision taken to manage the affected limb in a way that would prevent normal weight-bearing status or use of that limb, or both.
## Renal impairment
People with an estimated glomerular filtration rate (eGFR) of less than 30 ml/min/1.73 m2. For more detailed information on renal impairment, see the NICE guideline on chronic kidney disease in adults.
## Significantly reduced mobility
People who are bed bound, unable to walk unaided or likely to spend a substantial proportion of their day in bed or in a chair.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Risk assessment
What is the accuracy of individual risk assessment tools in predicting the risk of venous thromboembolism (VTE) and risk of bleeding in people admitted to hospital?
## Why this is important
Risk assessment is a mandatory for all people admitted or having day procedures in hospital. Since 2010, the National VTE Risk Assessment Tool has been widely used in the NHS to assess a person's risk of VTE. This tool has not been validated or tested against other tools to evaluate its diagnostic accuracy or effectiveness at correctly identifying people at risk of VTE. There is concern that the tool may not accurately identify those who are most likely to get VTE.
According to national figures, over 70% of medical patients in the UK have prophylaxis when the national tool has been used, with some trusts offering prophylaxis to over 90% of medical patients. Around 40% of medical patients have prophylaxis in largely US‑based populations when other tools are used (although this may partially relate to different indications for hospital admission). It is not known if this means that the national tool identifies too many people or the other tools do not identify enough. The potential impact of giving unnecessary prophylaxis is that people may be at increased risk of bleeding and discomfort through repeated injections. There is also the potential for reducing the cost of thromboprophylaxis by better defining 'at risk' populations, so that the number of those given thromboprophylaxis is reduced.
# Dose strategies for people who are obese
What is the clinical and cost effectiveness of weight-based dose-adjustment strategies of low-molecular-weight heparin (LMWH) compared with fixed-dose strategies of LMWH for preventing VTE in people who are very obese (BMI over 35) who are admitted to hospital or having day procedures (including surgery and chemotherapy)?
## Why this is important
Obesity is on the rise in England. The prevalence of obesity increased by 11% between 1993 and 2014 (15% in 1993 and 26% in 2014), which has resulted in more obese people being admitted to hospital. Obesity may as much as double a person's risk of developing hospital-acquired VTE, therefore most obese people will need prophylaxis. There is much uncertainty about what dose to use and the clinical and cost effectiveness of using weight-based dose-adjustment versus fixed-dose strategies. In current practice, a higher than usual dose is given but this may not be necessary, especially if the person has obesity-related liver disease. Several studies have reported effectiveness in terms of biological measures rather than clinical outcomes such as deep vein thrombosis (DVT) and bleeding events. It is important that there is a clearer understanding of the effects that different dose strategies can have in terms of clinical outcomes. This is because they can directly influence the quality of life of obese people admitted to hospital and help inform clinical decisions on patient care.
# Direct oral anticoagulants for people with lower limb immobilisation
What is the clinical and cost effectiveness of direct oral anticoagulants for preventing VTE in people with lower limb immobilisation?
## Why this is important
The Computerized registry of patients with venous thromboembolism (RIETE) study, a multicentre prospective cohort study of 30,886 patients with acute VTE, estimated that 5.7% of VTE events were associated with lower limb immobilisation for non-major orthopaedic surgery. Estimates of DVT risk in people with lower limb immobilisation, based on meta-analyses of trials comparing chemothromboprophylaxis with placebo, range between approximately 4% and 40%. Given that lower limb immobilisation following trauma or non-major orthopaedic surgery is so common, the consequent burden of disease from VTE from this cause in the whole population is very considerable. For example, the annual incidence of ankle fracture is 187 per 100,000, translating to over 120,000 incident fractures per year in the UK. If 10% of these fractures are complicated by VTE, then we might expect approximately 12,000 events per year only related to immobilisation following ankle trauma.
Despite this burden of ill-health, no randomised studies comparing modern anticoagulants that are available in oral preparations (perhaps more suitable for outpatient treatments) with established treatments such as LMWH or fondaparinux were identified in the evidence review. The committee were unable to make a recommendation to consider oral anticoagulants for this patient group given this lack of evidence.
# Aspirin prophylaxis for people with fragility fractures of the pelvis, hip or proximal femur
What is the clinical and cost effectiveness of aspirin alone versus other pharmacological and/or mechanical prophylaxis strategies (alone or in combination) for people with fragility fractures of the pelvis, hip or proximal femur?
## Why this is important
Fragility fractures are the greatest burden of musculoskeletal disease in hospitals in the UK. There are approximately 70,000 fragility hip fractures per year in England alone leading to 1.5 million bed days being used each year, which equates with the continuous occupation of over 4,000 NHS beds.
Current evidence supports a recommendation for prophylaxis with LMWH or fondaparinux. Both involve a subcutaneous injection for 28 days requiring either self-injection at home or a community nurse attending to deliver the injection. Patient adherence to treatment may be improved with an oral rather than injectable treatment.
A large but controversially reported trial suggests that aspirin may be at least as effective as currently recommended treatments. However, because of methodological and reporting limitations, the evidence for the effectiveness of aspirin alone is not clear. There is potentially a large cost saving if aspirin is clinically effective because it is very inexpensive.
# Duration of prophylaxis for elective total hip replacement surgery
What is the clinical and cost effectiveness of standard versus extended duration pharmacological prophylaxis for preventing VTE in people undergoing elective total hip replacement surgery?
## Why this is important
In 2015, there were 84,462 hip replacements in England, Wales and Northern Ireland. The current recommended duration of prophylaxis is 28 days in the elective total hip replacement population. This extended duration of prophylaxis is based on few, small and older trials. The quality of the evidence supporting extended duration prophylaxis is very low. Modern pharmaceutical trials of newer interventions use extended duration prophylaxis based on these historical data, with the added incentive of more expensive prophylaxis strategies. There is a large potential cost saving if a shorter duration of prophylaxis is as clinically effective, given the considerable cost of prophylaxis and the number of people for whom it is prescribed.# Putting this guideline into practice
We have produced NICE tools and resources to help you put this guideline into practice.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect them. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
Hospital-acquired venous thromboembolism (VTE), also known as hospital-acquired or hospital-associated thrombosis (HAT), covers all VTE that occurs in hospital and within 90 days after a hospital admission. It is a common and potentially preventable problem. VTE most frequently occurs in the deep veins of the legs or pelvis (a deep vein thrombosis ). If it dislodges and travels to the lungs, it is called a pulmonary embolism, which in some cases can be fatal.
Hospital-acquired VTE accounts for thousands of deaths annually in the NHS, and fatal pulmonary embolism remains a common cause of in‑hospital mortality. HAT accounts for 50% to 60% of all VTE seen. In 2013 to 2014, there were around 24,700 admissions for pulmonary embolism and 19,400 for DVT in England. In 2013 in England and Wales, there were 2,191 deaths recorded as due to pulmonary embolism and 2,816 due to DVT. Treatment of non-fatal symptomatic VTE and related long-term morbidities is associated with a considerable cost to the health service.
People admitted to hospital or mental health units have varying risk factors for VTE. The spectrum of VTE risk is broad, and understanding the scale of the problem has led to a paradigm shift in preventing and managing VTE in the NHS. In particular, patients now undergo VTE risk assessment as a routine event in all NHS care pathways. By July 2013, 96% of adult admissions to NHS-funded acute care hospitals were risk assessed for VTE compared with less than 50% of patients in July 2010.
VTE prophylaxis has been shown to reduce the incidence of DVT. It includes mechanical methods (such as anti-embolism stockings and intermittent pneumatic compression devices), and pharmacological treatments (such as heparin and other anticoagulant drugs).
This guideline is about reducing the risk of VTE in over 16s admitted to or treated as day procedures in hospitals. It provides recommendations on the most clinically and cost-effective measures to reduce the risk of VTE, while considering the potential risks of the various VTE prophylaxis options and patient preferences. It highlights the importance of risk assessment for VTE and for bleeding for all people being admitted and of clinical judgement in deciding on a prophylaxis strategy for each person at risk.
The 2018 update takes into account newer evidence and newer therapies and has been made more relevant for specific groups such as surgical sub-specialities, people with mental health conditions and pregnant women.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Risk assessment\n\n## All patients\n\nAssess all patients to identify the risk of venous thromboembolism (VTE) and bleeding (see the recommendation for all medical patients, for all surgical patients, for all pregnant women and all women who gave birth or had a miscarriage or termination of pregnancy in the past 6 weeks, for all people admitted to the critical care unit and for all acute psychiatric patients). \n\n## People admitted to hospital\n\nAssess all medical patients to identify the risk of VTE and bleeding:\n\nas soon as possible after admission to hospital or by the time of the first consultant review\n\nusing a tool published by a national UK body, professional network or peer-reviewed journal.A tool commonly used to develop a treatment plan for medical patients is the Department of Health VTE risk assessment tool. (Reproduced with the permission of the Department of Health and Social Care under the Open Government Licence.) [2018, amended 2021]\n\nBalance the person's individual risk of VTE against their risk of bleeding when deciding whether to offer pharmacological thromboprophylaxis to medical patients. \n\nIf using pharmacological VTE prophylaxis for medical patients, start it as soon as possible and within 14\xa0hours of admission, unless otherwise stated in the population-specific recommendations (see the sections on interventions for people with acute coronary syndromes or acute stroke or for acutely ill patients, interventions for people with renal impairment, interventions for people with cancer, interventions for people having palliative care, interventions for people admitted to critical care, and interventions for people with psychiatric illness). \n\nAssess all surgical and trauma patients to identify the risk of VTE and bleeding:\n\nas soon as possible after admission to hospital or by the time of the first consultant review\n\nusing a tool published by a national UK body, professional network or peer-reviewed journal.A tool commonly used to develop a treatment plan for surgical patients is the Department of Health VTE risk assessment tool. (Reproduced with the permission of the Department of Health and Social Care under the Open Government Licence.) [2018, amended 2021]\n\nBalance the person's individual risk of VTE against their risk of bleeding when deciding whether to offer pharmacological thromboprophylaxis to surgical and trauma patients. \n\nIf using pharmacological VTE prophylaxis for surgical and trauma patients, start it as soon as possible and within 14\xa0hours of admission, unless otherwise stated in the population-specific recommendations (see the sections on interventions when using anaesthesia, interventions for people having orthopaedic surgery, interventions for people having elective spinal surgery or cranial surgery people with spinal injury, interventions for people with major trauma, interventions for people having abdominal, thoracic or head and neck surgery, and interventions for people having cardiac or vascular surgery). \n\nReassess all medical, surgical and trauma patients for risk of VTE and bleeding at the point of consultant review or if their clinical condition changes. \n\n## Pregnant women and women who gave birth or had a miscarriage or termination of pregnancy in the past 6\xa0weeks\n\nAssess all women on admission to hospital or a midwife-led unit if they are pregnant or gave birth, had a miscarriage or had a termination of pregnancy in the past 6\xa0weeks, to identify their risk of VTE and bleeding. Use a tool published by a national UK body, professional network or peer-reviewed journal. The most commonly used tool is the Royal College of Obstetricians and Gynaecologists risk assessment tool. (Reproduced from: Royal College of Obstetricians and Gynaecologists. Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green-top Guideline No. 37a. London: RCOG, 2015, with the permission of the Royal College of Obstetricians and Gynaecologists.) \n\nReassess risk of VTE and bleeding, and assess the need for thromboprophylaxis for all women:\n\nwithin 6\xa0hours of giving birth, having a miscarriage or having a termination of pregnancy or\n\nif their clinical condition changes and they:\n\n\n\nare pregnant or\n\ngave birth, had a miscarriage or had a termination of pregnancy within the past 6\xa0weeks. \n\n\n\n# Giving information and planning for discharge\n\nOn admission ensure that people understand the reason for having a risk assessment for VTE and bleeding. \n\nFor people admitted to hospital who are at increased risk of VTE, give them and their family members or carers (as appropriate) verbal and written information on the following before offering VTE prophylaxis:\n\nthe person's risks and possible consequences of VTE\n\nthe importance of VTE prophylaxis and its possible side effects – for example, pharmacological prophylaxis can increase bleeding risk\n\nthe correct use of VTE prophylaxis – for example, anti-embolism stockings, intermittent pneumatic compression\n\nhow people can reduce their risk of VTE (such as keeping well hydrated and, if possible, exercising and becoming more mobile). \n\nBe aware that heparins are of animal origin and this may be of concern to some people (See Religion or belief: a practical guide for the NHS). Discuss the alternatives with people who have concerns about using animal products, after discussing their suitability, advantages and disadvantages with the person. \n\nAs part of the discharge plan, give patients and their family members or carers (as appropriate) verbal and written information on:\n\nthe signs and symptoms of deep vein thrombosis (DVT) and pulmonary embolism\n\nhow people can reduce their risk of VTE (such as keeping well hydrated and, if possible, exercising and becoming more mobile)\n\nthe importance of seeking help if DVT, pulmonary embolism or other adverse events are suspected. \n\nGive people discharged with VTE prophylaxis and their family members or carers (as appropriate) verbal and written information on:\n\nthe importance of using VTE prophylaxis correctly (including the correct administration and disposal of pharmacological prophylaxis)\n\nthe importance of continuing treatment for the recommended duration\n\nthe signs and symptoms of adverse events related to VTE prophylaxis\n\nthe importance of seeking help and who to contact if people have problems using VTE prophylaxis. \n\nEnsure that people who are discharged with anti-embolism stockings:\n\nunderstand the benefits of wearing them\n\nunderstand the importance of wearing them correctly\n\nunderstand the need to remove them daily for hygiene purposes\n\nare able to remove and replace them, or have someone available who will be able to do this for them\n\nknow what to look for if there is a problem – for example, skin marking, blistering or discolouration, particularly over the heels and bony prominences\n\nknow who to contact if there is a problem\n\nknow when to stop wearing them. \n\nEnsure that people who are discharged with pharmacological and/or mechanical VTE prophylaxis are able to use it correctly, or have arrangements made for someone to be available who will be able to help them. \n\nNotify the person's GP if the person has been discharged with pharmacological and/or mechanical VTE prophylaxis to be used at home. \n\n# All patients\n\n## Mechanical prophylaxis\n\nDo not offer anti-embolism stockings to people who have:\n\nsuspected or proven peripheral arterial disease\n\nperipheral arterial bypass grafting\n\nperipheral neuropathy or other causes of sensory impairment\n\nany local conditions in which anti-embolism stockings may cause damage – for example, fragile 'tissue paper' skin, dermatitis, gangrene or recent skin graft\n\nknown allergy to material of manufacture\n\nsevere leg oedema\n\nmajor limb deformity or unusual leg size or shape preventing correct fit.Use caution and clinical judgement when applying anti-embolism stockings over venous ulcers or wounds. [2010, amended 2018]\n\nEnsure that people who need anti-embolism stockings have their legs measured and that they are provided with the correct size of stocking. Anti-embolism stockings should be fitted and patients shown how to use them by staff trained in their use. \n\nEnsure that people who develop oedema or postoperative swelling have their legs re‑measured and anti-embolism stockings refitted. \n\nIf arterial disease is suspected, seek expert opinion before fitting anti-embolism stockings. \n\nUse anti-embolism stockings that provide graduated compression and produce a calf pressure of 14 \xa0mmHg to 15\xa0mmHg. (This relates to a pressure of 14 \xa0mmHg to18\xa0mmHg at the ankle and is in line with the British Standard Institution's BS 661210:2018 Specification for graduated compression hosiery, anti-embolism hosiery and graduated support hosiery.) \n\nEncourage people to wear their anti-embolism stockings day and night until they no longer have significantly reduced mobility. \n\nRemove anti-embolism stockings daily for hygiene purposes and to inspect skin condition. In people with a significant reduction in mobility, poor skin integrity or any sensory loss, inspect the skin 2\xa0or 3\xa0times a day, particularly over the heels and bony prominences. \n\nMonitor the use of anti-embolism stockings and offer assistance if they are not being worn correctly. \n\nStop the use of anti-embolism stockings if there is marking, blistering or discolouration of the skin, particularly over the heels and bony prominences, or if the person experiences pain or discomfort. If suitable, offer intermittent pneumatic compression as an alternative. [2010, amended 2018]\n\nDo not offer intermittent pneumatic compression to people with a known allergy to the material of manufacture. [2010, amended 2018]\n\nAdvise the person to wear their device for as much time as possible. [2010, amended 2018]\n\n## Pharmacological prophylaxis\n\nFor pharmacological VTE prophylaxis in people under\xa018, follow the recommendations on apixaban, aspirin, dabigatran etexilate, fondaparinux sodium, low-molecular-weight heparin (LMWH) and rivaroxaban in this guideline. In March\xa02018, the use of these drugs in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\n## All surgery\n\nAdvise people to consider stopping oestrogen-containing oral contraceptives or hormone replacement therapy 4\xa0weeks before elective surgery. If stopped, provide advice on alternative contraceptive methods. \n\n## Nursing care: early mobilisation and hydration\n\nEncourage people to mobilise as soon as possible. \n\nDo not allow people to become dehydrated unless clinically indicated. \n\n## People using antiplatelet agents\n\nConsider VTE prophylaxis for people who are having antiplatelet agents for other conditions and whose risk of VTE outweighs their risk of bleeding. Take into account the risk of bleeding and of comorbidities such as arterial thrombosis.\n\nIf the risk of VTE outweighs the risk of bleeding, consider pharmacological VTE prophylaxis based on their condition or procedure.\n\nIf the risk of bleeding outweighs the risk of VTE, consider mechanical VTE prophylaxis. \n\n## People using anticoagulation therapy\n\nConsider VTE prophylaxis for people at increased risk of VTE who are interrupting anticoagulant therapy. \n\n# Interventions for people with acute coronary syndromes or acute stroke or for acutely ill patients\n\n## Acute coronary syndromes\n\nBe aware that people receiving anticoagulant drugs as part of their treatment for an acute coronary syndrome do not usually need VTE prophylaxis. See also the recommendation in the section on people using anticoagulation therapy. \n\n## Acute stroke patients\n\nDo not offer anti-embolism stockings for VTE prophylaxis to people who are admitted for acute stroke. [2010, amended 2018]\n\nConsider intermittent pneumatic compression for VTE prophylaxis for people who are immobile and admitted with acute stroke. If using, start it within 3\xa0days of acute stroke. \n\nExplain to the person admitted with acute stroke and their family members or carers (as appropriate) that intermittent pneumatic compression:\n\nreduces the risk of DVT and may increase their chances of survival\n\nwill not help them recover from stroke, and there may be an associated increased risk of surviving with severe disability. \n\nWhen using intermittent pneumatic compression for people who are admitted with acute stroke, provide it for 30\xa0days or until the person is mobile or discharged, whichever is sooner. \n\n## Acutely ill medical patients\n\nFor guidance on pharmacological VTE prophylaxis for people with COVID-19 pneumonia who are being treated in a hospital or community setting, see our\xa0COVID-19 rapid guideline on managing COVID-19.\n\nOffer pharmacological VTE prophylaxis for a minimum of 7\xa0days to acutely ill medical patients whose risk of VTE outweighs their risk of bleeding:\n\nUse LMWH as first-line treatment.\n\nIf LMWH is contraindicated, use fondaparinux sodium. In March\xa02018, the use of LMWH and fondaparinux sodium in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\n# Interventions for people with renal impairment\n\nIn March\xa02018, the use of LMWH in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nIf using pharmacological VTE prophylaxis for people with renal impairment, choose either LMWH or unfractionated heparin (UFH). \n\nIf needed, reduce the dose of LMWH and UFH for people with renal impairment. Base the decision on multidisciplinary or senior opinion, or locally agreed protocols. \n\n# Interventions for people with cancer\n\nIn March\xa02018:\n\nthe use of LMWH in young people under\xa018 in recommendations 1.6.2 and 1.6.3 was off label\n\nthe use of aspirin in recommendation 1.6.2 was off label.\n\nSee NICE's information on prescribing medicines.\n\nDo not offer VTE prophylaxis to people with cancer who are receiving cancer-modifying treatments such as radiotherapy, chemotherapy or immunotherapy and who are mobile, except as outlined in recommendations 1.6.2 and\xa01.6.3, unless they are also at increased risk of VTE because of something other than the cancer. \n\nConsider pharmacological VTE prophylaxis for people with myeloma who are receiving chemotherapy with thalidomide, pomalidomide or lenalidomide with steroids. Choose either:\n\naspirin (75 mg\xa0or 150\xa0mg) or\n\nLMWH. \n\nConsider pharmacological VTE prophylaxis with LMWH for people with pancreatic cancer who are receiving chemotherapy. \n\nIf giving VTE prophylaxis to people with cancer (see recommendations 1.6.2 and\xa01.6.3), continue for as long as they are receiving chemotherapy. \n\n# Interventions for people having palliative care\n\nConsider pharmacological VTE prophylaxis for people who are having palliative care. Take into account temporary increases in thrombotic risk factors, risk of bleeding, likely life expectancy and the views of the person and their family members or carers (as appropriate):\n\nUse LMWH as first-line treatment.\n\nIf LMWH is contraindicated, use fondaparinux sodium. In March\xa02018, the use of LMWH and fondaparinux sodium in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nDo not offer VTE prophylaxis to people in the last days of life. \n\nFor recommendations on shared decision-making in the last days of life, see the NICE guideline on care of dying adults in the last days of life. \n\nReview VTE prophylaxis daily for people who are having palliative care, taking into account the views of the person, their family members or carers (as appropriate) and the multidisciplinary team. \n\n# Interventions for people admitted to critical care\n\nFor guidance on pharmacological VTE prophylaxis for people with COVID-19 pneumonia who are being treated in a hospital or community setting, see our\xa0COVID-19 rapid guideline on managing COVID-19.\n\nAssess all people admitted to the critical care unit for risk of VTE and bleeding. \n\nProvide LMWH to people admitted to the critical care unit if pharmacological VTE prophylaxis is not contraindicated. For people with renal impairment, see the recommendations on interventions for people with renal impairment. In March\xa02018, the use of LMWH in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nConsider mechanical VTE prophylaxis for people admitted to the critical care unit if pharmacological prophylaxis is contraindicated based on their condition or procedure. \n\nIf using mechanical VTE prophylaxis for people admitted to the critical care unit, start it on admission and continue until the person no longer has reduced mobility relative to their normal or anticipated mobility. \n\nReassess VTE and bleeding risk daily for people in critical care units. \n\nAssess VTE and bleeding risk more than once a day in people admitted to the critical care unit if the person's condition is changing rapidly. \n\n# Interventions for people with psychiatric illness\n\nIn March\xa02018:\n\nthe use of LMWH in young people under\xa018 in recommendations 1.9.3 and 1.9.4 was off label\n\nthe use of fondaparinux sodium in young people under\xa018 in recommendation 1.9.4 was off label.\n\nSee NICE's information on prescribing medicines.\n\nAssess all acute psychiatric patients to identify their risk of VTE and bleeding:\n\nas soon as possible after admission to hospital or by the time of the first consultant review\n\nusing a tool published by a national UK body, professional network or peer-reviewed journal.A tool commonly used to develop a treatment plan for surgical patients is the Department of Health VTE risk assessment tool. (Reproduced with the permission of the Department of Health and Social Care under the Open Government Licence.) [2018, amended 2021]\n\nReassess all people admitted to an acute psychiatric ward for risk of VTE and bleeding at the point of consultant review or if their clinical condition changes. \n\nConsider pharmacological VTE prophylaxis with LMWH for people admitted to an acute psychiatric ward whose risk of VTE outweighs their risk of bleeding. \n\nConsider pharmacological VTE prophylaxis with fondaparinux sodium if LMWH is contraindicated for people admitted to an acute psychiatric ward whose risk of VTE outweighs their risk of bleeding. \n\nContinue pharmacological VTE prophylaxis for people admitted to an acute psychiatric ward until the person is no longer at increased risk of VTE. \n\n# Interventions when using anaesthesia\n\nConsider regional anaesthesia for individual patients, in addition to other methods of VTE prophylaxis, as it carries a lower risk of VTE than general anaesthesia. Take into account the person's preferences, their suitability for regional anaesthesia and any other planned method of VTE prophylaxis. \n\nIf regional anaesthesia is used, plan the timing of pharmacological VTE prophylaxis to minimise the risk of epidural haematoma. If antiplatelet or anticoagulant agents are being used, or their use is planned, refer to the summary of product characteristics for guidance about the safety and timing of these in relation to the use of regional anaesthesia. \n\nDo not routinely offer pharmacological or mechanical VTE prophylaxis to people undergoing a surgical procedure with local anaesthesia by local infiltration with no limitation of mobility. \n\n# Interventions for people having orthopaedic surgery\n\n## Lower limb immobilisation\n\nConsider pharmacological VTE prophylaxis with LMWH or fondaparinux sodium for people with lower limb immobilisation whose risk of VTE outweighs their risk of bleeding. Consider stopping prophylaxis if lower limb immobilisation continues beyond 42\xa0days. In March\xa02018, the use of LMWH and fondaparinux sodium in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\n## Fragility fractures of the pelvis, hip and proximal femur\n\nIn March\xa02018, the use of LMWH and fondaparinux sodium in young people under\xa018 in recommendations 1.11.2 and 1.11.3 was off label. See NICE's information on prescribing medicines.\n\nOffer VTE prophylaxis for a month to people with fragility fractures of the pelvis, hip or proximal femur if the risk of VTE outweighs the risk of bleeding. Choose either:\n\nLMWH, starting 6 to12\xa0hours after surgery or\n\nfondaparinux sodium, starting 6\xa0hours after surgery, providing there is low risk of bleeding. \n\nConsider pre‑operative VTE prophylaxis for people with fragility fractures of the pelvis, hip or proximal femur if surgery is delayed beyond the day after admission. Give the last dose no less than 12\xa0hours before surgery for LMWH or 24\xa0hours before surgery for fondaparinux sodium. \n\nConsider intermittent pneumatic compression for people with fragility fractures of the pelvis, hip or proximal femur at the time of admission if pharmacological prophylaxis is contraindicated. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\n## Elective hip replacement\n\nIn March\xa02018:\n\nthe use of LMWH and rivaroxaban in young people under\xa018 in recommendation 1.11.5 was off label\n\nthe use of aspirin in recommendation 1.11.5 was off label\n\nthe use of apixaban and dabigatran etexilate in young people under\xa018 in recommendation 1.11.6 was off label.\n\nSee NICE's information on prescribing medicines.\n\nOffer VTE prophylaxis to people undergoing elective hip replacement surgery whose risk of VTE outweighs their risk of bleeding. Choose any one of:\n\nLMWH for 10\xa0days followed by aspirin (75 mg\xa0or 150\xa0mg) for a further 28\xa0days.\n\nLMWH for 28\xa0days combined with anti-embolism stockings (until discharge).\n\nRivaroxaban, within its marketing authorisation, is recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery. (This text is from NICE technology appraisal guidance on rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults [TA170 2009].) \n\nConsider one of the following if none of the options in recommendation 1.11.5 can be used:\n\nApixaban is recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery. (This text is from NICE technology appraisal guidance on apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults [TA245 2012].)\n\nDabigatran etexilate, within its marketing authorisation, is recommended as an option for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or elective total knee replacement surgery. (This text is from NICE technology appraisal guidance on dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults [TA157 2008].) \n\nConsider anti-embolism stockings until discharge from hospital if pharmacological interventions are contraindicated in people undergoing elective hip replacement surgery. \n\n## Elective knee replacement\n\nIn March\xa02018:\n\nthe use of LMWH and rivaroxaban in young people under\xa018 in recommendation 1.11.8 was off label\n\nthe use of aspirin in recommendation 1.11.8 was off label\n\nthe use of apixaban and dabigatran etexilate in young people under\xa018 in recommendation 1.11.9 was off label.\n\nSee NICE's information on prescribing medicines.\n\nOffer VTE prophylaxis to people undergoing elective knee replacement surgery whose VTE risk outweighs their risk of bleeding. Choose any one of:\n\nAspirin (75 mg\xa0or 150\xa0mg) for 14\xa0days.\n\nLMWH for 14\xa0days combined with anti-embolism stockings until discharge.\n\nRivaroxaban, within its marketing authorisation, is recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery. (This text is from NICE technology appraisal guidance on rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults [TA170 2009].) \n\nConsider one of the following if none of the options in recommendation 1.11.8 can be used:\n\nApixaban is recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery. (This text is from NICE technology appraisal guidance on apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults [TA245 2012].)\n\nDabigatran etexilate, within its marketing authorisation, is recommended as an option for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or elective total knee replacement surgery. (This text is from NICE technology appraisal guidance on dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults [TA157 2008].) \n\nConsider intermittent pneumatic compression if pharmacological prophylaxis is contraindicated in people undergoing elective knee replacement surgery. Continue until the person is mobile. \n\n## Non-arthroplasty orthopaedic knee surgery\n\nBe aware that VTE prophylaxis is generally not needed for people undergoing arthroscopic knee surgery where:\n\ntotal anaesthesia time is less than 90\xa0minutes and\n\nthe person is at low risk of VTE. \n\nConsider LMWH 6 to12\xa0hours after surgery for 14\xa0days for people undergoing arthroscopic knee surgery if:\n\ntotal anaesthesia time is more than 90\xa0minutes or the person's risk of VTE outweighs their risk of bleeding. In March\xa02018, the use of LMWH in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nConsider VTE prophylaxis for people undergoing other knee surgery (for example, osteotomy or fracture surgery) whose risk of VTE outweighs their risk of bleeding. \n\n## Foot and ankle orthopaedic surgery\n\nConsider pharmacological VTE prophylaxis for people undergoing foot or ankle surgery:\n\nthat requires immobilisation (for example, arthrodesis or arthroplasty); consider stopping prophylaxis if immobilisation continues beyond 42\xa0days (see the recommendation on lower limb immobilisation) or\n\nwhen total anaesthesia time is more than 90\xa0minutes or\n\nthe person's risk of VTE outweighs their risk of bleeding. \n\n## Upper limb orthopaedic surgery\n\nBe aware that VTE prophylaxis is generally not needed if giving local or regional anaesthetic for upper limb surgery. \n\nConsider VTE prophylaxis for people undergoing upper limb surgery if the person's total time under general anaesthetic is over 90\xa0minutes or where their operation is likely to make it difficult for them to mobilise. \n\n# Interventions for people having elective spinal surgery or cranial surgery or people with spinal injury\n\n## Elective spinal surgery\n\nIn March\xa02018, the use of LMWH in young people under\xa018 in recommendations 1.12.2, 1.12.3 and 1.12.4 was off label. See NICE's information on prescribing medicines.\n\nOffer mechanical VTE prophylaxis on admission to people undergoing elective spinal surgery. Choose either:\n\nanti-embolism stockings or\n\nintermittent pneumatic compression. Continue for 30\xa0days or until the person is mobile or discharged, whichever is sooner. \n\nConsider adding pharmacological VTE prophylaxis with LMWH for people undergoing elective spinal surgery whose risk of VTE outweighs their risk of bleeding, taking into account individual patient and surgical factors (major or complex surgery) and according to clinical judgement. \n\nIf using LMWH for people undergoing elective spinal surgery, start giving it 24 to 48\xa0hours postoperatively according to clinical judgement, taking into account patient characteristics and surgical procedure. Continue for 30\xa0days or until the person is mobile or discharged, whichever is sooner. \n\nIf needed, start LMWH earlier than 24\xa0hours after the operation for people undergoing elective spinal surgery. Base the decision on multidisciplinary or senior opinion, or a locally agreed protocol. \n\n## Cranial surgery\n\nIn March\xa02018, the use of LMWH in young people under\xa018 in recommendations 1.12.7, 1.12.8 and 1.12.9 was off label. See NICE's information on prescribing medicines.\n\nConsider mechanical VTE prophylaxis for people undergoing cranial surgery. \n\nIf using mechanical VTE prophylaxis for people undergoing cranial surgery, start it on admission. Choose either:\n\nanti-embolism stockings or\n\nintermittent pneumatic compression. Continue for 30\xa0days or until the person is mobile or discharged, whichever is sooner. \n\nConsider adding pre‑operative pharmacological VTE prophylaxis with LMWH. Give the last dose no less than 24\xa0hours before surgery for people undergoing cranial surgery whose risk of VTE outweighs their risk of bleeding. \n\nConsider adding pharmacological VTE prophylaxis with LMWH, starting 24 to 48\xa0hours after surgery for people undergoing cranial surgery whose risk of VTE outweighs their risk of bleeding. Continue for a minimum of 7\xa0days. \n\nIf needed, start LMWH earlier than 24\xa0hours after the operation for people undergoing cranial surgery. Base the decision on multidisciplinary or senior opinion, or a locally agreed protocol. \n\nDo not offer pharmacological VTE prophylaxis to people with ruptured cranial vascular malformations (for example, brain aneurysms) or people with intracranial haemorrhage (spontaneous or traumatic) until the lesion has been secured or the condition has stabilised. \n\n## Spinal injury\n\nConsider mechanical VTE prophylaxis on admission for people with spinal injury. Choose either:\n\nanti-embolism stockings (only in a specialist spinal injury unit and after multidisciplinary team discussion) or\n\nintermittent pneumatic compression. [2018, amended 2019]\n\nReassess risk of bleeding 24\xa0hours after initial admission in people with spinal injury. \n\nConsider adding pharmacological VTE prophylaxis with LMWH 24\xa0hours after initial admission for people with spinal injury who are not having surgery in the next 24 to 48\xa0hours, if the benefit of reducing the risk of VTE outweighs the risk of bleeding. In March\xa02018, the use of LMWH in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nContinue VTE prophylaxis in people with spinal injury for 30\xa0days or until the person is mobile or discharged, whichever is sooner. \n\n# Interventions for people with major trauma\n\nOffer mechanical VTE prophylaxis with intermittent pneumatic compression on admission to people with serious or major trauma. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\nReassess risk of VTE and bleeding in people with serious or major trauma whenever their clinical condition changes and at least daily. \n\nConsider pharmacological VTE prophylaxis for people with serious or major trauma as soon as possible after the risk assessment when the risk of VTE outweighs the risk of bleeding. Continue for a minimum of 7\xa0days. \n\n# Interventions for people having abdominal, thoracic or head and neck surgery\n\n## Abdominal surgery\n\nOffer VTE prophylaxis to people undergoing abdominal (gastrointestinal, gynaecological, urological) surgery who are at increased risk of VTE. For people undergoing bariatric surgery, follow the recommendations in the section on bariatric surgery. \n\nStart mechanical VTE prophylaxis on admission for people undergoing abdominal surgery. Choose either:\n\nanti-embolism stockings or\n\nintermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\nAdd pharmacological VTE prophylaxis for a minimum of 7\xa0days for people undergoing abdominal surgery whose risk of VTE outweighs their risk of bleeding, taking into account individual patient factors and according to clinical judgement. Choose either:\n\nLMWH or\n\nfondaparinux sodium. In March\xa02018, the use of LMWH and fondaparinux sodium in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nConsider extending pharmacological VTE prophylaxis to 28\xa0days postoperatively for people who have had major cancer surgery in the abdomen. \n\n## Bariatric surgery\n\nOffer VTE prophylaxis to people undergoing bariatric surgery. \n\nStart mechanical VTE prophylaxis on admission for people undergoing bariatric surgery. Choose either:\n\nanti-embolism stockings or\n\nintermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\nAdd pharmacological VTE prophylaxis for people undergoing bariatric surgery for a minimum of 7\xa0days for people whose risk of VTE outweighs their risk of bleeding. Choose either:\n\nLMWH or\n\nfondaparinux sodium. In March\xa02018, the use of LMWH and fondaparinux sodium in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\n## Thoracic surgery\n\nConsider VTE prophylaxis for people undergoing thoracic surgery who are at increased risk of VTE. \n\nStart mechanical VTE prophylaxis on admission for people undergoing thoracic surgery. Choose either:\n\nanti-embolism stockings or\n\nintermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\nConsider adding pharmacological VTE prophylaxis for people undergoing thoracic surgery for a minimum of 7\xa0days to people whose risk of VTE outweighs their risk of bleeding:\n\nUse LMWH as first-line treatment.\n\nIf LMWH is contraindicated, use fondaparinux sodium. In March\xa02018, the use of LMWH and fondaparinux sodium in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\n## Head and neck surgery\n\nConsider pharmacological VTE prophylaxis with LMWH for a minimum of 7\xa0days for people undergoing oral or maxillofacial surgery whose risk of VTE outweighs their risk of bleeding. In March\xa02018, the use of LMWH in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nConsider mechanical VTE prophylaxis on admission for people undergoing oral or maxillofacial surgery who are at increased risk of VTE and high risk of bleeding. Choose either:\n\nanti-embolism stockings or\n\nintermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\nConsider pharmacological VTE prophylaxis with LMWH for a minimum of 7\xa0days for people undergoing ears, nose or throat (ENT) surgery whose risk of VTE outweighs their risk of bleeding. In March\xa02018, the use of LMWH in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nConsider mechanical VTE prophylaxis on admission for people undergoing ENT surgery who are at increased risk of VTE and high risk of bleeding. Choose either:\n\nanti-embolism stockings or\n\nintermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\n# Interventions for people having cardiac or vascular surgery\n\n## Cardiac surgery\n\nConsider mechanical VTE prophylaxis on admission for people who are undergoing cardiac surgery who are at increased risk of VTE. Choose either:\n\nanti-embolism stockings or\n\nintermittent pneumatic compression. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\nConsider adding pharmacological VTE prophylaxis for a minimum of 7\xa0days for people who are undergoing cardiac surgery and are not having other anticoagulation therapy:\n\nUse LMWH as first-line treatment.\n\nIf LMWH is contraindicated, use fondaparinux sodium. In March\xa02018, the use of LMWH and fondaparinux sodium in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\n## Vascular surgery\n\nConsider pharmacological VTE prophylaxis with LMWH for a minimum of 7\xa0days for people who are undergoing open vascular surgery or major endovascular procedures, including endovascular aneurysm repair whose risk of VTE outweighs their risk of bleeding. In March\xa02018, the use of LMWH in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nConsider mechanical VTE prophylaxis on admission for people who are undergoing open vascular surgery or major endovascular procedures, including endovascular aneurysm repair, if pharmacological prophylaxis is contraindicated. Choose either:\n\nanti-embolism stockings or\n\nintermittent pneumatic compression.Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\nConsider pharmacological VTE prophylaxis with LMWH for a minimum of 7\xa0days for people who are undergoing lower limb amputation whose risk of VTE outweighs their risk of bleeding. In March\xa02018, the use of LMWH in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nConsider mechanical VTE prophylaxis with intermittent pneumatic compression on the contralateral leg, on admission, for people who are undergoing lower limb amputation and if pharmacological prophylaxis is contraindicated. \n\nFor people undergoing lower limb amputation, continue mechanical VTE prophylaxis until the person no longer has significantly reduced mobility relative to their anticipated mobility. \n\nBe aware that VTE prophylaxis is generally not needed for people undergoing varicose vein surgery where:\n\ntotal anaesthesia time is less than 90\xa0minutes and\n\nthe person is at low risk of VTE. \n\nConsider pharmacological VTE prophylaxis with LMWH, starting 6 to 12\xa0hours after surgery and continuing for 7\xa0days for people undergoing varicose vein surgery if:\n\ntotal anaesthesia time is more than 90\xa0minutes or\n\nthe person's risk of VTE outweighs their risk of bleeding. In March\xa02018, the use of LMWH in young people under\xa018 was off label. See NICE's information on prescribing medicines.\n\nConsider mechanical VTE prophylaxis with anti-embolism stockings, on admission, for people undergoing varicose vein surgery:\n\nwho are at increased risk of VTE and\n\nif pharmacological prophylaxis is contraindicated. \n\nIf using anti-embolism stockings for people undergoing varicose vein surgery, continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility. \n\n# Interventions for pregnant women and women who gave birth or had a miscarriage or termination of pregnancy in the past 6\xa0weeks\n\nIn March\xa02018, the use of LMWH in young people under\xa018 in recommendations 1.16.1, 1.16.4, 1.16.5 and 1.16.6 was off label. See NICE's information on prescribing medicines.\n\nConsider LMWH for all women who are admitted to hospital or a midwife-led unit if they are pregnant or gave birth, had a miscarriage or had a termination of pregnancy in the past 6\xa0weeks, and whose risk of VTE outweighs their risk of bleeding. \n\nDo not offer VTE prophylaxis to women admitted to hospital or a midwife-led unit who are in active labour. \n\nStop pharmacological VTE prophylaxis when women are in labour. \n\nIf using LMWH in pregnant women, start it as soon as possible and within 14\xa0hours of the risk assessment being completed and continue until the woman is no longer at increased risk of VTE or until discharge from hospital or the midwife-led unit. \n\nIf using LMWH in women who gave birth or had a miscarriage or termination of pregnancy, start 4 to 8\xa0hours after the event unless contraindicated and continue for a minimum of 7\xa0days. \n\nConsider combined prophylaxis with LMWH plus mechanical prophylaxis for pregnant women or women who gave birth or had a miscarriage or termination of pregnancy in the past 6\xa0weeks and who are likely to be immobilised, or have significantly reduced mobility relative to their normal or anticipated mobility for 3\xa0or more days after surgery, including caesarean section:\n\nUse intermittent pneumatic compression as first-line treatment.\n\nIf intermittent pneumatic compression is contraindicated, use anti-embolism stockings.Continue until the woman no longer has significantly reduced mobility relative to her normal or anticipated mobility or until discharge from hospital. \n\n# Terms used in this guideline\n\n## Admission\n\nAdmission in the context of this guideline refers to admission as an inpatient, where a bed is provided for 1 or more nights, or admission as a day patient, where a bed is provided for a procedure including surgery or chemotherapy but not for an overnight stay.\n\n## Discharge\n\nDischarge in the context of this guideline refers to discharge from hospital as an inpatient or after a day procedure.\n\n## Intermittent pneumatic compression\n\nA method of prophylaxis that includes an air pump and inflatable garments in a system designed to improve venous circulation in the lower limbs of people at risk of DVT or pulmonary embolism. The inflation–deflation cycle of intermittent pneumatic compression therapy simulates the thigh, calf and foot's normal ambulatory pump action increasing both the volume and rate of blood flow, eliminating venous stasis and replicating the effects of the natural muscle pump. Intermittent pneumatic compression devices can be thigh- or knee-length sleeves that are wrapped around the leg, or a garment that can be wrapped around or worn on the foot that is designed to mimic the actions of walking.\n\n## Lower limb immobilisation\n\nAny clinical decision taken to manage the affected limb in a way that would prevent normal weight-bearing status or use of that limb, or both.\n\n## Renal impairment\n\nPeople with an estimated glomerular filtration rate (eGFR) of less than 30\xa0ml/min/1.73\xa0m2. For more detailed information on renal impairment, see the NICE guideline on chronic kidney disease in adults.\n\n## Significantly reduced mobility\n\nPeople who are bed bound, unable to walk unaided or likely to spend a substantial proportion of their day in bed or in a chair.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Risk assessment\n\nWhat is the accuracy of individual risk assessment tools in predicting the risk of venous thromboembolism (VTE) and risk of bleeding in people admitted to hospital?\n\n## Why this is important\n\nRisk assessment is a mandatory for all people admitted or having day procedures in hospital. Since 2010, the National VTE Risk Assessment Tool has been widely used in the NHS to assess a person's risk of VTE. This tool has not been validated or tested against other tools to evaluate its diagnostic accuracy or effectiveness at correctly identifying people at risk of VTE. There is concern that the tool may not accurately identify those who are most likely to get VTE.\n\nAccording to national figures, over 70% of medical patients in the UK have prophylaxis when the national tool has been used, with some trusts offering prophylaxis to over 90% of medical patients. Around 40% of medical patients have prophylaxis in largely US‑based populations when other tools are used (although this may partially relate to different indications for hospital admission). It is not known if this means that the national tool identifies too many people or the other tools do not identify enough. The potential impact of giving unnecessary prophylaxis is that people may be at increased risk of bleeding and discomfort through repeated injections. There is also the potential for reducing the cost of thromboprophylaxis by better defining 'at risk' populations, so that the number of those given thromboprophylaxis is reduced.\n\n# Dose strategies for people who are obese\n\nWhat is the clinical and cost effectiveness of weight-based dose-adjustment strategies of low-molecular-weight heparin (LMWH) compared with fixed-dose strategies of LMWH for preventing VTE in people who are very obese (BMI over\xa035) who are admitted to hospital or having day procedures (including surgery and chemotherapy)?\n\n## Why this is important\n\nObesity is on the rise in England. The prevalence of obesity increased by 11% between 1993 and 2014 (15% in 1993 and 26% in 2014), which has resulted in more obese people being admitted to hospital. Obesity may as much as double a person's risk of developing hospital-acquired VTE, therefore most obese people will need prophylaxis. There is much uncertainty about what dose to use and the clinical and cost effectiveness of using weight-based dose-adjustment versus fixed-dose strategies. In current practice, a higher than usual dose is given but this may not be necessary, especially if the person has obesity-related liver disease. Several studies have reported effectiveness in terms of biological measures rather than clinical outcomes such as deep vein thrombosis (DVT) and bleeding events. It is important that there is a clearer understanding of the effects that different dose strategies can have in terms of clinical outcomes. This is because they can directly influence the quality of life of obese people admitted to hospital and help inform clinical decisions on patient care.\n\n# Direct oral anticoagulants for people with lower limb immobilisation\n\nWhat is the clinical and cost effectiveness of direct oral anticoagulants for preventing VTE in people with lower limb immobilisation?\n\n## Why this is important\n\nThe Computerized registry of patients with venous thromboembolism (RIETE) study, a multicentre prospective cohort study of 30,886\xa0patients with acute VTE, estimated that 5.7% of VTE events were associated with lower limb immobilisation for non-major orthopaedic surgery. Estimates of DVT risk in people with lower limb immobilisation, based on meta-analyses of trials comparing chemothromboprophylaxis with placebo, range between approximately 4% and 40%. Given that lower limb immobilisation following trauma or non-major orthopaedic surgery is so common, the consequent burden of disease from VTE from this cause in the whole population is very considerable. For example, the annual incidence of ankle fracture is\xa0187 per\xa0100,000, translating to over 120,000\xa0incident fractures per year in the UK. If 10% of these fractures are complicated by VTE, then we might expect approximately 12,000\xa0events per year only related to immobilisation following ankle trauma.\n\nDespite this burden of ill-health, no randomised studies comparing modern anticoagulants that are available in oral preparations (perhaps more suitable for outpatient treatments) with established treatments such as LMWH or fondaparinux were identified in the evidence review. The committee were unable to make a recommendation to consider oral anticoagulants for this patient group given this lack of evidence.\n\n# Aspirin prophylaxis for people with fragility fractures of the pelvis, hip or proximal femur\n\nWhat is the clinical and cost effectiveness of aspirin alone versus other pharmacological and/or mechanical prophylaxis strategies (alone or in combination) for people with fragility fractures of the pelvis, hip or proximal femur?\n\n## Why this is important\n\nFragility fractures are the greatest burden of musculoskeletal disease in hospitals in the UK. There are approximately 70,000\xa0fragility hip fractures per year in England alone leading to 1.5\xa0million bed days being used each year, which equates with the continuous occupation of over 4,000\xa0NHS beds.\n\nCurrent evidence supports a recommendation for prophylaxis with LMWH or fondaparinux. Both involve a subcutaneous injection for 28\xa0days requiring either self-injection at home or a community nurse attending to deliver the injection. Patient adherence to treatment may be improved with an oral rather than injectable treatment.\n\nA large but controversially reported trial suggests that aspirin may be at least as effective as currently recommended treatments. However, because of methodological and reporting limitations, the evidence for the effectiveness of aspirin alone is not clear. There is potentially a large cost saving if aspirin is clinically effective because it is very inexpensive.\n\n# Duration of prophylaxis for elective total hip replacement surgery\n\nWhat is the clinical and cost effectiveness of standard versus extended duration pharmacological prophylaxis for preventing VTE in people undergoing elective total hip replacement surgery?\n\n## Why this is important\n\nIn 2015, there were 84,462\xa0hip replacements in England, Wales and Northern Ireland. The current recommended duration of prophylaxis is 28\xa0days in the elective total hip replacement population. This extended duration of prophylaxis is based on few, small and older trials. The quality of the evidence supporting extended duration prophylaxis is very low. Modern pharmaceutical trials of newer interventions use extended duration prophylaxis based on these historical data, with the added incentive of more expensive prophylaxis strategies. There is a large potential cost saving if a shorter duration of prophylaxis is as clinically effective, given the considerable cost of prophylaxis and the number of people for whom it is prescribed.", 'Putting this guideline into practice': "We have produced NICE tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect them. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Context': 'Hospital-acquired venous thromboembolism (VTE), also known as hospital-acquired or hospital-associated thrombosis (HAT), covers all VTE that occurs in hospital and within 90\xa0days after a hospital admission. It is a common and potentially preventable problem. VTE most frequently occurs in the deep veins of the legs or pelvis (a deep vein thrombosis [DVT]). If it dislodges and travels to the lungs, it is called a pulmonary embolism, which in some cases can be fatal.\n\nHospital-acquired VTE accounts for thousands of deaths annually in the NHS, and fatal pulmonary embolism remains a common cause of in‑hospital mortality. HAT accounts for 50% to 60% of all VTE seen. In 2013 to 2014, there were around 24,700\xa0admissions for pulmonary embolism and 19,400\xa0for DVT in England. In 2013 in England and Wales, there were 2,191\xa0deaths recorded as due to pulmonary embolism and 2,816\xa0due to DVT. Treatment of non-fatal symptomatic VTE and related long-term morbidities is associated with a considerable cost to the health service.\n\nPeople admitted to hospital or mental health units have varying risk factors for VTE. The spectrum of VTE risk is broad, and understanding the scale of the problem has led to a paradigm shift in preventing and managing VTE in the NHS. In particular, patients now undergo VTE risk assessment as a routine event in all NHS care pathways. By July 2013, 96% of adult admissions to NHS-funded acute care hospitals were risk assessed for VTE compared with less than 50% of patients in July\xa02010.\n\nVTE prophylaxis has been shown to reduce the incidence of DVT. It includes mechanical methods (such as anti-embolism stockings and intermittent pneumatic compression devices), and pharmacological treatments (such as heparin and other anticoagulant drugs).\n\nThis guideline is about reducing the risk of VTE in over\xa016s admitted to or treated as day procedures in hospitals. It provides recommendations on the most clinically and cost-effective measures to reduce the risk of VTE, while considering the potential risks of the various VTE prophylaxis options and patient preferences. It highlights the importance of risk assessment for VTE and for bleeding for all people being admitted and of clinical judgement in deciding on a prophylaxis strategy for each person at risk.\n\nThe 2018 update takes into account newer evidence and newer therapies and has been made more relevant for specific groups such as surgical sub-specialities, people with mental health conditions and pregnant women.'}
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https://www.nice.org.uk/guidance/ng89
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This guideline covers assessing and reducing the risk of venous thromboembolism (VTE or blood clots, including deep vein thrombosis and pulmonary embolism) in people aged 16 and over in hospital. It aims to help healthcare professionals identify people most at risk and describes interventions that can be used to reduce the risk of VTE.
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cd1470951e3814d2ebce9e2640e011a625323b8a
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nice
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Alcohol interventions in secondary and further education
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Alcohol interventions in secondary and further education
This guideline covers interventions in secondary and further education to prevent and reduce alcohol use among children and young people aged 11 up to and including 18. It also covers people aged 11 to 25 with special educational needs or disabilities in full-time education. It will also be relevant to children aged 11 in year 6 of primary school.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Planning alcohol education
## Organising alcohol education
Plan and deliver alcohol education (universal and targeted interventions) as part of a whole-school approach to relationships education, relationships and sex education (RSE) and health education or personal, social, health and economic education (PSHE). Do this by using, for example:
classroom curriculum activities
pastoral support, school policies (including school ethos) and other actions to support pupils in the wider school environment
activities that involve parents or carers, families and communities (see the section on making it as easy as possible for people to get involved in NICE's guideline on community engagement).
Ensure those planning and delivering relationships education, RSE, health education or PSHE have the materials, planning time and training they need to support, promote and provide alcohol education. Be aware that there are resources available that can be used for planning and delivering alcohol education (see the Department for Education's guidance on relationships, sex education and health education).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organising alcohol education .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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## Planning alcohol education content
Use a spiral curriculum when planning and delivering alcohol education.
When planning alcohol education:
ensure it is appropriate for age and maturity and aims to minimise the risk of any unintended adverse consequences (see the recommendation on structuring alcohol education).
tailor it to take account of each pupil's learning needs and abilities
tailor it to the group's knowledge and perceptions of alcohol and alcohol use
take into account that those aged 18 and over can legally buy alcohol.
Think about how to adapt alcohol education for pupils with special educational needs and disabilities so that it is tailored to the pupil's learning needs, abilities and maturity (see chapter 6 of the Department for Education's SEND code of practice: 0 to 25 years).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on planning alcohol education content .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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## Confidentiality and safeguarding
Ensure all involved in giving the alcohol education sessions are aware of the school's process for handling confidential disclosures.
Ensure pupils understand:
how they can raise any concerns and how they will be supported
that any information or concerns they disclose will be dealt with at an appropriate level of confidentiality
how disclosures will be handled if there are safeguarding concerns.
Use safeguarding arrangements to refer pupils for extra support if they have:
raised concerns, for example about alcohol-related harm or
had concerns raised about them (see the Department for Education's keeping children safe in education).
Use existing school policies to deal with problems (such as bullying) that may arise if a pupil's disclosures are inappropriately shared by other pupils.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on confidentiality and safeguarding .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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## Referral for further support
Use clear referral pathways, for example into school nursing, school counselling, early help services, voluntary sector services, young people's drugs and alcohol services or to a youth worker, as needed.
Involve the pupil and their parents or carers, as appropriate, in any consultation and referral to external services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral for further support .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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# Delivering universal alcohol education
## Structuring alcohol education
When delivering alcohol education, aim to:
use a positive approach to help pupils to make informed, safe, healthy choices
encourage pupils to take part in discussions
avoid unintended consequences (for example the pupil becoming curious about alcohol and wanting to try it, or substituting it with another substance)
avoid using scare tactics
avoid only giving out information, for example by lectures or leaflets.
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on structuring alcohol education .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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## Using additional support for alcohol education
Use school nurses, local public health officers and drug and alcohol services or other external providers to provide additional support for alcohol education.
If using external providers to supplement alcohol education:
use providers offering content that is consistent with the school's planned alcohol education
follow guidance on quality assurance and delivery (see the section on working with external agencies in the Department for Education's guidance on relationships, sex education and health education).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on using additional support for alcohol education .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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# Targeted interventions
## Selecting pupils for targeted interventions
When selecting pupils to offer a targeted intervention to, avoid treating them in a way that could:
stigmatise them or
encourage them to see themselves as likely to use alcohol or see it as normal behaviour or
have a negative impact on their self-esteem.
When using targeted interventions, always seek to involve the pupils in decisions about them and the interventions offered to them.
Seek consent to include a pupil in a targeted intervention. This should be from the pupil themselves, or the pupil's parent or carer, as appropriate to the situation.
Offer a targeted individual or group intervention (for example counselling or a brief intervention) to pupils who are assessed as vulnerable to alcohol misuse.
Ensure a targeted group intervention is appropriate for the age and maturity of the pupils and aims to minimise the risk of any unintended adverse consequences and stigma (see recommendation 1.3.7).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on selecting pupils for targeted interventions .
Full details of the evidence and the committee's discussion are in evidence review B: targeted interventions.
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## Tailoring targeted interventions
For each person or group offered an intervention, identify their specific risk factors, vulnerabilities and any concerns about their behaviour so that the intervention can be tailored to their needs. Use, for example:
formal sources of information about risk factors (for example information provided by a level of needs assessment, children's services or through the whole-school approach)
informal sources of information about pupils' behaviour (for example reports from the local community informing the school after witnessing pupils drinking alcohol).
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on tailoring targeted interventions .
Full details of the evidence and the committee's discussion are in evidence review B: targeted interventions.
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## Avoiding unintended consequences of group interventions
Avoid normalising unhealthy drinking behaviours when delivering targeted group interventions (for example by not mixing different age groups).
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on avoiding unintended consequences of group interventions .
Full details of the evidence and the committee's discussion are in evidence review B: targeted interventions.
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# Terms used in this guideline
## Level of needs assessment
An agreed threshold document from the local children's safeguarding board or safeguarding partnership that sets out risk factors and considerations for what to do when worried about a child. From September 2019, all local authority areas in England should have completed their transition from local children's safeguarding boards to safeguarding partnerships.
## School
All schools (including academies, free schools and alternative provision academies) and pupil referral units (see the Department for Education's explanation of types of schools) and further education and sixth-form colleges as set out under the Further and Higher Education Act 1992 (see the Department for Education's keeping children safe in education).
## Spiral curriculum
A course of study in which pupils study the same topics in ever-increasing complexity throughout their time at school to reinforce previous lessons.
## Targeted intervention
Interventions for children and young people who are not necessarily seeking help but who have risk factors that make them vulnerable to alcohol misuse.
## Universal alcohol education
Education that addresses all pupils in the school. It is delivered to groups of pupils without assessing their risk.
## Vulnerable to alcohol misuse
This may include children and young people:
whose personal circumstances put them at increased risk
who may already be drinking alcohol
who may already be regularly using another harmful substance, such as cannabis.
## Whole-school approach
An ethos and environment that supports learning and promotes the health and wellbeing of everyone in the school community. The aim is to ensure pupils feel safe, happy and prepared for life in and beyond school. It covers:
curriculum subjects
general school policies on social, moral and spiritual wellbeing
cultural awareness.
It also promotes a proactive relationship between the school, children, young people and their parents or carers, outside agencies and the wider community.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Components of alcohol education delivery
What components of alcohol education delivery contribute to its effectiveness for children and young people aged 11 to 18 in full-time education, and those with special educational needs and disabilities (SEND) up to the age of 25?
For a short explanation of why the committee made the recommendation for research, see the rationale sections on planning alcohol education content and using additional support for alcohol education .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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# Targeted school-based interventions
How effective and cost effective are individual, compared with group, education-based interventions for children and young people aged 11 to 18 in full-time education who are thought to be vulnerable to alcohol misuse?
For a short explanation of why the committee made the recommendation for research, see the rationale section on selecting pupils for targeted interventions .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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# Universal interventions for people aged 11 to 25 with special educational needs and disabilities
How effective and cost effective are universal, education-based alcohol interventions for children and young people aged 11 to 25 with SEND?
For a short explanation of why the committee made the recommendation for research, see the rationale section on planning alcohol education content .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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# Targeted interventions for people aged 11 to 25 with SEND
How effective and cost effective are education-based alcohol interventions targeted at children and young people aged 11 to 25 with SEND who are thought to be vulnerable to alcohol misuse?
For a short explanation of why the committee made the recommendation for research, see the rationale sections on planning alcohol education content and selecting pupils for targeted interventions .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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# Preventive work for people aged 11 to 25 with SEND
How effective are education-based alcohol prevention interventions (universal or targeted) for children and young people aged 11 to 25 with SEND in full-time education?
For a short explanation of why the committee made the recommendation for research, see the rationale section on planning alcohol education content .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
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# Engaging parents and carers in the whole-school approach to alcohol education
What methods and techniques help secondary schools and providers to effectively engage with parents and carers as part of a whole-school approach to promote and support alcohol education?
For a short explanation of why the committee made the recommendation for research, see the rationale section for organising alcohol education .
Full details of the evidence and the committee's discussion are in evidence review A: universal interventions.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Organising alcohol education
Recommendations 1.1.1 to 1.1.2
## Why the committee made the recommendations
It is current practice for schools to use a whole-school approach for alcohol education (universal and targeted) and other health-related topics that have a personal, social, health and economic education (PSHE) component. This helps schools ensure that consistent messages are given about a topic, such as alcohol education, whether taught through relationships education, relationships and sex education (RSE) and health education, or PSHE and the national science curriculum. In England universal alcohol education forms part of the usual curriculum delivered through health education or PSHE.
Evidence was identified on delivering universal alcohol-specific education programmes in a mix of approaches and components (for example, in or out of the classroom, on its own or in combination with family or community). This evidence showed that the effectiveness of specific universal alcohol education programmes is no better than usual alcohol education. In England usual alcohol education is delivered through health education or PSHE, so the committee thought that alcohol education could continue to be delivered this way.
Although the published cost-effectiveness evidence was limited it indicated that universal interventions could be cost effective. The economic analysis showed the same. So the committee agreed that universal interventions could offer good value for money. However, they were mindful that cost effectiveness was closely related to the cost of the intervention. The benefits of the intervention, measured as a reduction in the number of related crime and hospital events, also had a significant impact on cost effectiveness because of their high associated costs.
The cost-effectiveness analysis showed that universal interventions are more likely to be cost effective in the older age groups that might be drinking already, than in the younger ones that might not. The committee were concerned that this might lead to a focus on interventions for older children and young people. However, they did not think the evidence justified prioritising interventions for these groups because of limitations in study design. In addition, the studies used short follow-up, compared the interventions with usual education, and used outcomes such as problematic drinking (which is less common in younger age groups and unlikely to capture other benefits of alcohol education).
One of the elements of the whole-school approach is the involvement of parents and carers. The committee acknowledged that parents or carers have an influence on their child's health behaviours. They considered that involving them in the school's approach to alcohol education is essential to improve the consistency of messages that pupils receive. Evidence was identified on universal alcohol programmes that involved parents, but it was inconclusive. The committee believed that limitations in study design, such as short follow-up, might explain this. The evidence also showed that it can be difficult to engage parents successfully (for example to attend family education activities at school). The committee agreed that more research was needed to evaluate the different ways to do this (see the recommendation for research on engaging parents and carers in the whole-school approach to alcohol education).
Evidence from qualitative studies showed that teachers may lack confidence in teaching alcohol education and don't know the best materials to use. The committee were aware of accredited materials and training resources (although not reviewed by NICE) based on their experience of current practice. These include materials from PSHE Association, Public Health England and Mentor-ADEPIS.
The committee also reiterated that it was the school's responsibility to use materials that are free from bias, and informed by evidence if possible. Also, the committee were mindful of a 2016 review noting that the delivery of education messages by the alcohol industry has no significant public health effects (see Public Health England's The public health burden of alcohol: evidence review). The committee were also aware of international criteria on how to select teaching materials and support resources (see the United Nations Office on Drugs and Crime guidance on school-based education for drug abuse prevention), but NICE did not review this.
The committee discussed that schools share experiences and knowledge and adopt examples of alcohol education that have worked in other local schools. However, there was no evidence to support this practice. There was also concern that adapting examples of good practice for local needs may alter the effectiveness of interventions (for example straying too far from key content and processes).
Evidence from qualitative studies shows that many schools find it difficult to prioritise alcohol education because of the demands of a crowded curriculum. But, given that health education will be compulsory from 2020, the committee thought it important that schools find time to plan for alcohol education in the curriculum.
## How the recommendations might affect practice
The recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following and will become mandatory. However, the statutory changes may mean that schools need to make changes in how they prioritise health education as part of their overall curriculum planning.
Return to recommendations
# Planning alcohol education content
Recommendations 1.1.3 to 1.1.5
## Why the committee made the recommendations
Evidence from qualitative studies showed that pupils and their teachers believe that the content of alcohol education needs to be age appropriate and should not be taught to a group of mixed ages. Pupils and teachers also believe that it should be tailored to the levels of need and maturity. Evidence from expert testimony highlighted that accounting for these factors will help avoid unintended consequences.
Experts told the committee that making alcohol education age appropriate can be achieved using a 'spiral curriculum' approach. Taking into consideration the need for alcohol education to be age appropriate to minimise harm, the committee agreed that the spiral curriculum concept is a logical approach to do this.
No evidence was identified for alcohol education specific to pupils with special educational needs and disabilities (SEND), and intervention studies carried out in schools often exclude pupils with SEND. Therefore the committee could not recommend any specific adaptations to alcohol education for SEND pupils. But they thought it was important for schools to consider adapting alcohol education to the needs of their SEND pupils. The Department for Education's SEND code of practice sets out how schools can ensure equality of access to the curriculum and inclusion in all school activities for SEND pupils. Therefore research is needed to evaluate the effectiveness of such interventions for this group and of alcohol education (see the recommendations for research on components of alcohol education delivery, universal interventions for people aged 11 to 25 with special educational needs and disabilities, targeted interventions for people aged 11 to 25 with SEND and preventive work for people aged 11 to 25 with SEND.
## How the recommendations might affect practice
The recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following. Schools should already be considering adapting education for their SEND pupils so it is not anticipated that there will be any resource impact.
Return to recommendations
# Confidentiality and safeguarding
Recommendations 1.1.6 to 1.1.9
## Why the committee made the recommendations
Alcohol education can touch on personal experiences or issues that could be sensitive or confidential in nature and may also involve a safeguarding issue. The evidence from qualitative studies suggested that pupils would be more comfortable discussing alcohol-related concerns if they were reassured that they could speak in a safe, non-judgemental environment and know that they will be supported, taken seriously and helped. Therefore the committee thought that it should be made clear to pupils how any concerns they raise will be dealt with. To make this possible, those in a position to hear these concerns must be aware of how to handle confidential disclosures. Expert testimony also suggested that schools should be prepared to deal with unintended consequences and so the committee made a recommendation that this should be planned for and anticipated.
The evidence from qualitative studies also showed that some pupils may be reluctant to share information in a group setting for fear of the information being shared, and of being teased or bullied by their peers. The committee wanted schools to be aware of this and suggested that following existing school policies, for example on bullying, should help to minimise this.
It is current practice for schools to have a process in place so that pupils know that they can speak confidentially, and to allow for concerns to be raised and local safeguarding processes to be followed. (For example, see Public Health England's guidance on safeguarding children affected by parental alcohol and drug use.)
## How the recommendations might affect practice
The recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following.
Return to recommendations
# Referral for further support
Recommendations 1.1.10 to 1.1.11
## Why the committee made the recommendations
Alcohol education may bring to light some matters that may lead to safeguarding issues or unmet mental health needs (see the Department for Health and Social Care and Department for Education's Transforming children and young people's mental health provision: a green paper). Schools should ensure that alcohol education is considered in policies and practices introduced or updated in response to the green paper.
The committee advised that it is best practice for schools to have clear referral pathways to relevant specialist agencies such as school nursing. The local availability of specialist agencies varies, so the committee suggested examples of services that fulfil this criterion. The committee wanted to reinforce the need for all those providing alcohol education to be aware of safeguarding and of the referral pathways in place. This would help to provide as much support for pupils as possible. For example, the Early Help Assessment is designed to help ensure a pupil is offered the right support at an early stage. If these external specialist interventions are needed, the school needs to involve the pupil and their parents or carers. The committee thought that this would be a way of increasing the chances of success of any intervention by allowing them to consult and agree on the best approach for referral to these services.
## How the recommendations might affect practice
The recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following. However, statutory changes may mean that schools need to make changes in how they prioritise health education as part of their overall curriculum planning. Schools currently refer pupils to school nursing, school counsellors or external specialist services such as young people's specialist drug and alcohol services. There may be some resource implications depending on who delivers the interventions if the number of referrals increases.
Return to recommendations
# Structuring alcohol education
Recommendation 1.2.1
## Why the committee made the recommendation
Evidence from qualitative studies and expert testimony suggests that negative messages, scare tactics or providing information about alcohol in isolation do not work and may lead to harm, especially when they are not age appropriate. These approaches are not likely to be tailored to pupils' current understanding and perceptions of alcohol and therefore pupils may rebel against such messages. The evidence showed that pupils favour a non-judgemental environment where they can discuss alcohol in the context of real-life situations.
Evidence from expert testimony highlighted that tailoring alcohol education to age, levels of need and maturity will help avoid unintended consequences. For example, a pupil who has not started drinking alcohol may want to try it once they start to learn more about it. Or when they learn that they should not drink alcohol or cannot buy it, they may choose another substance instead.
The committee acknowledged that the number of children and young people drinking is decreasing. They considered that this trend will help to frame alcohol education in a positive way by normalising not drinking. It will also promote inclusivity for those who choose to not drink or to delay starting to drink, or who do not drink for cultural or religious reasons.
Taking all this into consideration, the committee agreed that it is important to highlight the hazards of excessive drinking. Education that encourages discussion (for example around healthy lifestyle decisions) is more beneficial than merely giving out information, for example, using leaflets or 'one-way' lectures.
## How the recommendation might affect practice
The recommendation will aim to reinforce current best practice because it is based on existing processes that all schools should be following and will become mandatory. However, the statutory changes may mean that schools need to make changes in how they prioritise health education as part of their overall curriculum planning.
Return to recommendation
# Using additional support for alcohol education
Recommendations 1.2.2 to 1.2.3
## Why the committee made the recommendations
The evidence is consistent with current practice that school staff and other providers, including external speakers, can deliver alcohol education. However, there is conflicting evidence on who is best placed to deliver these interventions. Pupils favour a familiar member of school staff, but teachers may lack confidence in teaching alcohol education. Research is needed on the effectiveness of the different components of alcohol education delivery, including providers of the education (see the recommendation for research on components of alcohol education delivery).
Evidence suggests that using trained external providers to supplement alcohol education may benefit pupils, as well as offering a solution to teachers who are not confident in teaching the subject. However, evidence also supported the committee's experience that some external providers may be unsuccessful in getting the right message across and their approach may be potentially harmful. Experts on the committee said that negative approaches and scare tactics sometimes used by police officers or people who misuse alcohol (or are dependent on it), for example, could either scare pupils or inadvertently glamorise alcohol misuse. The committee agreed that it is the school's responsibility to ensure the external providers they choose meet standards that allow pupils to learn safely and effectively. The committee were aware of examples of how to access guidance to assess external providers, for example PSHE Association and Mentor-ADEPIS.
## How the recommendations might affect practice
The recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following. The use of external providers (such as school nurses, local public health officers and drug and alcohol services) to support alcohol education varies, and there may be a cost associated with this provision. This may then affect staff workload in terms of planning and delivering the alcohol education.
Return to recommendations
# Selecting pupils for targeted interventions
Recommendations 1.3.1 to 1.3.5
## Why the committee made the recommendations
Evidence suggests that targeted interventions for pupils who are vulnerable to alcohol misuse may be effective. These studies included individual or group brief interventions or counselling that are delivered over 1 to 5 sessions. The committee were unable to recommend specific details for these interventions because they thought the interventions would depend on the pupil's specific needs. For example, one pupil may benefit from a one-off session whereas another may need follow-up sessions or further support. It was not possible to determine the effectiveness of individual interventions compared with group interventions, and more research is needed on this (see recommendations for research on targeted school-based interventions and targeted interventions for people aged 11 to 25 with SEND).
Although the published cost-effectiveness evidence was limited, it indicated that targeted interventions could be cost effective. The economic analysis showed the same. So the committee agreed that targeted interventions could be good value for money. However, they were mindful that cost effectiveness was closely related to the cost of the intervention. The interventions' benefits, measured as a reduction in the number of related crime and hospital events also had a significant impact on cost effectiveness because of their high associated costs.
The cost-effectiveness analysis showed that targeted interventions are more likely to be cost effective in the older age groups that might be drinking already, than in the younger ones that might not. The committee were concerned that this might lead to a focus on interventions for older children and young people. However, they did not think the evidence justified prioritising interventions for these groups because of limitations in study design. In addition, the studies used short follow-up, compared the interventions with usual education, and used outcomes such as problematic drinking (which is less common in younger age groups and unlikely to capture other benefits of alcohol education).
Experts told the committee that when planning an intervention it is important to consider any potential unintended consequences. This supported the committee's view that care should be taken to avoid 'labelling' or stigmatising pupils when selecting vulnerable pupils for a targeted intervention. For example, if a pupil needs to leave lessons for a counselling session, classmates or teachers might treat them differently, and they could be at increased risk of bullying. They may become withdrawn or defiant as a result, and increase the behaviour that the intervention is intended to prevent.
The committee were clear that seeking consent from the pupil or their guardian when offering any intervention is best practice. Also, for alcohol education to be successful the pupil must be a willing participant and seeking consent from them (or their families and carers) is an important part of following a whole-school approach.
## How the recommendations might affect practice
The recommendations will reinforce best practice because they are based on existing processes and on guidance on individual sessions for vulnerable people. Using group, rather than one-to-one, interventions will potentially lead to savings but it is not clear how often these would be used.
Return to recommendations
# Tailoring targeted interventions
Recommendation 1.3.6
## Why the committee made the recommendation
The identified studies used varying risk factors to determine if a pupil was vulnerable to alcohol misuse – for example drinking in a risky way, using other substances, or showing challenging behaviour at school. This is consistent with how schools might consider whether a pupil is vulnerable to alcohol misuse. The committee also noted that other groups (for example children who do not drink but are vulnerable to other people's drinking, and those in the criminal justice system) may also be particularly vulnerable. How best to identify those who may benefit from targeted interventions was not included in the scope and so the committee were not able to make a recommendation on this issue.
Schools might use several factors to determine whether a pupil is vulnerable to alcohol misuse. In addition, the committee thought it important to ensure that the alcohol intervention is tailored to the pupil's needs. Therefore they agreed that there should be an assessment of the pupil's individual risk factors and needs, as well as planned outcomes in respect of this. The committee suggested using existing processes, for example by using information from a level of needs assessment. Other sources include information derived from the whole-school approach or children's services (including children's social care), as well as more informal sources such as reports from the local community.
## How the recommendation might affect practice
The recommendation will reinforce current practice because it is based on existing processes. These sources of information should be readily available to all concerned so there should not be any additional resource impact.
Return to recommendation
# Avoiding unintended consequences of group interventions
Recommendation 1.3.7
## Why the committee made the recommendation
There could be many reasons why someone is vulnerable to alcohol misuse, and including them in a targeted group intervention may lead to normalising unhealthy drinking behaviours. For example, if the group includes people of different ages and the older pupils are already drinking, the younger pupils (who may be non-drinkers) might try alcohol because they begin to see it as 'normal'. The committee agreed with expert testimony that unintended consequences of interventions should be avoided when deciding on the best approach for group interventions.
## How the recommendation might affect practice
The recommendation will reinforce best practice because it is based on existing processes and existing guidance. But having multiple groups based on age may result in additional resource impact depending on who delivers these interventions and how frequently they are run.
Return to recommendation# Context
Children and young people risk disease, poisoning, injury, violence, depression and damage to their development from drinking alcohol, especially those who drink heavily (Statistics on alcohol, England, 2018, National Statistics). Drinking at an early age is also associated with a higher likelihood of alcohol dependence.
The statistics on alcohol also show that:
% of 11- to 15‑year olds had tried alcohol
% of 11- to 15‑year olds had drunk alcohol in the past week
pupils who drank alcohol in the past week consumed an average (mean) of 9.6 units
girls (11%) were more likely than boys (7%) to report having been drunk in the past 4 weeks.
Since publication of NICE's guideline on alcohol and school-based interventions (PH7) in 2007, the public health and education sectors have changed a great deal. For example, academies and free schools have been introduced, leading to a reduction in local authority governance of schools. Some of the barriers and facilitators for implementing the previous NICE guidance have also changed.
In addition, the Chief Medical Officer's guidance on the consumption of alcohol by children and young people was published in 2009. This advises parents and children that an alcohol-free childhood is the healthiest and best option.
In light of all these changes, we decided to update the guideline.
The Department of Health and Social Care's youth alcohol action plan acknowledges that alcohol education in schools is crucial. In England, personal, social, health and economic education (PSHE) is the most common way to deliver this. Currently PSHE is not statutory (Personal, social, health and economic education, Department for Education). But from 2020 the health aspects will be compulsory in all schools.
This guideline covers children and young people aged 11 to 18 in full-time education and young people aged 18 to 25 with special educational needs and disabilities in full-time education. The latter group has been added to the groups covered by PH7, in line with the Children and Families Act 2014.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Planning alcohol education\n\n## Organising alcohol education\n\nPlan and deliver alcohol education (universal and targeted interventions) as part of a whole-school approach to relationships education, relationships and sex education (RSE) and health education or personal, social, health and economic education (PSHE). Do this by using, for example:\n\nclassroom curriculum activities\n\npastoral support, school policies (including school ethos) and other actions to support pupils in the wider school environment\n\nactivities that involve parents or carers, families and communities (see the section on making it as easy as possible for people to get involved in NICE's guideline on community engagement).\n\nEnsure those planning and delivering relationships education, RSE, health education or PSHE have the materials, planning time and training they need to support, promote and provide alcohol education. Be aware that there are resources available that can be used for planning and delivering alcohol education (see the Department for Education's guidance on relationships, sex education and health education).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organising alcohol education\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: universal interventions.\n\nLoading. Please wait.\n\n## Planning alcohol education content\n\nUse a spiral curriculum when planning and delivering alcohol education.\n\nWhen planning alcohol education:\n\nensure it is appropriate for age and maturity and aims to minimise the risk of any unintended adverse consequences (see the recommendation\xa0on structuring alcohol education).\n\ntailor it to take account of each pupil's learning needs and abilities\n\ntailor it to the group's knowledge and perceptions of alcohol and alcohol use\n\ntake into account that those aged\xa018 and over can legally buy alcohol.\n\nThink about how to adapt alcohol education for pupils with special educational needs and disabilities so that it is tailored to the pupil's learning needs, abilities and maturity (see chapter\xa06 of the Department for Education's SEND code of practice: 0 to 25 years).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on planning alcohol education content\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: universal interventions.\n\nLoading. Please wait.\n\n## Confidentiality and safeguarding\n\nEnsure all involved in giving the alcohol education sessions are aware of the school's process for handling confidential disclosures.\n\nEnsure pupils understand:\n\nhow they can raise any concerns and how they will be supported\n\nthat any information or concerns they disclose will be dealt with at an appropriate level of confidentiality\n\nhow disclosures will be handled if there are safeguarding concerns.\n\nUse safeguarding arrangements to refer pupils for extra support if they have:\n\nraised concerns, for example about alcohol-related harm or\n\nhad concerns raised about them (see the Department for Education's keeping children safe in education).\n\nUse existing school policies to deal with problems (such as bullying) that may arise if a pupil's disclosures are inappropriately shared by other pupils.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on confidentiality and safeguarding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: universal interventions.\n\nLoading. Please wait.\n\n## Referral for further support\n\nUse clear referral pathways, for example into school nursing, school counselling, early help services, voluntary sector services, young people's drugs and alcohol services or to a youth worker, as needed.\n\nInvolve the pupil and their parents or carers, as appropriate, in any consultation and referral to external services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral for further support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: universal interventions.\n\nLoading. Please wait.\n\n# Delivering universal alcohol education\n\n## Structuring alcohol education\n\nWhen delivering alcohol education, aim to:\n\nuse a positive approach to help pupils to make informed, safe, healthy choices\n\nencourage pupils to take part in discussions\n\navoid unintended consequences (for example the pupil becoming curious about alcohol and wanting to try it, or substituting it with another substance)\n\navoid using scare tactics\n\navoid only giving out information, for example by lectures or leaflets.\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on structuring alcohol education\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: universal interventions.\n\nLoading. Please wait.\n\n## Using additional support for alcohol education\n\nUse school nurses, local public health officers and drug and alcohol services or other external providers to provide additional support for alcohol education.\n\nIf using external providers to supplement alcohol education:\n\nuse providers offering content that is consistent with the school's planned alcohol education\n\nfollow guidance on quality assurance and delivery (see the section on working with external agencies in the Department for Education's guidance on relationships, sex education and health education).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on using additional support for alcohol education\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: universal interventions.\n\nLoading. Please wait.\n\n# Targeted interventions\n\n## Selecting pupils for targeted interventions\n\nWhen selecting pupils to offer a targeted intervention to, avoid treating them in a way that could:\n\nstigmatise them or\n\nencourage them to see themselves as likely to use alcohol or see it as normal behaviour or\n\nhave a negative impact on their self-esteem.\n\nWhen using targeted interventions, always seek to involve the pupils in decisions about them and the interventions offered to them.\n\nSeek consent to include a pupil in a targeted intervention. This should be from the pupil themselves, or the pupil's parent or carer, as appropriate to the situation.\n\nOffer a targeted individual or group intervention (for example counselling or a brief intervention) to pupils who are assessed as vulnerable to alcohol misuse.\n\nEnsure a targeted group intervention is appropriate for the age and maturity of the pupils and aims to minimise the risk of any unintended adverse consequences and stigma (see recommendation\xa01.3.7).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on selecting pupils for targeted interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: targeted interventions.\n\nLoading. Please wait.\n\n## Tailoring targeted interventions\n\nFor each person or group offered an intervention, identify their specific risk factors, vulnerabilities and any concerns about their behaviour so that the intervention can be tailored to their needs. Use, for example:\n\nformal sources of information about risk factors (for example information provided by a level of needs assessment, children's services [including children's social care] or through the whole-school approach)\n\ninformal sources of information about pupils' behaviour (for example reports from the local community informing the school after witnessing pupils drinking alcohol).\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on tailoring targeted interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: targeted interventions.\n\nLoading. Please wait.\n\n## Avoiding unintended consequences of group interventions\n\nAvoid normalising unhealthy drinking behaviours when delivering targeted group interventions (for example by not mixing different age groups).\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on avoiding unintended consequences of group interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: targeted interventions.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Level of needs assessment\n\nAn agreed threshold document from the local children's safeguarding board or safeguarding partnership that sets out risk factors and considerations for what to do when worried about a child. From September 2019, all local authority areas in England should have completed their transition from local children's safeguarding boards to safeguarding partnerships.\n\n## School\n\nAll schools (including academies, free schools and alternative provision academies) and pupil referral units (see the Department for Education's explanation of types of schools) and further education and sixth-form colleges as set out under the Further and Higher Education Act 1992 (see the Department for Education's keeping children safe in education).\n\n## Spiral curriculum\n\nA course of study in which pupils study the same topics in ever-increasing complexity throughout their time at school to reinforce previous lessons.\n\n## Targeted intervention\n\nInterventions for children and young people who are not necessarily seeking help but who have risk factors that make them vulnerable to alcohol misuse.\n\n## Universal alcohol education\n\nEducation that addresses all pupils in the school. It is delivered to groups of pupils without assessing their risk.\n\n## Vulnerable to alcohol misuse\n\nThis may include children and young people:\n\nwhose personal circumstances put them at increased risk\n\nwho may already be drinking alcohol\n\nwho may already be regularly using another harmful substance, such as cannabis.\n\n## Whole-school approach\n\nAn ethos and environment that supports learning and promotes the health and wellbeing of everyone in the school community. The aim is to ensure pupils feel safe, happy and prepared for life in and beyond school. It covers:\n\ncurriculum subjects\n\ngeneral school policies on social, moral and spiritual wellbeing\n\ncultural awareness.\n\nIt also promotes a proactive relationship between the school, children, young people and their parents or carers, outside agencies and the wider community.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Components of alcohol education delivery\n\nWhat components of alcohol education delivery contribute to its effectiveness for children and young people aged 11 to 18 in full-time education, and those with special educational needs and disabilities (SEND) up to the age of 25?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale sections on planning alcohol education content\xa0 and using additional support for alcohol education\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: universal interventions.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\n# Targeted school-based interventions\n\nHow effective and cost effective are individual, compared with group, education-based interventions for children and young people aged 11 to 18 in full-time education who are thought to be vulnerable to alcohol misuse?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on selecting pupils for targeted interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: universal interventions.\n\nLoading. Please wait.\n\n# Universal interventions for people aged 11 to 25 with special educational needs and disabilities\n\nHow effective and cost effective are universal, education-based alcohol interventions for children and young people aged 11 to 25 with SEND?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on planning alcohol education content\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: universal interventions.\n\nLoading. Please wait.\n\n# Targeted interventions for people aged 11 to 25 with SEND\n\nHow effective and cost effective are education-based alcohol interventions targeted at children and young people aged 11 to 25 with SEND who are thought to be vulnerable to alcohol misuse?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale sections on planning alcohol education content\xa0 and selecting pupils for targeted interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: universal interventions.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\n# Preventive work for people aged 11 to 25 with SEND\n\nHow effective are education-based alcohol prevention interventions (universal or targeted) for children and young people aged 11 to 25 with SEND in full-time education?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on planning alcohol education content\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: universal interventions.\n\nLoading. Please wait.\n\n# Engaging parents and carers in the whole-school approach to alcohol education\n\nWhat methods and techniques help secondary schools and providers to effectively engage with parents and carers as part of a whole-school approach to promote and support alcohol education?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section for organising alcohol education\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: universal interventions.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Organising alcohol education\n\nRecommendations 1.1.1 to 1.1.2\n\n## Why the committee made the recommendations\n\nIt is current practice for schools to use a whole-school approach for alcohol education (universal and targeted) and other health-related topics that have a personal, social, health and economic education (PSHE) component. This helps schools ensure that consistent messages are given about a topic, such as alcohol education, whether taught through relationships education, relationships and sex education (RSE) and health education, or PSHE and the national science curriculum. In England universal alcohol education forms part of the usual curriculum delivered through health education or PSHE.\n\nEvidence was identified on delivering universal alcohol-specific education programmes in a mix of approaches and components (for example, in or out of the classroom, on its own or in combination with family or community). This evidence showed that the effectiveness of specific universal alcohol education programmes is no better than usual alcohol education. In England usual alcohol education is delivered through health education or PSHE, so the committee thought that alcohol education could continue to be delivered this way.\n\nAlthough the published cost-effectiveness evidence was limited it indicated that universal interventions could be cost effective. The economic analysis showed the same. So the committee agreed that universal interventions could offer good value for money. However, they were mindful that cost effectiveness was closely related to the cost of the intervention. The benefits of the intervention, measured as a reduction in the number of related crime and hospital events, also had a significant impact on cost effectiveness because of their high associated costs.\n\nThe cost-effectiveness analysis showed that universal interventions are more likely to be cost effective in the older age groups that might be drinking already, than in the younger ones that might not. The committee were concerned that this might lead to a focus on interventions for older children and young people. However, they did not think the evidence justified prioritising interventions for these groups because of limitations in study design. In addition, the studies used short follow-up, compared the interventions with usual education, and used outcomes such as problematic drinking (which is less common in younger age groups and unlikely to capture other benefits of alcohol education).\n\nOne of the elements of the whole-school approach is the involvement of parents and carers. The committee acknowledged that parents or carers have an influence on their child's health behaviours. They considered that involving them in the school's approach to alcohol education is essential to improve the consistency of messages that pupils receive. Evidence was identified on universal alcohol programmes that involved parents, but it was inconclusive. The committee believed that limitations in study design, such as short follow-up, might explain this. The evidence also showed that it can be difficult to engage parents successfully (for example to attend family education activities at school). The committee agreed that more research was needed to evaluate the different ways to do this (see the recommendation for research on engaging parents and carers in the whole-school approach to alcohol education).\n\nEvidence from qualitative studies showed that teachers may lack confidence in teaching alcohol education and don't know the best materials to use. The committee were aware of accredited materials and training resources (although not reviewed by NICE) based on their experience of current practice. These include materials from PSHE Association, Public Health England and Mentor-ADEPIS.\n\nThe committee also reiterated that it was the school's responsibility to use materials that are free from bias, and informed by evidence if possible. Also, the committee were mindful of a 2016 review noting that the delivery of education messages by the alcohol industry has no significant public health effects (see Public Health England's The public health burden of alcohol: evidence review). The committee were also aware of international criteria on how to select teaching materials and support resources (see the United Nations Office on Drugs and Crime guidance on school-based education for drug abuse prevention), but NICE did not review this.\n\nThe committee discussed that schools share experiences and knowledge and adopt examples of alcohol education that have worked in other local schools. However, there was no evidence to support this practice. There was also concern that adapting examples of good practice for local needs may alter the effectiveness of interventions (for example straying too far from key content and processes).\n\nEvidence from qualitative studies shows that many schools find it difficult to prioritise alcohol education because of the demands of a crowded curriculum. But, given that health education will be compulsory from 2020, the committee thought it important that schools find time to plan for alcohol education in the curriculum.\n\n## How the recommendations might affect practice\n\nThe recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following and will become mandatory. However, the statutory changes may mean that schools need to make changes in how they prioritise health education as part of their overall curriculum planning.\n\nReturn to recommendations\n\n# Planning alcohol education content\n\nRecommendations 1.1.3 to 1.1.5\n\n## Why the committee made the recommendations\n\nEvidence from qualitative studies showed that pupils and their teachers believe that the content of alcohol education needs to be age appropriate and should not be taught to a group of mixed ages. Pupils and teachers also believe that it should be tailored to the levels of need and maturity. Evidence from expert testimony highlighted that accounting for these factors will help avoid unintended consequences.\n\nExperts told the committee that making alcohol education age appropriate can be achieved using a 'spiral curriculum' approach. Taking into consideration the need for alcohol education to be age appropriate to minimise harm, the committee agreed that the spiral curriculum concept is a logical approach to do this.\n\nNo evidence was identified for alcohol education specific to pupils with special educational needs and disabilities (SEND), and intervention studies carried out in schools often exclude pupils with SEND. Therefore the committee could not recommend any specific adaptations to alcohol education for SEND pupils. But they thought it was important for schools to consider adapting alcohol education to the needs of their SEND pupils. The Department for Education's SEND code of practice sets out how schools can ensure equality of access to the curriculum and inclusion in all school activities for SEND pupils. Therefore research is needed to evaluate the effectiveness of such interventions for this group and of alcohol education (see the recommendations for research on components of alcohol education delivery, universal interventions for people aged 11 to 25 with special educational needs and disabilities, targeted interventions for people aged 11 to 25 with SEND and preventive work for people aged 11 to 25 with SEND.\n\n## How the recommendations might affect practice\n\nThe recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following. Schools should already be considering adapting education for their SEND pupils so it is not anticipated that there will be any resource impact.\n\nReturn to recommendations\n\n# Confidentiality and safeguarding\n\nRecommendations 1.1.6 to 1.1.9\n\n## Why the committee made the recommendations\n\nAlcohol education can touch on personal experiences or issues that could be sensitive or confidential in nature and may also involve a safeguarding issue. The evidence from qualitative studies suggested that pupils would be more comfortable discussing alcohol-related concerns if they were reassured that they could speak in a safe, non-judgemental environment and know that they will be supported, taken seriously and helped. Therefore the committee thought that it should be made clear to pupils how any concerns they raise will be dealt with. To make this possible, those in a position to hear these concerns must be aware of how to handle confidential disclosures. Expert testimony also suggested that schools should be prepared to deal with unintended consequences and so the committee made a recommendation that this should be planned for and anticipated.\n\nThe evidence from qualitative studies also showed that some pupils may be reluctant to share information in a group setting for fear of the information being shared, and of being teased or bullied by their peers. The committee wanted schools to be aware of this and suggested that following existing school policies, for example on bullying, should help to minimise this.\n\nIt is current practice for schools to have a process in place so that pupils know that they can speak confidentially, and to allow for concerns to be raised and local safeguarding processes to be followed. (For example, see Public Health England's guidance on safeguarding children affected by parental alcohol and drug use.)\n\n## How the recommendations might affect practice\n\nThe recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following.\n\nReturn to recommendations\n\n# Referral for further support\n\nRecommendations 1.1.10 to 1.1.11\n\n## Why the committee made the recommendations\n\nAlcohol education may bring to light some matters that may lead to safeguarding issues or unmet mental health needs (see the Department for Health and Social Care and Department for Education's Transforming children and young people's mental health provision: a green paper). Schools should ensure that alcohol education is considered in policies and practices introduced or updated in response to the green paper.\n\nThe committee advised that it is best practice for schools to have clear referral pathways to relevant specialist agencies such as school nursing. The local availability of specialist agencies varies, so the committee suggested examples of services that fulfil this criterion. The committee wanted to reinforce the need for all those providing alcohol education to be aware of safeguarding and of the referral pathways in place. This would help to provide as much support for pupils as possible. For example, the Early Help Assessment is designed to help ensure a pupil is offered the right support at an early stage. If these external specialist interventions are needed, the school needs to involve the pupil and their parents or carers. The committee thought that this would be a way of increasing the chances of success of any intervention by allowing them to consult and agree on the best approach for referral to these services.\n\n## How the recommendations might affect practice\n\nThe recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following. However, statutory changes may mean that schools need to make changes in how they prioritise health education as part of their overall curriculum planning. Schools currently refer pupils to school nursing, school counsellors or external specialist services such as young people's specialist drug and alcohol services. There may be some resource implications depending on who delivers the interventions if the number of referrals increases.\n\nReturn to recommendations\n\n# Structuring alcohol education\n\nRecommendation 1.2.1\n\n## Why the committee made the recommendation\n\nEvidence from qualitative studies and expert testimony suggests that negative messages, scare tactics or providing information about alcohol in isolation do not work and may lead to harm, especially when they are not age appropriate. These approaches are not likely to be tailored to pupils' current understanding and perceptions of alcohol and therefore pupils may rebel against such messages. The evidence showed that pupils favour a non-judgemental environment where they can discuss alcohol in the context of real-life situations.\n\nEvidence from expert testimony highlighted that tailoring alcohol education to age, levels of need and maturity will help avoid unintended consequences. For example, a pupil who has not started drinking alcohol may want to try it once they start to learn more about it. Or when they learn that they should not drink alcohol or cannot buy it, they may choose another substance instead.\n\nThe committee acknowledged that the number of children and young people drinking is decreasing. They considered that this trend will help to frame alcohol education in a positive way by normalising not drinking. It will also promote inclusivity for those who choose to not drink or to delay starting to drink, or who do not drink for cultural or religious reasons.\n\nTaking all this into consideration, the committee agreed that it is important to highlight the hazards of excessive drinking. Education that encourages discussion (for example around healthy lifestyle decisions) is more beneficial than merely giving out information, for example, using leaflets or 'one-way' lectures.\n\n## How the recommendation might affect practice\n\nThe recommendation will aim to reinforce current best practice because it is based on existing processes that all schools should be following and will become mandatory. However, the statutory changes may mean that schools need to make changes in how they prioritise health education as part of their overall curriculum planning.\n\nReturn to recommendation\n\n# Using additional support for alcohol education\n\nRecommendations 1.2.2 to 1.2.3\n\n## Why the committee made the recommendations\n\nThe evidence is consistent with current practice that school staff and other providers, including external speakers, can deliver alcohol education. However, there is conflicting evidence on who is best placed to deliver these interventions. Pupils favour a familiar member of school staff, but teachers may lack confidence in teaching alcohol education. Research is needed on the effectiveness of the different components of alcohol education delivery, including providers of the education (see the recommendation for research on components of alcohol education delivery).\n\nEvidence suggests that using trained external providers to supplement alcohol education may benefit pupils, as well as offering a solution to teachers who are not confident in teaching the subject. However, evidence also supported the committee's experience that some external providers may be unsuccessful in getting the right message across and their approach may be potentially harmful. Experts on the committee said that negative approaches and scare tactics sometimes used by police officers or people who misuse alcohol (or are dependent on it), for example, could either scare pupils or inadvertently glamorise alcohol misuse. The committee agreed that it is the school's responsibility to ensure the external providers they choose meet standards that allow pupils to learn safely and effectively. The committee were aware of examples of how to access guidance to assess external providers, for example PSHE Association and Mentor-ADEPIS.\n\n## How the recommendations might affect practice\n\nThe recommendations will aim to reinforce current best practice because they are based on existing processes that all schools should be following. The use of external providers (such as school nurses, local public health officers and drug and alcohol services) to support alcohol education varies, and there may be a cost associated with this provision. This may then affect staff workload in terms of planning and delivering the alcohol education.\n\nReturn to recommendations\n\n# Selecting pupils for targeted interventions\n\nRecommendations 1.3.1 to 1.3.5\n\n## Why the committee made the recommendations\n\nEvidence suggests that targeted interventions for pupils who are vulnerable to alcohol misuse may be effective. These studies included individual or group brief interventions or counselling that are delivered over 1 to 5 sessions. The committee were unable to recommend specific details for these interventions because they thought the interventions would depend on the pupil's specific needs. For example, one pupil may benefit from a one-off session whereas another may need follow-up sessions or further support. It was not possible to determine the effectiveness of individual interventions compared with group interventions, and more research is needed on this (see recommendations for research on targeted school-based interventions and targeted interventions for people aged 11 to 25 with SEND).\n\nAlthough the published cost-effectiveness evidence was limited, it indicated that targeted interventions could be cost effective. The economic analysis showed the same. So the committee agreed that targeted interventions could be good value for money. However, they were mindful that cost effectiveness was closely related to the cost of the intervention. The interventions' benefits, measured as a reduction in the number of related crime and hospital events also had a significant impact on cost effectiveness because of their high associated costs.\n\nThe cost-effectiveness analysis showed that targeted interventions are more likely to be cost effective in the older age groups that might be drinking already, than in the younger ones that might not. The committee were concerned that this might lead to a focus on interventions for older children and young people. However, they did not think the evidence justified prioritising interventions for these groups because of limitations in study design. In addition, the studies used short follow-up, compared the interventions with usual education, and used outcomes such as problematic drinking (which is less common in younger age groups and unlikely to capture other benefits of alcohol education).\n\nExperts told the committee that when planning an intervention it is important to consider any potential unintended consequences. This supported the committee's view that care should be taken to avoid 'labelling' or stigmatising pupils when selecting vulnerable pupils for a targeted intervention. For example, if a pupil needs to leave lessons for a counselling session, classmates or teachers might treat them differently, and they could be at increased risk of bullying. They may become withdrawn or defiant as a result, and increase the behaviour that the intervention is intended to prevent.\n\nThe committee were clear that seeking consent from the pupil or their guardian when offering any intervention is best practice. Also, for alcohol education to be successful the pupil must be a willing participant and seeking consent from them (or their families and carers) is an important part of following a whole-school approach.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce best practice because they are based on existing processes and on guidance on individual sessions for vulnerable people. Using group, rather than one-to-one, interventions will potentially lead to savings but it is not clear how often these would be used.\n\nReturn to recommendations\n\n# Tailoring targeted interventions\n\nRecommendation 1.3.6\n\n## Why the committee made the recommendation\n\nThe identified studies used varying risk factors to determine if a pupil was vulnerable to alcohol misuse – for example drinking in a risky way, using other substances, or showing challenging behaviour at school. This is consistent with how schools might consider whether a pupil is vulnerable to alcohol misuse. The committee also noted that other groups (for example children who do not drink but are vulnerable to other people's drinking, and those in the criminal justice system) may also be particularly vulnerable. How best to identify those who may benefit from targeted interventions was not included in the scope and so the committee were not able to make a recommendation on this issue.\n\nSchools might use several factors to determine whether a pupil is vulnerable to alcohol misuse. In addition, the committee thought it important to ensure that the alcohol intervention is tailored to the pupil's needs. Therefore they agreed that there should be an assessment of the pupil's individual risk factors and needs, as well as planned outcomes in respect of this. The committee suggested using existing processes, for example by using information from a level of needs assessment. Other sources include information derived from the whole-school approach or children's services (including children's social care), as well as more informal sources such as reports from the local community.\n\n## How the recommendation might affect practice\n\nThe recommendation will reinforce current practice because it is based on existing processes. These sources of information should be readily available to all concerned so there should not be any additional resource impact.\n\nReturn to recommendation\n\n# Avoiding unintended consequences of group interventions\n\nRecommendation 1.3.7\n\n## Why the committee made the recommendation\n\nThere could be many reasons why someone is vulnerable to alcohol misuse, and including them in a targeted group intervention may lead to normalising unhealthy drinking behaviours. For example, if the group includes people of different ages and the older pupils are already drinking, the younger pupils (who may be non-drinkers) might try alcohol because they begin to see it as 'normal'. The committee agreed with expert testimony that unintended consequences of interventions should be avoided when deciding on the best approach for group interventions.\n\n## How the recommendation might affect practice\n\nThe recommendation will reinforce best practice because it is based on existing processes and existing guidance. But having multiple groups based on age may result in additional resource impact depending on who delivers these interventions and how frequently they are run.\n\nReturn to recommendation", 'Context': "Children and young people risk disease, poisoning, injury, violence, depression and damage to their development from drinking alcohol, especially those who drink heavily (Statistics on alcohol, England, 2018, National Statistics). Drinking at an early age is also associated with a higher likelihood of alcohol dependence.\n\nThe statistics on alcohol also show that:\n\n% of 11- to 15‑year olds had tried alcohol\n\n% of 11- to 15‑year olds had drunk alcohol in the past week\n\npupils who drank alcohol in the past week consumed an average (mean) of 9.6\xa0units\n\ngirls (11%) were more likely than boys (7%) to report having been drunk in the past 4\xa0weeks.\n\nSince publication of NICE's guideline on alcohol and school-based interventions (PH7) in 2007, the public health and education sectors have changed a great deal. For example, academies and free schools have been introduced, leading to a reduction in local authority governance of schools. Some of the barriers and facilitators for implementing the previous NICE guidance have also changed.\n\nIn addition, the Chief Medical Officer's guidance on the consumption of alcohol by children and young people was published in 2009. This advises parents and children that an alcohol-free childhood is the healthiest and best option.\n\nIn light of all these changes, we decided to update the guideline.\n\nThe Department of Health and Social Care's youth alcohol action plan acknowledges that alcohol education in schools is crucial. In England, personal, social, health and economic education (PSHE) is the most common way to deliver this. Currently PSHE is not statutory (Personal, social, health and economic education, Department for Education). But from 2020 the health aspects will be compulsory in all schools.\n\nThis guideline covers children and young people aged 11 to 18 in full-time education and young people aged 18 to 25 with special educational needs and disabilities in full-time education. The latter group has been added to the groups covered by PH7, in line with the Children and Families Act 2014."}
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https://www.nice.org.uk/guidance/ng135
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This guideline covers interventions in secondary and further education to prevent and reduce alcohol use among children and young people aged 11 up to and including 18. It also covers people aged 11 to 25 with special educational needs or disabilities in full-time education. It will also be relevant to children aged 11 in year 6 of primary school.
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80c4af2f0ac0bee86a105d4f974f1e0ccb5ae286
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nice
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PICO negative pressure wound dressings for closed surgical incisions
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PICO negative pressure wound dressings for closed surgical incisions
Evidence-based recommendations on PICO negative pressure wound dressings for closed surgical incisions.
# Recommendations
Evidence supports the case for adopting PICO negative pressure wound dressings for closed surgical incisions in the NHS. They are associated with fewer surgical site infections and seromas compared with standard wound dressings.
PICO negative pressure wound dressings should be considered as an option for closed surgical incisions in people who are at high risk of developing surgical site infections. Risk factors for surgical site infections are described in section 4.2.
Cost modelling suggests that PICO negative pressure wound dressings provide extra clinical benefits at a similar overall cost compared with standard wound dressings.
Why the committee made these recommendations
PICO negative pressure wound dressings are designed to allow an even distribution of negative pressure on the surface of a closed surgical incision. The system is also designed to be portable. Clinical evidence shows that using PICO dressings for closed surgical incisions can lead to fewer surgical site infections. Evidence also shows that using PICO dressings reduces the rate of seromas compared with standard wound dressings. Cost analyses suggest that using PICO dressings will not add to the overall costs of treatment.# The technology
Technology
PICO is a canister-free, single-use, negative pressure wound therapy system consisting of a sterile pump and multi-layered adhesive dressings. Each dressing has 4 layers: a silicone adhesive wound contact layer, which is designed to minimise pain and damage during peel-back and to reduce lateral tension; an airlock layer for even distribution of pressure; an absorbent layer to remove exudate and bacteria from the wound; and a top film layer, which acts as a physical barrier and allows moisture to evaporate. The pump is operated by 2 AA batteries and delivers a continuous negative pressure of 80 mmHg to a sealed wound. Once activated, using a push button, the battery drives the pump for up to 7 days and LEDs provide alerts for low-battery status and pressure leaks.
Standard PICO dressings come in 8 sizes: 10×20 cm, 10×30 cm, 10×40 cm, 15×15 cm, 15×20 cm, 15×30 cm, 20×20 cm and 25×25 cm. Multisite PICO dressings come in 2 sizes: small (15×20 cm) and large (20×25 cm).
The latest version of the technology is the PICO7 system. This differs from the version of PICO notified to NICE by having an improved pump to minimise leakage and an integrated belt clip to allow for easier transport. The PICO7 pump contains a magnet and it should be positioned at least 10 cm (4 inches) away from other medical devices that could be affected by magnetic interference.
Innovative aspects
PICO differs from conventional negative pressure wound dressings in that it:
has no separate canister
is portable and disposable
has a proprietary dressing layer that is designed to allow even distribution of negative pressure across the incision and zone of injury.
Intended use
PICO is intended for surgical incisions with low or moderate levels of exudate. This guidance focuses on the use of PICO dressings for closed surgical incisions. PICO dressings can be applied by healthcare professionals including surgeons and tissue viability nurses for people in a range of care settings. Training is needed to place the dressings correctly (see section 4.8).
Costs
Standard PICO dressings are available in 8 different sizes. Each pack includes a single-use pump and 2 dressings. The list prices for PICO dressings range from £127.06 to £145.68 (including VAT).
For more details, see the website for PICO dressings.# Evidence
# Clinical evidence
## Relevant evidence comes from 31 studies, 15 of which are randomised controlled trials
Of the 31 studies that provided evidence relevant to the decision problem, 15 were randomised controlled trials and 16 were non-randomised comparative observational studies. The 15 randomised controlled trials were done in secondary or tertiary care and were based on preventing surgical site complications in people with closed surgical incisions who were at high risk of complications after surgery. One was done in the UK. For full details of the clinical evidence, see section 3 of the assessment report.
## Randomised controlled trial evidence shows fewer surgical site infections with PICO dressings compared with standard wound dressings
Of the 15 randomised controlled trials, 8 compared PICO dressings with standard wound dressings in people with closed surgical incisions in Australia, Poland, the UK, Ireland, Japan, Denmark and the US (Chayboyer et al. 2014, Gillespie et al. 2015, Witt-Najchrazak et al. 2015, Karlakki et al. 2016, O'Leary et al. 2016, Uchino et al. 2016, Hyldig et al. 2018 and Galiano et al. 2018 respectively). The studies included a wide range of different types of surgery. The external assessment centre (EAC) considered these studies to have acceptable internal and external validity and to provide relevant evidence on the effectiveness of PICO dressings. Pooled effect estimates from a random-effects meta-analysis of the 8 studies showed a significant reduction in surgical site infection rates in favour of PICO dressings (n=1,804, odds ratio 0.51, 95% confidence interval 0.3 to 0.82; p=0.006).
## Results from observational studies support the randomised controlled trial evidence
Of the 16 non-randomised comparative observational studies, 10 compared the rates of surgical site infection using PICO dressings with standard wound dressings in people with closed surgical incisions (Adogwa et al. 2014, Matsumoto et al. 2014, Pellino et al. 2014, Pellino et al. 2014b, Selvaggi et al. 2014, Hickson et al. 2015, Fleming et al. 2017, Tan et al. 2017, van der Valk et al. 2017 and Dingemans et al. 2018). The studies included a wide range of different types of surgery. The EAC considered the included observational studies to have acceptable levels of both internal and external validity, and concluded that the evidence was relevant to the decision problem. Pooled effect estimates from a random-effects meta-analysis of the 10 studies showed a significant reduction in surgical site infection rates in favour of PICO dressings (n=2,669, OR 0.27, 95% CI 0.14 to 0.53; p=0.001). However, the EAC noted that the observational studies may overestimate the clinical benefits of PICO dressings because of potential selection and publication bias.
## Pooled analyses show a reduction in the rate of seromas with PICO dressings
Two of the randomised controlled trials and 5 of the observational studies also reported rates of seromas in people with closed surgical incisions. Pooled effect estimates from a random-effects meta-analysis of these 7 studies showed a significant reduction in the incidence of seromas in favour of PICO dressings in a range of different types of surgery (n=771, OR 0.19, 95% CI 0.08 to 0.47; p=0.0003). The EAC noted that this reduction in seroma rates was mainly driven by the observational study results.
## Reductions in surgical site infections with PICO dressings vary across different types of surgery
The included studies considered the use of PICO dressings for 6 different types of surgery:
-rthopaedic surgery (2 randomised controlled trials and 3 observational studies, n=607)
colorectal surgery (1 randomised controlled trial and 4 observational studies, n=209)
-bstetric surgery (2 randomised controlled trials and 1 observational study, n=2,911)
plastic/breast surgery (1 randomised controlled trial and 1 observational study, n=420)
vascular surgery (2 observational studies, n=193)
cardiothoracic surgery (1 randomised controlled trial, n=80).Analyses by surgery type showed that reductions in the rate of surgical site infection rates with PICO varied across different types of surgery: the reductions were only significant in obstetric surgery (OR 0.48, 95% CI 0.30 to 0.76; p=0.002) and orthopaedic surgery (OR 0.45, 95% CI 0.22 to 0.91; p=0.03).
## There are limitations in the evidence but it is relevant to the decision problem
The EAC noted the clinical and statistical heterogeneity of the studies that were included in the meta-analyses. There was wide variation in the risk characteristics of the populations, the definition of surgical site infections, how long the dressing was in place, and the length and frequency of follow up. The analyses based on surgery type also included relatively few studies. Nonetheless, the random-effects meta-analyses included a relatively large number of study populations and the EAC concluded that the results were relevant to the decision problem.
## PICO dressings may be linked to increased risk of skin blister and maceration in some people
One randomised controlled trial (Karlakki et al. 2016) reported a higher overall rate of blisters in people who had PICO dressings compared with those who had standard wound dressings (11% compared with 1%). The rate of blisters differed considerably between the 3 surgeons who took part in the study. For full details of the adverse events, see section 3.7 of the assessment report.
# Cost evidence
## The company's cost model shows that PICO dressings are cost saving in people with closed surgical incisions
The company's base-case model showed that 90 days after surgery, PICO dressings are cost saving by around £101 per person compared with standard wound dressings.
## The EAC's changes to the cost model more accurately reflect the costs and consequences to the NHS
The EAC considered that the structure of the company's cost model was adequate for decision making. However, it identified some limitations in the model parameters and made changes to better reflect potential resource use in the NHS. Specifically, the EAC:
applied baseline incidence rates and the cost of surgical site infections from a UK data source (Jenks et al. 2014)
calculated the mean cost of surgical site infections by dividing the cost by the number of infections
updated the number of PICO and comparator dressings used
used clinical-effectiveness estimates based on the pooled treatment effect from the meta-analysis of the randomised controlled trials.For full details of the changes and results, see section 4 of the assessment report.
## The EAC's updated analysis shows that PICO dressings are cost neutral overall but this varies by type of surgery
With the EAC's changes, the base-case model showed that 90 days after surgery, PICO dressings are cost saving by around £6 per person compared with standard wound dressings. The main drivers of these savings were the cost of PICO, the likelihood of a surgical site infection, the cost of a surgical site infection and the effectiveness of PICO in reducing the incidence of surgical site infections. The analyses by surgery type showed that PICO was cost saving for colorectal, cardiothoracic and vascular surgery, but was not cost saving for orthopaedic, obstetric and plastic/breast surgery. For full details of the cost evidence, see section 4 of the assessment report.# Committee discussion
# Clinical-effectiveness overview
## PICO dressings are associated with lower rates of surgical site infections in people with closed surgical incisions compared with standard dressings
The committee noted considerable evidence to show the effectiveness of PICO in reducing rates of surgical site infections (18 studies) and seromas (7 studies). The company did meta-analyses using a fixed-effect model, whereas the external assessment centre (EAC) used a random-effects model. The committee considered that the EAC's approach was more appropriate because of the wide variation in the study populations, interventions and the definitions of surgical site infections. The committee concluded that there was convincing evidence that using PICO dressings reduces surgical site infections and seromas in people with closed surgical incisions. The committee considered that there was less certainty about how PICO dressings affect other surgical site complications (such as wound dehiscence, haematoma, delayed healing or excessive scarring) because of the small number of studies in the analyses.
## Careful patient selection is important and should be informed by NICE guidance
The experts advised that careful patient selection was important when using PICO dressings. The committee noted that the included studies only recruited people who were considered to be at high risk of developing surgical site complications, but that many of the studies did not explicitly state the definition of high risk. The experts advised that there were a number of factors associated with an increased risk of surgical site complications, including age, obesity, cigarette smoking and diabetes. There are also several surgical situations that increase the risk, such as repeat operations and the need for emergency surgery. The committee noted that a NICE evidence review identified the main risk factors for surgical site infections as age, underlying illness, obesity, smoking, wound classification, and site and complexity of procedure. It concluded that healthcare professionals should take these factors into account when considering whether to use PICO dressings.
## PICO dressings should be used for closed surgical incisions which are unlikely to need multiple dressing changes
The committee noted that PICO is intended for closed surgical incisions in which the amount of exudate was anticipated to be low or moderate. The clinical experts advised that PICO dressings should be used for closed surgical incisions that are unlikely to need multiple dressing changes. Large amounts of exudate may lead to multiple dressing changes being needed, so PICO dressings should not be used for these types of wounds.
## Benefits of PICO dressings vary by type of surgery
The committee noted that the published evidence included the use of PICO dressings in 6 different types of surgery, and that the meta-analysis identified a statistically significant reduction in the risk of surgical site infections when it was used in orthopaedic and obstetric surgery. The committee concluded that the type of surgery was an important factor in selecting people for PICO dressings, and that it should be considered in the overall risk assessment for post-operative complications. However, the committee considered that the evidence was too limited to make recommendations on the use of PICO dressings by surgery type.
# Side effects and adverse events
## Adverse events are uncommon but some people may develop skin blisters and maceration with PICO dressings
The committee noted that adverse events were rare in the studies but that skin blisters and maceration may occur when using PICO dressings. A clinical expert advised that skin blisters may develop because of skin tension, which is likely to be the result of the dressing being stretched over the wound. This was corroborated by the results of 1 study, in which the highest incidence of skin blisters was in people whose dressings were applied by trainee staff.
## Pump failure may incur additional costs but this is rare
The company stated that there had been around 147 reported cases of the PICO pump failing since its launch in 2007. The committee considered that pump failure would incur additional costs, including application of additional dressings and pump replacement, but it acknowledged that the reported rates of pump failure were very low.
# Relevance to the NHS
## The evidence for PICO dressings is broadly generalisable to the NHS
The committee noted that only a small number of the studies included NHS settings; for example, only 1 of the randomised controlled trials was done in the UK. However, 9 of the studies included in the meta-analyses were done in European countries including Ireland, Italy, the Netherlands, Denmark and Poland. A clinical expert stated that PICO dressings are widely used across Europe and that both population demographics and the fundamentals of wound therapy were likely to be similar across Europe. The committee concluded that the evidence for PICO dressings was broadly generalisable to the NHS.
## The evidence is generalisable to the PICO7 system
The committee noted that since the technology was notified to NICE, newer versions of PICO dressings have been developed. The latest version available to the NHS is the PICO7 system. The company confirmed that the PICO7 has an improved pump design and belt clip but that the functional mechanism of the dressings remains the same. The committee considered that the evidence on which it evaluated PICO dressings was generalisable to the PICO7 system.
# NHS considerations
## Some training is needed in how to apply PICO dressings
The clinical experts advised that training was an important consideration in the use of PICO dressings. Maintaining a seal is integral to the continued effectiveness of negative pressure, but in creating the seal it is important to ensure that the skin is not placed under excessive tension. The experts also described certain situations in which applying the dressing was awkward (such as on the lower abdomen after a caesarean section or over bony protrusions, especially if there is excessive moisture). The experts also stated that training is important for healthcare staff who provide post-operative care both in hospital and in the community. They emphasised that a lack of knowledge may lead to dressings being removed too early, or to unnecessary dressing changes that are likely to negatively affect clinical outcomes and costs. The committee concluded that training was important in realising the benefits of PICO dressings.
# Cost modelling overview
## The EAC's updated model is more appropriate for decision making
The committee noted the EAC's changes to the company's cost model (see section 3.9) and agreed that the updated model better reflected cost and resource use in the NHS. The committee considered the numbers of PICO dressings and standard dressings that were likely to be needed per person, and the importance of length of stay in hospital in determining cost calculations. It noted that the instructions for use suggest that 1 PICO kit (1 pump and 2 dressings) will last for up to 7 days after surgery. However, the clinical experts indicated that the number of dressings used and the length of stay vary widely depending on the type of surgery. The EAC explained that its calculations were based on the use of 1.09 PICO dressings per person with an average of 5.3 days' stay in hospital. It also estimated the number of PICO dressings used by surgery type; for example, it estimated 1.81 PICO dressings used for colorectal surgery and 1.58 used for vascular surgery. The committee concluded that although it agreed with the EAC's approach to cost modelling, there were uncertainties because of the differences in the populations considered.
# Main cost drivers
## It is likely that the additional cost of PICO dressings will be offset by a reduction in surgical site infections
The committee noted how the rate and cost of surgical site infections affected the outcomes of the cost modelling. Having seen convincing evidence to support a reduction in the rate of surgical site infections with PICO dressings, the committee concluded it was plausible that the additional cost of PICO dressings compared with standard wound dressings would be offset by a reduction in the overall costs associated with treating surgical site infections.
## The model is most sensitive to the purchase cost and effectiveness of PICO dressings
The EAC did sensitivity analyses, which showed that the cost model was most sensitive to the purchase cost of PICO dressings and their effectiveness in reducing surgical site infections.
## The model does not include staff costs for applying dressings but these are negligible
The committee noted that neither the company's original model nor the EAC's updated model included staff costs associated with applying PICO and standard wound dressings. Although applying a PICO dressing could take an additional 1 or 2 minutes compared with applying a standard wound dressing, a clinical expert noted that for appropriately trained staff any additional time was negligible.
# Cost savings
## PICO dressings provide extra benefits at no additional cost to the NHS
The committee recalled the EAC's updated cost model, which suggested that PICO dressings are cost saving by around £6 per person (although the cost saving may vary by type of surgery). Overall, the committee concluded that PICO dressings are likely to provide extra clinical benefits at a similar overall cost compared with standard wound dressings.
The committee considered an evidence review done for NICE's 2008 guideline on preventing and treating surgical site infections (section 3).
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{'Recommendations': 'Evidence supports the case for adopting PICO negative pressure wound dressings for closed surgical incisions in the NHS. They are associated with fewer surgical site infections and seromas compared with standard wound dressings.\n\nPICO negative pressure wound dressings should be considered as an option for closed surgical incisions in people who are at high risk of developing surgical site infections. Risk factors for surgical site infections are described in section 4.2.\n\nCost modelling suggests that PICO negative pressure wound dressings provide extra clinical benefits at a similar overall cost compared with standard wound dressings.\n\nWhy the committee made these recommendations\n\nPICO negative pressure wound dressings are designed to allow an even distribution of negative pressure on the surface of a closed surgical incision. The system is also designed to be portable. Clinical evidence shows that using PICO dressings for closed surgical incisions can lead to fewer surgical site infections. Evidence also shows that using PICO dressings reduces the rate of seromas compared with standard wound dressings. Cost analyses suggest that using PICO dressings will not add to the overall costs of treatment.', 'The technology': 'Technology\n\nPICO is a canister-free, single-use, negative pressure wound therapy system consisting of a sterile pump and multi-layered adhesive dressings. Each dressing has 4 layers: a silicone adhesive wound contact layer, which is designed to minimise pain and damage during peel-back and to reduce lateral tension; an airlock layer for even distribution of pressure; an absorbent layer to remove exudate and bacteria from the wound; and a top film layer, which acts as a physical barrier and allows moisture to evaporate. The pump is operated by 2 AA batteries and delivers a continuous negative pressure of 80 mmHg to a sealed wound. Once activated, using a push button, the battery drives the pump for up to 7\xa0days and LEDs provide alerts for low-battery status and pressure leaks.\n\nStandard PICO dressings come in 8 sizes: 10×20\xa0cm, 10×30\xa0cm, 10×40\xa0cm, 15×15\xa0cm, 15×20\xa0cm, 15×30\xa0cm, 20×20\xa0cm and 25×25\xa0cm. Multisite PICO dressings come in 2 sizes: small (15×20\xa0cm) and large (20×25\xa0cm).\n\nThe latest version of the technology is the PICO7 system. This differs from the version of PICO notified to NICE by having an improved pump to minimise leakage and an integrated belt clip to allow for easier transport. The PICO7 pump contains a magnet and it should be positioned at least 10\xa0cm (4\xa0inches) away from other medical devices that could be affected by magnetic interference.\n\nInnovative aspects\n\nPICO differs from conventional negative pressure wound dressings in that it:\n\nhas no separate canister\n\nis portable and disposable\n\nhas a proprietary dressing layer that is designed to allow even distribution of negative pressure across the incision and zone of injury.\n\nIntended use\n\nPICO is intended for surgical incisions with low or moderate levels of exudate. This guidance focuses on the use of PICO dressings for closed surgical incisions. PICO dressings can be applied by healthcare professionals including surgeons and tissue viability nurses for people in a range of care settings. Training is needed to place the dressings correctly (see section\xa04.8).\n\nCosts\n\nStandard PICO dressings are available in 8 different sizes. Each pack includes a single-use pump and 2 dressings. The list prices for PICO dressings range from £127.06 to £145.68 (including VAT).\n\nFor more details, see the website for PICO dressings.', 'Evidence': "# Clinical evidence\n\n## Relevant evidence comes from 31 studies, 15 of which are randomised controlled trials\n\nOf the 31 studies that provided evidence relevant to the decision problem, 15 were randomised controlled trials and 16 were non-randomised comparative observational studies. The 15 randomised controlled trials were done in secondary or tertiary care and were based on preventing surgical site complications in people with closed surgical incisions who were at high risk of complications after surgery. One was done in the UK. For full details of the clinical evidence, see section 3 of the assessment report.\n\n## Randomised controlled trial evidence shows fewer surgical site infections with PICO dressings compared with standard wound dressings\n\nOf the 15 randomised controlled trials, 8 compared PICO dressings with standard wound dressings in people with closed surgical incisions in Australia, Poland, the UK, Ireland, Japan, Denmark and the US (Chayboyer\xa0et\xa0al.\xa02014, Gillespie\xa0et\xa0al.\xa02015, Witt-Najchrazak\xa0et\xa0al.\xa02015, Karlakki\xa0et\xa0al.\xa02016, O'Leary\xa0et\xa0al.\xa02016, Uchino\xa0et\xa0al.\xa02016, Hyldig\xa0et\xa0al.\xa02018 and Galiano\xa0et\xa0al.\xa02018 respectively). The studies included a wide range of different types of surgery. The external assessment centre (EAC) considered these studies to have acceptable internal and external validity and to provide relevant evidence on the effectiveness of PICO dressings. Pooled effect estimates from a random-effects meta-analysis of the 8 studies showed a significant reduction in surgical site infection rates in favour of PICO dressings (n=1,804, odds ratio [OR] 0.51, 95% confidence interval [CI] 0.3 to 0.82; p=0.006).\n\n## Results from observational studies support the randomised controlled trial evidence\n\nOf the 16 non-randomised comparative observational studies, 10 compared the rates of surgical site infection using PICO dressings with standard wound dressings in people with closed surgical incisions (Adogwa\xa0et\xa0al.\xa02014, Matsumoto\xa0et\xa0al.\xa02014, Pellino\xa0et\xa0al.\xa02014, Pellino\xa0et\xa0al.\xa02014b, Selvaggi\xa0et\xa0al.\xa02014, Hickson\xa0et\xa0al.\xa02015, Fleming\xa0et\xa0al.\xa02017, Tan\xa0et\xa0al.\xa02017, van der Valk\xa0et\xa0al.\xa02017 and Dingemans\xa0et\xa0al.\xa02018). The studies included a wide range of different types of surgery. The EAC considered the included observational studies to have acceptable levels of both internal and external validity, and concluded that the evidence was relevant to the decision problem. Pooled effect estimates from a random-effects meta-analysis of the 10 studies showed a significant reduction in surgical site infection rates in favour of PICO dressings (n=2,669, OR 0.27, 95% CI 0.14 to 0.53; p=0.001). However, the EAC noted that the observational studies may overestimate the clinical benefits of PICO dressings because of potential selection and publication bias.\n\n## Pooled analyses show a reduction in the rate of seromas with PICO dressings\n\nTwo of the randomised controlled trials and 5 of the observational studies also reported rates of seromas in people with closed surgical incisions. Pooled effect estimates from a random-effects meta-analysis of these 7 studies showed a significant reduction in the incidence of seromas in favour of PICO dressings in a range of different types of surgery (n=771, OR 0.19, 95% CI 0.08 to 0.47; p=0.0003). The EAC noted that this reduction in seroma rates was mainly driven by the observational study results.\n\n## Reductions in surgical site infections with PICO dressings vary across different types of surgery\n\nThe included studies considered the use of PICO dressings for 6 different types of surgery:\n\northopaedic surgery (2 randomised controlled trials and 3 observational studies, n=607)\n\ncolorectal surgery (1 randomised controlled trial and 4 observational studies, n=209)\n\nobstetric surgery (2 randomised controlled trials and 1 observational study, n=2,911)\n\nplastic/breast surgery (1 randomised controlled trial and 1 observational study, n=420)\n\nvascular surgery (2 observational studies, n=193)\n\ncardiothoracic surgery (1 randomised controlled trial, n=80).Analyses by surgery type showed that reductions in the rate of surgical site infection rates with PICO varied across different types of surgery: the reductions were only significant in obstetric surgery (OR 0.48, 95% CI 0.30 to 0.76; p=0.002) and orthopaedic surgery (OR 0.45, 95% CI 0.22 to 0.91; p=0.03).\n\n## There are limitations in the evidence but it is relevant to the decision problem\n\nThe EAC noted the clinical and statistical heterogeneity of the studies that were included in the meta-analyses. There was wide variation in the risk characteristics of the populations, the definition of surgical site infections, how long the dressing was in place, and the length and frequency of follow up. The analyses based on surgery type also included relatively few studies. Nonetheless, the random-effects meta-analyses included a relatively large number of study populations and the EAC concluded that the results were relevant to the decision problem.\n\n## PICO dressings may be linked to increased risk of skin blister and maceration in some people\n\nOne randomised controlled trial (Karlakki\xa0et\xa0al.\xa02016) reported a higher overall rate of blisters in people who had PICO dressings compared with those who had standard wound dressings (11% compared with 1%). The rate of blisters differed considerably between the 3 surgeons who took part in the study. For full details of the adverse events, see section 3.7 of the assessment report.\n\n# Cost evidence\n\n## The company's cost model shows that PICO dressings are cost saving in people with closed surgical incisions\n\nThe company's base-case model showed that 90\xa0days after surgery, PICO dressings are cost saving by around £101\xa0per\xa0person compared with standard wound dressings.\n\n## The EAC's changes to the cost model more accurately reflect the costs and consequences to the NHS\n\nThe EAC considered that the structure of the company's cost model was adequate for decision making. However, it identified some limitations in the model parameters and made changes to better reflect potential resource use in the NHS. Specifically, the EAC:\n\napplied baseline incidence rates and the cost of surgical site infections from a UK data source (Jenks\xa0et\xa0al.\xa02014)\n\ncalculated the mean cost of surgical site infections by dividing the cost by the number of infections\n\nupdated the number of PICO and comparator dressings used\n\nused clinical-effectiveness estimates based on the pooled treatment effect from the meta-analysis of the randomised controlled trials.For full details of the changes and results, see section 4 of the assessment report.\n\n## The EAC's updated analysis shows that PICO dressings are cost neutral overall but this varies by type of surgery\n\nWith the EAC's changes, the base-case model showed that 90\xa0days after surgery, PICO dressings are cost saving by around £6\xa0per\xa0person compared with standard wound dressings. The main drivers of these savings were the cost of PICO, the likelihood of a surgical site infection, the cost of a surgical site infection and the effectiveness of PICO in reducing the incidence of surgical site infections. The analyses by surgery type showed that PICO was cost saving for colorectal, cardiothoracic and vascular surgery, but was not cost saving for orthopaedic, obstetric and plastic/breast surgery. For full details of the cost evidence, see section\xa04 of the assessment report.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## PICO dressings are associated with lower rates of surgical site infections in people with closed surgical incisions compared with standard dressings\n\nThe committee noted considerable evidence to show the effectiveness of PICO in reducing rates of surgical site infections (18 studies) and seromas (7 studies). The company did meta-analyses using a fixed-effect model, whereas the external assessment centre (EAC) used a random-effects model. The committee considered that the EAC's approach was more appropriate because of the wide variation in the study populations, interventions and the definitions of surgical site infections. The committee concluded that there was convincing evidence that using PICO dressings reduces surgical site infections and seromas in people with closed surgical incisions. The committee considered that there was less certainty about how PICO dressings affect other surgical site complications (such as wound dehiscence, haematoma, delayed healing or excessive scarring) because of the small number of studies in the analyses.\n\n## Careful patient selection is important and should be informed by NICE guidance\n\nThe experts advised that careful patient selection was important when using PICO dressings. The committee noted that the included studies only recruited people who were considered to be at high risk of developing surgical site complications, but that many of the studies did not explicitly state the definition of high risk. The experts advised that there were a number of factors associated with an increased risk of surgical site complications, including age, obesity, cigarette smoking and diabetes. There are also several surgical situations that increase the risk, such as repeat operations and the need for emergency surgery. The committee noted that a NICE evidence review identified the main risk factors for surgical site infections as age, underlying illness, obesity, smoking, wound classification, and site and complexity of procedure. It concluded that healthcare professionals should take these factors into account when considering whether to use PICO dressings.\n\n## PICO dressings should be used for closed surgical incisions which are unlikely to need multiple dressing changes\n\nThe committee noted that PICO is intended for closed surgical incisions in which the amount of exudate was anticipated to be low or moderate. The clinical experts advised that PICO dressings should be used for closed surgical incisions that are unlikely to need multiple dressing changes. Large amounts of exudate may lead to multiple dressing changes being needed, so PICO dressings should not be used for these types of wounds.\n\n## Benefits of PICO dressings vary by type of surgery\n\nThe committee noted that the published evidence included the use of PICO dressings in 6 different types of surgery, and that the meta-analysis identified a statistically significant reduction in the risk of surgical site infections when it was used in orthopaedic and obstetric surgery. The committee concluded that the type of surgery was an important factor in selecting people for PICO dressings, and that it should be considered in the overall risk assessment for post-operative complications. However, the committee considered that the evidence was too limited to make recommendations on the use of PICO dressings by surgery type.\n\n# Side effects and adverse events\n\n## Adverse events are uncommon but some people may develop skin blisters and maceration with PICO dressings\n\nThe committee noted that adverse events were rare in the studies but that skin blisters and maceration may occur when using PICO dressings. A clinical expert advised that skin blisters may develop because of skin tension, which is likely to be the result of the dressing being stretched over the wound. This was corroborated by the results of 1 study, in which the highest incidence of skin blisters was in people whose dressings were applied by trainee staff.\n\n## Pump failure may incur additional costs but this is rare\n\nThe company stated that there had been around 147 reported cases of the PICO pump failing since its launch in 2007. The committee considered that pump failure would incur additional costs, including application of additional dressings and pump replacement, but it acknowledged that the reported rates of pump failure were very low.\n\n# Relevance to the NHS\n\n## The evidence for PICO dressings is broadly generalisable to the NHS\n\nThe committee noted that only a small number of the studies included NHS settings; for example, only 1 of the randomised controlled trials was done in the UK. However, 9 of the studies included in the meta-analyses were done in European countries including Ireland, Italy, the Netherlands, Denmark and Poland. A clinical expert stated that PICO dressings are widely used across Europe and that both population demographics and the fundamentals of wound therapy were likely to be similar across Europe. The committee concluded that the evidence for PICO dressings was broadly generalisable to the NHS.\n\n## The evidence is generalisable to the PICO7 system\n\nThe committee noted that since the technology was notified to NICE, newer versions of PICO dressings have been developed. The latest version available to the NHS is the PICO7 system. The company confirmed that the PICO7 has an improved pump design and belt clip but that the functional mechanism of the dressings remains the same. The committee considered that the evidence on which it evaluated PICO dressings was generalisable to the PICO7 system.\n\n# NHS considerations\n\n## Some training is needed in how to apply PICO dressings\n\nThe clinical experts advised that training was an important consideration in the use of PICO dressings. Maintaining a seal is integral to the continued effectiveness of negative pressure, but in creating the seal it is important to ensure that the skin is not placed under excessive tension. The experts also described certain situations in which applying the dressing was awkward (such as on the lower abdomen after a caesarean section or over bony protrusions, especially if there is excessive moisture). The experts also stated that training is important for healthcare staff who provide post-operative care both in hospital and in the community. They emphasised that a lack of knowledge may lead to dressings being removed too early, or to unnecessary dressing changes that are likely to negatively affect clinical outcomes and costs. The committee concluded that training was important in realising the benefits of PICO dressings.\n\n# Cost modelling overview\n\n## The EAC's updated model is more appropriate for decision making\n\nThe committee noted the EAC's changes to the company's cost model (see section 3.9) and agreed that the updated model better reflected cost and resource use in the NHS. The committee considered the numbers of PICO dressings and standard dressings that were likely to be needed\xa0per\xa0person, and the importance of length of stay in hospital in determining cost calculations. It noted that the instructions for use suggest that 1 PICO kit (1 pump and 2 dressings) will last for up to 7\xa0days after surgery. However, the clinical experts indicated that the number of dressings used and the length of stay vary widely depending on the type of surgery. The EAC explained that its calculations were based on the use of 1.09 PICO dressings\xa0per\xa0person with an average of 5.3\xa0days' stay in hospital. It also estimated the number of PICO dressings used by surgery type; for example, it estimated 1.81 PICO dressings used for colorectal surgery and 1.58 used for vascular surgery. The committee concluded that although it agreed with the EAC's approach to cost modelling, there were uncertainties because of the differences in the populations considered.\n\n# Main cost drivers\n\n## It is likely that the additional cost of PICO dressings will be offset by a reduction in surgical site infections\n\nThe committee noted how the rate and cost of surgical site infections affected the outcomes of the cost modelling. Having seen convincing evidence to support a reduction in the rate of surgical site infections with PICO dressings, the committee concluded it was plausible that the additional cost of PICO dressings compared with standard wound dressings would be offset by a reduction in the overall costs associated with treating surgical site infections.\n\n## The model is most sensitive to the purchase cost and effectiveness of PICO dressings\n\nThe EAC did sensitivity analyses, which showed that the cost model was most sensitive to the purchase cost of PICO dressings and their effectiveness in reducing surgical site infections.\n\n## The model does not include staff costs for applying dressings but these are negligible\n\nThe committee noted that neither the company's original model nor the EAC's updated model included staff costs associated with applying PICO and standard wound dressings. Although applying a PICO dressing could take an additional 1 or 2 minutes compared with applying a standard wound dressing, a clinical expert noted that for appropriately trained staff any additional time was negligible.\n\n# Cost savings\n\n## PICO dressings provide extra benefits at no additional cost to the NHS\n\nThe committee recalled the EAC's updated cost model, which suggested that PICO dressings are cost saving by around £6\xa0per\xa0person (although the cost saving may vary by type of surgery). Overall, the committee concluded that PICO dressings are likely to provide extra clinical benefits at a similar overall cost compared with standard wound dressings.\n\n The committee considered an evidence review done for NICE's 2008 guideline on preventing and treating surgical site infections (section 3)."}
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https://www.nice.org.uk/guidance/mtg43
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Evidence-based recommendations on PICO negative pressure wound dressings for closed surgical incisions.
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bc105bffb6a4e53dd1048242ffac66653075e3ae
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nice
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Fluocinolone acetonide intravitreal implant for treating recurrent non-infectious uveitis
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Fluocinolone acetonide intravitreal implant for treating recurrent non-infectious uveitis
Evidence-based recommendations on fluocinolone acetonide intravitreal implant (Iluvien) for treating recurrent non-infectious uveitis in adults.
# Recommendations
Fluocinolone acetonide intravitreal implant is recommended, within its marketing authorisation, as an option for preventing relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Treatments for recurrent non-infectious uveitis affecting the posterior segment of the eye include systemic corticosteroids, immunosuppressants and dexamethasone implants. These treatments can be disruptive to daily life, needing frequent hospital visits.
The clinical trial results for the fluocinolone acetonide intravitreal implant compared with limited current practice are difficult to interpret and very uncertain. The trial didn't directly measure health-related quality of life and the number of recurrences reported may be overestimated.
The cost-effectiveness estimates are also uncertain. However, if all the most plausible assumptions had been included in the model, most of the cost-effectiveness estimates would be within the range that NICE normally considers a cost-effective use of NHS resources, so the fluocinolone acetonide implant is recommended.# Information about fluocinolone acetonide intravitreal implant
Marketing authorisation indication
Fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) is indicated for 'prevention of relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye'.
Dosage in the marketing authorisation
Fluocinolone acetonide intravitreal implant is administered through intravitreal injection. Each implant contains 0.19 mg of fluocinolone acetonide and releases fluocinolone acetonide for up to 36 months.
Price
£5,500 per implant (excluding VAT, British national formulary online ).
The company has a commercial arrangement. This makes fluocinolone acetonide intravitreal implant available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Alimera Sciences and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with recurrent non-infectious uveitis affecting the posterior segment of the eye will welcome a new treatment option
Patient experts described the anxiety associated with having uveitis because of potentially worsening sight, if they will be able to continue working and how it affects their relationships and independence. They explained that existing treatments for controlling recurrent non-infectious uveitis can be burdensome and disruptive to daily life for both patients and their carers, needing frequent hospital visits for administration and monitoring. The patient experts described how having a treatment that lasts for 3 years had substantially increased their quality of life. They highlighted that the fluocinolone acetonide implant could be particularly beneficial for people who cannot have systemic treatments. One of the patient experts described how the effects of the dexamethasone implant had lasted for much less than the 6 months they had been expecting. The clinical experts also highlighted that biologic treatments are not effective in 20% to 30% of people with recurrent non-infectious uveitis and there is a need for alternative treatment options. The committee concluded that people with recurrent non-infectious uveitis affecting the posterior segment of the eye would welcome an additional treatment option, particularly one with long-lasting benefits.
# Clinical management
## The dexamethasone implant is a relevant comparator
The clinical experts explained that non-infectious uveitis is treated differently depending on whether the disease is:
active (that is, current inflammation in the eye) or inactive (that is, limited inflammation, usually because of treatment with corticosteroids or immunosuppressants)
systemic (when disease is not only in the eye) or non-systemic (when disease is limited to the eye)
unilateral (when 1 eye is affected) or bilateral (when both eyes are affected).There may also be local variation in treatment. Non-infectious uveitis without systemic disease may first be treated with local corticosteroids, followed by systemic corticosteroids or a dexamethasone implant. Multiple repeated dexamethasone implants may be given. Bilateral disease or unilateral disease with active systemic disease may first be treated with systemic corticosteroids, followed by immunosuppressants or dexamethasone implants. Treatments may also be used in combination. TNF-alpha inhibitors such as adalimumab may be an option after immunosuppressants. The marketing authorisation for the fluocinolone acetonide implant is for recurrent disease, so the clinical experts explained that they would most likely offer it to people who had already had corticosteroids. They explained that if the disease responded well to a dexamethasone implant, they would consider using a fluocinolone acetonide implant instead of another dexamethasone implant. The committee agreed that in NHS clinical practice in England, it was likely that the fluocinolone acetonide implant would be used after corticosteroids, as an alternative to the dexamethasone implant. The committee concluded that the dexamethasone implant was a relevant comparator for the fluocinolone acetonide implant.
# Clinical evidence
## The clinical trial may not fully reflect NHS clinical practice in England
The evidence for the fluocinolone acetonide implant came from the PSV-FAI-001 trial. This was a multicentre, randomised, double-blind trial in patients with chronic non-infectious uveitis affecting the posterior segment of the eye. It compared the fluocinolone acetonide implant with a sham injection. Patients in both treatment groups could have 'limited current practice': this was the corticosteroids and immunosuppressants that they had been having before enrolling in the trial but tapered off within the first 3 months. Other than treatments that were being tapered off, patients could not have corticosteroids or immunosuppressants until their uveitis recurred. This meant that after 3 months and before recurrence, people in the control group had no treatment. Additionally, before recurrence in the trial, trial investigators were encouraged to use systemic treatment only after local treatment had failed. The committee agreed that this may not reflect clinical practice in the NHS in England because the clinical experts had said that systemic treatment may be given first for bilateral or systemic disease (see section 3.2). The committee concluded that treatment in the trial may not fully reflect NHS clinical practice in England.
# Recurrence of uveitis
## Rates of recurrence of uveitis in the trial are likely overestimated
The primary outcome in the PSV-FAI-001 trial was the proportion of patients who had a recurrence of uveitis in the study eye within 6 months of having study treatment. After 12 months, the recurrence rate was 37.9% in the fluocinolone acetonide implant group and 97.6% in the control group. However, the committee noted that recurrence was assumed for patients who had missing data for the required eye examinations, or who had local or systemic treatments that were prohibited as part of the trial. The trial did not record why these treatments were given, but the committee considered that they may have been used to treat the other eye or for an underlying condition (rather than for recurrent uveitis in the study eye). So, it agreed that the recurrence rates reported in the trial were likely overestimated.
# Visual acuity
## The fluocinolone acetonide implant improves visual acuity
Visual acuity was a secondary outcome in the PSV-FAI-001 trial. After 12 months, mean best-corrected visual acuity (BCVA) in the control group had increased from 64.9 letters to 69.2 letters. In the fluocinolone acetonide implant group, mean BCVA increased from 66.9 letters to 72.8 letters. The clinical experts explained that a 5-letter increase in BCVA is clinically meaningful. They highlighted that most of the people in the control group had had a recurrence of uveitis by 12 months, so would have had other treatments, which could explain the increase in BCVA in this group. The committee concluded that the fluocinolone acetonide implant improves visual acuity compared with current practice. However, it noted that visual acuity was not directly included in the economic model.
# Adverse effects
## Adverse effects associated with the fluocinolone acetonide implant are manageable in clinical practice
Common adverse effects of the fluocinolone acetonide implant include cataract and increased intraocular pressure. One of the patient experts explained that although developing a cataract did affect their sight, which reduced their quality of life, the cataract surgery was relatively straightforward and there was no lasting effect on their quality of life. The clinical experts stated that there was unlikely to be a big difference in the adverse effects of the fluocinolone acetonide implant compared with those of the dexamethasone implant. The committee noted that there were more older people in the control group of the trial, which may have affected the rate of adverse effects compared with that in the fluocinolone acetonide implant group. But overall, the committee considered that the fluocinolone acetonide implant is well tolerated compared with other treatments for uveitis and that the adverse effects are manageable in clinical practice.
# The company's economic model
## A model that considers both eyes would have been preferred
The company presented a Markov model with 5 health states: on treatment, subsequent therapy, remission, permanent blindness and death. The model compared the fluocinolone acetonide implant with the treatments received in the control group in the PSV-FAI-001 trial (described as 'limited current practice', see section 3.3) in the study eye only. Treatment effectiveness was modelled using time to first uveitis recurrence in the study eye from the trial. The ERG highlighted that in a potentially bilateral disease, modelling should consider both eyes to fully capture the effect of sight loss on health-related quality of life, survival and costs. The clinical experts suggested that a large proportion of people with recurrent non-infectious uveitis have bilateral disease. In the trial, 67.8% in the fluocinolone acetonide implant group and 73.8% in the control group had bilateral disease at baseline. The company stated that it could not include both eyes in the full cost-effectiveness modelling because of a lack of data. The committee concluded that it would have preferred to have seen a model that took both eyes into account.
## The model should include the possibility of multiple implants
The company's model assumed that each patient had only 1 fluocinolone acetonide implant. However, the clinical experts stated that they would consider using another fluocinolone acetonide implant after 3 years, if the disease had responded well to the first implant. The committee concluded that the model should include an option for retreatment with multiple fluocinolone acetonide implants (see section 3.13).
## The ERG's model using the dexamethasone implant as a comparator is preferred
Based on the clinical experts' description of the treatment pathway, the committee considered that the dexamethasone implant was a relevant comparator for the fluocinolone acetonide implant (see section 3.2). The ERG did a naive analysis, estimating the potential effectiveness of the dexamethasone implant compared with limited current practice (based on evidence used to inform NICE technology appraisal guidance on adalimumab and dexamethasone for treating non-infectious uveitis) so that it could include the dexamethasone implant in the model as a comparator. The analysis assumed that the dexamethasone implant was more effective than limited current practice, with a hazard ratio for time to first recurrence of 0.456. The ERG also presented scenario analyses that assumed the effectiveness of the dexamethasone implant was equal to that of the fluocinolone acetonide implant. The clinical experts suggested that they expected the effectiveness of the fluocinolone acetonide implant to be similar to that of the dexamethasone implant, for the time that the treatments remain active. The committee noted that the benefit of the dexamethasone implant lasted for almost 6 months in the model, whereas patient experts had experience of the implant lasting less than 6 months (see section 3.1). The patient experts explained that repeated dexamethasone implants can only be given after vision has deteriorated, which means a patient may have several weeks of reduced vision between implants. The committee considered that while the treatments remain active, both the fluocinolone acetonide and dexamethasone implants are likely to have a similar effect on visual acuity. However, on average over 3 years (with repeated dexamethasone implants) the fluocinolone acetonide implant may be more effective in preventing recurrence of uveitis. In response to the appraisal consultation document, the company presented its own naive analysis comparing the fluocinolone acetonide implant with the dexamethasone implant. The company scaled down the time to recurrence curve for the fluocinolone acetonide implant from 3 years to 6 months, to model the efficacy of the dexamethasone implant. The ERG highlighted that using this method made the recurrence rate in the dexamethasone implant group higher than in the fluocinolone acetonide implant group. The committee agreed that the company's method of estimating the comparative effectiveness of the dexamethasone implant was implausible. In the company's updated analyses, patients could have another implant if treatment failed, rather than waiting until the end of the expected duration of the implants (6 months for the dexamethasone implant or 3 years for the fluocinolone acetonide implant). In the company's analyses, the maximum number of dexamethasone implants that someone could have was 3, which the company explained was because of constraints of the way the new analysis was implemented in the model. The committee noted that this led to more time on treatment in the fluocinolone acetonide implant group, because it could last for up to 3 years. The committee noted that in the ERG's original analysis, patients could have 6 dexamethasone implants in 3 years, which it agreed was a better comparison because the time on treatment was the same for both groups. The committee understood that both the company's and the ERG's methods of comparing the fluocinolone acetonide implant with the dexamethasone implant were based on assumptions but concluded that the ERG's method was more plausible.
## The model should not include a remission health state
In the company's model, patients who did not have a recurrence of uveitis within 2 years were assumed to be in the remission health state, in which their health-related quality of life was the same as the general population. The committee was aware that in the assessment group's model used when developing NICE's technology appraisal guidance on adalimumab and dexamethasone, the remission health state was only used in a scenario analysis. The clinical experts explained that although remission from uveitis is possible, about 30% of people would have a recurrence if treatment were stopped, even if they had not had a recurrence for 2 years. The committee considered it unlikely that everyone who did not have a recurrence of uveitis within 2 years would be in remission. Moreover, even people with uveitis in remission may have lower health-related quality of life than the general population because of bilateral disease or underlying systemic disease. The committee concluded that the model should not include a remission health state.
## Results both with and without a transition from on treatment to permanent blindness should be included
In the company's model, there was no transition between the on treatment and permanent blindness health states. The ERG added this transition in its base-case analysis, because it was included in the model used when developing NICE's technology appraisal guidance on adalimumab and dexamethasone. The committee was aware that the company's model was consistent with the results of the PSV-FAI-001 trial. The committee concluded that results both with and without this transition would be informative.
# Treatment effectiveness in the model
## The model should not include a treatment benefit with the fluocinolone acetonide implant after 3 years
The company's model extrapolated the treatment effect of the fluocinolone acetonide implant beyond the 3-year time horizon of the trial, even though the implant only releases fluocinolone acetonide for 3 years. The clinical experts suggested that for some people there may be residual effects of the treatment after 3 years, and there is an ongoing benefit of having had stable disease for 3 years. The committee agreed that it was possible there may be some benefit after 3 years, but that there was no evidence from the trial to support this. It concluded that the model should not include any treatment benefit with the fluocinolone acetonide implant after 3 years.
# Utility values in the economic model
## The company's method of incorporating disutility values related to adverse events is more reliable than the ERG's exploratory analyses
The company used health-related quality-of-life data from the MUST trial because the PSV-FAI-001 trial did not measure it. The MUST trial investigated a higher strength of fluocinolone acetonide implant in the same indication. To calculate utility values for the on treatment and subsequent therapy health states, the company mapped Visual Function Questionnaire-25 (VFQ-25) data from MUST to the EQ-5D. The ERG highlighted that as well as the implant being a higher strength, the population in MUST was different to that in PSV-FAI-001 (in MUST, 20% of patients had systemic treatment before recurrence, bilateral treatment with the fluocinolone acetonide implant was allowed, and there were fewer people with macular oedema at baseline). For the permanent blindness health state in its base case, the company used a utility value of 0.38, taken from a study by Czoski-Murray et al. (2009). The committee was aware that a utility value of 0.57 from Brown et al. (1999) had been preferred for the permanent blindness health state when developing NICE's technology appraisal guidance on adalimumab and dexamethasone. The committee was also aware that carers' health-related quality of life (see section 3.1) may also be affected, but that it had not been shown evidence to capture this. The ERG highlighted that the company's model did not include disutilities for adverse events. Because the ERG did not have information on the length and severity of each adverse event, it did 2 exploratory analyses assuming a disutility of 0.05 or 0.10 for every adverse event. This increased the cost-effectiveness estimates substantially, but the committee considered these analyses to be speculative and not reliable for decision making. In response to the appraisal consultation document, the company presented an analysis incorporating disutilities for adverse events. It sourced the rates of adverse events from the PSV-FAI-001 trial and the HURON trial (the trial investigating the dexamethasone implant) and the disutility values from a pragmatic literature search. The company included a disutility value of 0.071 for anxiety because of retreatment with multiple intravitreal injections, which hadn't been included in the company's or ERG's original analyses. The committee noted that the disutility values were not sourced from a systematic literature search as preferred in NICE's reference case, but the values were based on EQ-5D, which is preferred. The committee noted that, compared with the ERG's original exploratory analyses, the company's method resulted in lower cost-effectiveness estimates. The committee agreed that because of retreatment with multiple intravitreal injections, a disutility for anxiety should be included and that although the company's disutility of 0.071 may be an overestimate, even a small disutility value would have had a very favourable effect on the cost-effectiveness results. It concluded that, although there was some uncertainty because of the method of sourcing the disutility values, the company's new method was more reliable than the ERG's exploratory analyses.
# Costs and resources in the company's model
## Changes to the costs of permanent blindness and monitoring for immunosuppressants have little effect on the cost-effectiveness results
In the company's model, the costs in the permanent blindness health state were based on those used when developing NICE's technology appraisal guidance on adalimumab and dexamethasone. These were taken from a population with age-related macular oedema and included costs of hip replacement, community care and residential care. The committee noted that the ERG had excluded these costs for people under 65 years in its changes to the model, because uveitis generally affects a younger population than age-related macular oedema and so these costs would be less relevant. The ERG also included costs of a monitoring blood test every 12 weeks while having immunosuppressants in the subsequent treatment health state. The committee concluded that the ERG's changes to the costs were plausible but they did not have a large effect on the cost-effectiveness results.
# Cost-effectiveness results
## The company's updated cost-effectiveness results are below £30,000 per quality-adjusted life year (QALY) gained but associated with uncertainty
In response to the appraisal consultation document, the company incorporated its alternative method for modelling disutilities associated with adverse events into the model (see section 3.13). It presented 7 scenarios comparing the fluocinolone acetonide implant with the dexamethasone implant in different combinations of multiple implants. The company's scenarios included 2 analyses in which 1 dexamethasone implant was given before a fluocinolone acetonide implant, compared with multiple dexamethasone implants, because the clinical experts had said this was plausible (see section 3.2). The company presented all these analyses both with and without the transition between the on treatment health state and the permanent blindness health state (see section 3.11). All analyses included the patient access scheme for the fluocinolone acetonide implant. The results of the company's analyses ranged from the fluocinolone acetonide implant being dominant (that is, it was more effective and costs less), to an incremental cost-effectiveness ratio (ICER) of £29,461 per QALY gained, and most of the ICERs were below £20,000 per QALY gained. The committee noted that using the company's method of modelling disutilities associated with adverse events, which it had agreed was more reliable, none of the company's ICERs presented were above £30,000 per QALY gained. The committee considered that although the company's updated ICERs were within the range normally considered to represent cost-effective technologies, they were associated with a high degree of uncertainty because of the method used to incorporate the dexamethasone implant as a comparator (see section 3.9).
## In the ERG's original cost-effectiveness results assuming equal efficacy for both implants, the dexamethasone implant was dominant but some of the committee's preferred assumptions were not included
The committee then considered the ERG's original base-case results that assumed equal efficacy for both implants, acknowledging the clinical experts' expectation that the effectiveness would be similar. The committee noted that the dexamethasone implant dominated the fluocinolone acetonide implant. The committee considered that these results were also associated with some uncertainty because of the trial results (see section 3.3 and section 3.4). It considered the incremental costs, which are not reported here because they are commercial in confidence. The committee noted that the ERG's original results did not include the disutility for anxiety related to repeated intravitreal injections, and it was reassured that if this had been included it would favour the fluocinolone acetonide implant. The committee concluded that although the dexamethasone implant dominated the fluocinolone acetonide implant in the ERG's results, the results did not include the committee's preferred assumptions about disutilities for adverse events.
## The fluocinolone acetonide intravitreal implant can be recommended as a cost-effective use of NHS resources
The committee considered the patient experts' statements describing the burden of existing treatments and the effect this had on their quality of life (see section 3.1). The committee agreed that extending treatment choices in this disease area would benefit patients. It took into account the ERG's original estimated cost-effectiveness results, the company's analysis of adverse event disutilities, the clinicians' views and the patients' views. The committee agreed that, had all its preferred assumptions been included in the model, most of the cost-effectiveness estimates would be within the range that NICE normally considers a cost-effective use of NHS resources. It therefore recommended the fluocinolone acetonide intravitreal implant as an option for treating recurrent non-infectious uveitis affecting the posterior segment of the eye.
# Innovation
## The benefits of the fluocinolone acetonide implant are captured in the cost-effectiveness analysis
The company considered the fluocinolone acetonide implant to be innovative. It highlighted that the long-lasting design of the implant could lead to benefits such as a reduced treatment burden and more consistent disease control. The clinical experts also suggested that the implant was innovative because of the potential for 3 years of disease control with 1 implant. The committee concluded that the fluocinolone acetonide implant would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# Equality considerations
## There are no equality issues relevant to the recommendations
A stakeholder highlighted that the long-lasting design of the fluocinolone acetonide implant could improve adherence to treatment for some people, such as those with dementia or mental health problems. A stakeholder highlighted that that women may benefit more from the fluocinolone acetonide implant because high doses of systemic steroids may adversely affect women's bone density more than men's. Because the committee's recommendation is for the whole population covered by the marketing authorisation, the committee concluded that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. It concluded that there are no relevant equality issues.
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{'Recommendations': "Fluocinolone acetonide intravitreal implant is recommended, within its marketing authorisation, as an option for preventing relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nTreatments for recurrent non-infectious uveitis affecting the posterior segment of the eye include systemic corticosteroids, immunosuppressants and dexamethasone implants. These treatments can be disruptive to daily life, needing frequent hospital visits.\n\nThe clinical trial results for the fluocinolone acetonide intravitreal implant compared with limited current practice are difficult to interpret and very uncertain. The trial didn't directly measure health-related quality of life and the number of recurrences reported may be overestimated.\n\nThe cost-effectiveness estimates are also uncertain. However, if all the most plausible assumptions had been included in the model, most of the cost-effectiveness estimates would be within the range that NICE normally considers a cost-effective use of NHS resources, so the fluocinolone acetonide implant is recommended.", 'Information about fluocinolone acetonide intravitreal implant': "Marketing authorisation indication\n\nFluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) is indicated for 'prevention of relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye'.\n\nDosage in the marketing authorisation\n\nFluocinolone acetonide intravitreal implant is administered through intravitreal injection. Each implant contains 0.19\xa0mg of fluocinolone acetonide and releases fluocinolone acetonide for up to 36 months.\n\nPrice\n\n£5,500 per implant (excluding VAT, British national formulary online [accessed May 2019]).\n\n\n\nThe company has a commercial arrangement. This makes fluocinolone acetonide intravitreal implant available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Alimera Sciences and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with recurrent non-infectious uveitis affecting the posterior segment of the eye will welcome a new treatment option\n\nPatient experts described the anxiety associated with having uveitis because of potentially worsening sight, if they will be able to continue working and how it affects their relationships and independence. They explained that existing treatments for controlling recurrent non-infectious uveitis can be burdensome and disruptive to daily life for both patients and their carers, needing frequent hospital visits for administration and monitoring. The patient experts described how having a treatment that lasts for 3\xa0years had substantially increased their quality of life. They highlighted that the fluocinolone acetonide implant could be particularly beneficial for people who cannot have systemic treatments. One of the patient experts described how the effects of the dexamethasone implant had lasted for much less than the 6\xa0months they had been expecting. The clinical experts also highlighted that biologic treatments are not effective in 20% to 30% of people with recurrent non-infectious uveitis and there is a need for alternative treatment options. The committee concluded that people with recurrent non-infectious uveitis affecting the posterior segment of the eye would welcome an additional treatment option, particularly one with long-lasting benefits.\n\n# Clinical management\n\n## The dexamethasone implant is a relevant comparator\n\nThe clinical experts explained that non-infectious uveitis is treated differently depending on whether the disease is:\n\nactive (that is, current inflammation in the eye) or inactive (that is, limited inflammation, usually because of treatment with corticosteroids or immunosuppressants)\n\nsystemic (when disease is not only in the eye) or non-systemic (when disease is limited to the eye)\n\nunilateral (when 1 eye is affected) or bilateral (when both eyes are affected).There may also be local variation in treatment. Non-infectious uveitis without systemic disease may first be treated with local corticosteroids, followed by systemic corticosteroids or a dexamethasone implant. Multiple repeated dexamethasone implants may be given. Bilateral disease or unilateral disease with active systemic disease may first be treated with systemic corticosteroids, followed by immunosuppressants or dexamethasone implants. Treatments may also be used in combination. TNF-alpha inhibitors such as adalimumab may be an option after immunosuppressants. The marketing authorisation for the fluocinolone acetonide implant is for recurrent disease, so the clinical experts explained that they would most likely offer it to people who had already had corticosteroids. They explained that if the disease responded well to a dexamethasone implant, they would consider using a fluocinolone acetonide implant instead of another dexamethasone implant. The committee agreed that in NHS clinical practice in England, it was likely that the fluocinolone acetonide implant would be used after corticosteroids, as an alternative to the dexamethasone implant. The committee concluded that the dexamethasone implant was a relevant comparator for the fluocinolone acetonide implant.\n\n# Clinical evidence\n\n## The clinical trial may not fully reflect NHS clinical practice in England\n\nThe evidence for the fluocinolone acetonide implant came from the PSV-FAI-001 trial. This was a multicentre, randomised, double-blind trial in patients with chronic non-infectious uveitis affecting the posterior segment of the eye. It compared the fluocinolone acetonide implant with a sham injection. Patients in both treatment groups could have 'limited current practice': this was the corticosteroids and immunosuppressants that they had been having before enrolling in the trial but tapered off within the first 3\xa0months. Other than treatments that were being tapered off, patients could not have corticosteroids or immunosuppressants until their uveitis recurred. This meant that after 3\xa0months and before recurrence, people in the control group had no treatment. Additionally, before recurrence in the trial, trial investigators were encouraged to use systemic treatment only after local treatment had failed. The committee agreed that this may not reflect clinical practice in the NHS in England because the clinical experts had said that systemic treatment may be given first for bilateral or systemic disease (see section\xa03.2). The committee concluded that treatment in the trial may not fully reflect NHS clinical practice in England.\n\n# Recurrence of uveitis\n\n## Rates of recurrence of uveitis in the trial are likely overestimated\n\nThe primary outcome in the PSV-FAI-001 trial was the proportion of patients who had a recurrence of uveitis in the study eye within 6\xa0months of having study treatment. After 12\xa0months, the recurrence rate was 37.9% in the fluocinolone acetonide implant group and 97.6% in the control group. However, the committee noted that recurrence was assumed for patients who had missing data for the required eye examinations, or who had local or systemic treatments that were prohibited as part of the trial. The trial did not record why these treatments were given, but the committee considered that they may have been used to treat the other eye or for an underlying condition (rather than for recurrent uveitis in the study eye). So, it agreed that the recurrence rates reported in the trial were likely overestimated.\n\n# Visual acuity\n\n## The fluocinolone acetonide implant improves visual acuity\n\nVisual acuity was a secondary outcome in the PSV-FAI-001 trial. After 12 months, mean best-corrected visual acuity (BCVA) in the control group had increased from 64.9 letters to 69.2 letters. In the fluocinolone acetonide implant group, mean BCVA increased from 66.9 letters to 72.8 letters. The clinical experts explained that a 5-letter increase in BCVA is clinically meaningful. They highlighted that most of the people in the control group had had a recurrence of uveitis by 12 months, so would have had other treatments, which could explain the increase in BCVA in this group. The committee concluded that the fluocinolone acetonide implant improves visual acuity compared with current practice. However, it noted that visual acuity was not directly included in the economic model.\n\n# Adverse effects\n\n## Adverse effects associated with the fluocinolone acetonide implant are manageable in clinical practice\n\nCommon adverse effects of the fluocinolone acetonide implant include cataract and increased intraocular pressure. One of the patient experts explained that although developing a cataract did affect their sight, which reduced their quality of life, the cataract surgery was relatively straightforward and there was no lasting effect on their quality of life. The clinical experts stated that there was unlikely to be a big difference in the adverse effects of the fluocinolone acetonide implant compared with those of the dexamethasone implant. The committee noted that there were more older people in the control group of the trial, which may have affected the rate of adverse effects compared with that in the fluocinolone acetonide implant group. But overall, the committee considered that the fluocinolone acetonide implant is well tolerated compared with other treatments for uveitis and that the adverse effects are manageable in clinical practice.\n\n# The company's economic model\n\n## A model that considers both eyes would have been preferred\n\nThe company presented a Markov model with 5 health states: on treatment, subsequent therapy, remission, permanent blindness and death. The model compared the fluocinolone acetonide implant with the treatments received in the control group in the PSV-FAI-001 trial (described as 'limited current practice', see section\xa03.3) in the study eye only. Treatment effectiveness was modelled using time to first uveitis recurrence in the study eye from the trial. The ERG highlighted that in a potentially bilateral disease, modelling should consider both eyes to fully capture the effect of sight loss on health-related quality of life, survival and costs. The clinical experts suggested that a large proportion of people with recurrent non-infectious uveitis have bilateral disease. In the trial, 67.8% in the fluocinolone acetonide implant group and 73.8% in the control group had bilateral disease at baseline. The company stated that it could not include both eyes in the full cost-effectiveness modelling because of a lack of data. The committee concluded that it would have preferred to have seen a model that took both eyes into account.\n\n## The model should include the possibility of multiple implants\n\nThe company's model assumed that each patient had only 1 fluocinolone acetonide implant. However, the clinical experts stated that they would consider using another fluocinolone acetonide implant after 3 years, if the disease had responded well to the first implant. The committee concluded that the model should include an option for retreatment with multiple fluocinolone acetonide implants (see section\xa03.13).\n\n## The ERG's model using the dexamethasone implant as a comparator is preferred\n\nBased on the clinical experts' description of the treatment pathway, the committee considered that the dexamethasone implant was a relevant comparator for the fluocinolone acetonide implant (see section\xa03.2). The ERG did a naive analysis, estimating the potential effectiveness of the dexamethasone implant compared with limited current practice (based on evidence used to inform NICE technology appraisal guidance on adalimumab and dexamethasone for treating non-infectious uveitis) so that it could include the dexamethasone implant in the model as a comparator. The analysis assumed that the dexamethasone implant was more effective than limited current practice, with a hazard ratio for time to first recurrence of 0.456. The ERG also presented scenario analyses that assumed the effectiveness of the dexamethasone implant was equal to that of the fluocinolone acetonide implant. The clinical experts suggested that they expected the effectiveness of the fluocinolone acetonide implant to be similar to that of the dexamethasone implant, for the time that the treatments remain active. The committee noted that the benefit of the dexamethasone implant lasted for almost 6 months in the model, whereas patient experts had experience of the implant lasting less than 6 months (see section\xa03.1). The patient experts explained that repeated dexamethasone implants can only be given after vision has deteriorated, which means a patient may have several weeks of reduced vision between implants. The committee considered that while the treatments remain active, both the fluocinolone acetonide and dexamethasone implants are likely to have a similar effect on visual acuity. However, on average over 3\xa0years (with repeated dexamethasone implants) the fluocinolone acetonide implant may be more effective in preventing recurrence of uveitis. In response to the appraisal consultation document, the company presented its own naive analysis comparing the fluocinolone acetonide implant with the dexamethasone implant. The company scaled down the time to recurrence curve for the fluocinolone acetonide implant from 3\xa0years to 6\xa0months, to model the efficacy of the dexamethasone implant. The ERG highlighted that using this method made the recurrence rate in the dexamethasone implant group higher than in the fluocinolone acetonide implant group. The committee agreed that the company's method of estimating the comparative effectiveness of the dexamethasone implant was implausible. In the company's updated analyses, patients could have another implant if treatment failed, rather than waiting until the end of the expected duration of the implants (6\xa0months for the dexamethasone implant or 3\xa0years for the fluocinolone acetonide implant). In the company's analyses, the maximum number of dexamethasone implants that someone could have was 3, which the company explained was because of constraints of the way the new analysis was implemented in the model. The committee noted that this led to more time on treatment in the fluocinolone acetonide implant group, because it could last for up to 3\xa0years. The committee noted that in the ERG's original analysis, patients could have 6 dexamethasone implants in 3\xa0years, which it agreed was a better comparison because the time on treatment was the same for both groups. The committee understood that both the company's and the ERG's methods of comparing the fluocinolone acetonide implant with the dexamethasone implant were based on assumptions but concluded that the ERG's method was more plausible.\n\n## The model should not include a remission health state\n\nIn the company's model, patients who did not have a recurrence of uveitis within 2 years were assumed to be in the remission health state, in which their health-related quality of life was the same as the general population. The committee was aware that in the assessment group's model used when developing NICE's technology appraisal guidance on adalimumab and dexamethasone, the remission health state was only used in a scenario analysis. The clinical experts explained that although remission from uveitis is possible, about 30% of people would have a recurrence if treatment were stopped, even if they had not had a recurrence for 2 years. The committee considered it unlikely that everyone who did not have a recurrence of uveitis within 2 years would be in remission. Moreover, even people with uveitis in remission may have lower health-related quality of life than the general population because of bilateral disease or underlying systemic disease. The committee concluded that the model should not include a remission health state.\n\n## Results both with and without a transition from on treatment to permanent blindness should be included\n\nIn the company's model, there was no transition between the on treatment and permanent blindness health states. The ERG added this transition in its base-case analysis, because it was included in the model used when developing NICE's technology appraisal guidance on adalimumab and dexamethasone. The committee was aware that the company's model was consistent with the results of the PSV-FAI-001 trial. The committee concluded that results both with and without this transition would be informative.\n\n# Treatment effectiveness in the model\n\n## The model should not include a treatment benefit with the fluocinolone acetonide implant after 3 years\n\nThe company's model extrapolated the treatment effect of the fluocinolone acetonide implant beyond the 3-year time horizon of the trial, even though the implant only releases fluocinolone acetonide for 3 years. The clinical experts suggested that for some people there may be residual effects of the treatment after 3 years, and there is an ongoing benefit of having had stable disease for 3 years. The committee agreed that it was possible there may be some benefit after 3 years, but that there was no evidence from the trial to support this. It concluded that the model should not include any treatment benefit with the fluocinolone acetonide implant after 3 years.\n\n# Utility values in the economic model\n\n## The company's method of incorporating disutility values related to adverse events is more reliable than the ERG's exploratory analyses\n\nThe company used health-related quality-of-life data from the MUST trial because the PSV-FAI-001 trial did not measure it. The MUST trial investigated a higher strength of fluocinolone acetonide implant in the same indication. To calculate utility values for the on treatment and subsequent therapy health states, the company mapped Visual Function Questionnaire-25 (VFQ-25) data from MUST to the EQ-5D. The ERG highlighted that as well as the implant being a higher strength, the population in MUST was different to that in PSV-FAI-001 (in MUST, 20% of patients had systemic treatment before recurrence, bilateral treatment with the fluocinolone acetonide implant was allowed, and there were fewer people with macular oedema at baseline). For the permanent blindness health state in its base case, the company used a utility value of 0.38, taken from a study by Czoski-Murray et al. (2009). The committee was aware that a utility value of 0.57 from Brown et al. (1999) had been preferred for the permanent blindness health state when developing NICE's technology appraisal guidance on adalimumab and dexamethasone. The committee was also aware that carers' health-related quality of life (see section\xa03.1) may also be affected, but that it had not been shown evidence to capture this. The ERG highlighted that the company's model did not include disutilities for adverse events. Because the ERG did not have information on the length and severity of each adverse event, it did 2 exploratory analyses assuming a disutility of 0.05 or 0.10 for every adverse event. This increased the cost-effectiveness estimates substantially, but the committee considered these analyses to be speculative and not reliable for decision making. In response to the appraisal consultation document, the company presented an analysis incorporating disutilities for adverse events. It sourced the rates of adverse events from the PSV-FAI-001 trial and the HURON trial (the trial investigating the dexamethasone implant) and the disutility values from a pragmatic literature search. The company included a disutility value of 0.071 for anxiety because of retreatment with multiple intravitreal injections, which hadn't been included in the company's or ERG's original analyses. The committee noted that the disutility values were not sourced from a systematic literature search as preferred in NICE's reference case, but the values were based on EQ-5D, which is preferred. The committee noted that, compared with the ERG's original exploratory analyses, the company's method resulted in lower cost-effectiveness estimates. The committee agreed that because of retreatment with multiple intravitreal injections, a disutility for anxiety should be included and that although the company's disutility of 0.071 may be an overestimate, even a small disutility value would have had a very favourable effect on the cost-effectiveness results. It concluded that, although there was some uncertainty because of the method of sourcing the disutility values, the company's new method was more reliable than the ERG's exploratory analyses.\n\n# Costs and resources in the company's model\n\n## Changes to the costs of permanent blindness and monitoring for immunosuppressants have little effect on the cost-effectiveness results\n\nIn the company's model, the costs in the permanent blindness health state were based on those used when developing NICE's technology appraisal guidance on adalimumab and dexamethasone. These were taken from a population with age-related macular oedema and included costs of hip replacement, community care and residential care. The committee noted that the ERG had excluded these costs for people under 65\xa0years in its changes to the model, because uveitis generally affects a younger population than age-related macular oedema and so these costs would be less relevant. The ERG also included costs of a monitoring blood test every 12 weeks while having immunosuppressants in the subsequent treatment health state. The committee concluded that the ERG's changes to the costs were plausible but they did not have a large effect on the cost-effectiveness results.\n\n# Cost-effectiveness results\n\n## The company's updated cost-effectiveness results are below £30,000 per quality-adjusted life year (QALY) gained but associated with uncertainty\n\nIn response to the appraisal consultation document, the company incorporated its alternative method for modelling disutilities associated with adverse events into the model (see section\xa03.13). It presented 7 scenarios comparing the fluocinolone acetonide implant with the dexamethasone implant in different combinations of multiple implants. The company's scenarios included 2 analyses in which 1 dexamethasone implant was given before a fluocinolone acetonide implant, compared with multiple dexamethasone implants, because the clinical experts had said this was plausible (see section\xa03.2). The company presented all these analyses both with and without the transition between the on treatment health state and the permanent blindness health state (see section\xa03.11). All analyses included the patient access scheme for the fluocinolone acetonide implant. The results of the company's analyses ranged from the fluocinolone acetonide implant being dominant (that is, it was more effective and costs less), to an incremental cost-effectiveness ratio (ICER) of £29,461 per QALY gained, and most of the ICERs were below £20,000 per QALY gained. The committee noted that using the company's method of modelling disutilities associated with adverse events, which it had agreed was more reliable, none of the company's ICERs presented were above £30,000 per QALY gained. The committee considered that although the company's updated ICERs were within the range normally considered to represent cost-effective technologies, they were associated with a high degree of uncertainty because of the method used to incorporate the dexamethasone implant as a comparator (see section\xa03.9).\n\n## In the ERG's original cost-effectiveness results assuming equal efficacy for both implants, the dexamethasone implant was dominant but some of the committee's preferred assumptions were not included\n\nThe committee then considered the ERG's original base-case results that assumed equal efficacy for both implants, acknowledging the clinical experts' expectation that the effectiveness would be similar. The committee noted that the dexamethasone implant dominated the fluocinolone acetonide implant. The committee considered that these results were also associated with some uncertainty because of the trial results (see section\xa03.3 and section 3.4). It considered the incremental costs, which are not reported here because they are commercial in confidence. The committee noted that the ERG's original results did not include the disutility for anxiety related to repeated intravitreal injections, and it was reassured that if this had been included it would favour the fluocinolone acetonide implant. The committee concluded that although the dexamethasone implant dominated the fluocinolone acetonide implant in the ERG's results, the results did not include the committee's preferred assumptions about disutilities for adverse events.\n\n## The fluocinolone acetonide intravitreal implant can be recommended as a cost-effective use of NHS resources\n\nThe committee considered the patient experts' statements describing the burden of existing treatments and the effect this had on their quality of life (see section\xa03.1). The committee agreed that extending treatment choices in this disease area would benefit patients. It took into account the ERG's original estimated cost-effectiveness results, the company's analysis of adverse event disutilities, the clinicians' views and the patients' views. The committee agreed that, had all its preferred assumptions been included in the model, most of the cost-effectiveness estimates would be within the range that NICE normally considers a cost-effective use of NHS resources. It therefore recommended the fluocinolone acetonide intravitreal implant as an option for treating recurrent non-infectious uveitis affecting the posterior segment of the eye.\n\n# Innovation\n\n## The benefits of the fluocinolone acetonide implant are captured in the cost-effectiveness analysis\n\nThe company considered the fluocinolone acetonide implant to be innovative. It highlighted that the long-lasting design of the implant could lead to benefits such as a reduced treatment burden and more consistent disease control. The clinical experts also suggested that the implant was innovative because of the potential for 3 years of disease control with 1 implant. The committee concluded that the fluocinolone acetonide implant would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# Equality considerations\n\n## There are no equality issues relevant to the recommendations\n\nA stakeholder highlighted that the long-lasting design of the fluocinolone acetonide implant could improve adherence to treatment for some people, such as those with dementia or mental health problems. A stakeholder highlighted that that women may benefit more from the fluocinolone acetonide implant because high doses of systemic steroids may adversely affect women's bone density more than men's. Because the committee's recommendation is for the whole population covered by the marketing authorisation, the committee concluded that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. It concluded that there are no relevant equality issues."}
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https://www.nice.org.uk/guidance/ta590
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Evidence-based recommendations on fluocinolone acetonide intravitreal implant (Iluvien) for treating recurrent non-infectious uveitis in adults.
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44edaae848baefa4357b94db9595a5e4c589bf9d
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nice
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Letermovir for preventing cytomegalovirus disease after a stem cell transplant
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Letermovir for preventing cytomegalovirus disease after a stem cell transplant
Evidence-based recommendations on letermovir (Prevymis) for preventing cytomegalovirus disease after a stem cell transplant.
# Recommendations
Letermovir is recommended, within its marketing authorisation, as an option for preventing cytomegalovirus (CMV) reactivation and disease after an allogeneic haematopoietic stem cell transplant (HSCT) in adults who are seropositive for CMV. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Current management of CMV after an allogeneic HSCT (a stem cell transplant from a donor) involves regular blood tests to monitor CMV levels (with or without aciclovir). If CMV levels rise, treatment with ganciclovir, valganciclovir or foscarnet (pre-emptive therapy) is started to prevent disease but this can cause severe side effects. Letermovir is an option for reducing CMV and is safer than pre-emptive therapy.
Clinical trial evidence shows that letermovir is effective in reducing CMV infection and also reduces the need for pre-emptive therapy. The most plausible cost-effectiveness estimates for letermovir are within the range that NICE usually considers acceptable. Therefore, it is recommended.# Information about letermovir
Marketing authorisation indication
Letermovir (Prevymis, Merck, Sharpe & Dohme) is indicated 'for the prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult CMV-seropositive recipients of an allogeneic haematopoietic stem cell transplant'.
Dosage in the marketing authorisation
The recommended dose of letermovir is 480 mg once daily (oral tablets and solution for intravenous infusion), decreasing to 240 mg once daily if co‑administered with cyclosporin A.
Treatment with letermovir may be started on the day of transplant or on any day up to 28 days afterwards and should continue for 100 days after transplant; longer treatment may be considered in some patients at high risk for late CMV reactivation.
Price
The list price for oral letermovir is £3,723.16 for 28×240 mg tablets (excluding VAT; British national formulary online accessed April 2019).
The intravenous formulation is not currently available in England.
The company has a commercial arrangement. This makes letermovir available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Merck, Sharpe & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need
## Cytomegalovirus reactivation substantially affects the mental health and wellbeing of patients and their families
Cytomegalovirus (CMV) can become active again in about 60% to 80% of people who are seropositive for CMV and who have had an allogeneic haematopoietic stem cell transplant (HSCT). This can happen especially if the transplant involved T‑cell depletion therapy, which is common in the UK. The patient experts highlighted that CMV reactivation can have a substantial psychological effect on patients and their families, negatively affecting their mental health and wellbeing. Hospital admissions to treat CMV reactivation disrupt family and working life and are particularly stressful because of the worry and risk of further infections. Pre-emptive therapy for CMV reactivation (see section 3.2) can have serious side effects. The patient experts noted that better prevention of CMV reactivation would reduce hospital admissions and the need for toxic pre-emptive therapy, which would greatly reduce distress. The committee concluded that CMV reactivation can have a substantial psychological effect on patients and their families.
# Clinical management
## Patients and clinicians would welcome a new treatment that could prevent CMV reactivation and reduce the need for pre-emptive therapy
There are no licensed treatments available specifically for preventing CMV reactivation after an allogeneic HSCT. The current standard approach in the NHS is surveillance monitoring for viral reactivation. When viral DNA is detected, pre-emptive therapy is started with ganciclovir, valganciclovir or foscarnet, depending on the type of transplant received (T‑cell depletion or T‑cell repletion). The clinical experts stated that:
Practice varies on when to start pre-emptive therapy. Some centres would start based on a specific viral load count, but the assays for measuring viral load are not standardised.
Aciclovir is also used as prophylaxis in some centres although it may not be effective for this.
Letermovir reduces reactivation rates and the need for toxic pre-emptive therapy and improves quality of life.The committee concluded that an effective and tolerable treatment that specifically acts to prevent CMV reactivation would benefit people who are seropositive for CMV who have had an allogeneic HSCT.
# Clinical evidence
## The main evidence is from PN001, a randomised, double-blind, placebo-controlled trial
The main clinical evidence came from a phase III randomised placebo-controlled trial, PN001. This trial compared the efficacy and safety of letermovir (n=373) with placebo (n=192) in adults who were seropositive for CMV and who have had an allogeneic HSCT. Treatment continued to week 14 (about 100 days) and patients were monitored through to week 24 after transplant for the primary efficacy outcome. The primary outcome was the incidence of clinically significant CMV infection by week 24. This was assessed by the proportion of people with CMV end-organ disease or starting anti-CMV pre-emptive therapy (ganciclovir, valganciclovir or foscarnet with or without cidofovir) based on documented CMV viraemia (as measured by the central laboratory) and the clinical condition of the patient. Patients who completed the trial then entered a follow-up phase from week 24 to week 48 after transplant. The company presented results for 2 populations: the overall randomised population who had treatment (the 'all subjects as treated' population) and the main analysis population in the trial (the 'full analysis set' population). The full analysis set population excluded patients who were randomised and had treatment if they had detectable CMV DNA on day 1. To account for missing data, the company's preferred approach was to assume that if people did not complete treatment their treatment had not worked. This included people with missing data or who stopped the study early. The committee concluded that PN001 was a well conducted trial and agreed that it would consider the full analysis set population.
## The PN001 trial results are generalisable to clinical practice in England
The committee considered how generalisable the PN001 results were to NHS clinical practice in England. It discussed the following concerns:
Only 12 patients were from the UK.
The maximum treatment duration was 100 days. The ERG considered this inappropriate because in clinical practice, some people may need longer periods of prophylaxis, for example people having treatment for active graft versus host disease or those at high risk of CMV reactivation because of T‑cell depletion. During consultation, a clinical expert explained that although the marketing authorisation allows treatment for longer than 100 days, there is no evidence that patients benefit from longer prophylaxis. The clinical experts stated that until trial evidence supports such use, they would not continue letermovir prophylaxis for longer than 100 days. The committee accepted that in clinical practice in England, the maximum letermovir treatment duration was unlikely to be longer than 100 days.
There was a delay in starting prophylaxis (mean 11.5 days, 'all subjects as treated' population; mean 10.9 days, full analysis set population) after transplant in the trial, which could potentially underestimate the efficacy and treatment duration of letermovir. During consultation, the company explained that the delay was because of concerns about the safety of starting prophylaxis immediately after HSCT. The clinical experts stated that they were now reassured about the safety of starting prophylaxis immediately after HSCT, and therefore would not expect a delay in clinical practice. Also, at the second appraisal committee meeting, the company noted that because the clinical effectiveness estimates were based on the observed treatment duration from PN001 it was not appropriate to include an additional treatment delay. The committee accepted that a delay would not be likely in clinical practice but agreed there was some uncertainty about the estimates of treatment duration. It concluded that without a better estimate of treatment duration, estimates from the trial were acceptable.
The prevalence of ciclosporin A use in people who had letermovir in the trial was 51.7% (based on the 'all subjects as treated' population). Both the ERG and the clinical experts agreed that this was much lower than seen in clinical practice. They assumed that approximately 90% to 95% of people would have ciclosporin A and the remaining patients would have tacrolimus.
The limited use of alemtuzumab (used for depleting T‑cells to avoid graft versus host disease) in the trial (4%) compared with clinical practice in the NHS (around 60% to 85%) could potentially underestimate the CMV reactivation rate and overestimate the risk of graft versus host disease. The clinical experts stated that its use in clinical practice depends on the treating centre but suggested that approximately 60% to 85% of people would have alemtuzumab.
The ERG highlighted that clinically significant CMV reactivation leading to pre-emptive therapy is defined differently in the trial than in UK practice. In the trial, a viral load threshold between 150 to 300 copies/ml was used, depending on the patient's risk of CMV infection. The clinical experts stated that, in clinical practice, the threshold varied by centre but typically would be between 400 to 700 copies/ml. During consultation, 1 clinical expert noted that CMV infection would not be determined by the threshold level of viraemia, highlighting that the clinical difference between the stated threshold ranges was negligible. The committee acknowledged that there was some ambiguity about the definition of a clinically significant CMV infection. It agreed that it was unclear if CMV infection rate, and subsequently the use of pre-emptive therapy, were over or underestimated in the trial.During consultation 1 clinical expert commented that the PN001 results were generalisable to clinical practice in England, because the treatment duration from PN001 was realistic and the CMV infection rate was not overestimated. The committee therefore concluded that the trial results were generalisable to clinical practice, but accepted that its concerns about treatment duration, pre-emptive therapy use and the definition of a clinically significant CMV infection could make interpreting the results challenging.
## Letermovir reduces CMV infection at 24 weeks after allogeneic HSCT
In PN001, letermovir statistically significantly reduced the rate of clinically significant CMV infection at week 24 compared with placebo. The stratum-adjusted treatment difference between letermovir and placebo was −23.5 (95% confidence interval −32.5 to −14.6). The hazard ratio (HR) for time to onset of clinically significant CMV infection at week 24 was 0.29 (95% CI 0.21 to 0.42). There was also a statistically significant difference in starting pre-emptive therapy for documented viraemia by week 24 between letermovir and placebo (stratum-adjusted treatment difference −23.3 ). The committee concluded that compared with placebo, letermovir is effective in reducing the incidence of clinically significant CMV infection after allogeneic HSCT and in reducing the need for pre-emptive therapy.
## The all-cause mortality benefit of letermovir compared with placebo is not statistically significant at 48 weeks
In PN001, letermovir statistically significantly reduced the all-cause mortality rate at week 24 compared with placebo, with a hazard ratio of 0.57 (95% CI 0.34 to 0.96). The company also did an exploratory analysis using week 48 data, which included people who withdrew early from the trial but were confirmed to be alive after the trial had ended. The difference in all-cause mortality between letermovir and placebo was 3.8% but this was not statistically significant (HR 0.73, 95% CI 0.49 to 1.09). When people were stratified by prior CMV infection in another post hoc analysis, people on letermovir who had clinically significant CMV infection through week 24 had a lower all-cause mortality rate at week 48 when compared with people on placebo who had clinically significant CMV infection at week 24. Similar all-cause mortality rates were seen in both groups in people without clinically significant CMV infection at week 24. The committee acknowledged that these post hoc analyses could suggest that letermovir prevents additional all-cause mortality in people with prior CMV infection (CMV-related), despite not completely preventing CMV reactivation. It also noted that CMV-related mortality results were available, but the European Medicines Agency did not consider the data to be scientifically sound. During consultation, the company highlighted that although mortality was not a primary outcome in PN001, the exploratory analyses suggested letermovir could provide mortality benefit. The clinical experts stated that a mortality benefit with letermovir is plausible although it has not been proven. The committee agreed that the 48‑week post hoc analysis provided a more complete data set because it included mortality events in PN001 that occurred after week 24. It concluded that it would consider the 48‑week analysis for decision making, but acknowledged that the size of letermovir's mortality benefit is uncertain because of the limited trial follow up.
# Adverse events
## The safety profile of letermovir is acceptable
Overall, adverse events were similar between the letermovir group and the placebo group except for those leading to patients stopping treatment. There were no treatment-related deaths in either group. The most commonly reported adverse events in the 2 groups were graft versus host disease, nausea, vomiting, diarrhoea, pyrexia and rash. Cardiac disorder, hyperkalaemia, ear and labyrinth disorder and dyspnoea were more common in people on letermovir than on placebo. The ERG commented that the adverse event results were difficult to interpret because of the underlying conditions and treatments as well as the toxicity associated with various pre-emptive therapy regimens. Also, there were no safety data presented for letermovir use after 100 days. The committee was aware of the conclusions in the European public assessment report, which stated that the adverse event profile appeared similar to that of current standard care (that is, surveillance monitoring and pre-emptive therapy). The committee concluded that the safety profile of letermovir was acceptable and unlikely to be worse than current standard care.
# Health-related quality of life
## PN001 did not show a health-related quality-of-life benefit for letermovir compared with placebo but a benefit is plausible
Health-related quality-of-life data collected at the time of randomisation and at weeks 14, 24 and 48 after transplant using EQ-5D-3L and FACT-BMT questionnaires showed no statistically significant differences between letermovir and placebo. A small possible utility benefit on graft versus host disease, rehospitalisation and opportunistic infections was seen with letermovir compared with placebo, but these benefits were not statistically tested. The company explained that health-related quality of life was an exploratory outcome and PN001 was not powered to detect statistically significant differences between treatment groups. The ERG also highlighted that, other than at randomisation, the mean values for EQ‑5D-3L and FACT-BMT scores represent a mixture of people who have had CMV reactivation and started pre-emptive therapy and those who have not. Therefore, the direct effect of letermovir on health-related quality of life was confounded. Also, the clinical experts stated that showing improvement in quality of life in a clinical trial of this nature is challenging because of differences in timing of assessments in relation to letermovir dosing and administration of other treatments. During consultation, the company explained that health-related quality of life was assessed before starting pre-emptive therapy, therefore the disutility associated with toxicities from pre-emptive therapy was not captured. The committee recalled comments from the clinical and patient experts that reducing CMV reactivation rates and the need for toxic pre-emptive therapy would improve quality of life (see section 3.1). The committee acknowledged the trial's limitations, which made interpreting the results more challenging. It agreed that although the trial did not show a health-related quality-of-life benefit for letermovir compared with placebo from preventing CMV reactivation, it concluded that such a benefit was plausible and agreed it would take this into account in its decision making.
# Cost-effectiveness model structure
## The company's model is oversimplified but appropriate for decision making
The company's economic model had a lifetime time horizon. It consisted of a decision tree phase up to week 24 after transplant (week 48 in the scenario analysis) and a simple 2-state (alive or dead) Markov model phase covering the remaining time horizon of the model. The ERG considered that the company's model was too simplistic because it lacked explicit health states to capture differences in quality-adjusted life years (QALYs). The company's model approach does not link the rate of CMV events (the principal benefit of letermovir) with mortality. The committee was aware that this meant that nearly all the QALY benefits in the model for letermovir were derived from mortality differences. As such, the differences in the rate of CMV infection and other clinical events (for example, graft versus host disease) between the letermovir group and the placebo group and their effect on quality of life and mortality could not be fully explored. The committee agreed with the ERG that the company's model was oversimplified and acknowledged that this introduced some uncertainty about the cost-effectiveness estimates. Nevertheless, the committee recognised the difficulty in fully capturing the mortality benefits associated specifically with letermovir prophylaxis in the model because of the differences in mortality risk associated with patients' underlying conditions and the lack of available data to do this. The committee concluded that, although the model is oversimplified, it was appropriate for decision making.
# Clinical data in the economic model
## The 48‑week clinical data are more complete so should be used in the model
In the decision tree phase of the model, the company included the cumulative probabilities of 6 different clinical events from PN001 (starting pre-emptive therapy, CMV disease, rehospitalisation, opportunistic infection, graft versus host disease and all-cause mortality). These clinical events were drawn from the 24‑week data and used 'data as observed', meaning that no adjustments were made for the 13.5% incomplete follow-ups at week 24. The ERG considered it inappropriate to use 24‑week data when 48‑week data were available for most outcomes. The committee recalled that the company had collected mortality data at week 48, which included people who withdrew early from the trial but were alive after the end of the trial. The ERG considered this data set to be more complete because only 3.2% patients were lost to follow up. During consultation, the company highlighted that the trial follow-up phase to week 48 investigated the safety of letermovir. It also noted that in PN001 letermovir prophylaxis stopped after 14 weeks. Because of this, it was not appropriate to assess the effect of prophylaxis at week 48. The ERG explained that by ignoring mortality events in PN001 between weeks 24 and 48, the company assumed an additional mortality benefit for letermovir. At the second appraisal committee meeting, a clinical expert explained that it was logical to use the 48‑week data because it was more complete. The committee recalled its consideration that a 48‑week post hoc analysis provided a more complete data set for decision making (see section 3.6), and concluded that it preferred to use the 48‑week data instead of the 24‑week 'data as observed' in its decision making.
## Mortality data from the haematological malignancy research network (HMRN) is more relevant to clinical practice
In the company's model in the Markov model phase, the clinical outcome used was all-cause mortality. The mortality rate was assumed to be the same in both groups. This was based on general population mortality data from the Office for National Statistics, with a standardised mortality rate from Wingard et al. (2011) applied to account for the effect of the underlying condition. The ERG considered that the company's general approach was appropriate but that the HMRN was a more relevant source of UK data. The clinical experts at the committee meeting agreed. In the company's model the excess risk of mortality in year 2 was assumed to be equal to the excess risk in year 3. The clinical experts stated that mortality risk in year 2 was likely to be much higher than in year 3 and more in line with that reported by the HMRN (19% compared with the company's 3%). Also, the ERG highlighted that the Wingard study data were relatively old (from 1980 to 2003) and therefore their relevance to current practice was unclear. In addition, a substantial proportion (more than 40%) of the population in the Wingard study were children. During consultation, the company noted that the HMRN mortality data did not have the same level of detail about the underlying disease as the Wingard study data. However, it acknowledged that there were limitations with both data sources and agreed with the ERG's concerns about the Wingard study. The committee therefore concluded that it would consider the HMRN data in its decision making because they are more relevant to NHS clinical practice.
# Utility values in the economic model
## The ERG's approach to modelling long-term disutility associated with HSCT is preferred for decision making
In the original company submission, a scenario analysis included a disutility for the long-term effects (more than 48 weeks) of HSCT. However, the ERG did not consider this analysis to fully capture the long-term disutility associated with having HSCT because it was derived from a mix of EQ‑5D‑5L (Leunis et al. 2014) and EQ‑5D‑3L (Ara et al. 2011) values. The ERG suggested an alternative disutility based on the difference between the mean utility of patients in PN001 at 48 weeks and the mean general population utilities from Ara et al. The committee agreed that the company's approach to modelling long-term disutility associated with HSCT was inappropriate and concluded that the ERG's alternative approach was preferable.
## Modelling disutility associated with graft versus host disease is included in the company's updated base case
The ERG identified that disutility associated with graft versus host disease should have been included in the company's original base-case analysis. This is because it is a serious and common complication of allogeneic HSCT and is associated with significant morbidity and mortality. During consultation, the company provided an updated base-case analysis which included the disutility associated with chronic graft versus host disease (occurring more than 100 days after HSCT), and discounting any disutility occurring beyond the first year. The company noted that changes in utility values for acute graft versus host disease (occurring within 100 days of HSCT) would already be captured in the utility values, therefore additional disutility was not needed. The committee concluded that the company's approach to modelling the disutility associated with graft versus host disease in its updated base-case analysis was acceptable and would be considered in its decision making.
# Resource use and costs
## There is uncertainty around the actual treatment duration for letermovir, but it is likely to be between the company's and ERG's estimates
In its original base case, the company assumed that the mean duration of treatment in the model was 69.4 days. This was based on the 'all subjects as treated' population from PN001. The ERG considered that the duration of treatment may be considerably longer and assumed mean duration of treatment to be 83 days in its original base case. This was based on the duration of therapy in the full analysis set population (72.1 days) plus an additional 10.9 days from the delayed start of prophylaxis in the trial. The clinical experts explained that, because a delay in starting letermovir prophylaxis is not expected in clinical practice, the duration of treatment is likely to be longer than 69.4 days but should not be more than 100 days (see section 3.4). During consultation, the company acknowledged that treatment duration was likely to be longer than 69.4 days and assumed a treatment duration of 72.1 days in its updated base case. The clinical experts highlighted that because of the treatment delay in PN001 there was no accurate estimate of mean treatment duration. However, they noted that a mean treatment duration of between 72.1 days and 83 days was a reasonable estimate. The committee concluded that it would consider a mean letermovir treatment duration range of 72.1 days to 83 days in its decision making.
## The ERG's assumption about intravenous letermovir use is overestimated
Based on the 12 UK patients in PN001, the company's original model assumed that approximately 5% of patients would have intravenous letermovir. However, the ERG considered that the proportion of patients in PN001 who had intravenous letermovir (27%) was more representative of UK practice. The clinical experts explained that because T‑cell depletion is commonly used in current practice, they tend to use treatments that are less toxic to the gut. Therefore, they agreed with the company's assumption that only 5% of patients would have intravenous letermovir. The committee agreed that the company's assumption about intravenous letermovir use was more appropriate than the ERG's. During consultation, the company explained that the intravenous formulation of letermovir was not available in England, and provided analyses assuming 100% oral letermovir use. The committee agreed to take account of current availability and clinical expert opinion in its decision making and concluded that it would consider 0% and 5% intravenous letermovir use.
## Assuming 20% of people have foscarnet in the model is appropriate
The ERG was concerned that the company's original model assumed foscarnet use was 25%, which was too high, potentially overestimating the cost of pre-emptive therapy. The ERG's clinical experts stated that only 5% to 15% of patients would have foscarnet as part of their pre-emptive therapy. However, the clinical experts at the first meeting stated that its use varied between centres and often depended on the type of transplant received. For example, people having T‑cell depletion, which is common in NHS practice, would most likely have foscarnet because of their higher risk of earlier CMV reactivation. Therefore, the clinical experts suggested that the use of foscarnet is closer to 15% to 25%, and the committee agreed that foscarnet use in the model should be between 15% and 25%. During consultation the company updated its base case and assumed foscarnet use was 20%, which the committee concluded was appropriate.
# Cost-effectiveness estimates
## The company's updated base-case ICER comparing letermovir with placebo is £17,713 per QALY gained
The company's updated base case was based on the ERG's original base case, but included:
an increased discount in letermovir's commercial arrangement
‑week trial data instead of 48‑week data (see section 3.10)
a mean duration of therapy of 72.1 days (see section 3.14)
a discounted disutility associated with graft versus host disease and disease relapse beyond the first year (see section 3.13)
concomitant use of ciclosporin A of 90% and foscarnet use of 20% (see section 3.16).The committee noted that the company's updated base-case incremental cost-effectiveness ratio (ICER) was higher than its original base-case ICER and included some of its preferred assumptions. However, the company's updated base case did not use 48‑week data from PN001 (see section 3.10) and it assumed a treatment duration (72.1 days) at the lower end of the range the committee wished to consider (see section 3.14). The company's updated deterministic base-case ICER for letermovir (including the updated commercial arrangement) compared with placebo increased from £10,904 (original base case) to £17,713 per QALY gained.
## The ERG's updated base-case ICER for letermovir compared with placebo is £24,269 per QALY gained
The ERG's updated base case was similar to that of the company's, but included:
the 48‑week trial data together with the post hoc analysis of all-cause mortality (see section 3.6 and section 3.10)
a mean duration of therapy of 83 days (see section 3.14)
correction of the company's misinterpretation of the ERG model settings for some utility value inputs.The committee noted using both the 48‑week trial data and assuming a longer mean treatment duration for letermovir increased the ICER. The ERG's updated base-case ICER for letermovir (including the updated commercial arrangement) compared with placebo decreased from £27,536 (original base case) to £24,269 per QALY gained.
# Conclusion
## Letermovir is recommended
Having considered the company's and ERG's updated base-case ICERs, the committee agreed that the ERG's analysis aligned more closely with its preferred assumptions. However, it recalled that it would take into account the following considerations in its decision making:
Although a health-related quality-of-life benefit from preventing CMV reactivation was not shown in PN001, a benefit with letermovir was plausible (see section 3.8). It recognised that had these benefits been included in the model the ICER would decrease.
The company's model was too simplistic in that it did not fully capture the clinical signs and symptoms of CMV and their effect on quality of life (see section 3.9). It acknowledged that the effect of this on the ICER was unclear.
The estimated treatment duration for letermovir was uncertain and the committee agreed it would consider a mean treatment duration range of 72.1 days to 83 days (see section 3.14). It understood that assuming a shorter treatment duration would reduce the ICER and that the ERG's assumed treatment duration was at the top end of this range.
Intravenous letermovir use was assumed to be 5% in the ERG's updated base case, in line with clinical expert opinion (see section 3.15). The committee acknowledged that intravenous letermovir was not currently available in England, and assuming 100% oral use would decrease the ICER.The committee noted that when taking into account its preferred assumptions and other considerations, the ICER would be below £24,269 per QALY gained and could be lower than £20,000 per QALY gained. But it recognised that there was uncertainty about:
the size of the all-cause mortality benefit associated with letermovir (see section 3.6)
the structure of the economic model (see section 3.9) and
the health-related quality-of-life benefit of letermovir (see section 3.8).Having considered these factors, the committee agreed that the most plausible ICER for letermovir compared with placebo is within the range normally considered to be an acceptable use of NHS resources. Therefore, the committee recommended letermovir as an option for preventing CMV reactivation and disease after an HSCT in adults who are seropositive for CMV.
# Other factors
## Innovation
The committee agreed that there is an unmet need for an effective and tolerable treatment to prevent CMV reactivation and disease after an HSCT in adults who are seropositive for CMV. However, it concluded that it had taken all potential benefits into account in its decision making (see section 3.19).
## Equalities
No relevant equalities issues were identified.
|
{'Recommendations': 'Letermovir is recommended, within its marketing authorisation, as an option for preventing cytomegalovirus (CMV) reactivation and disease after an allogeneic haematopoietic stem cell transplant (HSCT) in adults who are seropositive for CMV. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent management of CMV after an allogeneic HSCT (a stem cell transplant from a donor) involves regular blood tests to monitor CMV levels (with or without aciclovir). If CMV levels rise, treatment with ganciclovir, valganciclovir or foscarnet (pre-emptive therapy) is started to prevent disease but this can cause severe side effects. Letermovir is an option for reducing CMV and is safer than pre-emptive therapy.\n\nClinical trial evidence shows that letermovir is effective in reducing CMV infection and also reduces the need for pre-emptive therapy. The most plausible cost-effectiveness estimates for letermovir are within the range that NICE usually considers acceptable. Therefore, it is recommended.', 'Information about letermovir': "Marketing authorisation indication\n\nLetermovir (Prevymis, Merck, Sharpe & Dohme) is indicated 'for the prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult CMV-seropositive [R+] recipients of an allogeneic haematopoietic stem cell transplant'.\n\nDosage in the marketing authorisation\n\nThe recommended dose of letermovir is 480\xa0mg once daily (oral tablets and solution for intravenous infusion), decreasing to 240\xa0mg once daily if co‑administered with cyclosporin\xa0A.\n\nTreatment with letermovir may be started on the day of transplant or on any day up to 28\xa0days afterwards and should continue for 100\xa0days after transplant; longer treatment may be considered in some patients at high risk for late CMV reactivation.\n\nPrice\n\nThe list price for oral letermovir is £3,723.16 for 28×240\xa0mg tablets (excluding VAT; British national formulary online accessed April 2019).\n\nThe intravenous formulation is not currently available in England.\n\nThe company has a commercial arrangement. This makes letermovir available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Merck, Sharpe & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## Cytomegalovirus reactivation substantially affects the mental health and wellbeing of patients and their families\n\nCytomegalovirus (CMV) can become active again in about 60% to 80% of people who are seropositive for CMV and who have had an allogeneic haematopoietic stem cell transplant (HSCT). This can happen especially if the transplant involved T‑cell depletion therapy, which is common in the UK. The patient experts highlighted that CMV reactivation can have a substantial psychological effect on patients and their families, negatively affecting their mental health and wellbeing. Hospital admissions to treat CMV reactivation disrupt family and working life and are particularly stressful because of the worry and risk of further infections. Pre-emptive therapy for CMV reactivation (see section\xa03.2) can have serious side effects. The patient experts noted that better prevention of CMV reactivation would reduce hospital admissions and the need for toxic pre-emptive therapy, which would greatly reduce distress. The committee concluded that CMV reactivation can have a substantial psychological effect on patients and their families.\n\n# Clinical management\n\n## Patients and clinicians would welcome a new treatment that could prevent CMV reactivation and reduce the need for pre-emptive therapy\n\nThere are no licensed treatments available specifically for preventing CMV reactivation after an allogeneic HSCT. The current standard approach in the NHS is surveillance monitoring for viral reactivation. When viral DNA is detected, pre-emptive therapy is started with ganciclovir, valganciclovir or foscarnet, depending on the type of transplant received (T‑cell depletion or T‑cell repletion). The clinical experts stated that:\n\nPractice varies on when to start pre-emptive therapy. Some centres would start based on a specific viral load count, but the assays for measuring viral load are not standardised.\n\nAciclovir is also used as prophylaxis in some centres although it may not be effective for this.\n\nLetermovir reduces reactivation rates and the need for toxic pre-emptive therapy and improves quality of life.The committee concluded that an effective and tolerable treatment that specifically acts to prevent CMV reactivation would benefit people who are seropositive for CMV who have had an allogeneic HSCT.\n\n# Clinical evidence\n\n## The main evidence is from PN001, a randomised, double-blind, placebo-controlled trial\n\nThe main clinical evidence came from a phase\xa0III randomised placebo-controlled trial, PN001. This trial compared the efficacy and safety of letermovir (n=373) with placebo (n=192) in adults who were seropositive for CMV and who have had an allogeneic HSCT. Treatment continued to week\xa014 (about\xa0100 days) and patients were monitored through to week\xa024 after transplant for the primary efficacy outcome. The primary outcome was the incidence of clinically significant CMV infection by week\xa024. This was assessed by the proportion of people with CMV end-organ disease or starting anti-CMV pre-emptive therapy (ganciclovir, valganciclovir or foscarnet with or without cidofovir) based on documented CMV viraemia (as measured by the central laboratory) and the clinical condition of the patient. Patients who completed the trial then entered a follow-up phase from week\xa024 to week\xa048 after transplant. The company presented results for 2\xa0populations: the overall randomised population who had treatment (the 'all subjects as treated' population) and the main analysis population in the trial (the 'full analysis set' population). The full analysis set population excluded patients who were randomised and had treatment if they had detectable CMV DNA on day\xa01. To account for missing data, the company's preferred approach was to assume that if people did not complete treatment their treatment had not worked. This included people with missing data or who stopped the study early. The committee concluded that PN001 was a well conducted trial and agreed that it would consider the full analysis set population.\n\n## The PN001 trial results are generalisable to clinical practice in England\n\nThe committee considered how generalisable the PN001 results were to NHS clinical practice in England. It discussed the following concerns:\n\nOnly 12\xa0patients were from the UK.\n\nThe maximum treatment duration was 100\xa0days. The ERG considered this inappropriate because in clinical practice, some people may need longer periods of prophylaxis, for example people having treatment for active graft versus host disease or those at high risk of CMV reactivation because of T‑cell depletion. During consultation, a clinical expert explained that although the marketing authorisation allows treatment for longer than 100\xa0days, there is no evidence that patients benefit from longer prophylaxis. The clinical experts stated that until trial evidence supports such use, they would not continue letermovir prophylaxis for longer than 100\xa0days. The committee accepted that in clinical practice in England, the maximum letermovir treatment duration was unlikely to be longer than 100\xa0days.\n\nThere was a delay in starting prophylaxis (mean 11.5\xa0days, 'all subjects as treated' population; mean 10.9\xa0days, full analysis set population) after transplant in the trial, which could potentially underestimate the efficacy and treatment duration of letermovir. During consultation, the company explained that the delay was because of concerns about the safety of starting prophylaxis immediately after HSCT. The clinical experts stated that they were now reassured about the safety of starting prophylaxis immediately after HSCT, and therefore would not expect a delay in clinical practice. Also, at the second appraisal committee meeting, the company noted that because the clinical effectiveness estimates were based on the observed treatment duration from PN001 it was not appropriate to include an additional treatment delay. The committee accepted that a delay would not be likely in clinical practice but agreed there was some uncertainty about the estimates of treatment duration. It concluded that without a better estimate of treatment duration, estimates from the trial were acceptable.\n\nThe prevalence of ciclosporin\xa0A use in people who had letermovir in the trial was 51.7% (based on the 'all subjects as treated' population). Both the ERG and the clinical experts agreed that this was much lower than seen in clinical practice. They assumed that approximately 90% to 95% of people would have ciclosporin\xa0A and the remaining patients would have tacrolimus.\n\nThe limited use of alemtuzumab (used for depleting T‑cells to avoid graft versus host disease) in the trial (4%) compared with clinical practice in the NHS (around 60% to 85%) could potentially underestimate the CMV reactivation rate and overestimate the risk of graft versus host disease. The clinical experts stated that its use in clinical practice depends on the treating centre but suggested that approximately 60% to 85% of people would have alemtuzumab.\n\nThe ERG highlighted that clinically significant CMV reactivation leading to pre-emptive therapy is defined differently in the trial than in UK practice. In the trial, a viral load threshold between 150 to 300\xa0copies/ml was used, depending on the patient's risk of CMV infection. The clinical experts stated that, in clinical practice, the threshold varied by centre but typically would be between 400 to 700\xa0copies/ml. During consultation, 1\xa0clinical expert noted that CMV infection would not be determined by the threshold level of viraemia, highlighting that the clinical difference between the stated threshold ranges was negligible. The committee acknowledged that there was some ambiguity about the definition of a clinically significant CMV infection. It agreed that it was unclear if CMV infection rate, and subsequently the use of pre-emptive therapy, were over or underestimated in the trial.During consultation 1\xa0clinical expert commented that the PN001 results were generalisable to clinical practice in England, because the treatment duration from PN001 was realistic and the CMV infection rate was not overestimated. The committee therefore concluded that the trial results were generalisable to clinical practice, but accepted that its concerns about treatment duration, pre-emptive therapy use and the definition of a clinically significant CMV infection could make interpreting the results challenging.\n\n## Letermovir reduces CMV infection at 24\xa0weeks after allogeneic HSCT\n\nIn PN001, letermovir statistically significantly reduced the rate of clinically significant CMV infection at week\xa024 compared with placebo. The stratum-adjusted treatment difference between letermovir and placebo was −23.5 (95% confidence interval [CI] −32.5 to −14.6). The hazard ratio (HR) for time to onset of clinically significant CMV infection at week\xa024 was 0.29 (95% CI 0.21 to 0.42). There was also a statistically significant difference in starting pre-emptive therapy for documented viraemia by week\xa024 between letermovir and placebo (stratum-adjusted treatment difference −23.3 [95% CI −32.3 to −14.3]). The committee concluded that compared with placebo, letermovir is effective in reducing the incidence of clinically significant CMV infection after allogeneic HSCT and in reducing the need for pre-emptive therapy.\n\n## The all-cause mortality benefit of letermovir compared with placebo is not statistically significant at 48\xa0weeks\n\nIn PN001, letermovir statistically significantly reduced the all-cause mortality rate at week\xa024 compared with placebo, with a hazard ratio of 0.57 (95% CI 0.34 to 0.96). The company also did an exploratory analysis using week\xa048 data, which included people who withdrew early from the trial but were confirmed to be alive after the trial had ended. The difference in all-cause mortality between letermovir and placebo was 3.8% but this was not statistically significant (HR 0.73, 95% CI 0.49 to 1.09). When people were stratified by prior CMV infection in another post hoc analysis, people on letermovir who had clinically significant CMV infection through week\xa024 had a lower all-cause mortality rate at week\xa048 when compared with people on placebo who had clinically significant CMV infection at week\xa024. Similar all-cause mortality rates were seen in both groups in people without clinically significant CMV infection at week\xa024. The committee acknowledged that these post hoc analyses could suggest that letermovir prevents additional all-cause mortality in people with prior CMV infection (CMV-related), despite not completely preventing CMV reactivation. It also noted that CMV-related mortality results were available, but the European Medicines Agency did not consider the data to be scientifically sound. During consultation, the company highlighted that although mortality was not a primary outcome in PN001, the exploratory analyses suggested letermovir could provide mortality benefit. The clinical experts stated that a mortality benefit with letermovir is plausible although it has not been proven. The committee agreed that the 48‑week post hoc analysis provided a more complete data set because it included mortality events in PN001 that occurred after week\xa024. It concluded that it would consider the 48‑week analysis for decision making, but acknowledged that the size of letermovir's mortality benefit is uncertain because of the limited trial follow up.\n\n# Adverse events\n\n## The safety profile of letermovir is acceptable\n\nOverall, adverse events were similar between the letermovir group and the placebo group except for those leading to patients stopping treatment. There were no treatment-related deaths in either group. The most commonly reported adverse events in the 2\xa0groups were graft versus host disease, nausea, vomiting, diarrhoea, pyrexia and rash. Cardiac disorder, hyperkalaemia, ear and labyrinth disorder and dyspnoea were more common in people on letermovir than on placebo. The ERG commented that the adverse event results were difficult to interpret because of the underlying conditions and treatments as well as the toxicity associated with various pre-emptive therapy regimens. Also, there were no safety data presented for letermovir use after 100\xa0days. The committee was aware of the conclusions in the European public assessment report, which stated that the adverse event profile appeared similar to that of current standard care (that is, surveillance monitoring and pre-emptive therapy). The committee concluded that the safety profile of letermovir was acceptable and unlikely to be worse than current standard care.\n\n# Health-related quality of life\n\n## PN001 did not show a health-related quality-of-life benefit for letermovir compared with placebo but a benefit is plausible\n\nHealth-related quality-of-life data collected at the time of randomisation and at weeks\xa014, 24\xa0and\xa048 after transplant using EQ-5D-3L and FACT-BMT questionnaires showed no statistically significant differences between letermovir and placebo. A small possible utility benefit on graft versus host disease, rehospitalisation and opportunistic infections was seen with letermovir compared with placebo, but these benefits were not statistically tested. The company explained that health-related quality of life was an exploratory outcome and PN001 was not powered to detect statistically significant differences between treatment groups. The ERG also highlighted that, other than at randomisation, the mean values for EQ‑5D-3L and FACT-BMT scores represent a mixture of people who have had CMV reactivation and started pre-emptive therapy and those who have not. Therefore, the direct effect of letermovir on health-related quality of life was confounded. Also, the clinical experts stated that showing improvement in quality of life in a clinical trial of this nature is challenging because of differences in timing of assessments in relation to letermovir dosing and administration of other treatments. During consultation, the company explained that health-related quality of life was assessed before starting pre-emptive therapy, therefore the disutility associated with toxicities from pre-emptive therapy was not captured. The committee recalled comments from the clinical and patient experts that reducing CMV reactivation rates and the need for toxic pre-emptive therapy would improve quality of life (see section\xa03.1). The committee acknowledged the trial's limitations, which made interpreting the results more challenging. It agreed that although the trial did not show a health-related quality-of-life benefit for letermovir compared with placebo from preventing CMV reactivation, it concluded that such a benefit was plausible and agreed it would take this into account in its decision making.\n\n# Cost-effectiveness model structure\n\n## The company's model is oversimplified but appropriate for decision making\n\nThe company's economic model had a lifetime time horizon. It consisted of a decision tree phase up to week\xa024 after transplant (week\xa048 in the scenario analysis) and a simple 2-state (alive or dead) Markov model phase covering the remaining time horizon of the model. The ERG considered that the company's model was too simplistic because it lacked explicit health states to capture differences in quality-adjusted life years (QALYs). The company's model approach does not link the rate of CMV events (the principal benefit of letermovir) with mortality. The committee was aware that this meant that nearly all the QALY benefits in the model for letermovir were derived from mortality differences. As such, the differences in the rate of CMV infection and other clinical events (for example, graft versus host disease) between the letermovir group and the placebo group and their effect on quality of life and mortality could not be fully explored. The committee agreed with the ERG that the company's model was oversimplified and acknowledged that this introduced some uncertainty about the cost-effectiveness estimates. Nevertheless, the committee recognised the difficulty in fully capturing the mortality benefits associated specifically with letermovir prophylaxis in the model because of the differences in mortality risk associated with patients' underlying conditions and the lack of available data to do this. The committee concluded that, although the model is oversimplified, it was appropriate for decision making.\n\n# Clinical data in the economic model\n\n## The 48‑week clinical data are more complete so should be used in the model\n\nIn the decision tree phase of the model, the company included the cumulative probabilities of 6\xa0different clinical events from PN001 (starting pre-emptive therapy, CMV disease, rehospitalisation, opportunistic infection, graft versus host disease and all-cause mortality). These clinical events were drawn from the 24‑week data and used 'data as observed', meaning that no adjustments were made for the 13.5% incomplete follow-ups at week\xa024. The ERG considered it inappropriate to use 24‑week data when 48‑week data were available for most outcomes. The committee recalled that the company had collected mortality data at week\xa048, which included people who withdrew early from the trial but were alive after the end of the trial. The ERG considered this data set to be more complete because only 3.2% patients were lost to follow up. During consultation, the company highlighted that the trial follow-up phase to week\xa048 investigated the safety of letermovir. It also noted that in PN001 letermovir prophylaxis stopped after 14\xa0weeks. Because of this, it was not appropriate to assess the effect of prophylaxis at week\xa048. The ERG explained that by ignoring mortality events in PN001 between weeks\xa024 and 48, the company assumed an additional mortality benefit for letermovir. At the second appraisal committee meeting, a clinical expert explained that it was logical to use the 48‑week data because it was more complete. The committee recalled its consideration that a 48‑week post hoc analysis provided a more complete data set for decision making (see section\xa03.6), and concluded that it preferred to use the 48‑week data instead of the 24‑week 'data as observed' in its decision making.\n\n## Mortality data from the haematological malignancy research network (HMRN) is more relevant to clinical practice\n\nIn the company's model in the Markov model phase, the clinical outcome used was all-cause mortality. The mortality rate was assumed to be the same in both groups. This was based on general population mortality data from the Office for National Statistics, with a standardised mortality rate from Wingard et al. (2011) applied to account for the effect of the underlying condition. The ERG considered that the company's general approach was appropriate but that the HMRN was a more relevant source of UK data. The clinical experts at the committee meeting agreed. In the company's model the excess risk of mortality in year\xa02 was assumed to be equal to the excess risk in year\xa03. The clinical experts stated that mortality risk in year\xa02 was likely to be much higher than in year\xa03 and more in line with that reported by the HMRN (19% compared with the company's 3%). Also, the ERG highlighted that the Wingard study data were relatively old (from 1980 to 2003) and therefore their relevance to current practice was unclear. In addition, a substantial proportion (more than 40%) of the population in the Wingard study were children. During consultation, the company noted that the HMRN mortality data did not have the same level of detail about the underlying disease as the Wingard study data. However, it acknowledged that there were limitations with both data sources and agreed with the ERG's concerns about the Wingard study. The committee therefore concluded that it would consider the HMRN data in its decision making because they are more relevant to NHS clinical practice.\n\n# Utility values in the economic model\n\n## The ERG's approach to modelling long-term disutility associated with HSCT is preferred for decision making\n\nIn the original company submission, a scenario analysis included a disutility for the long-term effects (more than 48\xa0weeks) of HSCT. However, the ERG did not consider this analysis to fully capture the long-term disutility associated with having HSCT because it was derived from a mix of EQ‑5D‑5L (Leunis et al. 2014) and EQ‑5D‑3L (Ara et al. 2011) values. The ERG suggested an alternative disutility based on the difference between the mean utility of patients in PN001 at 48\xa0weeks and the mean general population utilities from Ara et al. The committee agreed that the company's approach to modelling long-term disutility associated with HSCT was inappropriate and concluded that the ERG's alternative approach was preferable.\n\n## Modelling disutility associated with graft versus host disease is included in the company's updated base case\n\nThe ERG identified that disutility associated with graft versus host disease should have been included in the company's original base-case analysis. This is because it is a serious and common complication of allogeneic HSCT and is associated with significant morbidity and mortality. During consultation, the company provided an updated base-case analysis which included the disutility associated with chronic graft versus host disease (occurring more than 100\xa0days after HSCT), and discounting any disutility occurring beyond the first year. The company noted that changes in utility values for acute graft versus host disease (occurring within 100\xa0days of HSCT) would already be captured in the utility values, therefore additional disutility was not needed. The committee concluded that the company's approach to modelling the disutility associated with graft versus host disease in its updated base-case analysis was acceptable and would be considered in its decision making.\n\n# Resource use and costs\n\n## There is uncertainty around the actual treatment duration for letermovir, but it is likely to be between the company's and ERG's estimates\n\nIn its original base case, the company assumed that the mean duration of treatment in the model was 69.4\xa0days. This was based on the 'all subjects as treated' population from PN001. The ERG considered that the duration of treatment may be considerably longer and assumed mean duration of treatment to be 83\xa0days in its original base case. This was based on the duration of therapy in the full analysis set population (72.1\xa0days) plus an additional 10.9\xa0days from the delayed start of prophylaxis in the trial. The clinical experts explained that, because a delay in starting letermovir prophylaxis is not expected in clinical practice, the duration of treatment is likely to be longer than 69.4\xa0days but should not be more than 100\xa0days (see section\xa03.4). During consultation, the company acknowledged that treatment duration was likely to be longer than 69.4\xa0days and assumed a treatment duration of 72.1\xa0days in its updated base case. The clinical experts highlighted that because of the treatment delay in PN001 there was no accurate estimate of mean treatment duration. However, they noted that a mean treatment duration of between 72.1\xa0days and 83\xa0days was a reasonable estimate. The committee concluded that it would consider a mean letermovir treatment duration range of 72.1\xa0days to 83\xa0days in its decision making.\n\n## The ERG's assumption about intravenous letermovir use is overestimated\n\nBased on the 12\xa0UK patients in PN001, the company's original model assumed that approximately 5% of patients would have intravenous letermovir. However, the ERG considered that the proportion of patients in PN001 who had intravenous letermovir (27%) was more representative of UK practice. The clinical experts explained that because T‑cell depletion is commonly used in current practice, they tend to use treatments that are less toxic to the gut. Therefore, they agreed with the company's assumption that only 5% of patients would have intravenous letermovir. The committee agreed that the company's assumption about intravenous letermovir use was more appropriate than the ERG's. During consultation, the company explained that the intravenous formulation of letermovir was not available in England, and provided analyses assuming 100% oral letermovir use. The committee agreed to take account of current availability and clinical expert opinion in its decision making and concluded that it would consider 0% and 5% intravenous letermovir use.\n\n## Assuming 20% of people have foscarnet in the model is appropriate\n\nThe ERG was concerned that the company's original model assumed foscarnet use was 25%, which was too high, potentially overestimating the cost of pre-emptive therapy. The ERG's clinical experts stated that only 5% to 15% of patients would have foscarnet as part of their pre-emptive therapy. However, the clinical experts at the first meeting stated that its use varied between centres and often depended on the type of transplant received. For example, people having T‑cell depletion, which is common in NHS practice, would most likely have foscarnet because of their higher risk of earlier CMV reactivation. Therefore, the clinical experts suggested that the use of foscarnet is closer to 15% to 25%, and the committee agreed that foscarnet use in the model should be between 15% and 25%. During consultation the company updated its base case and assumed foscarnet use was 20%, which the committee concluded was appropriate.\n\n# Cost-effectiveness estimates\n\n## The company's updated base-case ICER comparing letermovir with placebo is £17,713 per QALY gained\n\nThe company's updated base case was based on the ERG's original base case, but included:\n\nan increased discount in letermovir's commercial arrangement\n\n‑week trial data instead of 48‑week data (see section\xa03.10)\n\na mean duration of therapy of 72.1\xa0days (see section\xa03.14)\n\na discounted disutility associated with graft versus host disease and disease relapse beyond the first year (see section\xa03.13)\n\nconcomitant use of ciclosporin\xa0A of 90% and foscarnet use of 20% (see section\xa03.16).The committee noted that the company's updated base-case incremental cost-effectiveness ratio (ICER) was higher than its original base-case ICER and included some of its preferred assumptions. However, the company's updated base case did not use 48‑week data from PN001 (see section\xa03.10) and it assumed a treatment duration (72.1\xa0days) at the lower end of the range the committee wished to consider (see section\xa03.14). The company's updated deterministic base-case ICER for letermovir (including the updated commercial arrangement) compared with placebo increased from £10,904 (original base case) to £17,713 per QALY gained.\n\n## The ERG's updated base-case ICER for letermovir compared with placebo is £24,269 per QALY gained\n\nThe ERG's updated base case was similar to that of the company's, but included:\n\nthe 48‑week trial data together with the post hoc analysis of all-cause mortality (see section\xa03.6 and section\xa03.10)\n\na mean duration of therapy of 83\xa0days (see section\xa03.14)\n\ncorrection of the company's misinterpretation of the ERG model settings for some utility value inputs.The committee noted using both the 48‑week trial data and assuming a longer mean treatment duration for letermovir increased the ICER. The ERG's updated base-case ICER for letermovir (including the updated commercial arrangement) compared with placebo decreased from £27,536 (original base case) to £24,269 per QALY gained.\n\n# Conclusion\n\n## Letermovir is recommended\n\nHaving considered the company's and ERG's updated base-case ICERs, the committee agreed that the ERG's analysis aligned more closely with its preferred assumptions. However, it recalled that it would take into account the following considerations in its decision making:\n\nAlthough a health-related quality-of-life benefit from preventing CMV reactivation was not shown in PN001, a benefit with letermovir was plausible (see section\xa03.8). It recognised that had these benefits been included in the model the ICER would decrease.\n\nThe company's model was too simplistic in that it did not fully capture the clinical signs and symptoms of CMV and their effect on quality of life (see section\xa03.9). It acknowledged that the effect of this on the ICER was unclear.\n\nThe estimated treatment duration for letermovir was uncertain and the committee agreed it would consider a mean treatment duration range of 72.1\xa0days to 83\xa0days (see section\xa03.14). It understood that assuming a shorter treatment duration would reduce the ICER and that the ERG's assumed treatment duration was at the top end of this range.\n\nIntravenous letermovir use was assumed to be 5% in the ERG's updated base case, in line with clinical expert opinion (see section\xa03.15). The committee acknowledged that intravenous letermovir was not currently available in England, and assuming 100% oral use would decrease the ICER.The committee noted that when taking into account its preferred assumptions and other considerations, the ICER would be below £24,269\xa0per QALY gained and could be lower than £20,000 per QALY gained. But it recognised that there was uncertainty about:\n\nthe size of the all-cause mortality benefit associated with letermovir (see section\xa03.6)\n\nthe structure of the economic model (see section\xa03.9) and\n\nthe health-related quality-of-life benefit of letermovir (see section\xa03.8).Having considered these factors, the committee agreed that the most plausible ICER for letermovir compared with placebo is within the range normally considered to be an acceptable use of NHS resources. Therefore, the committee recommended letermovir as an option for preventing CMV reactivation and disease after an HSCT in adults who are seropositive for CMV.\n\n# Other factors\n\n## Innovation\n\nThe committee agreed that there is an unmet need for an effective and tolerable treatment to prevent CMV reactivation and disease after an HSCT in adults who are seropositive for CMV. However, it concluded that it had taken all potential benefits into account in its decision making (see section\xa03.19).\n\n## Equalities\n\nNo relevant equalities issues were identified."}
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https://www.nice.org.uk/guidance/ta591
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Evidence-based recommendations on letermovir (Prevymis) for preventing cytomegalovirus disease after a stem cell transplant.
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e9d03d807502e60b1d25d4bae5aac7901c35c676
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nice
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Chronic obstructive pulmonary disease in over 16s: diagnosis and management
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Chronic obstructive pulmonary disease in over 16s: diagnosis and management
This guideline covers diagnosing and managing chronic obstructive pulmonary disease or COPD (which includes emphysema and chronic bronchitis) in people aged 16 and older. It aims to help people with COPD to receive a diagnosis earlier so that they can benefit from treatments to reduce symptoms, improve quality of life and keep them healthy for longer.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Diagnosing COPD
The diagnosis of chronic obstructive pulmonary disease (COPD) depends on thinking of it as a cause of breathlessness or cough. The diagnosis is suspected on the basis of symptoms and signs and is supported by spirometry.
## Symptoms
Suspect a diagnosis of COPD in people over 35 who have a risk factor (generally smoking or a history of smoking) and who present with 1 or more of the following symptoms:
exertional breathlessness
chronic cough
regular sputum production
frequent winter 'bronchitis'
wheeze.
When thinking about a diagnosis of COPD, ask the person if they have:
weight loss
reduced exercise tolerance
waking at night with breathlessness
ankle swelling
fatigue
-ccupational hazards
chest pain
haemoptysis (coughing up blood).These last 2 symptoms are uncommon in COPD and raise the possibility of alternative diagnoses.
One of the primary symptoms of COPD is breathlessness. The Medical Research Council (MRC) dyspnoea scale (see table 1) should be used to grade the breathlessness according to the level of exertion required to elicit it.
Grade
Degree of breathlessness related to activities
Not troubled by breathlessness except on strenuous exercise
Short of breath when hurrying or walking up a slight hill
Walks slower than contemporaries on level ground because of breathlessness, or has to stop for breath when walking at own pace
Stops for breath after walking about 100 metres or after a few minutes on level ground
Too breathless to leave the house, or breathless when dressing or undressing
Adapted from Fletcher CM, Elmes PC, Fairbairn MB et al. (1959) The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. British Medical Journal 2: 257–66.
## Spirometry
Perform spirometry:
at diagnosis
to reconsider the diagnosis, for people who show an exceptionally good response to treatment
to monitor disease progression.
Measure post-bronchodilator spirometry to confirm the diagnosis of COPD.
Think about alternative diagnoses or investigations for older people who have an FEV1/FVC ratio below 0.7 but do not have typical symptoms of COPD.
Think about a diagnosis of COPD in younger people who have symptoms of COPD, even when their FEV1/FVC ratio is above 0.7.
All healthcare professionals who care for people with COPD should have access to spirometry and be competent in interpreting the results.
Spirometry can be performed by any healthcare worker who has had appropriate training and has up-to-date skills.
Spirometry services should be supported by quality control processes.
It is recommended that European Respiratory Journal GLI 2012 reference values are used, but it is recognised that these values are not applicable for all ethnic groups.
## Incidental findings on chest X‑ray or CT scans
Consider primary care respiratory review and spirometry (see the recommendations on symptoms and spirometry) for people with emphysema or signs of chronic airways disease on a chest X-ray or CT scan.
If the person is a current smoker, their spirometry results are normal and they have no symptoms or signs of respiratory disease:
-ffer smoking cessation advice and treatment, and referral to specialist stop smoking services (see the NICE guideline on stop smoking interventions and services)
warn them that they are at higher risk of lung disease
advise them to return if they develop respiratory symptoms
be aware that the presence of emphysema on a CT scan is an independent risk factor for lung cancer.
If the person is not a current smoker, their spirometry is normal and they have no symptoms or signs of respiratory disease:
ask them if they have a personal or family history of lung or liver disease and consider alternative diagnoses, such as alpha‑1 antitrypsin deficiency
reassure them that their emphysema or chronic airways disease is unlikely to get worse
advise them to return if they develop respiratory symptoms
be aware that the presence of emphysema on a CT scan is an independent risk factor for lung cancer.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on incidental findings on chest X-ray or CT scans .
Full details of the evidence and the committee's discussion are in evidence review D: Diagnosing COPD and predicting outcomes.
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## Further investigations
At the time of their initial diagnostic evaluation in addition to spirometry all patients should have:
a chest radiograph to exclude other pathologies
a full blood count to identify anaemia or polycythaemia
body mass index (BMI) calculated.
Perform additional investigations when needed, as detailed in table 2.
Investigation
Role
Sputum culture
To identify organisms if sputum is persistently present and purulent
Serial home peak flow measurements
To exclude asthma if diagnostic doubt remains
ECG and serum natriuretic peptides
To assess cardiac status if cardiac disease or pulmonary hypertension are suspected because of:
a history of cardiovascular disease, hypertension or hypoxia or
clinical signs such as tachycardia, oedema, cyanosis or features of cor pulmonale
See the NICE guideline on chronic heart failure in adults for recommendations on using serum natriuretic peptides to diagnose heart failure.
Echocardiogram
To assess cardiac status if cardiac disease or pulmonary hypertension are suspected
CT scan of the thorax
To investigate symptoms that seem disproportionate to the spirometric impairment
To investigate signs that may suggest another lung diagnosis (such as fibrosis or bronchiectasis)
To investigate abnormalities seen on a chest X-ray
To assess suitability for lung volume reduction procedures
Serum alpha-1 antitrypsin
To assess for alpha-1 antitrypsin deficiency if early onset, minimal smoking history or family history
Transfer factor for carbon monoxide (TLCO)
To investigate symptoms that seem disproportionate to the spirometric impairment
To assess suitability for lung volume reduction procedures
Offer people with alpha 1 antitrypsin deficiency a referral to a specialist centre to discuss how to manage their condition.
## Reversibility testing
For most people, routine spirometric reversibility testing is not necessary as part of the diagnostic process or to plan initial therapy with bronchodilators or corticosteroids. It may be unhelpful or misleading because:
repeated FEV1 measurements can show small spontaneous fluctuations
the results of a reversibility test performed on different occasions can be inconsistent and not reproducible
-ver-reliance on a single reversibility test may be misleading unless the change in FEV1 is greater than 400 ml
the definition of the magnitude of a significant change is purely arbitrary
response to long-term therapy is not predicted by acute reversibility testing.
Untreated COPD and asthma are frequently distinguishable on the basis of history (and examination) in people presenting for the first time. Whenever possible, use features from the history and examination (such as those listed in table 3) to differentiate COPD from asthma. For more information on diagnosing asthma see the NICE guideline on asthma.
COPD
Asthma
Smoker or ex-smoker
Nearly all
Possibly
Symptoms under age 35
Rare
Often
Chronic productive cough
Common
Uncommon
Breathlessness
Persistent and progressive
Variable
Night time waking with breathlessness and/or wheeze
Uncommon
Common
Significant diurnal or day-to-day variability of symptoms
Uncommon
Common
In addition to the features in table 3, use longitudinal observation of people (with spirometry, peak flow or symptoms) to help differentiate COPD from asthma.
When diagnostic uncertainty remains, or both COPD and asthma are present, use the following findings to help identify asthma:
a large (over 400 ml) response to bronchodilators
a large (over 400 ml) response to 30 mg oral prednisolone daily for 2 weeks
serial peak flow measurements showing 20% or greater diurnal or day-to-day variability.Clinically significant COPD is not present if the FEV1 and FEV1/FVC ratio return to normal with drug therapy.
If diagnostic uncertainty remains, think about referral for more detailed investigations, including imaging and measurement of transfer factor for carbon monoxide (TLCO).
Reconsider the diagnosis of COPD for people who report a marked improvement in symptoms in response to inhaled therapy.
## Assessing severity and using prognostic factors
COPD is heterogeneous, so no single measure can adequately assess disease severity in an individual. Severity assessment is, nevertheless, important because it has implications for therapy and relates to prognosis.
Do not use a multidimensional index (such as BODE) to assess prognosis in people with stable COPD.
From diagnosis onwards, when discussing prognosis and treatment decisions with people with stable COPD, think about the following factors that are individually associated with prognosis:
FEV1
smoking status
breathlessness (MRC scale)
chronic hypoxia and/or cor pulmonale
low BMI
severity and frequency of exacerbations
hospital admissions
symptom burden (for example, COPD Assessment Test score)
exercise capacity (for example, 6‑minute walk test)
TLCO
whether the person meets the criteria for long-term oxygen therapy and/or home non-invasive ventilation
multimorbidity
frailty.
For a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on assessing severity and using prognostic factors .
Full details of the evidence and the committee's discussion are in evidence review D: Diagnosing COPD and predicting outcomes.
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## Assessing and classifying the severity of airflow obstruction
Assess the severity of airflow obstruction according to the reduction in FEV1, as shown in table 4.
For people with mild airflow obstruction, only diagnose COPD if they have one or more of the symptoms in the recommendation on symptoms.
Post-broncho-dilator FEV1/FVC
FEV1 % predicted
NICE guideline CG12 (2004) severity of airflow obstruction
ATS/ERS 2004 severity of airflow obstruction (post-broncho-dilator)
GOLD 2008 severity of airflow obstruction (post-broncho-dilator)
NICE guideline CG101 (2010) severity of airflow obstruction (post-broncho-dilator)
Not categorised
Mild
Stage 1 – Mild
Stage 1 – Mild
Mild
Moderate
Stage 2 – Moderate
Stage 2 – Moderate
Moderate
Severe
Stage 3 – Severe
Stage 3 – Severe
Severe
Very severe
Stage 4 – Very severe (or FEV1 below 50% with respiratory failure)
Stage 4 – Very severe (or FEV1 below 50% with respiratory failure)
ATS/ERS guidance: Celli BR, MacNee W (2004) Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. European Respiratory Journal 23(6): 932–46.
GOLD guidance: Global Initiative for Chronic Obstructive Lung Disease (GOLD; 2008) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.
## Identifying early disease
Perform spirometry in people who are over 35, current or ex‑smokers, and have a chronic cough.
Consider spirometry in people with chronic bronchitis. A significant proportion of these people will go on to develop airflow limitation.
## Referral for specialist advice
When clinically indicated, refer people for specialist advice. Referral may be appropriate at all stages of the disease and not solely in the most severely disabled people (see table 5).
Reason
Purpose
There is diagnostic uncertainty
Confirm diagnosis and optimise therapy
Suspected severe COPD
Confirm diagnosis and optimise therapy
The person with COPD requests a second opinion
Confirm diagnosis and optimise therapy
Onset of cor pulmonale
Confirm diagnosis and optimise therapy
Assessment for oxygen therapy
Optimise therapy and measure blood gases
Assessment for long-term nebuliser therapy
Optimise therapy and exclude inappropriate prescriptions
Assessment for oral corticosteroid therapy
Justify need for continued treatment or supervise withdrawal
Bullous lung disease
Identify candidates for lung volume reduction procedures
A rapid decline in FEV1
Encourage early intervention
Assessment for pulmonary rehabilitation
Identify candidates for pulmonary rehabilitation
Assessment for a lung volume reduction procedure
Identify candidates for surgical or bronchoscopic lung volume reduction
Assessment for lung transplantation
Identify candidates for surgery
Dysfunctional breathing
Confirm diagnosis, optimise pharmacotherapy and access other therapists
Onset of symptoms under 40 years or a family history of alpha‑1 antitrypsin deficiency
Identify alpha‑1 antitrypsin deficiency, consider therapy and screen family
Symptoms disproportionate to lung function deficit
Look for other explanations including cardiac impairment, pulmonary hypertension, depression and hyperventilation
Frequent infections
Exclude bronchiectasis
Haemoptysis
Exclude carcinoma of the bronchus
People who are referred do not always have to be seen by a respiratory physician. In some cases they may be seen by members of the COPD team who have appropriate training and expertise.
# Managing stable COPD
NICE has also produced a visual summary covering non-pharmacological management and use of inhaled therapies.
For guidance on the management of multimorbidity, see the NICE guideline on multimorbidity.
## Smoking cessation
Document an up-to-date smoking history, including pack years smoked (number of cigarettes smoked per day, divided by 20, multiplied by the number of years smoked) for everyone with COPD.
At every opportunity, advise and encourage every person with COPD who is still smoking (regardless of their age) to stop, and offer them help to do so.
Unless contraindicated, offer nicotine replacement therapy, varenicline or bupropion as appropriate to people who want to stop smoking, combined with an appropriate support programme to optimise smoking quit rates for people with COPD.
For more guidance on helping people to quit smoking, see the NICE guideline on stop smoking interventions and services.
For more guidance on varenicline see the NICE technology appraisal guidance on varenicline for smoking cessation.
## Inhaled therapy
Use short-acting bronchodilators, as necessary, as the initial empirical treatment to relieve breathlessness and exercise limitation.
Do not use oral corticosteroid reversibility tests to identify which people should be prescribed inhaled corticosteroids, because they do not predict response to inhaled corticosteroid therapy.
Be aware of, and be prepared to discuss with the person, the risk of side effects (including pneumonia) in people who take inhaled corticosteroids for COPD. Follow the MHRA safety advice on the risk of psychological and behavioural side effects associated with inhaled corticosteroids.
Inhaled combination therapy refers to combinations of long-acting muscarinic antagonists (LAMA), long-acting beta2 agonists (LABA), and inhaled corticosteroids (ICS).
Do not assess the effectiveness of bronchodilator therapy using lung function alone. Include a variety of other measures such as improvement in symptoms, activities of daily living, exercise capacity, and rapidity of symptom relief.
Offer LAMA+LABA to people who:
have spirometrically confirmed COPD and
do not have asthmatic features/features suggesting steroid responsiveness and
remain breathless or have exacerbations despite:
having used or been offered treatment for tobacco dependence if they smoke and
-ptimised non-pharmacological management and relevant vaccinations and
using a short-acting bronchodilator. Follow the MHRA safety advice on Respimat and Handihaler inhalers.
Consider LABA+ICS for people who:
have spirometrically confirmed COPD and
have asthmatic features/features suggesting steroid responsiveness and
remain breathless or have exacerbations despite:
having used or been offered treatment for tobacco dependence if they smoke and
-ptimised non-pharmacological management and relevant vaccinations and
using a short-acting bronchodilator.
For people who are using long-acting bronchodilators outside of the recommendations on offering LAMA and LABA and considering LABA+ICS and whose symptoms are under control, explain to them that they can continue with their current treatment until both they and their NHS healthcare professional agree it is appropriate to change.
Before starting LAMA+LABA+ICS, conduct a clinical review to ensure that:
the person's non-pharmacological COPD management is optimised and they have used or been offered treatment for tobacco dependence if they smoke
acute episodes of worsening symptoms are caused by COPD exacerbations and not by another physical or mental health condition
the person's day-to-day symptoms that are adversely impacting their quality of life are caused by COPD and not by another physical or mental health condition.
For people with COPD who are taking LABA+ICS, offer LAMA+LABA+ICS if:
their day-to-day symptoms continue to adversely impact their quality of life or
they have a severe exacerbation (requiring hospitalisation) or
they have 2 moderate exacerbations within a year.
For people with COPD who are taking LAMA+LABA, consider LAMA+LABA+ICS if:
they have a severe exacerbation (requiring hospitalisation) or
they have 2 moderate exacerbations within a year.
For people with COPD who are taking LAMA+LABA and whose day-to-day symptoms adversely impact their quality of life:
consider a trial of LAMA+LABA+ICS, lasting for 3 months only
after 3 months, conduct a clinical review to establish whether or not LAMA+LABA+ICS has improved their symptoms:
if symptoms have not improved, stop LAMA+LABA+ICS and switch back to LAMA+LABA
if symptoms have improved, continue with LAMA+LABA+ICS.
Document the reason for continuing ICS use in clinical records and review at least annually.
Base the choice of drugs and inhalers on:
how much they improve symptoms
the person's preferences and ability to use the inhalers
the drugs' potential to reduce exacerbations
their side effects
their cost.Minimise the number of inhalers and the number of different types of inhaler used by each person as far as possible.
When prescribing long-acting drugs, ensure people receive inhalers they have been trained to use (for example, by specifying the brand and inhaler in prescriptions).
For a short explanation of why the committee made the 2018 and 2019 recommendations and how they might affect practice, see the rationale and impact section on inhaled combination therapy.
Full details of the evidence and the committee's discussion are in evidence review F: Inhaled therapies and evidence review I: Inhaled triple therapy.
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Most people with COPD – whatever their age – can develop adequate inhaler technique if they are given training. However, people with significant cognitive impairment may be unable to use any form of inhaler device. In most people with COPD, however, a pragmatic approach guided by individual patient assessment is needed when choosing a device.
In most cases bronchodilator therapy is best administered using a hand-held inhaler (including a spacer if appropriate).
Provide an alternative inhaler if a person cannot use a particular one correctly or it is not suitable for them.
Only prescribe inhalers after people have been trained to use them and can demonstrate satisfactory technique.
People with COPD should have their ability to use an inhaler regularly assessed and corrected if necessary by a healthcare professional competent to do so.
Provide a spacer that is compatible with the person's metered-dose inhaler.
Advise people to use a spacer with a metered-dose inhaler in the following way:
administer the drug by single actuations of the metered-dose inhaler into the spacer, inhaling after each actuation
there should be minimal delay between inhaler actuation and inhalation
normal tidal breathing can be used as it is as effective as single breaths
repeat if a second dose is required.
Advise people on spacer cleaning. Tell them:
not to clean the spacer more than monthly, because more frequent cleaning affects their performance (because of a build-up of static)
to hand wash using warm water and washing-up liquid, and allow the spacer to air dry.
Think about nebuliser therapy for people with distressing or disabling breathlessness despite maximal therapy using inhalers.
Do not prescribe nebulised therapy without an assessment of the person's and/or carer's ability to use it.
Do not continue nebulised therapy without assessing and confirming that 1 or more of the following occurs:
a reduction in symptoms
an increase in the ability to undertake activities of daily living
an increase in exercise capacity
an improvement in lung function.
Use a nebuliser system that is known to be efficient. Follow the MHRA safety advice on non-CE-marked nebulisers for COPD.
Offer people a choice between a facemask and a mouthpiece to administer their nebulised therapy, unless the drug specifically requires a mouthpiece (for example, anticholinergic drugs).
If nebuliser therapy is prescribed, provide the person with equipment, servicing, and ongoing advice and support.
## Oral therapy
Long-term use of oral corticosteroid therapy in COPD is not normally recommended. Some people with advanced COPD may need long-term oral corticosteroids when these cannot be withdrawn following an exacerbation. In these cases, the dose of oral corticosteroids should be kept as low as possible.
Monitor people who are having long-term oral corticosteroid therapy for osteoporosis, and give them appropriate prophylaxis. Start prophylaxis without monitoring for people over 65.
In this section of the guideline, the term theophylline refers to slow-release formulations of the drug.
Theophylline should only be used after a trial of short-acting bronchodilators and long-acting bronchodilators, or for people who are unable to use inhaled therapy, as plasma levels and interactions need to be monitored.
Take particular caution when using theophylline in older people, because of differences in pharmacokinetics, the increased likelihood of comorbidities and the use of other medications.
Assess the effectiveness of theophylline by improvements in symptoms, activities of daily living, exercise capacity and lung function.
Reduce the dose of theophylline for people who are having an exacerbation if they are prescribed macrolide or fluoroquinolone antibiotics (or other drugs known to interact).
Consider mucolytic drug therapy for people with a chronic cough productive of sputum.
Only continue mucolytic therapy if there is symptomatic improvement (for example, reduction in frequency of cough and sputum production).
Do not routinely use mucolytic drugs to prevent exacerbations in people with stable COPD.
Treatment with alpha-tocopherol and beta-carotene supplements, alone or in combination, is not recommended.
Anti-tussive therapy should not be used in the management of stable COPD.
Before starting prophylactic antibiotic therapy in a person with COPD, think about whether respiratory specialist input is needed.
Consider azithromycin (usually 250 mg 3 times a week) for people with COPD if they:
do not smoke and
have optimised non-pharmacological management and inhaled therapies, relevant vaccinations and (if appropriate) have been referred for pulmonary rehabilitation and
continue to have 1 or more of the following, particularly if they have significant daily sputum production:
frequent (typically 4 or more per year) exacerbations with sputum production
prolonged exacerbations with sputum production
exacerbations resulting in hospitalisation. In July 2019, this was an off-label use of azithromycin. See NICE's information on prescribing medicines.
Before offering prophylactic antibiotics, ensure that the person has had:
sputum culture and sensitivity (including tuberculosis culture), to identify other possible causes of persistent or recurrent infection that may need specific treatment (for example, antibiotic-resistant organisms, atypical mycobacteria or Pseudomonas aeruginosa)
training in airway clearance techniques to optimise sputum clearance (see the recommendation in the section on physiotherapy)
a CT scan of the thorax to rule out bronchiectasis and other lung pathologies.
Before starting azithromycin, ensure the person has had:
an electrocardiogram (ECG) to rule out prolonged QT interval and
baseline liver function tests.
When prescribing azithromycin, advise people about the small risk of hearing loss and tinnitus, and tell them to contact a healthcare professional if this occurs.
Review prophylactic azithromycin after the first 3 months, and then at least every 6 months.
Only continue treatment if the continued benefits outweigh the risks. Be aware that there are no long-term studies on the use of prophylactic antibiotics in people with COPD.
For people who are taking prophylactic azithromycin and are still at risk of exacerbations, provide a non-macrolide antibiotic to keep at home as part of their exacerbation action plan (see the recommendation on offering antibiotics to keep at home in the section on self-management).
Be aware that it is not necessary to stop prophylactic azithromycin during an acute exacerbation of COPD.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on oral prophylactic antibiotic therapy .
Full details of the evidence and the committee's discussion are in evidence review E: Predicting and preventing exacerbations.
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For guidance on treating severe COPD with roflumilast, see NICE's technology appraisal guidance on roflumilast for treating chronic obstructive pulmonary disease.
## Oxygen
Be aware that inappropriate oxygen therapy in people with COPD may cause respiratory depression.
Assess the need for oxygen therapy in people with:
very severe airflow obstruction (FEV1 below 30% predicted)
cyanosis (blue tint to skin)
polycythaemia
peripheral oedema (swelling)
a raised jugular venous pressure
-xygen saturations of 92% or less breathing air.Also consider assessment for people with severe airflow obstruction (FEV1 30–49% predicted).Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Assess people for long-term oxygen therapy by measuring arterial blood gases on 2 occasions at least 3 weeks apart in people who have a confident diagnosis of COPD, who are receiving optimum medical management and whose COPD is stable.
Consider long-term oxygen therapy for people with COPD who do not smoke and who:
have a partial pressure of oxygen in arterial blood (PaO2) below 7.3 kPa when stable or
have a PaO2 above 7.3 and below 8 kPa when stable, if they also have 1 or more of the following:
secondary polycythaemia
peripheral oedema
pulmonary hypertension.See the MHRA alert on the risk of death and severe harm from failure to obtain and continue flow from oxygen cylinders.
Conduct and document a structured risk assessment for people being assessed for long-term oxygen therapy who meet the criteria in the recommendation on considering long-term oxygen therapy. As part of the risk assessment, cover the risks for both the person with COPD and the people who live with them, including:
the risks of falls from tripping over the equipment
the risks of burns and fires, and the increased risk of these for people who live in homes where someone smokes (including e‑cigarettes).Base the decision on whether long-term oxygen therapy is suitable on the results of the structured risk assessment.
For people who smoke or live with people who smoke, but who meet the other criteria for long-term oxygen therapy, ensure the person who smokes is offered smoking cessation advice and treatment, and referral to specialist stop smoking services (see the NICE guidelines on stop smoking interventions and services and medicines optimisation).
Do not offer long-term oxygen therapy to people who continue to smoke despite being offered smoking cessation advice and treatment, and referral to specialist stop smoking services.
Advise people who are having long-term oxygen therapy that they should breathe supplemental oxygen for a minimum of 15 hours per day.
Do not offer long-term oxygen therapy to treat isolated nocturnal hypoxaemia caused by COPD.
To ensure everyone eligible for long-term oxygen therapy is identified, pulse oximetry should be available in all healthcare settings.
Oxygen concentrators should be used to provide the fixed supply at home for long-term oxygen therapy.
People who are having long-term oxygen therapy should be reviewed at least once per year by healthcare professionals familiar with long-term oxygen therapy. This review should include pulse oximetry.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on long-term oxygen therapy .
Full details of the evidence and the committee's discussion are in evidence review B: Oxygen therapy in people with stable COPD.
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Do not offer ambulatory oxygen to manage breathlessness in people with COPD who have mild or no hypoxaemia at rest.
Consider ambulatory oxygen in people with COPD who have exercise desaturation and are shown to have an improvement in exercise capacity with oxygen, and have the motivation to use oxygen.
Prescribe ambulatory oxygen to people who are already on long-term oxygen therapy, who wish to continue oxygen therapy outside the home, and who are prepared to use it.
Only prescribe ambulatory oxygen therapy after an appropriate assessment has been performed by a specialist. The purpose of the assessment is to assess the extent of desaturation, the improvement in exercise capacity with supplemental oxygen, and the oxygen flow rate needed to correct desaturation.
Small light-weight cylinders, oxygen-conserving devices and portable liquid oxygen systems should be available for people with COPD.
When choosing which equipment to prescribe, take account of the hours of ambulatory oxygen use and oxygen flow rate needed.
Do not offer short-burst oxygen therapy to manage breathlessness in people with COPD who have mild or no hypoxaemia at rest.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on ambulatory and oxygen short-burst oxygen therapy .
Full details of the evidence and the committee's discussion are in evidence review B: Oxygen therapy in people with stable COPD.
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Refer people who are adequately treated but have chronic hypercapnic respiratory failure and have needed assisted ventilation (whether invasive or non-invasive) during an exacerbation, or who are hypercapnic or acidotic on long-term oxygen therapy, to a specialist centre for consideration of long-term non-invasive ventilation.
## Managing pulmonary hypertension and cor pulmonale
In this guideline 'cor pulmonale' is defined as a clinical condition that is identified and managed on the basis of clinical features. It includes people who have right heart failure secondary to lung disease and people whose primary pathology is salt and water retention, leading to the development of peripheral oedema (swelling).
Suspect a diagnosis of cor pulmonale for people with:
peripheral oedema (swelling)
a raised venous pressure
a systolic parasternal heave
a loud pulmonary second heart sound.
It is recommended that the diagnosis of cor pulmonale is made clinically and that this process should involve excluding other causes of peripheral oedema (swelling).
Do not offer the following treatments solely to manage pulmonary hypertension caused by COPD, except as part of a randomised controlled trial:
bosentan
losartan
nifedipine
nitric oxide
pentoxifylline
phosphodiesterase-5 inhibitors
statins.
Ensure that people with cor pulmonale caused by COPD are offered optimal COPD treatment, including advice and interventions to help them stop smoking. For people who need treatment for hypoxia, see the section on long-term oxygen therapy.
Oedema associated with cor pulmonale can usually be controlled symptomatically with diuretic therapy.
Do not use the following to treat cor pulmonale caused by COPD:
alpha-blockers
angiotensin-converting enzyme inhibitors
calcium channel blockers
digoxin (unless there is atrial fibrillation).
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on managing pulmonary hypertension and cor pulmonale .
Full details of the evidence and the committee's discussion are in evidence review A: Managing pulmonary hypertension and cor pulmonale.
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## Pulmonary rehabilitation
Pulmonary rehabilitation is defined as a multidisciplinary programme of care for people with chronic respiratory impairment. It is individually tailored and designed to optimise each person's physical and social performance and autonomy.
Make pulmonary rehabilitation available to all appropriate people with COPD (see the recommendation on offering pulmonary rehabilitation), including people who have had a recent hospitalisation for an acute exacerbation.
Offer pulmonary rehabilitation to all people who view themselves as functionally disabled by COPD (usually Medical Research Council grade 3 and above). Pulmonary rehabilitation is not suitable for people who are unable to walk, who have unstable angina or who have had a recent myocardial infarction.
For pulmonary rehabilitation programmes to be effective, and to improve adherence, they should be held at times that suit people, in buildings that are easy to get to and that have good access for people with disabilities. Places should be available within a reasonable time of referral.
Pulmonary rehabilitation programmes should include multicomponent, multidisciplinary interventions that are tailored to the individual person's needs. The rehabilitation process should incorporate a programme of physical training, disease education, and nutritional, psychological and behavioural intervention.
Advise people of the benefits of pulmonary rehabilitation and the commitment needed to gain these.
## Vaccination and anti-viral therapy
Offer pneumococcal vaccination and an annual flu vaccination to all people with COPD, as recommended by the Chief Medical Officer.
For guidance on preventing and treating flu, see the NICE technology appraisals on oseltamivir, amantadine (review) and zanamivir for the prophylaxis of influenza and amantadine, oseltamivir and zanamivir for the treatment of influenza.
## Lung surgery and lung volume reduction procedures
Offer a respiratory review to assess whether a lung volume reduction procedure is a possibility for people with COPD when they complete pulmonary rehabilitation and at other subsequent reviews, if all of the following apply:
they have severe COPD, with FEV1 less than 50% and breathlessness that affects their quality of life despite optimal medical treatment (see recommendations 1.2.11 to 1.2.17 in the section on inhaled combination therapy)
they do not smoke
they can complete a 6‑minute walk distance of at least 140 m (if limited by breathlessness).
At the respiratory review, refer the person with COPD to a lung volume reduction multidisciplinary team to assess whether lung volume reduction surgery or endobronchial valves are suitable if they have:
hyperinflation, assessed by lung function testing with body plethysmography and
emphysema on unenhanced CT chest scan and
-ptimised treatment for other comorbidities.
Only offer endobronchial coils as part of a clinical trial and after assessment by a lung volume reduction multidisciplinary team.
For more guidance on lung volume reduction procedures, see the NICE interventional procedures guidance on lung volume reduction surgery, endobronchial valves and endobronchial coils.
Refer people with COPD for an assessment for bullectomy if they are breathless and a CT scan shows a bulla occupying at least one third of the hemithorax.
Consider referral to a specialist multidisciplinary team to assess for lung transplantation for people who:
have severe COPD, with FEV1 less than 50% and breathlessness that affects their quality of life despite optimal medical treatment (see recommendations 1.2.11 to 1.2.17 in the section on inhaled combination therapy) and
do not smoke and
have completed pulmonary rehabilitation and
do not have contraindications for transplantation (for example, comorbidities or frailty).
Do not use previous lung volume reduction procedures as a reason not to refer a person for assessment for lung transplantation.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on lung volume reduction procedures, bullectomy and lung transplantation .
Full details of the evidence and the committee's discussion are in evidence review G: Referral criteria for lung volume reduction procedures, bullectomy or lung transplantation.
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## Alpha‑1 antitrypsin replacement therapy
Alpha‑1 antitrypsin replacement therapy is not recommended for people with alpha‑1 antitrypsin deficiency (see also the recommendation on referral in the section on further investigations).
## Multidisciplinary management
COPD care should be delivered by a multidisciplinary team.
When defining the activity of the multidisciplinary team, think about the following functions:
assessment (including performing spirometry, assessing which delivery systems to use for inhaled therapy, the need for aids for daily living and assessing the need for oxygen)
care and treatment, including:
pulmonary rehabilitation
identifying and managing anxiety and depression
advising people on relaxation techniques
dietary issues
exercise
social security benefits and travel
hospital-at-home/early discharge schemes
non-invasive ventilation and palliative care
advising people on self-management strategies
identifying and monitoring people at high risk of exacerbations and undertaking activities to avoid emergency admissions
education for people with COPD, their carers, and for healthcare professionals.
It is recommended that the multidisciplinary COPD team includes respiratory nurse specialists.
If people have excessive sputum, they should be taught:
how to use positive expiratory pressure devices
active cycle of breathing techniques.
Be alert for anxiety and depression in people with COPD. Consider whether people have anxiety or depression, particularly if they:
have severe breathlessness
are hypoxic
have been seen at or admitted to a hospital with an exacerbation of COPD.
For guidance on diagnosing and managing depression, see the NICE guideline on depression in adults with a chronic physical health problem.
For guidance on managing anxiety, see the NICE guideline on generalised anxiety disorder and panic disorder in adults.
Calculate BMI for people with COPD:
the normal range for BMI is 20 to less than 25 kg/m2
refer people for dietetic advice if they have a BMI that is abnormal (high or low) or changing over time
for people with a low BMI, give nutritional supplements to increase their total calorific intake and encourage them to exercise to augment the effects of nutritional supplementation. The NICE guideline on obesity states that a healthy BMI range is 18.5 to 24.9 kg/m2, but note that this may not be appropriate for people with COPD.
For guidance on nutrition support, see the NICE guideline on nutrition support for adults.
Pay attention to changes in weight in older people, particularly if the change is more than 3 kg.
When appropriate, use opioids to relieve breathlessness in people with end-stage COPD that is unresponsive to other medical therapy.
When appropriate, use benzodiazepines, tricyclic antidepressants, major tranquillisers and oxygen for breathlessness in people with end-stage COPD that is unresponsive to other medical therapy.
People with end-stage COPD and their family members or carers (as appropriate) should have access to the full range of services offered by multidisciplinary palliative care teams, including admission to hospices.
For standards and measures on palliative care, see the NICE quality standard on end of life care for adults.
For guidance on care for people in the last days of life, see the NICE guideline on care of dying adults.
Regularly ask people with COPD about their ability to undertake activities of daily living and how breathless these activities make them.
Clinicians that care for people with COPD should assess their need for occupational therapy using validated tools.
Consider referring people for assessment by social services if they have disabilities caused by COPD.
Assess people who are using long-term oxygen therapy and who are planning air travel in line with the British Thoracic Society recommendations.
Assess people with an FEV1 below 50% predicted who are planning air travel in line with the BTS recommendations.
Warn people with bullous disease that they are at a theoretically increased risk of a pneumothorax during air travel.
Scuba diving is not generally recommended for people with COPD. Advise people with queries to seek specialist advice.
There are significant differences in the response of people with COPD and asthma to education programmes. Programmes designed for asthma should not be used in COPD.
At diagnosis and at each review appointment, offer people with COPD and their family members or carers (as appropriate):
written information about their condition
-pportunities for discussion with a healthcare professional who has experience in caring for people with COPD.
Ensure the information provided is:
available on an ongoing basis
relevant to the stage of the person's condition
tailored to the person's needs.
At minimum, the information should cover:
an explanation of COPD and its symptoms
advice on quitting smoking (if relevant) and how this will help with the person's COPD
advice on avoiding passive smoke exposure
managing breathlessness
physical activity and pulmonary rehabilitation
medicines, including inhaler technique and the importance of adherence
vaccinations
identifying and managing exacerbations
details of local and national organisations and online resources that can provide more information and support
how COPD will affect other long-term conditions that are common in people with COPD (for example hypertension, heart disease, anxiety, depression and musculoskeletal problems).
Be aware of the obligation to provide accessible information as detailed in the NHS Accessible Information Standard. For more guidance on providing information to people and discussing their preferences with them, see the NICE guideline on patient experience in adult NHS services.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on self-management, education and telehealth monitoring .
Full details of the evidence and the committee's discussion are in evidence review C: Self-management interventions, education and telehealth monitoring.
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Advise people with COPD that the following factors increase their risk of exacerbations:
continued smoking or relapse for ex‑smokers
exposure to passive smoke
viral or bacterial infection
indoor and outdoor air pollution
lack of physical activity
seasonal variation (winter and spring).
For a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on risk factors for COPD exacerbations .
Full details of the evidence and the committee's discussion are in evidence review E: Predicting and preventing exacerbations.
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Develop an individualised self-management plan in collaboration with each person with COPD and their family members or carers (as appropriate), and:
include education on all relevant points from the recommendation on the information that should be covered in the section on education
review the plan at future appointments.
Develop an individualised exacerbation action plan in collaboration with each person with COPD who is at risk of exacerbations.
Offer people a short course of oral corticosteroids and a short course of oral antibiotics to keep at home as part of their exacerbation action plan if:
they have had an exacerbation within the last year, and remain at risk of exacerbations
they understand and are confident about when and how to take these medicines, and the associated benefits and harms
they know to tell their healthcare professional when they have used the medicines, and to ask for replacements.
For guidance on the choice of antibiotics see the NICE guideline on antimicrobial prescribing for acute exacerbations of COPD.
At all review appointments, discuss corticosteroid and antibiotic use with people who keep these medicines at home, to check that they still understand how to use them. For people who have used 3 or more courses of oral corticosteroids and/or oral antibiotics in the last year, investigate the possible reasons for this.
See the recommendations on systemic corticosteroids for more guidance on oral corticosteroids.
Encourage people with COPD to respond promptly to exacerbation symptoms by following their action plan, which may include:
adjusting their short-acting bronchodilator therapy to treat their symptoms
taking a short course of oral corticosteroids if their increased breathlessness interferes with activities of daily living
adding oral antibiotics if their sputum changes colour and increases in volume or thickness beyond their normal day-to-day variation
telling their healthcare professional.
Ask people with COPD if they experience breathlessness they find frightening. If they do, consider including a cognitive behavioural component in their self-management plan to help them manage anxiety and cope with breathlessness.
For people at risk of hospitalisation, explain to them and their family members or carers (as appropriate) what to expect if this happens (including non-invasive ventilation and discussions on future treatment preferences, ceilings of care and resuscitation).
Do not offer routine telehealth monitoring of physiological status as part of management for stable COPD.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on self-management, education and telehealth monitoring .
Full details of the evidence and the committee's discussion are in evidence review C: Self-management interventions, education and telehealth monitoring.
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## Fitness for general surgery
The ultimate clinical decision about whether or not to proceed with surgery should rest with a consultant anaesthetist and consultant surgeon, taking account of comorbidities, functional status and the need for the surgery.
It is recommended that lung function should not be the only criterion used to assess people with COPD before surgery. Composite assessment tools such as the ASA scoring system are the best predictors of risk.
If time permits, optimise the medical management of people with COPD before surgery. This might include a course of pulmonary rehabilitation.
## Follow-up of people with COPD
Follow-up of all people with COPD should include:
highlighting the diagnosis of COPD in the case record and recording this using Read Codes on a computer database
recording the values of spirometric tests performed at diagnosis (both absolute and percent predicted)
-ffering advice and treatment to help them stop smoking, and referral to specialist stop smoking services (see the NICE guideline on stop smoking interventions and services)
recording the opportunistic measurement of spirometric parameters (a loss of 500 ml or more over 5 years will show which people have rapidly progressing disease and may need specialist referral and investigation).
Review people with COPD at least once per year and more frequently if indicated, and cover the issues listed in table 6.
For most people with stable severe COPD regular hospital review is not necessary, but there should be locally agreed mechanisms to allow rapid access to hospital assessment when needed.
When people with very severe COPD are reviewed in primary care they should be seen at least twice per year, and specific attention should be paid to the issues listed in table 6.
Specialists should regularly review people with severe COPD who need interventions such as long-term non-invasive ventilation.
Mild/moderate/severe (stages 1 to 3)
Very severe (stage 4)
Frequency
At least annual
At least twice per year
Clinical assessment
Smoking status and motivation to quit
Adequacy of symptom control:
breathlessness
exercise tolerance
estimated exacerbation frequency
Need for pulmonary rehabilitation
Presence of complications
Effects of each drug treatment
Inhaler technique
Need for referral to specialist and therapy services
Smoking status and motivation to quit
Adequacy of symptom control:
breathlessness
exercise tolerance
estimated exacerbation frequency
Presence of cor pulmonale
Need for long-term oxygen therapy
Person with COPD's nutritional state
Presence of depression
Effects of each drug treatment
Inhaler technique
Need for social services and occupational therapy input
Need for referral to specialist and therapy services
Need for pulmonary rehabilitation
Measurements to make
FEV1 and FVC
calculate BMI
MRC dyspnoea score
FEV1 and FVC
calculate BMI
MRC dyspnoea score
SaO2
# Managing exacerbations of COPD
## Definition of an exacerbation
An exacerbation is a sustained worsening of the patient's symptoms from their usual stable state which is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. The change in these symptoms often necessitates a change in medication.
## Assessing the need for hospital treatment
Use the factors in table 7 to assess whether people with COPD need hospital treatment.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Factor
Treat at home
Treat in hospital
Able to cope at home
Yes
No
Breathlessness
Mild
Severe
General condition
Good
Poor/deteriorating
Level of activity
Good
Poor/confined to bed
Cyanosis
No
Yes
Worsening peripheral oedema
No
Yes
Level of consciousness
Normal
Impaired
Already receiving long-term oxygen therapy
No
Yes
Social circumstances
Good
Living alone/not coping
Acute confusion
No
Yes
Rapid rate of onset
No
Yes
Significant comorbidity (particularly cardiac disease and insulin-dependent diabetes)
No
Yes
SaO2 < 90%
No
Yes
Changes on chest radiograph
No
Present
Arterial pH level
Arterial PaO2
≥ 7 kPa
< 7 kPa
## Investigating an exacerbation
The diagnosis of an exacerbation is made clinically and does not depend on the results of investigations. However, investigations may sometimes be useful in ensuring appropriate treatment is given. Different investigation strategies are needed for people in hospital (who will tend to have more severe exacerbations) and people in the community.
For people who have their exacerbation managed in primary care:
sending sputum samples for culture is not recommended in routine practice
pulse oximetry is of value if there are clinical features of a severe exacerbation. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
In all people presenting to hospital with an acute exacerbation:
-btain a chest X-ray
measure arterial blood gas tensions and record the inspired oxygen concentration
record an ECG (to exclude comorbidities)
perform a full blood count and measure urea and electrolyte concentrations
measure a theophylline level on admission in people who are taking theophylline therapy
send a sputum sample for microscopy and culture if the sputum is purulent
take blood cultures if the person has pyrexia.
## Hospital-at-home and assisted-discharge schemes
Hospital-at-home and assisted-discharge schemes are safe and effective and should be used as an alternative way of caring for people with exacerbations of COPD who would otherwise need to be admitted or stay in hospital.
The multiprofessional team that operates these schemes should include allied health professionals with experience in managing COPD, and may include nurses, physiotherapists, occupational therapists and other health workers.
There are currently insufficient data to make firm recommendations about which people with COPD with an exacerbation are most suitable for hospital-at-home or early discharge. Selection should depend on the resources available and absence of factors associated with a worse prognosis (for example, acidosis).
Include people's preferences about treatment at home or in hospital in decision-making.
## Pharmacological management
Increased breathlessness is a common feature of COPD exacerbations. This is usually managed by taking increased doses of short-acting bronchodilators.
Both nebulisers and hand-held inhalers can be used to administer inhaled therapy during exacerbations of COPD.
The choice of delivery system should reflect the dose of drug needed, the person's ability to use the device, and the resources available to supervise therapy administration.
Change people to hand-held inhalers as soon as their condition has stabilised, because this may allow them to be discharged from hospital earlier.
If a person with COPD is hypercapnic or acidotic the nebuliser should be driven by compressed air rather than oxygen (to avoid worsening hypercapnia). If oxygen therapy is needed, administer it simultaneously by nasal cannulae.
The driving gas for nebulised therapy should always be specified in the prescription.
In the absence of significant contraindications, use oral corticosteroids, in conjunction with other therapies, in all people admitted to hospital with a COPD exacerbation.
In the absence of significant contraindications, consider oral corticosteroids for people in the community who have an exacerbation with a significant increase in breathlessness that interferes with daily activities.
Encourage people who need corticosteroid therapy to present early to get maximum benefits.
Offer 30 mg oral prednisolone daily for 5 days.
For guidance on stopping oral corticosteroid therapy it is recommended that clinicians refer to the BNF.
Think about osteoporosis prophylaxis for people who need frequent courses of oral corticosteroids.
Make people aware of the optimum duration of treatment and the adverse effects of prolonged therapy.
Give people (particularly people discharged from hospital) clear instructions on why, when and how to stop their corticosteroid treatment.
For a short explanation of why the committee made the 2019 recommendation and how it might affect practice, see the rationale and impact section on duration of oral corticosteroid for managing exacerbations .
Full details of the evidence and the committee's discussion are in evidence review J: Length of corticosteroid use during exacerbations.
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For guidance on using antibiotics to treat COPD exacerbations, see the NICE guideline on antimicrobial prescribing for acute exacerbations of COPD.
Only use intravenous theophylline as an adjunct to exacerbation management if there is an inadequate response to nebulised bronchodilators.
Take care when using intravenous theophylline, because of its interactions with other drugs and potential toxicity if the person has been taking oral theophylline.
Monitor theophylline levels within 24 hours of starting treatment, and as frequently as indicated by the clinical circumstances after this.
It is recommended that doxapram is used only when non-invasive ventilation is either unavailable or inappropriate.
## Oxygen therapy during exacerbations of COPD
Measure oxygen saturation in people with an exacerbation if there are no facilities to measure arterial blood gases.
If necessary, prescribe oxygen to keep the oxygen saturation of arterial blood (SaO2) within the individualised target range.
Pulse oximeters should be available to all healthcare professionals involved in the care of people with exacerbations of COPD, and they should be trained in their use. Clinicians should be aware that pulse oximetry gives no information about the PaCO2 or pH.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Measure arterial blood gases and note the inspired oxygen concentration in all people who arrive at hospital with an exacerbation of COPD. Repeat arterial blood gas measurements regularly, according to the response to treatment.
## Non-invasive ventilation (NIV) and COPD exacerbations
Use NIV as the treatment of choice for persistent hypercapnic ventilatory failure during exacerbations despite optimal medical therapy.
It is recommended that NIV should be delivered in a dedicated setting, with staff who have been trained in its application, who are experienced in its use and who are aware of its limitations.
When people are started on NIV there should be a clear plan covering what to do in the event of deterioration, and ceilings of therapy should be agreed.
## Invasive ventilation and intensive care
Treat hospitalised exacerbations of COPD on intensive care units, including invasive ventilation when this is thought to be necessary.
When assessing suitability for intubation and ventilation during exacerbations, think about functional status, BMI, need for oxygen when stable, comorbidities and previous admissions to intensive care units, in addition to age and FEV1. Neither age nor FEV1 should be used in isolation when assessing suitability.
Consider NIV for people who are slow to wean from invasive ventilation.
## Respiratory physiotherapy and exacerbations
Consider physiotherapy using positive expiratory pressure devices for selected people with exacerbations of COPD, to help with clearing sputum.
## Monitoring recovery from an exacerbation
Monitor people's recovery by regular clinical assessment of their symptoms and observation of their functional capacity.
Use pulse oximetry to monitor the recovery of people with non-hypercapnic, non-acidotic respiratory failure.
Use intermittent arterial blood gas measurements to monitor the recovery of people with respiratory failure who are hypercapnic or acidotic, until they are stable.
Do not routinely perform daily monitoring of peak expiratory flow (PEF) or FEV1 to monitor recovery from an exacerbation, because the magnitude of changes is small compared with the variability of the measurement.
## Discharge planning
Measure spirometry in all people before discharge.
Re-establish people on their optimal maintenance bronchodilator therapy before discharge.
People who have had an episode of respiratory failure should have satisfactory oximetry or arterial blood gas results before discharge.
Assess all aspects of the routine care that people receive (including appropriateness and risk of side effects) before discharge.
Give people (or home carers) appropriate information to enable them to fully understand the correct use of medications, including oxygen, before discharge.
Make arrangements for follow-up and home care (such as visiting nurse, oxygen delivery or referral for other support) before discharge.
The person, their family and their physician should be confident that they can manage successfully before they are discharged. A formal activities of daily living assessment may be helpful when there is still doubt.
# Terms used in this guideline
## Asthmatic features/features suggesting steroid responsiveness
This includes any previous, secure diagnosis of asthma or of atopy, a higher blood eosinophil count, substantial variation in FEV1 over time (at least 400 ml) or substantial diurnal variation in peak expiratory flow (at least 20%).
## Exacerbation
An exacerbation is a sustained worsening of the patient's symptoms from their usual stable state which is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. The change in these symptoms often necessitates a change in medication.
A general classification of the severity of an acute exacerbation (from a Cochrane Library systematic review) is:
mild exacerbation, the person has an increased need for medication, which they can manage in their own normal environment
moderate exacerbation, the person has a sustained worsening of respiratory status that requires treatment with systemic corticosteroids and/or antibiotics
severe exacerbation, the person experiences a rapid deterioration in respiratory status that requires hospitalisation.
## Mild or no hypoxaemia
People who are not taking long-term oxygen and who have a mean PaO2 greater than 7.3k Pa.# Recommendations for research
The guideline committee has made the following recommendations for research. As part of the 2018 update, the guideline committee made additional research recommendations on prognostic indices, inhaled therapies, prophylactic antibiotics, pulmonary hypertension and the diagnosis of COPD through incidental CT scans.
# Key recommendations for research
## Pulmonary rehabilitation during hospital admission
In people with COPD, does pulmonary rehabilitation during hospital admission for exacerbation and/or in the early recovery period (within 1 month of an exacerbation) improve quality of life and reduce hospitalisations and exacerbations compared with a later (defined as after 1 month) pulmonary rehabilitation programme, and in which groups is it most clinically and cost effective?
The greatest reconditioning and potential benefit from rehabilitation may occur in the early post-exacerbation phase. If inpatient pulmonary rehabilitation is demonstrated to be effective this may potentially impact on service delivery (for example, early discharge schemes). The cost effectiveness of early versus later pulmonary rehabilitation programmes should also be evaluated. Studies should be cluster randomised, be of sufficiently long duration and be adequately powered.
## Multidimensional assessment of outcomes
How can the individual factors associated with COPD prognosis (collected from a range of sources including primary care, imaging and pulmonary rehabilitation results) be combined into a multidimensional analysis that provides accurate and useful information on prognosis?
People with COPD can experience anxiety concerning their disease prognosis. Suitable prognostic tools could help alleviate this stress and allow people to make plans for the future. Existing multidimensional indices are:
unable to classify people reliably into high- and low-risk groups better than FEV1 alone or
no better at predicting outcomes than FEV1 alone or
time-consuming and consisting of components that would not be routinely available in primary care.
However, many individual factors are known to provide information, and the development of an index/indices combining these factors could help with prognosis. These indices should be validated in a general UK COPD population, and in primary care, in a wider range of outcomes than mortality alone.
For a short explanation of why the committee made the recommendation for research, see the rationale on assessing severity and using prognostic factors .
Full details of the evidence and the committee's discussion are in evidence review D: Diagnosing COPD and predicting outcomes.
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## Inhaled therapies for people with COPD and asthma
What is the clinical and cost effectiveness of inhaled therapies (bronchodilators and/or inhaled corticosteroids) in people with both stable COPD and asthma?
There are a large number of trials that look at the effectiveness of bronchodilators and/or steroids in people with COPD, but the majority of them specifically excluded people with comorbid asthma. As a result, there is a lack of evidence concerning the most clinically and cost-effective treatments for this subgroup of people with COPD. Trials that recruit people with asthma and COPD could provide this evidence and ensure that these people receive the most effective maintenance treatments for their COPD and asthma.
## Inhaled corticosteroid responsiveness
What features predict inhaled corticosteroid responsiveness most accurately in people with COPD?
Bronchodilators and/or steroids are the main pharmacological treatments used to manage COPD. People with asthma or asthmatic features that may make them steroid responsive may need a different combination of drugs to other groups of people with COPD for the most effective treatment of their symptoms. Identifying these people would help ensure that they receive appropriate treatment.
## Prophylactic antibiotics for preventing exacerbations
Which subgroups of people with stable COPD who are at high risk of exacerbations are most likely to benefit from prophylactic antibiotics?
People with COPD commonly experience exacerbations, which have a negative impact on their quality of life and are linked to worse disease prognosis. Certain groups of people with COPD are at higher risk of exacerbations, and reducing the number of exacerbations they experience should improve quality of life for them and their families. However, subgroups of these people may benefit particularly from this treatment. Identifying and targeting prophylactic antibiotics for these people should help improve their quality of life. It may also identify people who would not benefit from prophylactic antibiotics, and so reduce the risk of antibiotic resistance by reducing the overall number of people taking prophylactic antibiotics for COPD. Randomised trials that include subgroup analysis of participants based on factors such as biomarkers, clinical features, bacterial patterns and comorbidities could provide useful information on this topic.
# Other recommendations for research
## Diagnosing COPD
What are the characteristics of people diagnosed with COPD as a result of an incidental finding of emphysema on a CT scan, compared with those diagnosed with symptoms?
For a short explanation of why the committee made the recommendation for research, see the rationale on incidental findings on chest X-ray or CT scans .
Full details of the evidence and the committee's discussion are in evidence review D: Diagnosing COPD and predicting outcomes.
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## Prophylactic antibiotics for preventing exacerbations
What is the long-term clinical and cost effectiveness of prophylactic antibiotics for people with stable COPD who are at high risk of exacerbations?
What is the comparative effectiveness of different antibiotics, doses and regimens of prophylactic antibiotics for people with stable COPD who are at high risk of exacerbations?
What is the comparative effectiveness of seasonal versus continuous prophylactic antibiotics for people with stable COPD who are at high risk of exacerbations?
## Pulmonary hypertension
What are the most clinical and cost-effective treatments for pulmonary hypertension in people with COPD?
For a short explanation of why the committee made the recommendation for research, see the rationale on pulmonary hypertension .
Full details of the evidence and the committee's discussion are in evidence review A: Managing pulmonary hypertension and cor pulmonale.
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## Mucolytic therapy
In people with COPD, does mucolytic drug therapy prevent exacerbations in comparison with placebo and other therapies?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Incidental findings on chest X-ray or CT scans
Recommendations 1.1.12 to 1.1.14
## Why the committee made the recommendations
The evidence showed that CT scans and chest X‑rays are accurate tests for identifying people who would test positive for COPD using spirometry, including people without symptoms. However, some of the CT and chest X‑ray techniques used in the studies are not routinely used in UK clinical practice. This limited how applicable the evidence was to the NHS, so the committee was unable to make a wider recommendation on using CT scans and chest X‑rays for diagnosing COPD. The committee therefore made recommendations on what to do if a CT scan or X‑ray that was performed for another reason showed signs of emphysema or chronic airways disease.
There was no evidence on what to do for people who have emphysema or signs of chronic airways disease on a CT scan or chest X‑ray, but who have no symptoms. Because of this, the committee made consensus recommendations based on their experience and on current practice in the NHS. The committee also made a recommendation for research on the characteristics of people diagnosed with COPD as a result of incidental findings on chest X-ray or CT scan, to try to determine whether they differ in ways that might mean standard COPD treatment has to be modified for them.
The committee also reviewed evidence on using pulse oximetry or high-sensitivity C‑reactive protein (hs‑CRP) for diagnosing COPD. They did not recommend these because:
pulse oximetry is normally used to measure the severity of COPD rather than to diagnose it, and there are other possible causes of low oxygen saturation
elevated hs‑CRP levels are not specifically linked to COPD, and could be caused by other conditions
the evidence showed that they were not effective diagnostic tests.
The committee amended the 'Additional investigations' table, based on their knowledge and experience, to more accurately reflect good practice.
## How the recommendations might affect practice
As the recommendation only covers CT scans or chest X‑rays taken for other purposes, there would be no additional costs from these tests. The recommendation to consider spirometry and GP respiratory review and the amendments to the 'Additional investigations' table all reflect current practice. There may be a small number of additional referrals for spirometry, but this is expected to have a minimal resource impact.
Return to recommendations
# Assessing severity and using prognostic factors
Recommendations 1.1.24 and 1.1.25
## Why the committee made the recommendations
The committee recommended against using multidimensional indices, such as BODE, because they were:
unable to classify people reliably into high- and low-risk groups better than FEV1 alone or
no better at predicting outcomes than FEV1 alone or
time-consuming and consisted of components that would not be routinely available in primary care.
However, the committee recognised the need for an effective prognostic tool that did not have these problems, so they made a recommendation for research on multidimensional assessment of outcomes to address this.
The committee used their knowledge and experience to list factors associated with prognosis. In the absence of a single prognostic tool, thinking about these factors can help guide discussions, and help people with COPD to understand how their condition is likely to progress and decide which treatments are right for them.
## How the recommendations might affect practice
The BODE index is not used routinely in the NHS and no alternative indices have been recommended, so there should be minimal impact on practice.
Return to recommendations
# Inhaled combination therapy
Recommendations 1.2.11 to 1.2.20
## Why the committee made the recommendations
The evidence showed that, compared with other dual therapy combinations and with monotherapy, LAMA+LABA:
provides the greatest benefit to overall quality of life
is better than other inhaled treatments for many individual outcomes (such as reducing the risk of moderate to severe exacerbations)
is the most cost-effective option.
The committee did not recommend a particular LAMA because they were not convinced that the evidence showed any meaningful differences in effectiveness between the drugs in this class. Instead, they updated the existing recommendation on drug and inhaler choice, based on their experience of what factors should be taken into account. In particular, minimising the number and types of inhalers prescribed will make it easier for people to use their inhalers correctly.
Most of the trials specifically excluded people with COPD and asthma, so there was no direct evidence for this group. The committee recommended LABA+ICS based on their clinical experience and knowledge of the likely benefit of inhaled corticosteroids in certain specific COPD phenotypes.
Although the combination therapies recommended in this guideline are the most effective options, some people are currently using different therapies, such as LAMA or LABA monotherapy, and may have their symptoms under control with these. The committee did not want to make people change treatments unnecessarily, so they made a recommendation highlighting that people did not need to switch treatments until their clinical needs changed.
Not everyone with COPD will benefit from triple therapy. In addition, for some people the symptoms that give them the most problems are caused by other conditions (such as heart failure or anxiety) rather than their COPD. Because of this, a clinical review is needed first, to ensure that people only receive triple therapy if they will benefit from it. The committee envisaged that this review would take the form of a conversation with the person with COPD about their symptoms, rather than relying on tools such as the CAT score or MRC breathlessness score in isolation.
The committee decided that there should be separate recommendations on triple therapy for people who are currently taking LABA+ICS and for people taking LAMA+LABA. They agreed that there was stronger evidence from a greater number of studies that triple therapy benefits people taking LABA+ICS, compared with people taking LAMA+LABA.
For people currently taking LABA+ICS, the evidence showed that LAMA+LABA+ICS reduced the rate of severe exacerbations, improved FEV1, and did not increase the risk of pneumonia or other serious adverse events.
For people currently taking LAMA+LABA, the evidence showed that LAMA+LABA+ICS reduced the rate of serious exacerbations and provides some quality of life improvement. However, these improvements were smaller than the ones for people who were taking LABA+ICS before they started triple therapy. In addition, people who switched from LAMA+LABA to triple therapy were more likely to get pneumonia.
The criteria for starting triple therapy are based on the inclusion criteria for the studies the committee reviewed and their clinical judgement. For people who are currently taking LAMA+LABA, the committee made separate recommendations for:
people who are having severe or frequent exacerbations, for whom the benefit of fewer exacerbations outweighs the increased risk of pneumonia
people with less severe symptoms, for whom it is less clear if triple therapy provides enough benefits to outweigh the risk of pneumonia.
The 3-month trial is recommended to help identify people in the group with less severe symptoms who will benefit from triple therapy, while ensuring that people who do not benefit can easily switch back to LAMA+LABA. This is to avoid the situation where people continue on triple therapy, with the accompanying risks, without seeing any benefit. As part of the review at the end of the trial, the committee agreed that it was important to explicitly ask the person with COPD if taking the drug had improved their COPD symptoms.
The committee also recommended documenting the reason for continuing ICS, to encourage treatment review so that people are not exposed to the risks of this treatment if they do not benefit from it.
The committee looked at making recommendations for people with asthmatic features. However, the evidence excluded people with asthma and did not provide much information on asthmatic features (such as eosinophil count). Because of this, and because people with asthmatic features are likely to be covered by the recommendation for people taking LABA+ICS, the committee agreed not to make a specific recommendation for this group.
The committee did not make a recommendation in favour of single or multiple inhaler devices as the included evidence did not show a meaningful difference in clinical effectiveness between triple therapy compared to dual therapy based on the number of devices. From the economic evidence, using a single inhaler device was more cost effective, but the committee agreed that there were circumstances where using more than one inhaler to deliver triple therapy may be more appropriate for a particular person with COPD. Finally, the committee had already made a recommendation about the factors to be taken into account when choosing an inhaler device and these included minimising the numbers and types of inhalers where possible and cost so an additional recommendation on this issue was unnecessary.
## How the recommendations might affect practice
The recommendation on LAMA+LABA dual therapy is likely to increase the number of people with COPD who are having this treatment. The higher cost of dual therapy compared with monotherapy may result in a significant resource impact, but cost savings are also likely from a reduction in treatments needed for exacerbations (including hospitalisation).
Using LABA+ICS for people with features of asthma/features suggesting steroid responsiveness is in line with current practice.
The recommendations may result in an increase in the number of people who are prescribed triple therapy and an increase in the number of people who need treatment for pneumonia, although this may be mitigated by the relatively widespread current use of triple therapy. However, the criteria for who should be offered triple therapy and the recommendation for a trial period should limit the impact of both of these changes.
Triple therapy regimens have a higher cost than dual long-acting bronchodilator regimens. However, this cost is likely to be at least partially offset by savings from reduced numbers of exacerbations and better management of symptoms for people switching to triple therapy.
It is already routine in practice to have a clinical review before starting triple therapy. The recommendation on clinical review may increase the scope of this review. However, any costs incurred from this should be offset by savings from more optimal management of symptoms in people with COPD, which should be associated with fewer primary care and/ or hospital visits.
The recommendation on how to choose drugs and inhalers covers factors that prescribers routinely consider, so is not a change in practice. However, minimising the number and type of inhaler devices and avoiding unnecessary within-class switching may produce cost savings through lower upfront spending and better symptom control.
Return to recommendations
# Oral prophylactic antibiotic therapy
Recommendations 1.2.45 to 1.2.53
## Why the committee made the recommendations
The evidence showed that prophylactic antibiotics reduce the risk of people having an exacerbation and the number of exacerbations per year in people with COPD and sputum production. However, prescribing these to large numbers of people with COPD could increase levels of antibiotic resistance. Problems with adherence may make this worse, as people are not taking the antibiotics to help with any current symptoms and (for azithromycin) have to remember to take it 3 times a week. In addition, the longest follow-up in the trials was 12 months, so there is no evidence on the long-term effects of prophylactic antibiotics. With this in mind, the committee made recommendations for the people who would benefit the most from prophylactic antibiotics, and whose exacerbations were not being managed well by other treatments.
The committee recommended azithromycin because this antibiotic had the most evidence of effectiveness (based on the numbers of trials and study participants). The recommended dosage is taken from the trials the committee reviewed.
People taking prophylactic azithromycin may also keep antibiotics at home as part of their exacerbation action plan (see the recommendation on offering antibiotics to keep at home in the section on self-management). This should be a different class of antibiotic to ensure that it is effective when they need it, as the person may develop resistance to azithromycin.
The committee recommended strict criteria for using and reviewing prophylactic antibiotics, to ensure that:
the risk of antibiotic resistance is minimised, both for the person taking them and for society
people only take them if it is safe to do so
people do not continue taking them if there is no benefit.
## How the recommendations might affect practice
It is likely that these recommendations will increase the number of people taking prophylactic antibiotics. This is unlikely to have a significant resource impact, given the relatively low cost of antibiotics. By reducing exacerbation frequency it is likely to reduce the amount of oral corticosteroids taken by people with COPD.
Return to recommendations
# Long-term oxygen therapy
Recommendations 1.2.58 to 1.2.63
## Why the committee made the recommendations
There is evidence that continuous long-term oxygen therapy improves survival in people with more severe hypoxaemia, but not for people with mild hypoxaemia. The specific thresholds for long-term oxygen therapy are taken from the trials that provided the evidence.
The recommendation that people should use supplemental oxygen for more than 15 hours a day is based on the available evidence. There is also evidence that long-term oxygen therapy was not effective for isolated nocturnal hypoxaemia caused by COPD.
The evidence showed risks of harm from the use of long-term oxygen therapy, in particular burns and fires as a result of smoking while using oxygen and falls from tripping over equipment. Given these risks to the person with COPD and the people they live with, the committee agreed that it is important to conduct a detailed risk assessment before offering this treatment.
The committee decided that there were 2 levels of risk posed by smoking around oxygen and the recommendations they made reflect these differences:
People with COPD who do not smoke but who live with people who smoke. Using cigarettes near oxygen could cause fires or burns, but this risk is likely to be lower because the person who smokes can keep away from the oxygen. Oxygen therapy may benefit these people if they meet the eligibility criteria and the risk assessment is favourable.
People with COPD who smoke. They will be smoking in close proximity to the oxygen, and the risks to them, the people they live with and their neighbours outweigh the potential benefits of long-term oxygen therapy.
## How the recommendations might affect practice
These recommendations may result in an increase in demand for stop smoking services, but these are known to provide good value for money. Additional time may be needed to conduct risk assessments. As these should prevent people from being given oxygen therapy if they would not benefit or may be harmed by it, it would be an appropriate use of resources and should not lead to an overall increase in resource use. These recommendations may also reduce the cost of managing harms associated with oxygen use, including falls, burns and the wider costs of fires.
Return to recommendations
# Ambulatory and short-burst oxygen therapy
Recommendations 1.2.67 and 1.2.73
## Why the committee made the recommendations
The evidence for people with mild or no hypoxaemia showed that neither ambulatory oxygen nor short-burst oxygen provide a clinically meaningful improvement in breathlessness.
## How the recommendations might affect practice
Reducing the use of ambulatory and short-burst oxygen therapy in people who would not benefit is likely to be cost saving and will allow resources to be invested in effective treatments for breathlessness instead.
Return to recommendations
# Managing pulmonary hypertension and cor pulmonale
Recommendations 1.2.77, 1.2.78 and 1.2.80
## Why the committee made the recommendations
The committee agreed that there was not enough evidence to recommend any of the reviewed treatments for pulmonary hypertension in people with COPD. Although some of the treatments improved blood pressure readings, there was no evidence that they improved quality of life and the clinical trials only involved small numbers of people.
There is a shortage of good evidence in this area, so the committee made an exception for using these treatments in randomised controlled trials, and made a recommendation for research on treatments for pulmonary hypertension.
The evidence on long-term oxygen therapy for people with COPD and cor pulmonale showed no improvement in survival. However, long-term oxygen therapy can also help with hypoxia. The committee saw no evidence that people with cor pulmonale should be treated or assessed for long-term oxygen therapy differently than other people with COPD.
## How the recommendations might affect practice
The recommendations will not change practice, as none of the treatments the committee has recommended against for pulmonary hypertension or cor pulmonale are currently in routine use specifically for these conditions in people with COPD.
Return to recommendations
# Lung volume reduction procedures, bullectomy and lung transplantation
Recommendations 1.2.88 to 1.2.94
## Why the committee made the recommendations
The evidence showed that people with severe COPD show improvements in lung function, exercise capacity, quality of life and long-term mortality as a result of lung volume reduction surgery. The criteria for who should be referred for this procedure are based on the criteria used in the trials reviewed by the committee and the committee's clinical expertise, taking into account current practice in the NHS.
It was not clear from the evidence whether endobronchial coils work better than standard lung volume reduction surgery. In addition, the procedure is relatively new. For these reasons, the committee recommended that it is only offered as part of a clinical trial.
The recommendations on referral for bullectomy and lung transplantation are based on the committee's knowledge and experience. The lung transplantation referral criteria were adapted from the criteria used for the respiratory review for lung volume reduction surgery. The committee noted that some people are refused lung transplantation because they have had previous lung volume reduction procedures. These people could still benefit from transplantation, so the committee made a recommendation to reflect this.
## How the recommendations might affect practice
It is current clinical practice to assess for future treatment plans after pulmonary rehabilitation. However, the criteria for referring people to a multidisciplinary team to assess for lung volume reduction assessment have been broadened, as recommended treatment options now include endobronchial valves. The broadening of criteria will lead to more referrals and improved access to these treatments. This will have an impact on resource use, in particular, as a new group of people for whom lung volume reduction surgery was unsuitable may now be treated with endobronchial valves.
Return to recommendations
# Risk factors for COPD exacerbations
Recommendation 1.2.123
## Why the committee made the recommendation
The factors associated with exacerbations are taken from the evidence available and the committee's experience. The evidence on physical activity was not reviewed, but as promoting exercise and physical activity is an important part of management for stable COPD the committee agreed to include it. The list only covers the factors that people can avoid or reduce their exposure to. Other factors are also associated with exacerbations (for example, disease-related factors, biomarkers and other medicines), but people cannot avoid these on their own and these factors are addressed in other areas of the guideline.
## How the recommendation might affect practice
These recommendations are unlikely to have a significant impact on resources, as the marginal cost of providing advice on exacerbations to people with COPD is very low. An increased emphasis on physical activity may lead to an increase in referrals to pulmonary rehabilitation, which is known to be a highly cost-effective intervention for people with COPD. The recommendations may produce some cost savings by reducing the number of exacerbations people have.
Return to recommendations
# Self-management, education and telehealth monitoring
Recommendations 1.2.119 to 1.2.121 and 1.2.124 to 1.2.133
## Why the committee made the recommendations
Evidence showed that self-management plans improve quality of life and reduce hospital admissions. The committee recommended that self-management plans include:
patient education, because this was a common component of the self-management plans they examined and because education alone was shown to improve knowledge about COPD
cognitive behavioural components for people with frightening breathlessness, because there is some evidence that these reduce distress (although they do not help with the symptoms of breathlessness).
The list of topics to be covered in information about COPD is taken from the self-management plans the committee examined and their own clinical and personal experience.
Exacerbation action plans were shown to improve quality of life and reduce hospital admissions for people at risk of exacerbations. Most of the exacerbation action plans that the committee examined provided people with short courses of antibiotics and corticosteroids to use at home to respond to symptoms, and monitoring to make sure they were using those medicines appropriately. Therefore these components were included in the recommendations. The committee also discussed the potential for antibiotic overuse, and stressed the importance of continued monitoring to ensure people are using these medicines appropriately.
Telehealth monitoring does not improve quality of life or reduce hospitalisations for people with COPD, and it leads to higher costs. However, the committee did not want to prevent telehealth monitoring being used for specific reasons that were not covered in the evidence they reviewed, such as short-term monitoring following hospital discharge, so they only recommended against routine telehealth monitoring.
## How the recommendations might affect practice
Self-management plans are already in place for some people with COPD. The recommendations may change the content of these plans, and may increase the number of people using a self-management plan. However, self-management plans are highly cost effective and the increased cost of providing them should be offset by cost savings from a reduction in hospitalisations.
The number of people with stable COPD who are having telehealth monitoring should decrease, which is likely to reduce costs.
Return to recommendations
# Duration of oral corticosteroids for managing exacerbations
Recommendation 1.3.16
## Why the committee made the recommendations
There are risks associated with long-term corticosteroid use, so it is important to use the shortest effective treatment duration. Treatment is recommended for 5 days because the evidence showed no benefit from taking corticosteroids for more than 7 days and shorter courses of 5 days are routinely used in clinical practice already. The 2019 review did not look at corticosteroid doses, so the dose from the original 2004 recommendation was retained.
## How the recommendations might affect practice
The recommendation may reduce the amount of corticosteroids used in clinical practice, which may result in a cost saving. However, the overall impact is likely to be small because oral corticosteroids are cheap, and because prescribing corticosteroids for 5 days is current practice for many clinicians.
Return to recommendations# Context
British Lung Foundation statistics show that there are approximately 1.2 million people with a diagnosis of chronic obstructive pulmonary disease (COPD) in the UK. Although there are 115,000 new diagnoses per year, most people with COPD are not diagnosed until they are in their fifties or older and many more people may remain undiagnosed. The UK has the 12th highest recorded deaths from COPD in the world, with an age-standardised mortality rate of 210.7 deaths per million people between 2001 and 2010.
Recently, new evidence has emerged and practice has changed in relation to the use of inhaled triple therapy and oral corticosteroids. This evidence and the changes in how care is delivered may have a significant impact on people with COPD who are still experiencing symptoms despite being prescribed triple therapy.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosing COPD\n\nThe diagnosis of chronic obstructive pulmonary disease (COPD) depends on thinking of it as a cause of breathlessness or cough. The diagnosis is suspected on the basis of symptoms and signs and is supported by spirometry.\n\n## Symptoms\n\nSuspect a diagnosis of COPD in people over 35 who have a risk factor (generally smoking or a history of smoking) and who present with 1 or more of the following symptoms:\n\nexertional breathlessness\n\nchronic cough\n\nregular sputum production\n\nfrequent winter 'bronchitis'\n\nwheeze. \n\nWhen thinking about a diagnosis of COPD, ask the person if they have:\n\nweight loss\n\nreduced exercise tolerance\n\nwaking at night with breathlessness\n\nankle swelling\n\nfatigue\n\noccupational hazards\n\nchest pain\n\nhaemoptysis (coughing up blood).These last 2 symptoms are uncommon in COPD and raise the possibility of alternative diagnoses. \n\nOne of the primary symptoms of COPD is breathlessness. The Medical Research Council (MRC) dyspnoea scale (see table\xa01) should be used to grade the breathlessness according to the level of exertion required to elicit it. \n\nGrade\n\nDegree of breathlessness related to activities\n\n\n\nNot troubled by breathlessness except on strenuous exercise\n\n\n\nShort of breath when hurrying or walking up a slight hill\n\n\n\nWalks slower than contemporaries on level ground because of breathlessness, or has to stop for breath when walking at own pace\n\n\n\nStops for breath after walking about 100 metres or after a few minutes on level ground\n\n\n\nToo breathless to leave the house, or breathless when dressing or undressing\n\nAdapted from Fletcher CM, Elmes PC, Fairbairn MB et al. (1959) The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. British Medical Journal 2: 257–66.\n\n## Spirometry\n\nPerform spirometry:\n\nat diagnosis\n\nto reconsider the diagnosis, for people who show an exceptionally good response to treatment\n\nto monitor disease progression. [2004, amended 2018]\n\nMeasure post-bronchodilator spirometry to confirm the diagnosis of COPD. \n\nThink about alternative diagnoses or investigations for older people who have an FEV1/FVC ratio below\xa00.7 but do not have typical symptoms of COPD. \n\nThink about a diagnosis of COPD in younger people who have symptoms of COPD, even when their FEV1/FVC ratio is above\xa00.7. \n\nAll healthcare professionals who care for people with COPD should have access to spirometry and be competent in interpreting the results. \n\nSpirometry can be performed by any healthcare worker who has had appropriate training and has up-to-date skills. \n\nSpirometry services should be supported by quality control processes. \n\nIt is recommended that European Respiratory Journal GLI 2012 reference values are used, but it is recognised that these values are not applicable for all ethnic groups. [2004, amended 2018]\n\n## Incidental findings on chest X‑ray or CT scans\n\nConsider primary care respiratory review and spirometry (see the recommendations on symptoms and spirometry) for people with emphysema or signs of chronic airways disease on a chest X-ray or CT scan. \n\nIf the person is a current smoker, their spirometry results are normal and they have no symptoms or signs of respiratory disease:\n\noffer smoking cessation advice and treatment, and referral to specialist stop smoking services (see the NICE guideline on stop smoking interventions and services)\n\nwarn them that they are at higher risk of lung disease\n\nadvise them to return if they develop respiratory symptoms\n\nbe aware that the presence of emphysema on a CT scan is an independent risk factor for lung cancer. \n\nIf the person is not a current smoker, their spirometry is normal and they have no symptoms or signs of respiratory disease:\n\nask them if they have a personal or family history of lung or liver disease and consider alternative diagnoses, such as alpha‑1 antitrypsin deficiency\n\nreassure them that their emphysema or chronic airways disease is unlikely to get worse\n\nadvise them to return if they develop respiratory symptoms\n\nbe aware that the presence of emphysema on a CT scan is an independent risk factor for lung cancer. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on incidental findings on chest X-ray or CT scans\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: Diagnosing COPD and predicting outcomes.\n\nLoading. Please wait.\n\n## Further investigations\n\nAt the time of their initial diagnostic evaluation in addition to spirometry all patients should have:\n\na chest radiograph to exclude other pathologies\n\na full blood count to identify anaemia or polycythaemia\n\nbody mass index (BMI) calculated. \n\nPerform additional investigations when needed, as detailed in table\xa02. [2004, amended 2018]\n\nInvestigation\n\nRole\n\nSputum culture\n\nTo identify organisms if sputum is persistently present and purulent\n\nSerial home peak flow measurements\n\nTo exclude asthma if diagnostic doubt remains\n\nECG and serum natriuretic peptides\n\nTo assess cardiac status if cardiac disease or pulmonary hypertension are suspected because of:\n\na history of cardiovascular disease, hypertension or hypoxia or\n\nclinical signs such as tachycardia, oedema, cyanosis or features of cor pulmonale\n\nSee the NICE guideline on chronic heart failure in adults for recommendations on using serum natriuretic peptides to diagnose heart failure.\n\nEchocardiogram\n\nTo assess cardiac status if cardiac disease or pulmonary hypertension are suspected\n\nCT scan of the thorax\n\nTo investigate symptoms that seem disproportionate to the spirometric impairment\n\nTo investigate signs that may suggest another lung diagnosis (such as fibrosis or bronchiectasis)\n\nTo investigate abnormalities seen on a chest X-ray\n\nTo assess suitability for lung volume reduction procedures\n\nSerum alpha-1 antitrypsin\n\nTo assess for alpha-1 antitrypsin deficiency if early onset, minimal smoking history or family history\n\nTransfer factor for carbon monoxide (TLCO)\n\nTo investigate symptoms that seem disproportionate to the spirometric impairment\n\nTo assess suitability for lung volume reduction procedures\n\nOffer people with alpha\xa01 antitrypsin deficiency a referral to a specialist centre to discuss how to manage their condition. \n\n## Reversibility testing\n\nFor most people, routine spirometric reversibility testing is not necessary as part of the diagnostic process or to plan initial therapy with bronchodilators or corticosteroids. It may be unhelpful or misleading because:\n\nrepeated FEV1 measurements can show small spontaneous fluctuations\n\nthe results of a reversibility test performed on different occasions can be inconsistent and not reproducible\n\nover-reliance on a single reversibility test may be misleading unless the change in FEV1 is greater than 400\xa0ml\n\nthe definition of the magnitude of a significant change is purely arbitrary\n\nresponse to long-term therapy is not predicted by acute reversibility testing. \n\nUntreated COPD and asthma are frequently distinguishable on the basis of history (and examination) in people presenting for the first time. Whenever possible, use features from the history and examination (such as those listed in table\xa03) to differentiate COPD from asthma. For more information on diagnosing asthma see the NICE guideline on asthma. [2004, amended 2018]\n\n\n\n\n\nCOPD\n\nAsthma\n\nSmoker or ex-smoker\n\nNearly all\n\nPossibly\n\nSymptoms under age 35\n\nRare\n\nOften\n\nChronic productive cough\n\nCommon\n\nUncommon\n\nBreathlessness\n\nPersistent and progressive\n\nVariable\n\nNight time waking with breathlessness and/or wheeze\n\nUncommon\n\nCommon\n\nSignificant diurnal or day-to-day variability of symptoms\n\nUncommon\n\nCommon\n\nIn addition to the features in table\xa03, use longitudinal observation of people (with spirometry, peak flow or symptoms) to help differentiate COPD from asthma. \n\nWhen diagnostic uncertainty remains, or both COPD and asthma are present, use the following findings to help identify asthma:\n\na large (over 400\xa0ml) response to bronchodilators\n\na large (over 400\xa0ml) response to 30\xa0mg oral prednisolone daily for 2\xa0weeks\n\nserial peak flow measurements showing 20% or greater diurnal or day-to-day variability.Clinically significant COPD is not present if the FEV1 and FEV1/FVC ratio return to normal with drug therapy. \n\nIf diagnostic uncertainty remains, think about referral for more detailed investigations, including imaging and measurement of transfer factor for carbon monoxide (TLCO). \n\nReconsider the diagnosis of COPD for people who report a marked improvement in symptoms in response to inhaled therapy. \n\n## Assessing severity and using prognostic factors\n\nCOPD is heterogeneous, so no single measure can adequately assess disease severity in an individual. Severity assessment is, nevertheless, important because it has implications for therapy and relates to prognosis.\n\nDo not use a multidimensional index (such as BODE) to assess prognosis in people with stable COPD. \n\nFrom diagnosis onwards, when discussing prognosis and treatment decisions with people with stable COPD, think about the following factors that are individually associated with prognosis:\n\nFEV1\n\nsmoking status\n\nbreathlessness (MRC scale)\n\nchronic hypoxia and/or cor pulmonale\n\nlow BMI\n\nseverity and frequency of exacerbations\n\nhospital admissions\n\nsymptom burden (for example, COPD Assessment Test [CAT] score)\n\nexercise capacity (for example, 6‑minute walk test)\n\nTLCO\n\nwhether the person meets the criteria for long-term oxygen therapy and/or home non-invasive ventilation\n\nmultimorbidity\n\nfrailty. [2010, amended 2018]\n\nFor a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on assessing severity and using prognostic factors\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: Diagnosing COPD and predicting outcomes.\n\nLoading. Please wait.\n\n## Assessing and classifying the severity of airflow obstruction\n\nAssess the severity of airflow obstruction according to the reduction in FEV1, as shown in table\xa04. \n\nFor people with mild airflow obstruction, only diagnose COPD if they have one or more of the symptoms in the recommendation on symptoms. \n\nPost-broncho-dilator FEV1/FVC\n\nFEV1 % predicted\n\nNICE guideline CG12 (2004) severity of airflow obstruction\n\nATS/ERS 2004 severity of airflow obstruction (post-broncho-dilator)\n\nGOLD 2008 severity of airflow obstruction (post-broncho-dilator)\n\nNICE guideline CG101 (2010) severity of airflow obstruction (post-broncho-dilator)\n\n< 0.7\n\n≥ 80%\n\nNot categorised\n\nMild\n\nStage 1 – Mild\n\nStage 1 – Mild\n\n< 0.7\n\n–79%\n\nMild\n\nModerate\n\nStage 2 – Moderate\n\nStage 2 – Moderate\n\n< 0.7\n\n–49%\n\nModerate\n\nSevere\n\nStage 3 – Severe\n\nStage 3 – Severe\n\n< 0.7\n\n< 30%\n\nSevere\n\nVery severe\n\nStage 4 – Very severe (or FEV1 below 50% with respiratory failure)\n\nStage 4 – Very severe (or FEV1 below 50% with respiratory failure)\n\nATS/ERS guidance: Celli BR, MacNee W (2004) Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. European Respiratory Journal 23(6): 932–46.\n\nGOLD guidance: Global Initiative for Chronic Obstructive Lung Disease (GOLD; 2008) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.\n\n## Identifying early disease\n\nPerform spirometry in people who are over\xa035, current or ex‑smokers, and have a chronic cough. \n\nConsider spirometry in people with chronic bronchitis. A significant proportion of these people will go on to develop airflow limitation. \n\n## Referral for specialist advice\n\nWhen clinically indicated, refer people for specialist advice. Referral may be appropriate at all stages of the disease and not solely in the most severely disabled people (see table\xa05). \n\nReason\n\nPurpose\n\nThere is diagnostic uncertainty\n\nConfirm diagnosis and optimise therapy\n\nSuspected severe COPD\n\nConfirm diagnosis and optimise therapy\n\nThe person with COPD requests a second opinion\n\nConfirm diagnosis and optimise therapy\n\nOnset of cor pulmonale\n\nConfirm diagnosis and optimise therapy\n\nAssessment for oxygen therapy\n\nOptimise therapy and measure blood gases\n\nAssessment for long-term nebuliser therapy\n\nOptimise therapy and exclude inappropriate prescriptions\n\nAssessment for oral corticosteroid therapy\n\nJustify need for continued treatment or supervise withdrawal\n\nBullous lung disease\n\nIdentify candidates for lung volume reduction procedures\n\nA rapid decline in FEV1\n\nEncourage early intervention\n\nAssessment for pulmonary rehabilitation\n\nIdentify candidates for pulmonary rehabilitation\n\nAssessment for a lung volume reduction procedure\n\nIdentify candidates for surgical or bronchoscopic lung volume reduction\n\nAssessment for lung transplantation\n\nIdentify candidates for surgery\n\nDysfunctional breathing\n\nConfirm diagnosis, optimise pharmacotherapy and access other therapists\n\nOnset of symptoms under 40 years or a family history of alpha‑1 antitrypsin deficiency\n\nIdentify alpha‑1 antitrypsin deficiency, consider therapy and screen family\n\nSymptoms disproportionate to lung function deficit\n\nLook for other explanations including cardiac impairment, pulmonary hypertension, depression and hyperventilation\n\nFrequent infections\n\nExclude bronchiectasis\n\nHaemoptysis\n\nExclude carcinoma of the bronchus\n\nPeople who are referred do not always have to be seen by a respiratory physician. In some cases they may be seen by members of the COPD team who have appropriate training and expertise. \n\n# Managing stable COPD\n\nNICE has also produced a visual summary covering non-pharmacological management and use of inhaled therapies.\n\nFor guidance on the management of multimorbidity, see the NICE guideline on multimorbidity. \n\n## Smoking cessation\n\nDocument an up-to-date smoking history, including pack years smoked (number of cigarettes smoked per day, divided by 20, multiplied by the number of years smoked) for everyone with COPD. \n\nAt every opportunity, advise and encourage every person with COPD who is still smoking (regardless of their age) to stop, and offer them help to do so. \n\nUnless contraindicated, offer nicotine replacement therapy, varenicline or bupropion as appropriate to people who want to stop smoking, combined with an appropriate support programme to optimise smoking quit rates for people with COPD. \n\nFor more guidance on helping people to quit smoking, see the NICE guideline on stop smoking interventions and services. \n\nFor more guidance on varenicline see the NICE technology appraisal guidance on varenicline for smoking cessation. \n\n## Inhaled therapy\n\nUse short-acting bronchodilators, as necessary, as the initial empirical treatment to relieve breathlessness and exercise limitation. \n\nDo not use oral corticosteroid reversibility tests to identify which people should be prescribed inhaled corticosteroids, because they do not predict response to inhaled corticosteroid therapy. \n\nBe aware of, and be prepared to discuss with the person, the risk of side effects (including pneumonia) in people who take inhaled corticosteroids for COPD. Follow the MHRA safety advice on the risk of psychological and behavioural side effects associated with inhaled corticosteroids. [2010, amended 2018]\n\nInhaled combination therapy refers to combinations of long-acting muscarinic antagonists (LAMA), long-acting beta2 agonists (LABA), and inhaled corticosteroids (ICS).\n\nDo not assess the effectiveness of bronchodilator therapy using lung function alone. Include a variety of other measures such as improvement in symptoms, activities of daily living, exercise capacity, and rapidity of symptom relief. \n\nOffer LAMA+LABA to people who:\n\nhave spirometrically confirmed COPD and\n\ndo not have asthmatic features/features suggesting steroid responsiveness\xa0and\n\nremain breathless or have exacerbations despite:\n\n\n\nhaving used or been offered treatment for tobacco dependence if they smoke and\n\noptimised non-pharmacological management and relevant vaccinations and\n\n\n\nusing a short-acting bronchodilator. Follow the MHRA safety advice on Respimat and Handihaler inhalers.\n\nConsider LABA+ICS for people who:\n\nhave spirometrically confirmed COPD and\n\nhave asthmatic features/features suggesting steroid responsiveness\xa0and\n\nremain breathless or have exacerbations despite:\n\n\n\nhaving used or been offered treatment for tobacco dependence if they smoke and\n\noptimised non-pharmacological management and relevant vaccinations and\n\n\n\nusing a short-acting bronchodilator. \n\nFor people who are using long-acting bronchodilators outside of the recommendations on offering LAMA and LABA and considering LABA+ICS and whose symptoms are under control, explain to them that they can continue with their current treatment until both they and their NHS healthcare professional agree it is appropriate to change. \n\nBefore starting LAMA+LABA+ICS, conduct a clinical review to ensure that:\n\nthe person's non-pharmacological COPD management is optimised and they have used or been offered treatment for tobacco dependence if they smoke\n\nacute episodes of worsening symptoms are caused by COPD exacerbations and not by another physical or mental health condition\n\nthe person's day-to-day symptoms that are adversely impacting their quality of life are caused by COPD and not by another physical or mental health condition. \n\nFor people with COPD who are taking LABA+ICS, offer LAMA+LABA+ICS if:\n\ntheir day-to-day symptoms continue to adversely impact their quality of life or\n\nthey have a severe exacerbation (requiring hospitalisation) or\n\nthey have 2 moderate exacerbations within a year. \n\nFor people with COPD who are taking LAMA+LABA, consider LAMA+LABA+ICS if:\n\nthey have a severe exacerbation (requiring hospitalisation) or\n\nthey have 2 moderate exacerbations within a year. \n\nFor people with COPD who are taking LAMA+LABA and whose day-to-day symptoms adversely impact their quality of life:\n\nconsider a trial of LAMA+LABA+ICS, lasting for 3\xa0months only\n\nafter 3\xa0months, conduct a clinical review to establish whether or not LAMA+LABA+ICS has improved their symptoms:\n\n\n\nif symptoms have not improved, stop LAMA+LABA+ICS and switch back to LAMA+LABA\n\nif symptoms have improved, continue with LAMA+LABA+ICS. \n\n\n\nDocument the reason for continuing ICS use in clinical records and review at least annually. \n\nBase the choice of drugs and inhalers on:\n\nhow much they improve symptoms\n\nthe person's preferences and ability to use the inhalers\n\nthe drugs' potential to reduce exacerbations\n\ntheir side effects\n\ntheir cost.Minimise the number of inhalers and the number of different types of inhaler used by each person as far as possible. \n\nWhen prescribing long-acting drugs, ensure people receive inhalers they have been trained to use (for example, by specifying the brand and inhaler in prescriptions). \n\nFor a short explanation of why the committee made the 2018 and 2019 recommendations and how they might affect practice, see the rationale and impact section on inhaled combination therapy.\n\nFull details of the evidence and the committee's discussion are in evidence review F: Inhaled therapies and evidence review I: Inhaled triple therapy.\n\nLoading. Please wait.\n\nMost people with COPD – whatever their age – can develop adequate inhaler technique if they are given training. However, people with significant cognitive impairment may be unable to use any form of inhaler device. In most people with COPD, however, a pragmatic approach guided by individual patient assessment is needed when choosing a device.\n\nIn most cases bronchodilator therapy is best administered using a hand-held inhaler (including a spacer if appropriate). \n\nProvide an alternative inhaler if a person cannot use a particular one correctly or it is not suitable for them. \n\nOnly prescribe inhalers after people have been trained to use them and can demonstrate satisfactory technique. \n\nPeople with COPD should have their ability to use an inhaler regularly assessed and corrected if necessary by a healthcare professional competent to do so. \n\nProvide a spacer that is compatible with the person's metered-dose inhaler. \n\nAdvise people to use a spacer with a metered-dose inhaler in the following way:\n\nadminister the drug by single actuations of the metered-dose inhaler into the spacer, inhaling after each actuation\n\nthere should be minimal delay between inhaler actuation and inhalation\n\nnormal tidal breathing can be used as it is as effective as single breaths\n\nrepeat if a second dose is required. \n\nAdvise people on spacer cleaning. Tell them:\n\nnot to clean the spacer more than monthly, because more frequent cleaning affects their performance (because of a build-up of static)\n\nto hand wash using warm water and washing-up liquid, and allow the spacer to air dry. [2004, amended 2018]\n\nThink about nebuliser therapy for people with distressing or disabling breathlessness despite maximal therapy using inhalers. \n\nDo not prescribe nebulised therapy without an assessment of the person's and/or carer's ability to use it. \n\nDo not continue nebulised therapy without assessing and confirming that 1 or more of the following occurs:\n\na reduction in symptoms\n\nan increase in the ability to undertake activities of daily living\n\nan increase in exercise capacity\n\nan improvement in lung function. \n\nUse a nebuliser system that is known to be efficient. Follow the MHRA safety advice on non-CE-marked nebulisers for COPD.\n\nOffer people a choice between a facemask and a mouthpiece to administer their nebulised therapy, unless the drug specifically requires a mouthpiece (for example, anticholinergic drugs). \n\nIf nebuliser therapy is prescribed, provide the person with equipment, servicing, and ongoing advice and support. \n\n## Oral therapy\n\nLong-term use of oral corticosteroid therapy in COPD is not normally recommended. Some people with advanced COPD may need long-term oral corticosteroids when these cannot be withdrawn following an exacerbation. In these cases, the dose of oral corticosteroids should be kept as low as possible. \n\nMonitor people who are having long-term oral corticosteroid therapy for osteoporosis, and give them appropriate prophylaxis. Start prophylaxis without monitoring for people over\xa065. \n\nIn this section of the guideline, the term theophylline refers to slow-release formulations of the drug.\n\nTheophylline should only be used after a trial of short-acting bronchodilators and long-acting bronchodilators, or for people who are unable to use inhaled therapy, as plasma levels and interactions need to be monitored. \n\nTake particular caution when using theophylline in older people, because of differences in pharmacokinetics, the increased likelihood of comorbidities and the use of other medications. \n\nAssess the effectiveness of theophylline by improvements in symptoms, activities of daily living, exercise capacity and lung function. \n\nReduce the dose of theophylline for people who are having an exacerbation if they are prescribed macrolide or fluoroquinolone antibiotics (or other drugs known to interact). \n\nConsider mucolytic drug therapy for people with a chronic cough productive of sputum. \n\nOnly continue mucolytic therapy if there is symptomatic improvement (for example, reduction in frequency of cough and sputum production). \n\nDo not routinely use mucolytic drugs to prevent exacerbations in people with stable COPD. \n\nTreatment with alpha-tocopherol and beta-carotene supplements, alone or in combination, is not recommended. \n\nAnti-tussive therapy should not be used in the management of stable COPD. \n\nBefore starting prophylactic antibiotic therapy in a person with COPD, think about whether respiratory specialist input is needed. \n\nConsider azithromycin (usually 250\xa0mg 3\xa0times a week) for people with COPD if they:\n\ndo not smoke and\n\nhave optimised non-pharmacological management and inhaled therapies, relevant vaccinations and (if appropriate) have been referred for pulmonary rehabilitation and\n\ncontinue to have 1 or more of the following, particularly if they have significant daily sputum production:\n\n\n\nfrequent (typically 4 or more per year) exacerbations with sputum production\n\nprolonged exacerbations with sputum production\n\nexacerbations resulting in hospitalisation. In July 2019, this was an off-label use of azithromycin. See NICE's information on prescribing medicines.\n\n\n\nBefore offering prophylactic antibiotics, ensure that the person has had:\n\nsputum culture and sensitivity (including tuberculosis culture), to identify other possible causes of persistent or recurrent infection that may need specific treatment (for example, antibiotic-resistant organisms, atypical mycobacteria or Pseudomonas aeruginosa)\n\ntraining in airway clearance techniques to optimise sputum clearance (see the recommendation in the section on physiotherapy)\n\na CT scan of the thorax to rule out bronchiectasis and other lung pathologies. \n\nBefore starting azithromycin, ensure the person has had:\n\nan electrocardiogram (ECG) to rule out prolonged QT interval and\n\nbaseline liver function tests. \n\nWhen prescribing azithromycin, advise people about the small risk of hearing loss and tinnitus, and tell them to contact a healthcare professional if this occurs. \n\nReview prophylactic azithromycin after the first 3\xa0months, and then at least every 6\xa0months. \n\nOnly continue treatment if the continued benefits outweigh the risks. Be aware that there are no long-term studies on the use of prophylactic antibiotics in people with COPD. \n\nFor people who are taking prophylactic azithromycin and are still at risk of exacerbations, provide a non-macrolide antibiotic to keep at home as part of their exacerbation action plan (see the recommendation on offering antibiotics to keep at home in the section on self-management). \n\nBe aware that it is not necessary to stop prophylactic azithromycin during an acute exacerbation of COPD. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on oral prophylactic antibiotic therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: Predicting and preventing exacerbations.\n\nLoading. Please wait.\n\nFor guidance on treating severe COPD with roflumilast, see NICE's technology appraisal guidance on roflumilast for treating chronic obstructive pulmonary disease. \n\n## Oxygen\n\nBe aware that inappropriate oxygen therapy in people with COPD may cause respiratory depression. \n\nAssess the need for oxygen therapy in people with:\n\nvery severe airflow obstruction (FEV1 below\xa030% predicted)\n\ncyanosis (blue tint to skin)\n\npolycythaemia\n\nperipheral oedema (swelling)\n\na raised jugular venous pressure\n\noxygen saturations of\xa092% or less breathing air.Also consider assessment for people with severe airflow obstruction (FEV1 30–49% predicted).Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nAssess people for long-term oxygen therapy by measuring arterial blood gases on 2 occasions at least 3\xa0weeks apart in people who have a confident diagnosis of COPD, who are receiving optimum medical management and whose COPD is stable. \n\nConsider long-term oxygen therapy for people with COPD who do not smoke and who:\n\nhave a partial pressure of oxygen in arterial blood (PaO2) below 7.3\xa0kPa when stable or\n\nhave a PaO2 above 7.3 and below 8\xa0kPa when stable, if they also have 1 or more of the following:\n\n\n\nsecondary polycythaemia\n\nperipheral oedema\n\npulmonary hypertension.See the MHRA alert on the risk of death and severe harm from failure to obtain and continue flow from oxygen cylinders. \n\n\n\nConduct and document a structured risk assessment for people being assessed for long-term oxygen therapy who meet the criteria in the recommendation on considering long-term oxygen therapy. As part of the risk assessment, cover the risks for both the person with COPD and the people who live with them, including:\n\nthe risks of falls from tripping over the equipment\n\nthe risks of burns and fires, and the increased risk of these for people who live in homes where someone smokes (including e‑cigarettes).Base the decision on whether long-term oxygen therapy is suitable on the results of the structured risk assessment. \n\nFor people who smoke or live with people who smoke, but who meet the other criteria for long-term oxygen therapy, ensure the person who smokes is offered smoking cessation advice and treatment, and referral to specialist stop smoking services (see the NICE guidelines on stop smoking interventions and services and medicines optimisation). \n\nDo not offer long-term oxygen therapy to people who continue to smoke despite being offered smoking cessation advice and treatment, and referral to specialist stop smoking services. \n\nAdvise people who are having long-term oxygen therapy that they should breathe supplemental oxygen for a minimum of 15\xa0hours per day. \n\nDo not offer long-term oxygen therapy to treat isolated nocturnal hypoxaemia caused by COPD. \n\nTo ensure everyone eligible for long-term oxygen therapy is identified, pulse oximetry should be available in all healthcare settings. \n\nOxygen concentrators should be used to provide the fixed supply at home for long-term oxygen therapy. \n\nPeople who are having long-term oxygen therapy should be reviewed at least once per year by healthcare professionals familiar with long-term oxygen therapy. This review should include pulse oximetry. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on long-term oxygen therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: Oxygen therapy in people with stable COPD.\n\nLoading. Please wait.\n\nDo not offer ambulatory oxygen to manage breathlessness in people with COPD who have mild or no hypoxaemia at rest. \n\nConsider ambulatory oxygen in people with COPD who have exercise desaturation and are shown to have an improvement in exercise capacity with oxygen, and have the motivation to use oxygen. [2004, amended 2018]\n\nPrescribe ambulatory oxygen to people who are already on long-term oxygen therapy, who wish to continue oxygen therapy outside the home, and who are prepared to use it. \n\nOnly prescribe ambulatory oxygen therapy after an appropriate assessment has been performed by a specialist. The purpose of the assessment is to assess the extent of desaturation, the improvement in exercise capacity with supplemental oxygen, and the oxygen flow rate needed to correct desaturation. \n\nSmall light-weight cylinders, oxygen-conserving devices and portable liquid oxygen systems should be available for people with COPD. \n\nWhen choosing which equipment to prescribe, take account of the hours of ambulatory oxygen use and oxygen flow rate needed. \n\nDo not offer short-burst oxygen therapy to manage breathlessness in people with COPD who have mild or no hypoxaemia at rest. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on ambulatory and oxygen short-burst oxygen therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: Oxygen therapy in people with stable COPD.\n\nLoading. Please wait.\n\nRefer people who are adequately treated but have chronic hypercapnic respiratory failure and have needed assisted ventilation (whether invasive or non-invasive) during an exacerbation, or who are hypercapnic or acidotic on long-term oxygen therapy, to a specialist centre for consideration of long-term non-invasive ventilation. \n\n## Managing pulmonary hypertension and cor pulmonale\n\nIn this guideline 'cor pulmonale' is defined as a clinical condition that is identified and managed on the basis of clinical features. It includes people who have right heart failure secondary to lung disease and people whose primary pathology is salt and water retention, leading to the development of peripheral oedema (swelling).\n\nSuspect a diagnosis of cor pulmonale for people with:\n\nperipheral oedema (swelling)\n\na raised venous pressure\n\na systolic parasternal heave\n\na loud pulmonary second heart sound. \n\nIt is recommended that the diagnosis of cor pulmonale is made clinically and that this process should involve excluding other causes of peripheral oedema (swelling). \n\nDo not offer the following treatments solely to manage pulmonary hypertension caused by COPD, except as part of a randomised controlled trial:\n\nbosentan\n\nlosartan\n\nnifedipine\n\nnitric oxide\n\npentoxifylline\n\nphosphodiesterase-5 inhibitors\n\nstatins. \n\nEnsure that people with cor pulmonale caused by COPD are offered optimal COPD treatment, including advice and interventions to help them stop smoking. For people who need treatment for hypoxia, see the section on long-term oxygen therapy. \n\nOedema associated with cor pulmonale can usually be controlled symptomatically with diuretic therapy. \n\nDo not use the following to treat cor pulmonale caused by COPD:\n\nalpha-blockers\n\nangiotensin-converting enzyme inhibitors\n\ncalcium channel blockers\n\ndigoxin (unless there is atrial fibrillation). \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on managing pulmonary hypertension and cor pulmonale\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: Managing pulmonary hypertension and cor pulmonale.\n\nLoading. Please wait.\n\n## Pulmonary rehabilitation\n\nPulmonary rehabilitation is defined as a multidisciplinary programme of care for people with chronic respiratory impairment. It is individually tailored and designed to optimise each person's physical and social performance and autonomy.\n\nMake pulmonary rehabilitation available to all appropriate people with COPD (see the recommendation on offering pulmonary rehabilitation), including people who have had a recent hospitalisation for an acute exacerbation. \n\nOffer pulmonary rehabilitation to all people who view themselves as functionally disabled by COPD (usually Medical Research Council [MRC] grade\xa03 and above). Pulmonary rehabilitation is not suitable for people who are unable to walk, who have unstable angina or who have had a recent myocardial infarction. \n\nFor pulmonary rehabilitation programmes to be effective, and to improve adherence, they should be held at times that suit people, in buildings that are easy to get to and that have good access for people with disabilities. Places should be available within a reasonable time of referral. \n\nPulmonary rehabilitation programmes should include multicomponent, multidisciplinary interventions that are tailored to the individual person's needs. The rehabilitation process should incorporate a programme of physical training, disease education, and nutritional, psychological and behavioural intervention. \n\nAdvise people of the benefits of pulmonary rehabilitation and the commitment needed to gain these. \n\n## Vaccination and anti-viral therapy\n\nOffer pneumococcal vaccination and an annual flu vaccination to all people with COPD, as recommended by the Chief Medical Officer. \n\nFor guidance on preventing and treating flu, see the NICE technology appraisals on oseltamivir, amantadine (review) and zanamivir for the prophylaxis of influenza and amantadine, oseltamivir and zanamivir for the treatment of influenza. \n\n## Lung surgery and lung volume reduction procedures\n\nOffer a respiratory review to assess whether a lung volume reduction procedure is a possibility for people with COPD when they complete pulmonary rehabilitation and at other subsequent reviews, if all of the following apply:\n\nthey have severe COPD, with FEV1 less than 50% and breathlessness that affects their quality of life despite optimal medical treatment (see recommendations 1.2.11 to 1.2.17 in the section on inhaled combination therapy)\n\nthey do not smoke\n\nthey can complete a 6‑minute walk distance of at least 140\xa0m (if limited by breathlessness). \n\nAt the respiratory review, refer the person with COPD to a lung volume reduction multidisciplinary team to assess whether lung volume reduction surgery or endobronchial valves are suitable if they have:\n\nhyperinflation, assessed by lung function testing with body plethysmography and\n\nemphysema on unenhanced CT chest scan and\n\noptimised treatment for other comorbidities. \n\nOnly offer endobronchial coils as part of a clinical trial and after assessment by a lung volume reduction multidisciplinary team. \n\nFor more guidance on lung volume reduction procedures, see the NICE interventional procedures guidance on lung volume reduction surgery, endobronchial valves and endobronchial coils. \n\nRefer people with COPD for an assessment for bullectomy if they are breathless and a CT scan shows a bulla occupying at least one third of the hemithorax. \n\nConsider referral to a specialist multidisciplinary team to assess for lung transplantation for people who:\n\nhave severe COPD, with FEV1 less than 50% and breathlessness that affects their quality of life despite optimal medical treatment (see recommendations 1.2.11 to 1.2.17 in the section on inhaled combination therapy) and\n\ndo not smoke and\n\nhave completed pulmonary rehabilitation and\n\ndo not have contraindications for transplantation (for example, comorbidities or frailty). \n\nDo not use previous lung volume reduction procedures as a reason not to refer a person for assessment for lung transplantation. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on lung volume reduction procedures, bullectomy and lung transplantation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: Referral criteria for lung volume reduction procedures, bullectomy or lung transplantation.\n\nLoading. Please wait.\n\n## Alpha‑1 antitrypsin replacement therapy\n\nAlpha‑1 antitrypsin replacement therapy is not recommended for people with alpha‑1 antitrypsin deficiency (see also the recommendation on referral in the section on further investigations). \n\n## Multidisciplinary management\n\nCOPD care should be delivered by a multidisciplinary team. \n\nWhen defining the activity of the multidisciplinary team, think about the following functions:\n\nassessment (including performing spirometry, assessing which delivery systems to use for inhaled therapy, the need for aids for daily living and assessing the need for oxygen)\n\ncare and treatment, including:\n\n\n\npulmonary rehabilitation\n\nidentifying and managing anxiety and depression\n\nadvising people on relaxation techniques\n\ndietary issues\n\nexercise\n\nsocial security benefits and travel\n\nhospital-at-home/early discharge schemes\n\nnon-invasive ventilation and palliative care\n\n\n\nadvising people on self-management strategies\n\nidentifying and monitoring people at high risk of exacerbations and undertaking activities to avoid emergency admissions\n\neducation for people with COPD, their carers, and for healthcare professionals. \n\nIt is recommended that the multidisciplinary COPD team includes respiratory nurse specialists. \n\nIf people have excessive sputum, they should be taught:\n\nhow to use positive expiratory pressure devices\n\nactive cycle of breathing techniques. [2004, amended 2018]\n\nBe alert for anxiety and depression in people with COPD. Consider whether people have anxiety or depression, particularly if they:\n\nhave severe breathlessness\n\nare hypoxic\n\nhave been seen at or admitted to a hospital with an exacerbation of COPD. [2004, amended 2018]\n\nFor guidance on diagnosing and managing depression, see the NICE guideline on depression in adults with a chronic physical health problem. \n\nFor guidance on managing anxiety, see the NICE guideline on generalised anxiety disorder and panic disorder in adults. \n\nCalculate BMI for people with COPD:\n\nthe normal range for BMI is 20 to less than 25\xa0kg/m2\n\nrefer people for dietetic advice if they have a BMI that is abnormal (high or low) or changing over time\n\nfor people with a low BMI, give nutritional supplements to increase their total calorific intake and encourage them to exercise to augment the effects of nutritional supplementation. The NICE guideline on obesity states that a healthy BMI range is 18.5 to 24.9\xa0kg/m2, but note that this may not be appropriate for people with COPD.\n\nFor guidance on nutrition support, see the NICE guideline on nutrition support for adults. \n\nPay attention to changes in weight in older people, particularly if the change is more than 3\xa0kg. \n\nWhen appropriate, use opioids to relieve breathlessness in people with end-stage COPD that is unresponsive to other medical therapy. \n\nWhen appropriate, use benzodiazepines, tricyclic antidepressants, major tranquillisers and oxygen for breathlessness in people with end-stage COPD that is unresponsive to other medical therapy. \n\nPeople with end-stage COPD and their family members or carers (as appropriate) should have access to the full range of services offered by multidisciplinary palliative care teams, including admission to hospices. \n\nFor standards and measures on palliative care, see the NICE quality standard on end of life care for adults. \n\nFor guidance on care for people in the last days of life, see the NICE guideline on care of dying adults. \n\nRegularly ask people with COPD about their ability to undertake activities of daily living and how breathless these activities make them. \n\nClinicians that care for people with COPD should assess their need for occupational therapy using validated tools. \n\nConsider referring people for assessment by social services if they have disabilities caused by COPD. \n\nAssess people who are using long-term oxygen therapy and who are planning air travel in line with the British Thoracic Society recommendations. \n\nAssess people with an FEV1 below 50% predicted who are planning air travel in line with the BTS recommendations. \n\nWarn people with bullous disease that they are at a theoretically increased risk of a pneumothorax during air travel. \n\nScuba diving is not generally recommended for people with COPD. Advise people with queries to seek specialist advice. \n\nThere are significant differences in the response of people with COPD and asthma to education programmes. Programmes designed for asthma should not be used in COPD. \n\nAt diagnosis and at each review appointment, offer people with COPD and their family members or carers (as appropriate):\n\nwritten information about their condition\n\nopportunities for discussion with a healthcare professional who has experience in caring for people with COPD. \n\nEnsure the information provided is:\n\navailable on an ongoing basis\n\nrelevant to the stage of the person's condition\n\ntailored to the person's needs. \n\nAt minimum, the information should cover:\n\nan explanation of COPD and its symptoms\n\nadvice on quitting smoking (if relevant) and how this will help with the person's COPD\n\nadvice on avoiding passive smoke exposure\n\nmanaging breathlessness\n\nphysical activity and pulmonary rehabilitation\n\nmedicines, including inhaler technique and the importance of adherence\n\nvaccinations\n\nidentifying and managing exacerbations\n\ndetails of local and national organisations and online resources that can provide more information and support\n\nhow COPD will affect other long-term conditions that are common in people with COPD (for example hypertension, heart disease, anxiety, depression and musculoskeletal problems). \n\nBe aware of the obligation to provide accessible information as detailed in the NHS\xa0Accessible Information Standard. For more guidance on providing information to people and discussing their preferences with them, see the NICE guideline on\xa0patient experience in adult NHS services. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on self-management, education and telehealth monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: Self-management interventions, education and telehealth monitoring.\n\nLoading. Please wait.\n\nAdvise people with COPD that the following factors increase their risk of exacerbations:\n\ncontinued smoking or relapse for ex‑smokers\n\nexposure to passive smoke\n\nviral or bacterial infection\n\nindoor and outdoor air pollution\n\nlack of physical activity\n\nseasonal variation (winter and spring). \n\nFor a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on risk factors for COPD exacerbations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: Predicting and preventing exacerbations.\n\nLoading. Please wait.\n\nDevelop an individualised self-management plan in collaboration with each person with COPD and their family members or carers (as appropriate), and:\n\ninclude education on all relevant points from the recommendation on the information that should be covered in the section on education\n\nreview the plan at future appointments. \n\nDevelop an individualised exacerbation action plan in collaboration with each person with COPD who is at risk of exacerbations. \n\nOffer people a short course of oral corticosteroids and a short course of oral antibiotics to keep at home as part of their exacerbation action plan if:\n\nthey have had an exacerbation within the last year, and remain at risk of exacerbations\n\nthey understand and are confident about when and how to take these medicines, and the associated benefits and harms\n\nthey know to tell their healthcare professional when they have used the medicines, and to ask for replacements. \n\nFor guidance on the choice of antibiotics see the NICE guideline on antimicrobial prescribing for acute exacerbations of COPD. \n\nAt all review appointments, discuss corticosteroid and antibiotic use with people who keep these medicines at home, to check that they still understand how to use them. For people who have used 3 or more courses of oral corticosteroids and/or oral antibiotics in the last year, investigate the possible reasons for this. \n\nSee the recommendations on systemic corticosteroids for more guidance on oral corticosteroids. \n\nEncourage people with COPD to respond promptly to exacerbation symptoms by following their action plan, which may include:\n\nadjusting their short-acting bronchodilator therapy to treat their symptoms\n\ntaking a short course of oral corticosteroids if their increased breathlessness interferes with activities of daily living\n\nadding oral antibiotics if their sputum changes colour and increases in volume or thickness beyond their normal day-to-day variation\n\ntelling their healthcare professional. \n\nAsk people with COPD if they experience breathlessness they find frightening. If they do, consider including a cognitive behavioural component in their self-management plan to help them manage anxiety and cope with breathlessness. \n\nFor people at risk of hospitalisation, explain to them and their family members or carers (as appropriate) what to expect if this happens (including non-invasive ventilation and discussions on future treatment preferences, ceilings of care and resuscitation). \n\nDo not offer routine telehealth monitoring of physiological status as part of management for stable COPD. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on self-management, education and telehealth monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: Self-management interventions, education and telehealth monitoring.\n\nLoading. Please wait.\n\n## Fitness for general surgery\n\nThe ultimate clinical decision about whether or not to proceed with surgery should rest with a consultant anaesthetist and consultant surgeon, taking account of comorbidities, functional status and the need for the surgery. \n\nIt is recommended that lung function should not be the only criterion used to assess people with COPD before surgery. Composite assessment tools such as the ASA scoring system are the best predictors of risk. \n\nIf time permits, optimise the medical management of people with COPD before surgery. This might include a course of pulmonary rehabilitation. \n\n## Follow-up of people with COPD\n\nFollow-up of all people with COPD should include:\n\nhighlighting the diagnosis of COPD in the case record and recording this using Read Codes on a computer database\n\nrecording the values of spirometric tests performed at diagnosis (both absolute and percent predicted)\n\noffering advice and treatment to help them stop smoking, and referral to specialist stop smoking services (see the NICE guideline on stop smoking interventions and services)\n\nrecording the opportunistic measurement of spirometric parameters (a loss of 500\xa0ml or more over 5\xa0years will show which people have rapidly progressing disease and may need specialist referral and investigation). [2004, amended 2018]\n\nReview people with COPD at least once per year and more frequently if indicated, and cover the issues listed in table\xa06. \n\nFor most people with stable severe COPD regular hospital review is not necessary, but there should be locally agreed mechanisms to allow rapid access to hospital assessment when needed. \n\nWhen people with very severe COPD are reviewed in primary care they should be seen at least twice per year, and specific attention should be paid to the issues listed in table\xa06. \n\nSpecialists should regularly review people with severe COPD who need interventions such as long-term non-invasive ventilation. \n\n\n\nMild/moderate/severe (stages 1 to 3)\n\nVery severe (stage 4)\n\nFrequency\n\nAt least annual\n\nAt least twice per year\n\nClinical assessment\n\nSmoking status and motivation to quit\n\nAdequacy of symptom control:\n\n\n\nbreathlessness\n\nexercise tolerance\n\nestimated exacerbation frequency\n\n\n\nNeed for pulmonary rehabilitation\n\nPresence of complications\n\nEffects of each drug treatment\n\nInhaler technique\n\nNeed for referral to specialist and therapy services\n\nSmoking status and motivation to quit\n\nAdequacy of symptom control:\n\n\n\nbreathlessness\n\nexercise tolerance\n\nestimated exacerbation frequency\n\n\n\nPresence of cor pulmonale\n\nNeed for long-term oxygen therapy\n\nPerson with COPD's nutritional state\n\nPresence of depression\n\nEffects of each drug treatment\n\nInhaler technique\n\nNeed for social services and occupational therapy input\n\nNeed for referral to specialist and therapy services\n\nNeed for pulmonary rehabilitation\n\nMeasurements to make\n\nFEV1 and FVC\n\ncalculate BMI\n\nMRC dyspnoea score\n\nFEV1 and FVC\n\ncalculate BMI\n\nMRC dyspnoea score\n\nSaO2\n\n# Managing exacerbations of COPD\n\n## Definition of an exacerbation\n\nAn exacerbation is a sustained worsening of the patient's symptoms from their usual stable state which is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. The change in these symptoms often necessitates a change in medication.\n\n## Assessing the need for hospital treatment\n\nUse the factors in table\xa07 to assess whether people with COPD need hospital treatment.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. \n\nFactor\n\nTreat at home\n\nTreat in hospital\n\nAble to cope at home\n\nYes\n\nNo\n\nBreathlessness\n\nMild\n\nSevere\n\nGeneral condition\n\nGood\n\nPoor/deteriorating\n\nLevel of activity\n\nGood\n\nPoor/confined to bed\n\nCyanosis\n\nNo\n\nYes\n\nWorsening peripheral oedema\n\nNo\n\nYes\n\nLevel of consciousness\n\nNormal\n\nImpaired\n\nAlready receiving long-term oxygen therapy\n\nNo\n\nYes\n\nSocial circumstances\n\nGood\n\nLiving alone/not coping\n\nAcute confusion\n\nNo\n\nYes\n\nRapid rate of onset\n\nNo\n\nYes\n\nSignificant comorbidity (particularly cardiac disease and insulin-dependent diabetes)\n\nNo\n\nYes\n\nSaO2 < 90%\n\nNo\n\nYes\n\nChanges on chest radiograph\n\nNo\n\nPresent\n\nArterial pH level\n\n≥ 7.35\n\n< 7.35\n\nArterial PaO2\n\n≥ 7\xa0kPa\n\n< 7\xa0kPa\n\n## Investigating an exacerbation\n\nThe diagnosis of an exacerbation is made clinically and does not depend on the results of investigations. However, investigations may sometimes be useful in ensuring appropriate treatment is given. Different investigation strategies are needed for people in hospital (who will tend to have more severe exacerbations) and people in the community.\n\nFor people who have their exacerbation managed in primary care:\n\nsending sputum samples for culture is not recommended in routine practice\n\npulse oximetry is of value if there are clinical features of a severe exacerbation. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. \n\nIn all people presenting to hospital with an acute exacerbation:\n\nobtain a chest X-ray\n\nmeasure arterial blood gas tensions and record the inspired oxygen concentration\n\nrecord an ECG (to exclude comorbidities)\n\nperform a full blood count and measure urea and electrolyte concentrations\n\nmeasure a theophylline level on admission in people who are taking theophylline therapy\n\nsend a sputum sample for microscopy and culture if the sputum is purulent\n\ntake blood cultures if the person has pyrexia. [2004, amended 2018]\n\n## Hospital-at-home and assisted-discharge schemes\n\nHospital-at-home and assisted-discharge schemes are safe and effective and should be used as an alternative way of caring for people with exacerbations of COPD who would otherwise need to be admitted or stay in hospital. \n\nThe multiprofessional team that operates these schemes should include allied health professionals with experience in managing COPD, and may include nurses, physiotherapists, occupational therapists and other health workers. \n\nThere are currently insufficient data to make firm recommendations about which people with COPD with an exacerbation are most suitable for hospital-at-home or early discharge. Selection should depend on the resources available and absence of factors associated with a worse prognosis (for example, acidosis). \n\nInclude people's preferences about treatment at home or in hospital in decision-making. \n\n## Pharmacological management\n\nIncreased breathlessness is a common feature of COPD exacerbations. This is usually managed by taking increased doses of short-acting bronchodilators.\n\nBoth nebulisers and hand-held inhalers can be used to administer inhaled therapy during exacerbations of COPD. \n\nThe choice of delivery system should reflect the dose of drug needed, the person's ability to use the device, and the resources available to supervise therapy administration. \n\nChange people to hand-held inhalers as soon as their condition has stabilised, because this may allow them to be discharged from hospital earlier. \n\nIf a person with COPD is hypercapnic or acidotic the nebuliser should be driven by compressed air rather than oxygen (to avoid worsening hypercapnia). If oxygen therapy is needed, administer it simultaneously by nasal cannulae. \n\nThe driving gas for nebulised therapy should always be specified in the prescription. \n\nIn the absence of significant contraindications, use oral corticosteroids, in conjunction with other therapies, in all people admitted to hospital with a COPD exacerbation. \n\nIn the absence of significant contraindications, consider oral corticosteroids for people in the community who have an exacerbation with a significant increase in breathlessness that interferes with daily activities. \n\nEncourage people who need corticosteroid therapy to present early to get maximum benefits. \n\nOffer 30\xa0mg oral prednisolone daily for 5\xa0days. \n\nFor guidance on stopping oral corticosteroid therapy it is recommended that clinicians refer to the BNF. \n\nThink about osteoporosis prophylaxis for people who need frequent courses of oral corticosteroids. \n\nMake people aware of the optimum duration of treatment and the adverse effects of prolonged therapy. \n\nGive people (particularly people discharged from hospital) clear instructions on why, when and how to stop their corticosteroid treatment. \n\nFor a short explanation of why the committee made the 2019 recommendation and how it might affect practice, see the rationale and impact section on duration of oral corticosteroid for managing exacerbations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: Length of corticosteroid use during exacerbations.\n\nLoading. Please wait.\n\nFor guidance on using antibiotics to treat COPD exacerbations, see the NICE guideline on antimicrobial prescribing for acute exacerbations of COPD. \n\nOnly use intravenous theophylline as an adjunct to exacerbation management if there is an inadequate response to nebulised bronchodilators. \n\nTake care when using intravenous theophylline, because of its interactions with other drugs and potential toxicity if the person has been taking oral theophylline. \n\nMonitor theophylline levels within 24 hours of starting treatment, and as frequently as indicated by the clinical circumstances after this. \n\nIt is recommended that doxapram is used only when non-invasive ventilation is either unavailable or inappropriate. \n\n## Oxygen therapy during exacerbations of COPD\n\nMeasure oxygen saturation in people with an exacerbation if there are no facilities to measure arterial blood gases. \n\nIf necessary, prescribe oxygen to keep the oxygen saturation of arterial blood (SaO2) within the individualised target range. \n\nPulse oximeters should be available to all healthcare professionals involved in the care of people with exacerbations of COPD, and they should be trained in their use. Clinicians should be aware that pulse oximetry gives no information about the PaCO2 or pH.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. \n\nMeasure arterial blood gases and note the inspired oxygen concentration in all people who arrive at hospital with an exacerbation of COPD. Repeat arterial blood gas measurements regularly, according to the response to treatment. \n\n## Non-invasive ventilation (NIV) and COPD exacerbations\n\nUse NIV as the treatment of choice for persistent hypercapnic ventilatory failure during exacerbations despite optimal medical therapy. \n\nIt is recommended that NIV should be delivered in a dedicated setting, with staff who have been trained in its application, who are experienced in its use and who are aware of its limitations. \n\nWhen people are started on NIV there should be a clear plan covering what to do in the event of deterioration, and ceilings of therapy should be agreed. \n\n## Invasive ventilation and intensive care\n\nTreat hospitalised exacerbations of COPD on intensive care units, including invasive ventilation when this is thought to be necessary. \n\nWhen assessing suitability for intubation and ventilation during exacerbations, think about functional status, BMI, need for oxygen when stable, comorbidities and previous admissions to intensive care units, in addition to age and FEV1. Neither age nor FEV1 should be used in isolation when assessing suitability. \n\nConsider NIV for people who are slow to wean from invasive ventilation. \n\n## Respiratory physiotherapy and exacerbations\n\nConsider physiotherapy using positive expiratory pressure devices for selected people with exacerbations of COPD, to help with clearing sputum. [2004, amended 2018]\n\n## Monitoring recovery from an exacerbation\n\nMonitor people's recovery by regular clinical assessment of their symptoms and observation of their functional capacity. \n\nUse pulse oximetry to monitor the recovery of people with non-hypercapnic, non-acidotic respiratory failure. \n\nUse intermittent arterial blood gas measurements to monitor the recovery of people with respiratory failure who are hypercapnic or acidotic, until they are stable. \n\nDo not routinely perform daily monitoring of peak expiratory flow (PEF) or FEV1 to monitor recovery from an exacerbation, because the magnitude of changes is small compared with the variability of the measurement. \n\n## Discharge planning\n\nMeasure spirometry in all people before discharge. \n\nRe-establish people on their optimal maintenance bronchodilator therapy before discharge. \n\nPeople who have had an episode of respiratory failure should have satisfactory oximetry or arterial blood gas results before discharge. \n\nAssess all aspects of the routine care that people receive (including appropriateness and risk of side effects) before discharge. \n\nGive people (or home carers) appropriate information to enable them to fully understand the correct use of medications, including oxygen, before discharge. \n\nMake arrangements for follow-up and home care (such as visiting nurse, oxygen delivery or referral for other support) before discharge. \n\nThe person, their family and their physician should be confident that they can manage successfully before they are discharged. A formal activities of daily living assessment may be helpful when there is still doubt. \n\n# Terms used in this guideline\n\n## Asthmatic features/features suggesting steroid responsiveness\n\nThis includes any previous, secure diagnosis of asthma or of atopy, a higher blood eosinophil count, substantial variation in FEV1 over time (at least 400\xa0ml) or substantial diurnal variation in peak expiratory flow (at least\xa020%).\n\n## Exacerbation\n\nAn exacerbation is a sustained worsening of the patient's symptoms from their usual stable state which is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. The change in these symptoms often necessitates a change in medication.\n\nA general classification of the severity of an acute exacerbation (from a Cochrane Library systematic review) is:\n\nmild exacerbation, the person has an increased need for medication, which they can manage in their own normal environment\n\nmoderate exacerbation, the person has a sustained worsening of respiratory status that requires treatment with systemic corticosteroids and/or antibiotics\n\nsevere exacerbation, the person experiences a rapid deterioration in respiratory status that requires hospitalisation.\n\n## Mild or no hypoxaemia\n\nPeople who are not taking long-term oxygen and who have a mean PaO2 greater than 7.3k\xa0Pa.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. As part of the 2018 update, the guideline committee made additional research recommendations on prognostic indices, inhaled therapies, prophylactic antibiotics, pulmonary hypertension and the diagnosis of COPD through incidental CT scans.\n\n# Key recommendations for research\n\n## Pulmonary rehabilitation during hospital admission\n\nIn people with COPD, does pulmonary rehabilitation during hospital admission for exacerbation and/or in the early recovery period (within 1\xa0month of an exacerbation) improve quality of life and reduce hospitalisations and exacerbations compared with a later (defined as after 1\xa0month) pulmonary rehabilitation programme, and in which groups is it most clinically and cost effective?\n\nThe greatest reconditioning and potential benefit from rehabilitation may occur in the early post-exacerbation phase. If inpatient pulmonary rehabilitation is demonstrated to be effective this may potentially impact on service delivery (for example, early discharge schemes). The cost effectiveness of early versus later pulmonary rehabilitation programmes should also be evaluated. Studies should be cluster randomised, be of sufficiently long duration and be adequately powered.\n\n## Multidimensional assessment of outcomes\n\nHow can the individual factors associated with COPD prognosis (collected from a range of sources including primary care, imaging and pulmonary rehabilitation results) be combined into a multidimensional analysis that provides accurate and useful information on prognosis?\n\nPeople with COPD can experience anxiety concerning their disease prognosis. Suitable prognostic tools could help alleviate this stress and allow people to make plans for the future. Existing multidimensional indices are:\n\nunable to classify people reliably into high- and low-risk groups better than FEV1 alone or\n\nno better at predicting outcomes than FEV1 alone or\n\ntime-consuming and consisting of components that would not be routinely available in primary care.\n\nHowever, many individual factors are known to provide information, and the development of an index/indices combining these factors could help with prognosis. These indices should be validated in a general UK COPD population, and in primary care, in a wider range of outcomes than mortality alone.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on assessing severity and using prognostic factors\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: Diagnosing COPD and predicting outcomes.\n\nLoading. Please wait.\n\n## Inhaled therapies for people with COPD and asthma\n\nWhat is the clinical and cost effectiveness of inhaled therapies (bronchodilators and/or inhaled corticosteroids) in people with both stable COPD and asthma?\n\nThere are a large number of trials that look at the effectiveness of bronchodilators and/or steroids in people with COPD, but the majority of them specifically excluded people with comorbid asthma. As a result, there is a lack of evidence concerning the most clinically and cost-effective treatments for this subgroup of people with COPD. Trials that recruit people with asthma and COPD could provide this evidence and ensure that these people receive the most effective maintenance treatments for their COPD and asthma.\n\n## Inhaled corticosteroid responsiveness\n\nWhat features predict inhaled corticosteroid responsiveness most accurately in people with COPD?\n\nBronchodilators and/or steroids are the main pharmacological treatments used to manage COPD. People with asthma or asthmatic features that may make them steroid responsive may need a different combination of drugs to other groups of people with COPD for the most effective treatment of their symptoms. Identifying these people would help ensure that they receive appropriate treatment.\n\n## Prophylactic antibiotics for preventing exacerbations\n\nWhich subgroups of people with stable COPD who are at high risk of exacerbations are most likely to benefit from prophylactic antibiotics?\n\nPeople with COPD commonly experience exacerbations, which have a negative impact on their quality of life and are linked to worse disease prognosis. Certain groups of people with COPD are at higher risk of exacerbations, and reducing the number of exacerbations they experience should improve quality of life for them and their families. However, subgroups of these people may benefit particularly from this treatment. Identifying and targeting prophylactic antibiotics for these people should help improve their quality of life. It may also identify people who would not benefit from prophylactic antibiotics, and so reduce the risk of antibiotic resistance by reducing the overall number of people taking prophylactic antibiotics for COPD. Randomised trials that include subgroup analysis of participants based on factors such as biomarkers, clinical features, bacterial patterns and comorbidities could provide useful information on this topic.\n\n# Other recommendations for research\n\n## Diagnosing COPD\n\nWhat are the characteristics of people diagnosed with COPD as a result of an incidental finding of emphysema on a CT scan, compared with those diagnosed with symptoms?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on incidental findings on chest X-ray or CT scans\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: Diagnosing COPD and predicting outcomes.\n\nLoading. Please wait.\n\n## Prophylactic antibiotics for preventing exacerbations\n\nWhat is the long-term clinical and cost effectiveness of prophylactic antibiotics for people with stable COPD who are at high risk of exacerbations?\n\nWhat is the comparative effectiveness of different antibiotics, doses and regimens of prophylactic antibiotics for people with stable COPD who are at high risk of exacerbations?\n\nWhat is the comparative effectiveness of seasonal versus continuous prophylactic antibiotics for people with stable COPD who are at high risk of exacerbations?\n\n## Pulmonary hypertension\n\nWhat are the most clinical and cost-effective treatments for pulmonary hypertension in people with COPD?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on pulmonary hypertension\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: Managing pulmonary hypertension and cor pulmonale.\n\nLoading. Please wait.\n\n## Mucolytic therapy\n\nIn people with COPD, does mucolytic drug therapy prevent exacerbations in comparison with placebo and other therapies?", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Incidental findings on chest X-ray or CT scans\n\nRecommendations 1.1.12 to 1.1.14\n\n## Why the committee made the recommendations\n\nThe evidence showed that CT scans and chest X‑rays are accurate tests for identifying people who would test positive for COPD using spirometry, including people without symptoms. However, some of the CT and chest X‑ray techniques used in the studies are not routinely used in UK clinical practice. This limited how applicable the evidence was to the NHS, so the committee was unable to make a wider recommendation on using CT scans and chest X‑rays for diagnosing COPD. The committee therefore made recommendations on what to do if a CT scan or X‑ray that was performed for another reason showed signs of emphysema or chronic airways disease.\n\nThere was no evidence on what to do for people who have emphysema or signs of chronic airways disease on a CT scan or chest X‑ray, but who have no symptoms. Because of this, the committee made consensus recommendations based on their experience and on current practice in the NHS. The committee also made a recommendation for research on the characteristics of people diagnosed with COPD as a result of incidental findings on chest X-ray or CT scan, to try to determine whether they differ in ways that might mean standard COPD treatment has to be modified for them.\n\nThe committee also reviewed evidence on using pulse oximetry or high-sensitivity C‑reactive protein (hs‑CRP) for diagnosing COPD. They did not recommend these because:\n\npulse oximetry is normally used to measure the severity of COPD rather than to diagnose it, and there are other possible causes of low oxygen saturation\n\nelevated hs‑CRP levels are not specifically linked to COPD, and could be caused by other conditions\n\nthe evidence showed that they were not effective diagnostic tests.\n\nThe committee amended the 'Additional investigations' table, based on their knowledge and experience, to more accurately reflect good practice.\n\n## How the recommendations might affect practice\n\nAs the recommendation only covers CT scans or chest X‑rays taken for other purposes, there would be no additional costs from these tests. The recommendation to consider spirometry and GP respiratory review and the amendments to the 'Additional investigations' table all reflect current practice. There may be a small number of additional referrals for spirometry, but this is expected to have a minimal resource impact.\n\nReturn to recommendations\n\n# Assessing severity and using prognostic factors\n\nRecommendations 1.1.24 and 1.1.25\n\n## Why the committee made the recommendations\n\nThe committee recommended against using multidimensional indices, such as BODE, because they were:\n\nunable to classify people reliably into high- and low-risk groups better than FEV1 alone or\n\nno better at predicting outcomes than FEV1 alone or\n\ntime-consuming and consisted of components that would not be routinely available in primary care.\n\nHowever, the committee recognised the need for an effective prognostic tool that did not have these problems, so they made a recommendation for research on multidimensional assessment of outcomes to address this.\n\nThe committee used their knowledge and experience to list factors associated with prognosis. In the absence of a single prognostic tool, thinking about these factors can help guide discussions, and help people with COPD to understand how their condition is likely to progress and decide which treatments are right for them.\n\n## How the recommendations might affect practice\n\nThe BODE index is not used routinely in the NHS and no alternative indices have been recommended, so there should be minimal impact on practice.\n\nReturn to recommendations\n\n# Inhaled combination therapy\n\nRecommendations 1.2.11 to 1.2.20\n\n## Why the committee made the recommendations\n\nThe evidence showed that, compared with other dual therapy combinations and with monotherapy, LAMA+LABA:\n\nprovides the greatest benefit to overall quality of life\n\nis better than other inhaled treatments for many individual outcomes (such as reducing the risk of moderate to severe exacerbations)\n\nis the most cost-effective option.\n\nThe committee did not recommend a particular LAMA because they were not convinced that the evidence showed any meaningful differences in effectiveness between the drugs in this class. Instead, they updated the existing recommendation on drug and inhaler choice, based on their experience of what factors should be taken into account. In particular, minimising the number and types of inhalers prescribed will make it easier for people to use their inhalers correctly.\n\nMost of the trials specifically excluded people with COPD and asthma, so there was no direct evidence for this group. The committee recommended LABA+ICS based on their clinical experience and knowledge of the likely benefit of inhaled corticosteroids in certain specific COPD phenotypes.\n\nAlthough the combination therapies recommended in this guideline are the most effective options, some people are currently using different therapies, such as LAMA or LABA monotherapy, and may have their symptoms under control with these. The committee did not want to make people change treatments unnecessarily, so they made a recommendation highlighting that people did not need to switch treatments until their clinical needs changed.\n\nNot everyone with COPD will benefit from triple therapy. In addition, for some people the symptoms that give them the most problems are caused by other conditions (such as heart failure or anxiety) rather than their COPD. Because of this, a clinical review is needed first, to ensure that people only receive triple therapy if they will benefit from it. The committee envisaged that this review would take the form of a conversation with the person with COPD about their symptoms, rather than relying on tools such as the CAT score or MRC breathlessness score in isolation.\n\nThe committee decided that there should be separate recommendations on triple therapy for people who are currently taking LABA+ICS and for people taking LAMA+LABA. They agreed that there was stronger evidence from a greater number of studies that triple therapy benefits people taking LABA+ICS, compared with people taking LAMA+LABA.\n\nFor people currently taking LABA+ICS, the evidence showed that LAMA+LABA+ICS reduced the rate of severe exacerbations, improved FEV1, and did not increase the risk of pneumonia or other serious adverse events.\n\nFor people currently taking LAMA+LABA, the evidence showed that LAMA+LABA+ICS reduced the rate of serious exacerbations and provides some quality of life improvement. However, these improvements were smaller than the ones for people who were taking LABA+ICS before they started triple therapy. In addition, people who switched from LAMA+LABA to triple therapy were more likely to get pneumonia.\n\nThe criteria for starting triple therapy are based on the inclusion criteria for the studies the committee reviewed and their clinical judgement. For people who are currently taking LAMA+LABA, the committee made separate recommendations for:\n\npeople who are having severe or frequent exacerbations, for whom the benefit of fewer exacerbations outweighs the increased risk of pneumonia\n\npeople with less severe symptoms, for whom it is less clear if triple therapy provides enough benefits to outweigh the risk of pneumonia.\n\nThe 3-month trial is recommended to help identify people in the group with less severe symptoms who will benefit from triple therapy, while ensuring that people who do not benefit can easily switch back to LAMA+LABA. This is to avoid the situation where people continue on triple therapy, with the accompanying risks, without seeing any benefit. As part of the review at the end of the trial, the committee agreed that it was important to explicitly ask the person with COPD if taking the drug had improved their COPD symptoms.\n\nThe committee also recommended documenting the reason for continuing ICS, to encourage treatment review so that people are not exposed to the risks of this treatment if they do not benefit from it.\n\nThe committee looked at making recommendations for people with asthmatic features. However, the evidence excluded people with asthma and did not provide much information on asthmatic features (such as eosinophil count). Because of this, and because people with asthmatic features are likely to be covered by the recommendation for people taking LABA+ICS, the committee agreed not to make a specific recommendation for this group.\n\nThe committee did not make a recommendation in favour of single or multiple inhaler devices as the included evidence did not show a meaningful difference in clinical effectiveness between triple therapy compared to dual therapy based on the number of devices. From the economic evidence, using a single inhaler device was more cost effective, but the committee agreed that there were circumstances where using more than one inhaler to deliver triple therapy may be more appropriate for a particular person with COPD. Finally, the committee had already made a recommendation about the factors to be taken into account when choosing an inhaler device and these included minimising the numbers and types of inhalers where possible and cost so an additional recommendation on this issue was unnecessary.\n\n## How the recommendations might affect practice\n\nThe recommendation on LAMA+LABA dual therapy is likely to increase the number of people with COPD who are having this treatment. The higher cost of dual therapy compared with monotherapy may result in a significant resource impact, but cost savings are also likely from a reduction in treatments needed for exacerbations (including hospitalisation).\n\nUsing LABA+ICS for people with features of asthma/features suggesting steroid responsiveness is in line with current practice.\n\nThe recommendations may result in an increase in the number of people who are prescribed triple therapy and an increase in the number of people who need treatment for pneumonia, although this may be mitigated by the relatively widespread current use of triple therapy. However, the criteria for who should be offered triple therapy and the recommendation for a trial period should limit the impact of both of these changes.\n\nTriple therapy regimens have a higher cost than dual long-acting bronchodilator regimens. However, this cost is likely to be at least partially offset by savings from reduced numbers of exacerbations and better management of symptoms for people switching to triple therapy.\n\nIt is already routine in practice to have a clinical review before starting triple therapy. The recommendation on clinical review may increase the scope of this review. However, any costs incurred from this should be offset by savings from more optimal management of symptoms in people with COPD, which should be associated with fewer primary care and/ or hospital visits.\n\nThe recommendation on how to choose drugs and inhalers covers factors that prescribers routinely consider, so is not a change in practice. However, minimising the number and type of inhaler devices and avoiding unnecessary within-class switching may produce cost savings through lower upfront spending and better symptom control.\n\nReturn to recommendations\n\n# Oral prophylactic antibiotic therapy\n\nRecommendations 1.2.45 to 1.2.53\n\n## Why the committee made the recommendations\n\nThe evidence showed that prophylactic antibiotics reduce the risk of people having an exacerbation and the number of exacerbations per year in people with COPD and sputum production. However, prescribing these to large numbers of people with COPD could increase levels of antibiotic resistance. Problems with adherence may make this worse, as people are not taking the antibiotics to help with any current symptoms and (for azithromycin) have to remember to take it 3 times a week. In addition, the longest follow-up in the trials was 12 months, so there is no evidence on the long-term effects of prophylactic antibiotics. With this in mind, the committee made recommendations for the people who would benefit the most from prophylactic antibiotics, and whose exacerbations were not being managed well by other treatments.\n\nThe committee recommended azithromycin because this antibiotic had the most evidence of effectiveness (based on the numbers of trials and study participants). The recommended dosage is taken from the trials the committee reviewed.\n\nPeople taking prophylactic azithromycin may also keep antibiotics at home as part of their exacerbation action plan (see the recommendation on offering antibiotics to keep at home in the section on self-management). This should be a different class of antibiotic to ensure that it is effective when they need it, as the person may develop resistance to azithromycin.\n\nThe committee recommended strict criteria for using and reviewing prophylactic antibiotics, to ensure that:\n\nthe risk of antibiotic resistance is minimised, both for the person taking them and for society\n\npeople only take them if it is safe to do so\n\npeople do not continue taking them if there is no benefit.\n\n## How the recommendations might affect practice\n\nIt is likely that these recommendations will increase the number of people taking prophylactic antibiotics. This is unlikely to have a significant resource impact, given the relatively low cost of antibiotics. By reducing exacerbation frequency it is likely to reduce the amount of oral corticosteroids taken by people with COPD.\n\nReturn to recommendations\n\n# Long-term oxygen therapy\n\nRecommendations 1.2.58 to 1.2.63\n\n## Why the committee made the recommendations\n\nThere is evidence that continuous long-term oxygen therapy improves survival in people with more severe hypoxaemia, but not for people with mild hypoxaemia. The specific thresholds for long-term oxygen therapy are taken from the trials that provided the evidence.\n\nThe recommendation that people should use supplemental oxygen for more than 15 hours a day is based on the available evidence. There is also evidence that long-term oxygen therapy was not effective for isolated nocturnal hypoxaemia caused by COPD.\n\nThe evidence showed risks of harm from the use of long-term oxygen therapy, in particular burns and fires as a result of smoking while using oxygen and falls from tripping over equipment. Given these risks to the person with COPD and the people they live with, the committee agreed that it is important to conduct a detailed risk assessment before offering this treatment.\n\nThe committee decided that there were 2 levels of risk posed by smoking around oxygen and the recommendations they made reflect these differences:\n\nPeople with COPD who do not smoke but who live with people who smoke. Using cigarettes near oxygen could cause fires or burns, but this risk is likely to be lower because the person who smokes can keep away from the oxygen. Oxygen therapy may benefit these people if they meet the eligibility criteria and the risk assessment is favourable.\n\nPeople with COPD who smoke. They will be smoking in close proximity to the oxygen, and the risks to them, the people they live with and their neighbours outweigh the potential benefits of long-term oxygen therapy.\n\n## How the recommendations might affect practice\n\nThese recommendations may result in an increase in demand for stop smoking services, but these are known to provide good value for money. Additional time may be needed to conduct risk assessments. As these should prevent people from being given oxygen therapy if they would not benefit or may be harmed by it, it would be an appropriate use of resources and should not lead to an overall increase in resource use. These recommendations may also reduce the cost of managing harms associated with oxygen use, including falls, burns and the wider costs of fires.\n\nReturn to recommendations\n\n# Ambulatory and short-burst oxygen therapy\n\nRecommendations 1.2.67 and 1.2.73\n\n## Why the committee made the recommendations\n\nThe evidence for people with mild or no hypoxaemia showed that neither ambulatory oxygen nor short-burst oxygen provide a clinically meaningful improvement in breathlessness.\n\n## How the recommendations might affect practice\n\nReducing the use of ambulatory and short-burst oxygen therapy in people who would not benefit is likely to be cost saving and will allow resources to be invested in effective treatments for breathlessness instead.\n\nReturn to recommendations\n\n# Managing pulmonary hypertension and cor pulmonale\n\nRecommendations 1.2.77, 1.2.78 and 1.2.80\n\n## Why the committee made the recommendations\n\nThe committee agreed that there was not enough evidence to recommend any of the reviewed treatments for pulmonary hypertension in people with COPD. Although some of the treatments improved blood pressure readings, there was no evidence that they improved quality of life and the clinical trials only involved small numbers of people.\n\nThere is a shortage of good evidence in this area, so the committee made an exception for using these treatments in randomised controlled trials, and made a recommendation for research on treatments for pulmonary hypertension.\n\nThe evidence on long-term oxygen therapy for people with COPD and cor pulmonale showed no improvement in survival. However, long-term oxygen therapy can also help with hypoxia. The committee saw no evidence that people with cor pulmonale should be treated or assessed for long-term oxygen therapy differently than other people with COPD.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change practice, as none of the treatments the committee has recommended against for pulmonary hypertension or cor pulmonale are currently in routine use specifically for these conditions in people with COPD.\n\nReturn to recommendations\n\n# Lung volume reduction procedures, bullectomy and lung transplantation\n\nRecommendations 1.2.88 to 1.2.94\n\n## Why the committee made the recommendations\n\nThe evidence showed that people with severe COPD show improvements in lung function, exercise capacity, quality of life and long-term mortality as a result of lung volume reduction surgery. The criteria for who should be referred for this procedure are based on the criteria used in the trials reviewed by the committee and the committee's clinical expertise, taking into account current practice in the NHS.\n\nIt was not clear from the evidence whether endobronchial coils work better than standard lung volume reduction surgery. In addition, the procedure is relatively new. For these reasons, the committee recommended that it is only offered as part of a clinical trial.\n\nThe recommendations on referral for bullectomy and lung transplantation are based on the committee's knowledge and experience. The lung transplantation referral criteria were adapted from the criteria used for the respiratory review for lung volume reduction surgery. The committee noted that some people are refused lung transplantation because they have had previous lung volume reduction procedures. These people could still benefit from transplantation, so the committee made a recommendation to reflect this.\n\n## How the recommendations might affect practice\n\nIt is current clinical practice to assess for future treatment plans after pulmonary rehabilitation. However, the criteria for referring people to a multidisciplinary team to assess for lung volume reduction assessment have been broadened, as recommended treatment options now include endobronchial valves. The broadening of criteria will lead to more referrals and improved access to these treatments. This will have an impact on resource use, in particular, as a new group of people for whom lung volume reduction surgery was unsuitable may now be treated with endobronchial valves.\n\nReturn to recommendations\n\n# Risk factors for COPD exacerbations\n\nRecommendation 1.2.123\n\n## Why the committee made the recommendation\n\nThe factors associated with exacerbations are taken from the evidence available and the committee's experience. The evidence on physical activity was not reviewed, but as promoting exercise and physical activity is an important part of management for stable COPD the committee agreed to include it. The list only covers the factors that people can avoid or reduce their exposure to. Other factors are also associated with exacerbations (for example, disease-related factors, biomarkers and other medicines), but people cannot avoid these on their own and these factors are addressed in other areas of the guideline.\n\n## How the recommendation might affect practice\n\nThese recommendations are unlikely to have a significant impact on resources, as the marginal cost of providing advice on exacerbations to people with COPD is very low. An increased emphasis on physical activity may lead to an increase in referrals to pulmonary rehabilitation, which is known to be a highly cost-effective intervention for people with COPD. The recommendations may produce some cost savings by reducing the number of exacerbations people have.\n\nReturn to recommendations\n\n# Self-management, education and telehealth monitoring\n\nRecommendations 1.2.119 to 1.2.121 and 1.2.124 to 1.2.133\n\n## Why the committee made the recommendations\n\nEvidence showed that self-management plans improve quality of life and reduce hospital admissions. The committee recommended that self-management plans include:\n\npatient education, because this was a common component of the self-management plans they examined and because education alone was shown to improve knowledge about COPD\n\ncognitive behavioural components for people with frightening breathlessness, because there is some evidence that these reduce distress (although they do not help with the symptoms of breathlessness).\n\nThe list of topics to be covered in information about COPD is taken from the self-management plans the committee examined and their own clinical and personal experience.\n\nExacerbation action plans were shown to improve quality of life and reduce hospital admissions for people at risk of exacerbations. Most of the exacerbation action plans that the committee examined provided people with short courses of antibiotics and corticosteroids to use at home to respond to symptoms, and monitoring to make sure they were using those medicines appropriately. Therefore these components were included in the recommendations. The committee also discussed the potential for antibiotic overuse, and stressed the importance of continued monitoring to ensure people are using these medicines appropriately.\n\nTelehealth monitoring does not improve quality of life or reduce hospitalisations for people with COPD, and it leads to higher costs. However, the committee did not want to prevent telehealth monitoring being used for specific reasons that were not covered in the evidence they reviewed, such as short-term monitoring following hospital discharge, so they only recommended against routine telehealth monitoring.\n\n## How the recommendations might affect practice\n\nSelf-management plans are already in place for some people with COPD. The recommendations may change the content of these plans, and may increase the number of people using a self-management plan. However, self-management plans are highly cost effective and the increased cost of providing them should be offset by cost savings from a reduction in hospitalisations.\n\nThe number of people with stable COPD who are having telehealth monitoring should decrease, which is likely to reduce costs.\n\nReturn to recommendations\n\n# Duration of oral corticosteroids for managing exacerbations\n\nRecommendation 1.3.16\n\n## Why the committee made the recommendations\n\nThere are risks associated with long-term corticosteroid use, so it is important to use the shortest effective treatment duration. Treatment is recommended for 5 days because the evidence showed no benefit from taking corticosteroids for more than 7 days and shorter courses of 5 days are routinely used in clinical practice already. The 2019 review did not look at corticosteroid doses, so the dose from the original 2004 recommendation was retained.\n\n## How the recommendations might affect practice\n\nThe recommendation may reduce the amount of corticosteroids used in clinical practice, which may result in a cost saving. However, the overall impact is likely to be small because oral corticosteroids are cheap, and because prescribing corticosteroids for 5 days is current practice for many clinicians.\n\nReturn to recommendations", 'Context': 'British Lung Foundation statistics show that there are approximately 1.2\xa0million people with a diagnosis of chronic obstructive pulmonary disease (COPD) in the UK. Although there are 115,000 new diagnoses per year, most people with COPD are not diagnosed until they are in their fifties or older and many more people may remain undiagnosed. The UK has the 12th highest recorded deaths from COPD in the world, with an age-standardised mortality rate of 210.7 deaths per million people between 2001 and 2010.\n\nRecently, new evidence has emerged and practice has changed in relation to the use of inhaled triple therapy and oral corticosteroids. This evidence and the changes in how care is delivered may have a significant impact on people with COPD who are still experiencing symptoms despite being prescribed triple therapy.'}
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https://www.nice.org.uk/guidance/ng115
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This guideline covers diagnosing and managing chronic obstructive pulmonary disease or COPD (which includes emphysema and chronic bronchitis) in people aged 16 and older. It aims to help people with COPD to receive a diagnosis earlier so that they can benefit from treatments to reduce symptoms, improve quality of life and keep them healthy for longer.
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4714e8032e2e7cc66e4e5c28830fbc287eec81cc
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nice
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End of life care for infants, children and young people with life-limiting conditions: planning and management
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End of life care for infants, children and young people with life-limiting conditions: planning and management
This guideline covers the planning and management of end of life and palliative care for infants, children and young people (aged 0 to 17 years) with life-limiting conditions. It aims to involve children, young people and their families in decisions about their care, and improve the support that is available to them throughout their lives.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
In this guideline:
'Children and young people' refers to everyone under 18 years old. This includes neonates and infants.
'Parents or carers' refers to the people with parental responsibility for a child or young person. If the child or young person or their parents or carers (as appropriate) wish, other family members (for example siblings or grandparents) or people important to them (for example friends, boyfriends or girlfriends) should also be given information, and be involved in discussions about care.
# General principles
NICE has produced a guideline on babies, children and young people's experience of healthcare.
Recognise that children and young people with life-limiting conditions and their parents or carers have a central role in decision-making and care planning.
Discuss and regularly review with children and young people and their parents or carers how they want to be involved in making decisions about their care, because this varies between individuals, at different times, and depending on what decisions are being made.
Explain to children and young people and to their parents or carers that their contribution to decisions about their care is very important, but that they do not have to make decisions alone and the multidisciplinary team will be involved as well.
When difficult decisions must be made about end of life care, give children and young people and their parents or carers enough time and opportunities for discussions.
Be aware that continuity of care is important to children and young people and their parents or carers. If possible, avoid frequent changes to the healthcare professionals caring for them.
Be aware that siblings will need support to cope with:
their brother's or sister's condition and death
the effects of their parents' or carers' grieving.This may include social, practical, psychological and spiritual support.
Be aware that other family members (for example grandparents) and people important to the child or young person (for example friends, boyfriends or girlfriends) may need support. This may include social, practical, emotional, psychological, and spiritual support.
When developing plans for the care of the child or the young person with a life-limiting condition, use parallel planning to take account of possible unpredictability in the course of the condition.
## Communication
Think about how to provide information for children and young people with life-limiting conditions, taking into account their age and level of understanding. When appropriate, use formats such as:
-ne-to-one discussion
play, art and music activities
written materials and pictures
digital media, for example social media.
When deciding how best to communicate with the individual child or young person and their parents or carers, focus on their views and take account of:
their personal and family situation
their religious, spiritual and cultural beliefs and values
any special needs, such as communication aids or the need for interpreters.
Ask children and young people with life-limiting conditions and their parents or carers:
if there are other people important to them (such as friends, boyfriends or girlfriends, teachers, or foster parents) who they would like to be involved, and if so
how they would like those people to provide a supporting role.
Think about how best to communicate with each child or young person and their parents or carers:
when the life-limiting condition is first recognised
when reviewing and developing the Advance Care Plan
if their condition worsens
when they are approaching the end of life.
Ensure that all parents or carers are given the information and opportunities for discussion that they need.
When deciding which healthcare professional should lead on communication at a particular stage in a child or young person's illness, take account of:
their expertise and ability to discuss the topics that are important at that time
their availability, for example if frequent discussions are needed during an acute illness or near the end of life
the views of the child or young person and their parents or carers.
## Providing information
Be aware that most children and young people with life-limiting conditions and their parents or carers want to be fully informed about the condition and its management, and they value information that is:
specific to the child's or young person's individual circumstances
clearly explained and understandable
consistent
up-to-date
provided verbally and in writing.
Be aware that some children and young people and parents or carers may be anxious about receiving information about their condition.
Ask how children and young people and their parents or carers would like to discuss the life-limiting condition. For example:
Ask which topics they feel are important and would particularly want information on.
Ask whether there are topics they do not want detailed information on, and discuss their concerns.
If appropriate, ask parents or carers whether they think their child understands their condition and its management, and which professional their child would like to talk to about it.
If appropriate, ask parents or carers what they think their child should be told about their condition.
Discuss with the child or young person and their parents or carers their right to confidentiality and how information about their condition will be shared.
Review these issues with them regularly, because their feelings and circumstances may change over time, and they may need different information at different times.
When talking to children or young people and their parents or carers:
be sensitive, honest and realistic
give reassurance when appropriate
discuss any uncertainties about the condition and treatment.
Be alert for signs or situations that the child or young person or their parents or carers need more information or discussions, for example if:
they are more anxious or concerned
the child or young person's condition deteriorates
a significant change to the treatment plan is needed.
Provide children and young people and their parents and carers with the information they need on:
their role and participation in Advance Care Planning (see Advance Care Planning)
the membership of their multidisciplinary team and the responsibilities of each professional (see multidisciplinary team)
the care options available to them, including specific treatments and their preferred place of care and place of death (see preferred place of care and place of death)
any relevant resources or support available to them.
# Care planning and support throughout the child or young person's life
When a life-limiting condition is diagnosed, tell the child or young person (if appropriate) and their parents or carers about the condition and what it may mean for them (see also recommendations 1.1.6 and 1.1.7 on support for other family members and people who are important to the child or young person).
Every child or young person with a life-limiting condition should have a named medical specialist who leads on and coordinates their care. Explain to the child or young person and their parents or carers that their named medical specialist may change if the care that is needed or the care setting changes.
Manage transition from children's to adults' services in line with the NICE guideline on transition from children's to adults' services.
In all discussions with children and young people and their parents or carers explore with them whether, based on their beliefs and values, there are any aspects of care about which they have particular views or feelings.
## Advance Care Planning
Develop and record an Advance Care Plan at an appropriate time for the current and future care of each child or young person with a life-limiting condition. The Advance Care Plan should include:
demographic information about the child or young person and their family
up-to-date contact information for:
the child or young person's parents or carers and
the key professionals involved in care
a statement about who has responsibility for giving consent
a summary of the life-limiting condition
an agreed approach to communicating with and providing information to the child or young person and their parents or carers
an outline of the child or young person's life ambitions and wishes, for example on:
family and other relationships
social activities and participation
education
how to incorporate their religious, spiritual, and cultural beliefs and values into their care
a record of significant discussions with the child or young person and their parents or carers
agreed treatment plans and objectives
education plans, if relevant
a record of any discussions and decisions that have taken place on:
preferred place of care and place of death
-rgan and tissue donation (see recommendation 1.2.17)
management of life-threatening events, including plans for resuscitation or life support
specific wishes, for example on funeral arrangements and care of the body
a distribution list for the Advance Care Plan.
Begin discussing an Advance Care Plan with parents during the pregnancy if there is an antenatal diagnosis of a life-limiting condition. For each individual think about who should take part in the discussion, for example:
-bstetricians
midwives
neonatologists
specialists in the life-limiting condition
a member of the specialist paediatric palliative care team (see recommendation 1.5.4).
Develop and regularly review Advance Care Plans:
with relevant members of the multidisciplinary team and
in discussion with the child or young person and their parents or carers.
When developing the Advance Care Plan, take account of the beliefs and values of the child or young person and their parents or carers.
Explain to children and young people and their parents or carers that Advance Care Planning should:
help them be involved in planning their care and give them time to think about their views carefully
help them to understand the life-limiting condition and its management
help to prepare for possible future difficulties or complications
support continuity of care, for example if there are changes in the professionals involved or in the care setting (such as a hospital admission or discharge).
Share the Advance Care Plan with the child or young person and their parents or carers (as appropriate), and think about which professionals and services involved in the individual child or young person's care should also see it, for example:
GPs
hospital consultants
hospices
respite centres
nursing services (community or specialist)
school and other education services
ambulance services.
Update the Advance Care Plan when needed, for example if:
new professionals become involved
the care setting changes (for example hospital admission or discharge)
the child or young person and their parents or carers move home.Discuss the changes with the child or young person (if appropriate) and their parents or carers.
Share the Advance Care Plan with everyone involved each time it is updated.
When making an Advance Care Plan, discuss with the child or young person and their parents or carers:
the nature of the life-limiting condition, its likely consequences and its prognosis
the expected benefits and possible harms of the management options.
Be aware that all children and young people with life-limiting conditions should have an Advance Care Plan in their medical record, and that this should not be confused with a do-not-attempt-resuscitation order.
Be aware that any existing resuscitation plan for a child or young person may need to be changed in some circumstances, for example if they are undergoing general anaesthesia.
## Organ and tissue donation
For information on organ donation (including donor identification and consent, and when and how to discuss the topic), see the NICE guideline on organ donation for transplantation.
Talk to the child or young person and their parents or carers about organ or tissue donation, and explore their views and feelings on this.
Explain to the child or young person and their parents or carers which organs or tissues (if any) it may be possible to donate.
Involve the organ donation service if needed. If organ or tissue donation is not possible, explain why.
If the child or young person is eligible to donate organs or tissue, ask them if they and their parents or carers (as appropriate) would like to discuss this, and if so:
provide written information if needed
discuss how deciding to donate could affect their care, for example by changing their place of care and place of death
explain the practical policies and procedures involved.
If the child or young person does not have the capacity to decide about organ and tissue donation, ask their parents or carers to make the decision.
## Emotional and psychological support and interventions
Be aware that children and young people with life-limiting conditions and their parents or carers may have:
emotional and psychological distress and crises
relationship difficulties
mental health problems.
Be aware that children and young people and their parents or carers may need support, and sometimes expert psychological intervention, to help with distress, coping, and building resilience.
Be aware that children and young people may experience rapid changes in their condition and so might need emergency interventions and urgent access to psychological services.
Be aware of the specific emotional and psychological difficulties that may affect children and young people who have learning difficulties or problems with communication.
Provide information to children and young people and their parents or carers about the emotional and psychological support available and how to access it.
Regularly discuss emotional and psychological wellbeing with children and young people and their parents or carers, particularly at times of change such as:
when the life-limiting condition is diagnosed
if their clinical condition deteriorates
if their personal circumstances change
if there are changes to their nursery care, school or college arrangements, or their employment
if there are changes to their clinical care, for example if their care changes focus from treating the condition to end of life care.
## Social and practical support
Be aware that children and young people with life-limiting conditions and their parents or carers have varied social and practical support needs, and that those needs may change during the course of their condition. This may include:
material support, for example housing or adaptations to their home, or equipment for home drug infusions
practical support, such as access to respite care
technical support, such as training and help with administering drug infusions at home
education support, for example from hospital school services
financial support.
## Religious, spiritual and cultural support
Ask children and young people with life-limiting conditions and their parents or carers if they want to discuss the beliefs and values (for example religious, spiritual or cultural) that are important to them, and how these should influence their care. Be aware that they may need to discuss their beliefs and values more than once.
Take account of the beliefs and values of children and young people and of their parents and carers in all discussions with them and when making decisions about their care.
Be aware that:
some children and young people and their parents or carers find discussions about their beliefs and values difficult or upsetting
-thers find these discussions reassuring and helpful.
Be aware that children and young people may feel differently to their parents, carers, or healthcare professionals about how their beliefs and values should influence their care. If there is disagreement, try to make a mutually acceptable care plan, and if necessary involve the chaplaincy service or another facilitator.
# Care of the child or young person who is approaching the end of life
Attempt resuscitation for children and young people with life-limiting conditions, unless there is a 'do not attempt resuscitation' order in place.
Be aware that discussing the Advance Care Plan can be distressing for children and young people who are approaching the end of life and their parents or carers, and they may:
be reluctant to think about end of life care
have difficulties discussing end of life care with the professionals or with one another
have differences of opinion about the care plan.
When making or reviewing the Advance Care Plan for a child or young person approaching the end of life, talk to the parents or carers about the care and support they can expect when the child or young person dies. Discuss their personal needs and feelings about this.
When a child or young person is approaching the end of life, think about and discuss with them and their parents or carers their specific support needs. Review these needs regularly.
When thinking about the possibility of treatment withdrawal for a child or young person who is approaching the end of life, take into account their beliefs, values and wishes and those of their parents or carers.
Be aware of the importance of talking about dying, and if appropriate discuss with children and young people and their parents or carers:
whether they want and are able to talk about dying
whether they or their parents or carers would like support in talking to each other about this.
Take account of the beliefs and values of children and young people and their parents or carers when thinking about funeral arrangements and the care of the child or young person's body after death.
When a child or young person is approaching the end of life, discuss with their parents or carers what would help them, for example:
important rituals
recording or preserving memories (for example with photographs, hair locks or hand prints)
plans for social media content.
## Preferred place of care and place of death
Discuss with children and young people with life-limiting conditions and their parents or carers where they would prefer to be cared for and where they would prefer to die.
Agree the preferred place of care and place of death with children and young people and their parents or carers, taking into account:
their wishes, which are personal and individual
their religious, spiritual and cultural values
the views of relevant and experienced healthcare professionals
safety and practicality.
If possible, services should ensure that children and young people can be cared for at their preferred place of care and die at their preferred place of death.
Explain that the place of care or place of death may change, for example:
if the child or young person and their parents or carers change their minds or
for clinical reasons or
due to problems with service provision.
When discussing possible places of care or places of death with children and young people and their parents or carers, provide information about:
the various care settings (for example home, hospice or hospital care)
the care and support available in each setting
practical and safety issues.
If the child or young person and their parents or carers prefer care at home, take into account and discuss the practical considerations with them, such as the possible need for:
home adaptations
changes to living arrangements
equipment and support.
If it is suspected that a child or young person may die soon and they are not in their preferred place of death, think about whether rapid transfer is possible and in their best interest. Discuss this with them and their parents or carers.
When planning rapid transfer to the preferred place of death, review and if necessary update the Advance Care Plan in discussion with the child or young person and their parents or carers and with the healthcare professionals who will be involved following the transfer. The updated Advance Care Plan should include a record of:
any intended changes to care and when they should happen
care plans that cover:
the final hours or days of life
what will happen if the child or young person lives longer than expected
support for the family after the child or young person dies
care of the child's or young person's body after death
the professionals who will be involved and their responsibilities
the professionals who will help with the practical and administrative arrangements after the death.
When planning rapid transfer of a child or young person to their intended place of death:
be aware that the course of their condition may be unpredictable, and that they may die sooner or later than expected
discuss any uncertainties about the course of their condition and how this could affect their care with them and their parents or carers
ensure that relevant changes to the Advance Care Plan are implemented.
Think about using a rapid transfer process (see recommendation 1.5.8) to allow the child or young person to be in their preferred place of death when withdrawing life-sustaining treatments, such as ventilation.
Before rapid transfer, agree with the parents or carers where the child's or young person's body will be cared for after their death.
## Managing distressing symptoms
Involve the specialist paediatric palliative care team if a child or young person has unresolved distressing symptoms as they approach the end of life (see recommendation 1.5.4 for who should be in this team).
When assessing and managing pain, be aware that various factors can contribute to it, including:
biological factors, for example musculoskeletal disorders or constipation
environmental factors, such as an uncomfortable or noisy care setting
psychological factors, such as anxiety and depression
social, emotional, religious, spiritual or cultural considerations.
When assessing pain in children and young people:
use an age-appropriate approach that takes account of their stage of development and ability to communicate
try to identify what is causing or contributing to their pain, and be aware that this may not relate to the life-limiting condition
take into account the following causes of pain and distress that might have been overlooked, particularly in children and young people who cannot communicate:
neuropathic pain (for example associated with cancer)
gastrointestinal pain (for example associated with diarrhoea or constipation)
bladder pain (for example caused by urinary retention)
bone pain (for example associated with metabolic diseases)
pressure ulcers
headache (for example caused by raised intracranial pressure)
musculoskeletal pain (particularly if they have neurological disabilities)
dental pain.
Be aware that pain, discomfort and distress may be caused by a combination of factors, which will need an individualised management approach.
For children and young people who have pain or have had it before, regularly reassess for its presence and severity even if they are not having treatment for it.
Think about non-pharmacological interventions for pain management, such as:
changes that may help them to relax, for example:
environmental adjustments (for example reducing noise)
music
physical contact such as touch, holding or massage
local hot or cold applications to the site of pain
comfort measures, such as sucrose for neonates.
When tailoring pain treatment for an individual child or young person, take into account their views and those of their parents or carers on:
the benefits of pain treatment
the possible side effects of analgesia for moderate to severe pain (such as opioids), for example:
unwanted sedation
reduced mobility
constipation.
Consider using a stepwise approach to analgesia in children and young people, based on pain severity and persistence:
For mild pain, consider paracetamol or ibuprofen sequentially, and then in combination if needed
For moderate to severe pain, consider one of the following options:
paracetamol or ibuprofen sequentially, and then in combination if needed or
low-dose oral opioids (such as morphine) or
transmucosal opioids or
subcutaneous opioids or
intravenously infused opioids (if a central venous catheter is in place).In December 2016, these uses were off-label: oral paracetamol for children under 2 months, intravenous paracetamol for pre-term infants, concentrated liquid paracetamol (500 mg/5 ml) for children under 16 years, ibuprofen for children under 3 months or weighing under 5 kg, oramorph liquid for children under 1 year, and sevredol tablets for children under 6 years. See NICE's information on prescribing medicines.
If treatment with a specific opioid does not give adequate pain relief or if it causes unacceptable side effects, think about trying an alternative opioid preparation.
When using opioids, titrate treatment to find the minimal effective dose that will relieve and prevent pain.
Titrate treatment to provide continuous background analgesia, and prescribe additional doses for breakthrough pain if this occurs.
In addition to background analgesia, consider giving anticipatory doses of analgesia for children and young people who have pain at predictable times (for example when changing dressings, or when moving and handling). Do not include anticipatory doses when calculating the required daily background dose of analgesia.
Calculate opioid dosages for children and young people who are approaching the end of life using weight rather than age, because they may be underweight for their age.
If you suspect neuropathic pain and standard analgesia is not helping, consider a trial with other medicines, such as:
gabapentin or
a low-dose tricyclic antidepressant (for example amitriptyline) or
an anti-NMDA agent (for example ketamine or methadone), used under guidance from a specialist.In December 2016, this was an off-label use of gabapentin, amitriptyline, ketamine and methadone. See NICE's information on prescribing medicines, and the MHRA drug safety update on gabapentin.
Be aware that as children and young people with life-limiting conditions approach the end of life they may:
become agitated, shown by restlessness, irritability, aggressive behaviour, crying or other distress
show signs of delirium, such as confusion, disrupted attention, disordered speech and hallucinations.
If a child or young person who is approaching the end of life becomes agitated or delirious, make sure that they are safe from physical injury.
If a child or young person becomes agitated as they are approaching the end of life, look for causes and factors that may be contributing to this, including:
medical disorders and conditions such as pain, hypoxia, anaemia, dehydration, urinary retention or constipation
psychological factors such as fear, anxiety or depression
adverse effects from medication.
For children and young people with a neurological disability who are approaching the end of life, be aware that the signs and symptoms of agitation or delirium can be mistaken for the signs and symptoms of seizures or dystonia.
If a child or young person who is approaching the end of life needs treatment for agitation:
identify and if possible treat any medical or psychological conditions that may be contributing to it
think about non-pharmacological interventions, such as:
calm speaking, reassurance, distraction, and physical contact such as holding and touch
changes to the environment to make it more comfortable, calm and reassuring, to reduce noise and lighting, to maintain a comfortable room temperature, and to provide familiar objects and people and relaxing music
religious and spiritual support if this is wanted and helpful
think about pharmacological interventions (beginning with low doses and increasing if necessary). Drugs to think about using include:
benzodiazepines, such as midazolam, diazepam or lorazepam
neuroleptics, such as haloperidol or levomepromazine.In December 2016, these uses were off-label: midazolam injections, buccolam, diazepam rectal tubes in children under 1 year, lorazepam, haloperidol, and levomepromazine. See NICE's information on prescribing medicines.
If a child or young person is approaching the end of life and has a seizure, look for and if possible treat or remove any potential causes, triggers or contributing factors, for example:
fever
electrolyte disturbances
drug reactions
sleep deprivation
pain
excessive environmental stimulation.
If a child or young person is thought to be at increased risk of seizures (for example because they have had seizures before or because of an existing brain disorder), include seizure management in their Advance Care Plan. Think about the benefits and drawbacks of specific seizure treatments and:
take into account how any decisions could affect the choices available for place of care and place of death and
discuss this with the child or young person and their parents or carers.
For children and young people who are approaching the end of life, be aware that abnormal movements (such as dystonic spasms) might be mistaken for seizures. If in doubt seek specialist advice.
If a child or young person is approaching the end of life and is thought to be at increased risk of seizures, explain to them and their parents or carers:
how likely it is that they may have a seizure
what they might notice if a seizure happens
that seizures can be frightening or upsetting
what parents or carers should do if a seizure happens at home (for example placing the child or young person in a safe position).
Ensure that parents or carers who have been provided with anticonvulsive therapy (such as buccal midazolam) know how and when to use it if the child or young person has a seizure at home.
If a child or young person is approaching the end of life and has respiratory distress, breathlessness or noisy breathing, think about and if possible treat the likely contributing factors or causes. If these are likely to be caused by:
Anxiety:
discuss why they are anxious
reassure them and manage the anxiety accordingly
consider breathing techniques and guided imagery
consider anxiolytic agents.
Physical discomfort – think about what could be causing the discomfort (for example their position) and help them with it if possible.
Environmental factors – think about environmental changes such as changing the temperature.
Accumulated airway secretions – think about repositioning, airway suctioning, physiotherapy or anti-secretory drugs.
Medical disorders (for example pneumonia, heart failure, sepsis or acidosis) – use appropriate interventions such as:
bronchodilators
nebulised saline
-pioids
-xygen supplementation.
For children and young people who are approaching the end of life and have respiratory distress, breathlessness or noisy breathing that needs further assessment, consider referral to an appropriate specialist (for example a respiratory or cardiac specialist).
If a child or young person is approaching the end of life and has respiratory distress, breathlessness or noisy breathing:
explain to them and to their parents or carers that these symptoms are common
discuss the likely causes or contributing factors
discuss any treatments that may help.
## Managing hydration
If a child or young person with a life-limiting condition is approaching the end of life or is dying, discuss how to manage their fluid needs with them and their parents or carers.
If a child or young person is dying, encourage and support them to drink if they want to and are able.
If a child or young person is dying, continue to provide them with lip and mouth care.
If a child or young person is dying and cannot drink, discuss with them (as appropriate) and their parents or carers whether starting or continuing enteral tube or intravenous fluids is in their best interests.
Be aware that enteral tube and intravenous fluids may have a significant effect on care, may be a burden for children and young people, and may mean the place of care and place of death need to be changed.
If a child or young person is given enteral or intravenous fluids, review this decision regularly to make sure it continues to be in their best interests.
## Managing nutrition
If a child or young person is approaching the end of life or is dying, discuss how to manage their nutritional needs with them and their parents or carers.
If a child or young person with a life-limiting condition is dying, encourage and support them to eat if they want to and are able.
If a child or young person is dying and they are receiving enteral tube feeding or intravenous nutrition:
discuss with them (as appropriate) and their parents or carers whether continuing this is in their best interest and
review this decision regularly.
## Recognising that a child or young person is likely to die within hours or days
For children and young people with life-limiting conditions who are approaching the end of life:
be aware that there is often uncertainty around when they are likely to die
be aware that there are various symptoms and signs (individually or in combination) that indicate they are likely to die within hours or days
take into account the wider clinical context.
When assessing whether a child or young person is likely to die within hours or days, be aware that the following signs are common in the last hours or days of life, and monitor these non-invasively as far as possible:
a change of breathing pattern (for example noisy, laboured or irregular breathing)
impaired peripheral perfusion (which can be indicated by a pale or grey appearance, or a prolonged capillary refill time), including temperature instability
loss of interest in or ability to tolerate drinks or food
a marked and unexplained fall in urine output
an altered level of awareness (for example reduced consciousness, alertness or responsiveness, excessive sleeping, or confusion)
intractable seizures that keep occurring even with optimal management
new onset of profound weakness
increasing pain and need for analgesia.
When assessing symptoms and signs to decide whether a child or young person is likely to die within hours or days, take into account the wider clinical context, including:
their normal clinical baseline
past clinical events (such as previous episodes of temporary deterioration)
the overall progression of their condition.
When assessing whether a child or young person is likely to die within hours or days, take into account the clinical judgement of healthcare professionals experienced in end of life care.
If the child or young person or their parents or carers feel that they are likely to die within hours or days:
be aware that they may be correct
discuss their concerns with them.
When a child or young person is likely to die within hours or days, support them and their parents or carers by:
listening to any fears or anxieties they have and
showing empathy and compassion.
When a child or young person is likely to die within hours or days:
be aware that they or their parents or carers may not express their feelings openly, and may:
have intense and varied feelings such as fear, hopelessness or anger or
become more accepting of the inevitability of death
give them and their parents or carers opportunities to talk.
If a child or young person is likely to die within hours or days, explain to them and their parents or carers:
why you think this is likely, and any uncertainties
what clinical changes can be expected
whether you think the treatment plan should be changed.
When children and young people become seriously ill and are likely to die within hours or days, provide care as specified in their Advance Care Plan and review if needed.
Be aware that children and young people may have difficulty asking directly if they are going to die or are dying. Explore and discuss their concerns if you think they want to talk about this.
Be aware that parents or carers may have difficulty asking directly if a child or young person is dying. Explore and discuss their concerns if you think they want to talk about this.
If a child or young person may be approaching the end of life and they or their parents or carers want to be involved in making decisions about their care, discuss and review their Advance Care Plan with them.
When a child or young person is approaching the end of life, discuss with them and their parents or carers and with relevant healthcare professionals:
any available invasive treatments that might be in their best interest
any interventions they are currently receiving that may no longer be in their best interest.
If withdrawing a treatment for a child or young person who is dying, explain to them and to their parents or carers that it is often difficult to tell if or how this may affect them, or when they will die.
When a child or young person is likely to die within hours or days, ensure that they can have private time with their parents or carers.
# Care and support for parents, carers and healthcare professionals in relation to the death of a child or young person
Discuss with parents or carers the practical arrangements that will be needed after the death of their child, and provide this information in writing. This should cover matters such as:
the care of the body
relevant legal considerations, including
the involvement of the child death overview panel
the involvement of the coroner
registration of the death
funeral arrangements
post-mortem examination (if this is to be performed).
When a child or young person is approaching the end of life, discuss the bereavement support available with their parents or carers and provide them with written information.
When a child or young person is approaching the end of life, talk to their parents or carers about available psychological bereavement support groups.
Offer bereavement support from a professional with appropriate expertise to the parents or carers both before and after the death of a child or young person.
When planning bereavement support for parents or carers:
talk to them about the support that is available and explore with them what they would find helpful and acceptable
think about what support different professionals could provide, for example:
their GP
healthcare professionals who know the child or young person and are involved in their care
think about the role of individual professionals in providing specific aspects of support
inform the multidisciplinary team about the support plan.
When making a bereavement support plan with parents or carers, discuss possible options with them such as:
-pportunities to talk to the professionals caring for the child or young person, to:
discuss memories and events
answer any concerns or questions they may have
home visits from the healthcare professionals caring for the child or young person
bereavement support groups.
Ensure that arrangements are in place for professionals to talk about their thoughts and feelings with colleagues when a child or young person they are caring for is approaching the end of life or has died.
Following the death of a child or young person, a member of the multidisciplinary team should arrange in a timely manner for all relevant organisations and people to be informed.
Update relevant documents and databases after the death of a child or young person (to avoid, for example, clinical appointments being offered by mistake).
# Service delivery
## Multidisciplinary team
Children and young people with life-limiting conditions should be cared for by a defined multidisciplinary team.
As the child or young person's circumstances change (for example if they change from having care primarily to manage their condition to having end of life care), the membership of the multidisciplinary team should be adjusted accordingly.
Depending on the needs of the child or young person, the multidisciplinary team may include:
healthcare professionals from primary, secondary or tertiary services, including specialists in the child's underlying life-limiting condition, hospice professionals and members of the specialist palliative care team (see recommendation 1.5.4)
social care practitioners
education professionals
chaplains
allied health professionals (for example physiotherapists, occupational therapists, and psychological therapists).
The specialist paediatric palliative care team should include at a minimum:
a paediatric palliative care consultant
a nurse with expertise in paediatric palliative care
a pharmacist with expertise in specialist paediatric palliative care
experts in child and family support who have experience in end of life care (for example in providing social, practical, emotional, psychological and spiritual support).
Explain to children and young people and their parents or carers:
who the multidisciplinary team members are and how they are involved in their care
how the multidisciplinary team membership will change if the care that is needed or the care setting changes.
Think about involving children and young people and their parents or carers in multidisciplinary team meetings (when appropriate).
Think about having a named individual from the multidisciplinary team to act as a first point of contact for the child or young person and their parents or carers.
## Rapid transfer arrangements
In collaboration with local hospitals, hospices, and community, primary care and ambulance services, ensure there is a rapid transfer process for children and young people with life-limiting conditions to allow urgent transfer to the preferred place (for example from the intensive care unit to their home or to a children's hospice). See recommendations 1.3.15 to 1.3.19 for the planning and practical arrangements of this transfer.
## Care at home
For children and young people with life-limiting conditions who are approaching the end of life and are being cared for at home, services should provide (when needed):
advice from a consultant in paediatric palliative care (for example by telephone) at any time (day and night)
paediatric nursing care at any time (day and night)
home visits by a healthcare professional from the specialist paediatric palliative care team (see recommendation 1.5.4), for example for symptom management
practical support and equipment for interventions including oxygen, enteral nutrition, and subcutaneous and intravenous therapies
anticipatory prescribing for children and young people who are likely to develop symptoms.
Services should have agreed strategies and processes to support children and young people who are approaching the end of life and are being cared for at home. These services should be based on managed clinical networks, and should collaborate on care planning and service delivery.
Services for children and young people who are approaching the end of life and are being cared for at home should be able to support parenteral drug administration (for example continuous subcutaneous opioid or anticonvulsant infusions).
# Terms used in this guideline
## Advance Care Plan
A formal care plan that includes details about the child or young person's condition, decisions made with them and their parents or carers (for example about managing symptoms), and their wishes and ambitions. This plan is a core element of their palliative care.
## Approaching the end of life
The phase of illness after a change in the person's condition that means they are likely to die within weeks.
## Chaplain
An expert (with any or no religious beliefs) in religious, spiritual and or pastoral care for patients, families and staff. Chaplains also provide education and advice to organisations or trusts. They work to a nationally recognised code of conduct and a set of standards and competencies.
## Children
Aged 0 to 12 years. This includes neonates and infants.
## Dying
When the child or young person is likely to die in hours or days.
## End of life care
In this guideline, end of life care includes the care and support given in the final days, weeks and months of life, and the planning and preparation for this.
## Life-limiting condition
Conditions that are expected to result in an early death, either for everyone with the condition or for a specific person.
## Neonates
Babies aged up to 28 days.
## Paediatric palliative care
An approach to care covering physical, emotional, social and spiritual support. Paediatric palliative care focuses on improving the quality of life for the child or young person and supporting their family members or carers, and includes managing distressing symptoms, providing respite care, and support with death and bereavement.
## Parallel planning
Planning for end of life care while taking account of the often unpredictable course of life‑limiting conditions. It involves making multiple plans for care, and using the one that best fits the child or young person's circumstances at the time.
## Perinatal palliative care
Perinatal palliative care involves providing integrated ongoing support from the diagnosis of a life-limiting condition in a fetus, and during pregnancy, delivery, postnatal care, and (if needed) bereavement care.
## Young people
Aged 13 to 17 years.# Context
The Royal College of Physicians report Why children die: death in infants, children and young people in the UK (2014) noted that, despite improving mortality rates, in 2012 more than 2,000 children and young people aged between 1 and 19 died in England and Wales. Approximately 40% of deaths in children and young people under 15 are neonatal deaths (Office for National Statistics, 2016). In addition, it is estimated that almost 50,000 children and young people aged 19 or under in the UK (40,000 of these in England) are living with a life-limiting condition and may need palliative care. They may have widely varying needs, as there are over 300 conditions that could be classed as life-limiting or life-threatening in this age group. Some of these children and young people also have severe disabilities and multiple complex health and social care needs.
End of life care combines a broad range of health and other care services, including hospitals, hospices, primary care and community professionals, ambulance services, dedicated palliative care teams, and other support providers. Services span the public sector and charities. Because of this, good communication, care coordination, and effective networking are essential. Children and young people are likely to need different services at different stages of their illness and they will get the best care possible when services communicate with and support each other.
Palliative care for adults is a well-established discipline, with evidence that if it starts early it can both enhance and even prolong life. Paediatric palliative and end of life care generally lasts longer and is for a wider range of life-limiting conditions than for adults. It begins when a life-limiting condition is diagnosed (which could be diagnosed during the antenatal period), and continues even if a child is having treatment for the underlying condition (World Health Organization 1998). Young people may continue to have palliative care after they turn 18, and it may be part of the transition to adult care (see the NICE guideline on transition from children's to adults' services).
Children, young people and their parents or carers can have varied ideas about what represents good palliative and end of life care, and they may have differences of opinion with each other. They may also have different priorities at different stages in their lives.
This guideline covers the physical, emotional, social and spiritual elements of end of life care, and focuses on improving the child's or young person's quality of life and supporting their family. There are for instance recommendations on managing distressing symptoms and providing care and bereavement support after death. It also includes recommendations on how services should be delivered. The guideline is aimed at all providers of paediatric palliative and end of life care (whatever their level of practise), as well as children and young people with life-limiting conditions and their parents and carers.
To help develop this guideline, a focus group of young people with life-limiting conditions were asked for their views and experiences of care. See the full guideline for the report presenting these findings.
The guideline covers children and young people with life-limiting conditions. It does not make recommendations for children or young people who die suddenly and unexpectedly (for example accidental death).# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Preferred place of care and place of death
When planning and managing end of life care, what factors help children and young people with life-limiting conditions and their parents or carers to decide where they would like end of life care to be provided and where they prefer to die?
## Why this is important
When deciding the place of care and place of death, paediatric palliative care services sometimes assume that the main concern of parents and carers is that their child is able to die at home. However, the guideline committee's experience suggests that there are other significant factors for children and young people as well as their parents and carers (in particular, treatment of distressing symptoms) that may affect their choice of care setting. No research has been done to identify these factors, but it is important to recognise any reasons why a care setting might not be suitable. Understanding this would allow services to provide more personalised care, improve planning, and reduce waste and the cost of care.
# Perinatal palliative care
What impact does timely perinatal palliative care have on the experience of bereaved parents?
## Why this is important
Parents with a baby that is diagnosed antenatally with a life‑limiting condition are increasingly being offered perinatal palliative care before the birth (or very soon afterwards) if they decide to continue with the pregnancy.
Perinatal palliative care should help clinical staff (obstetric, neonatal and specialist palliative care) to deliver consistent high-quality care and ensure that families are offered meaningful and realistic choices for the care of their baby. If it is done well, perinatal palliative care also ensures that everyone involved understands the medical, social and legal frameworks for any decisions on critical care before and after birth.
There is little evidence on the experience families have of the death of a baby with or without specific support from a perinatal palliative care team. Individual case reports on family experience are very positive about perinatal palliative care, but published evidence is scarce.
# Emotional and psychological support and interventions
What emotional support do children and young people with life-limiting conditions and their parents or carers need, and how would they like these needs to be addressed?
## Why this is important
Previous UK studies, such as The Big Study for Life-Limited Children and their Families from Together for Short Lives, have explored broad themes of psychological support needs. However, no studies have tried to understand psychological difficulties using standardised measures of psychological and relationship distress, or looked at what families want from psychological therapies.
Before research into effective interventions can be carried out, the following aspects of psychological difficulties need to be better understood:
their range (for example low mood, worry, stigma, conflict in family relationships, avoidance, and distress about medical procedures)
their severity (from mild long-term low mood to severe depression with suicidal thoughts)
their context (for example socioeconomic status, and communication or mobility needs).
# Managing breakthrough pain
What is the acceptability, safety, and effectiveness of different types of opioid analgesia for breakthrough pain in children and young people with life-limiting conditions who are having end of life care in the community?
## Why this is important
Opioids (with morphine the most common first-line agent) are effective as background analgesia for children and young people who are having end of life care. However, no evidence was identified on how to provide safe and effective breakthrough analgesia (particularly in community settings). This potentially exposes children and young people who are having end of life care in the community to untreated pain or significant side effects. Studies should aim to provide evidence-based options to help manage breakthrough pain in the community. This would improve the safety and effectiveness of care for breakthrough pain, and would be likely to reduce emergency hospital admissions.
# Recognising that a child or young person may be dying
What signs and symptoms indicate that a child or young person with a life-limiting condition is likely to die within hours or days?
## Why this is important
Healthcare professionals are often asked to estimate how close a child or young person may be to death. There is very little evidence on which to base any such estimate. To help predict when a child or young person is in the last hours or days of life, a clearer understanding is needed of which groups of signs and symptoms indicate this most clearly. This would improve healthcare planning, but importantly would also allow families to realistically address their 'hopes and wishes' for their child's care while preparing themselves for the child's or young person's last hours and days of life.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nIn this guideline:\n\n'Children and young people' refers to everyone under 18\xa0years old. This includes neonates and infants.\n\n'Parents or carers' refers to the people with parental responsibility for a child or young person. If the child or young person or their parents or carers (as appropriate) wish, other family members (for example siblings or grandparents) or people important to them (for example friends, boyfriends or girlfriends) should also be given information, and be involved in discussions about care.\n\n# General principles\n\nNICE has produced a guideline on babies, children and young people's experience of healthcare.\n\nRecognise that children and young people with life-limiting conditions and their parents or carers have a central role in decision-making and care planning.\n\nDiscuss and regularly review with children and young people and their parents or carers how they want to be involved in making decisions about their care, because this varies between individuals, at different times, and depending on what decisions are being made.\n\nExplain to children and young people and to their parents or carers that their contribution to decisions about their care is very important, but that they do not have to make decisions alone and the multidisciplinary team will be involved as well.\n\nWhen difficult decisions must be made about end of life care, give children and young people and their parents or carers enough time and opportunities for discussions.\n\nBe aware that continuity of care is important to children and young people and their parents or carers. If possible, avoid frequent changes to the healthcare professionals caring for them.\n\nBe aware that siblings will need support to cope with:\n\ntheir brother's or sister's condition and death\n\nthe effects of their parents' or carers' grieving.This may include social, practical, psychological and spiritual support.\n\nBe aware that other family members (for example grandparents) and people important to the child or young person (for example friends, boyfriends or girlfriends) may need support. This may include social, practical, emotional, psychological, and spiritual support.\n\nWhen developing plans for the care of the child or the young person with a life-limiting condition, use parallel planning to take account of possible unpredictability in the course of the condition.\n\n## Communication\n\nThink about how to provide information for children and young people with life-limiting conditions, taking into account their age and level of understanding. When appropriate, use formats such as:\n\none-to-one discussion\n\nplay, art and music activities\n\nwritten materials and pictures\n\ndigital media, for example social media.\n\nWhen deciding how best to communicate with the individual child or young person and their parents or carers, focus on their views and take account of:\n\ntheir personal and family situation\n\ntheir religious, spiritual and cultural beliefs and values\n\nany special needs, such as communication aids or the need for interpreters.\n\nAsk children and young people with life-limiting conditions and their parents or carers:\n\nif there are other people important to them (such as friends, boyfriends or girlfriends, teachers, or foster parents) who they would like to be involved, and if so\n\nhow they would like those people to provide a supporting role.\n\nThink about how best to communicate with each child or young person and their parents or carers:\n\nwhen the life-limiting condition is first recognised\n\nwhen reviewing and developing the Advance Care Plan\n\nif their condition worsens\n\nwhen they are approaching the end of life.\n\nEnsure that all parents or carers are given the information and opportunities for discussion that they need.\n\nWhen deciding which healthcare professional should lead on communication at a particular stage in a child or young person's illness, take account of:\n\ntheir expertise and ability to discuss the topics that are important at that time\n\ntheir availability, for example if frequent discussions are needed during an acute illness or near the end of life\n\nthe views of the child or young person and their parents or carers.\n\n## Providing information\n\nBe aware that most children and young people with life-limiting conditions and their parents or carers want to be fully informed about the condition and its management, and they value information that is:\n\nspecific to the child's or young person's individual circumstances\n\nclearly explained and understandable\n\nconsistent\n\nup-to-date\n\nprovided verbally and in writing.\n\nBe aware that some children and young people and parents or carers may be anxious about receiving information about their condition.\n\nAsk how children and young people and their parents or carers would like to discuss the life-limiting condition. For example:\n\nAsk which topics they feel are important and would particularly want information on.\n\nAsk whether there are topics they do not want detailed information on, and discuss their concerns.\n\nIf appropriate, ask parents or carers whether they think their child understands their condition and its management, and which professional their child would like to talk to about it.\n\nIf appropriate, ask parents or carers what they think their child should be told about their condition.\n\nDiscuss with the child or young person and their parents or carers their right to confidentiality and how information about their condition will be shared.\n\nReview these issues with them regularly, because their feelings and circumstances may change over time, and they may need different information at different times.\n\nWhen talking to children or young people and their parents or carers:\n\nbe sensitive, honest and realistic\n\ngive reassurance when appropriate\n\ndiscuss any uncertainties about the condition and treatment.\n\nBe alert for signs or situations that the child or young person or their parents or carers need more information or discussions, for example if:\n\nthey are more anxious or concerned\n\nthe child or young person's condition deteriorates\n\na significant change to the treatment plan is needed.\n\nProvide children and young people and their parents and carers with the information they need on:\n\ntheir role and participation in Advance Care Planning (see Advance Care Planning)\n\nthe membership of their multidisciplinary team and the responsibilities of each professional (see multidisciplinary team)\n\nthe care options available to them, including specific treatments and their preferred place of care and place of death (see preferred place of care and place of death)\n\nany relevant resources or support available to them.\n\n# Care planning and support throughout the child or young person's life\n\nWhen a life-limiting condition is diagnosed, tell the child or young person (if appropriate) and their parents or carers about the condition and what it may mean for them (see also recommendations 1.1.6 and 1.1.7 on support for other family members and people who are important to the child or young person).\n\nEvery child or young person with a life-limiting condition should have a named medical specialist who leads on and coordinates their care. Explain to the child or young person and their parents or carers that their named medical specialist may change if the care that is needed or the care setting changes.\n\nManage transition from children's to adults' services in line with the NICE guideline on transition from children's to adults' services.\n\nIn all discussions with children and young people and their parents or carers explore with them whether, based on their beliefs and values, there are any aspects of care about which they have particular views or feelings.\n\n## Advance Care Planning\n\nDevelop and record an Advance Care Plan at an appropriate time for the current and future care of each child or young person with a life-limiting condition. The Advance Care Plan should include:\n\ndemographic information about the child or young person and their family\n\nup-to-date contact information for:\n\n\n\nthe child or young person's parents or carers and\n\nthe key professionals involved in care\n\n\n\na statement about who has responsibility for giving consent\n\na summary of the life-limiting condition\n\nan agreed approach to communicating with and providing information to the child or young person and their parents or carers\n\nan outline of the child or young person's life ambitions and wishes, for example on:\n\n\n\nfamily and other relationships\n\nsocial activities and participation\n\neducation\n\nhow to incorporate their religious, spiritual, and cultural beliefs and values into their care\n\n\n\na record of significant discussions with the child or young person and their parents or carers\n\nagreed treatment plans and objectives\n\neducation plans, if relevant\n\na record of any discussions and decisions that have taken place on:\n\n\n\npreferred place of care and place of death\n\norgan and tissue donation (see recommendation 1.2.17)\n\nmanagement of life-threatening events, including plans for resuscitation or life support\n\nspecific wishes, for example on funeral arrangements and care of the body\n\n\n\na distribution list for the Advance Care Plan.\n\nBegin discussing an Advance Care Plan with parents during the pregnancy if there is an antenatal diagnosis of a life-limiting condition. For each individual think about who should take part in the discussion, for example:\n\nobstetricians\n\nmidwives\n\nneonatologists\n\nspecialists in the life-limiting condition\n\na member of the specialist paediatric palliative care team (see recommendation\xa01.5.4).\n\nDevelop and regularly review Advance Care Plans:\n\nwith relevant members of the multidisciplinary team and\n\nin discussion with the child or young person and their parents or carers.\n\nWhen developing the Advance Care Plan, take account of the beliefs and values of the child or young person and their parents or carers.\n\nExplain to children and young people and their parents or carers that Advance Care Planning should:\n\nhelp them be involved in planning their care and give them time to think about their views carefully\n\nhelp them to understand the life-limiting condition and its management\n\nhelp to prepare for possible future difficulties or complications\n\nsupport continuity of care, for example if there are changes in the professionals involved or in the care setting (such as a hospital admission or discharge).\n\nShare the Advance Care Plan with the child or young person and their parents or carers (as appropriate), and think about which professionals and services involved in the individual child or young person's care should also see it, for example:\n\nGPs\n\nhospital consultants\n\nhospices\n\nrespite centres\n\nnursing services (community or specialist)\n\nschool and other education services\n\nambulance services.\n\nUpdate the Advance Care Plan when needed, for example if:\n\nnew professionals become involved\n\nthe care setting changes (for example hospital admission or discharge)\n\nthe child or young person and their parents or carers move home.Discuss the changes with the child or young person (if appropriate) and their parents or carers.\n\nShare the Advance Care Plan with everyone involved each time it is updated.\n\nWhen making an Advance Care Plan, discuss with the child or young person and their parents or carers:\n\nthe nature of the life-limiting condition, its likely consequences and its prognosis\n\nthe expected benefits and possible harms of the management options.\n\nBe aware that all children and young people with life-limiting conditions should have an Advance Care Plan in their medical record, and that this should not be confused with a do-not-attempt-resuscitation order.\n\nBe aware that any existing resuscitation plan for a child or young person may need to be changed in some circumstances, for example if they are undergoing general anaesthesia.\n\n## Organ and tissue donation\n\nFor information on organ donation (including donor identification and consent, and when and how to discuss the topic), see the NICE guideline on organ donation for transplantation.\n\nTalk to the child or young person and their parents or carers about organ or tissue donation, and explore their views and feelings on this.\n\nExplain to the child or young person and their parents or carers which organs or tissues (if any) it may be possible to donate.\n\nInvolve the organ donation service if needed. If organ or tissue donation is not possible, explain why.\n\nIf the child or young person is eligible to donate organs or tissue, ask them if they and their parents or carers (as appropriate) would like to discuss this, and if so:\n\nprovide written information if needed\n\ndiscuss how deciding to donate could affect their care, for example by changing their place of care and place of death\n\nexplain the practical policies and procedures involved.\n\nIf the child or young person does not have the capacity to decide about organ and tissue donation, ask their parents or carers to make the decision.\n\n## Emotional and psychological support and interventions\n\nBe aware that children and young people with life-limiting conditions and their parents or carers may have:\n\nemotional and psychological distress and crises\n\nrelationship difficulties\n\nmental health problems.\n\nBe aware that children and young people and their parents or carers may need support, and sometimes expert psychological intervention, to help with distress, coping, and building resilience.\n\nBe aware that children and young people may experience rapid changes in their condition and so might need emergency interventions and urgent access to psychological services.\n\nBe aware of the specific emotional and psychological difficulties that may affect children and young people who have learning difficulties or problems with communication.\n\nProvide information to children and young people and their parents or carers about the emotional and psychological support available and how to access it.\n\nRegularly discuss emotional and psychological wellbeing with children and young people and their parents or carers, particularly at times of change such as:\n\nwhen the life-limiting condition is diagnosed\n\nif their clinical condition deteriorates\n\nif their personal circumstances change\n\nif there are changes to their nursery care, school or college arrangements, or their employment\n\nif there are changes to their clinical care, for example if their care changes focus from treating the condition to end of life care.\n\n## Social and practical support\n\nBe aware that children and young people with life-limiting conditions and their parents or carers have varied social and practical support needs, and that those needs may change during the course of their condition. This may include:\n\nmaterial support, for example housing or adaptations to their home, or equipment for home drug infusions\n\npractical support, such as access to respite care\n\ntechnical support, such as training and help with administering drug infusions at home\n\neducation support, for example from hospital school services\n\nfinancial support.\n\n## Religious, spiritual and cultural support\n\nAsk children and young people with life-limiting conditions and their parents or carers if they want to discuss the beliefs and values (for example religious, spiritual or cultural) that are important to them, and how these should influence their care. Be aware that they may need to discuss their beliefs and values more than once.\n\nTake account of the beliefs and values of children and young people and of their parents and carers in all discussions with them and when making decisions about their care.\n\nBe aware that:\n\nsome children and young people and their parents or carers find discussions about their beliefs and values difficult or upsetting\n\nothers find these discussions reassuring and helpful.\n\nBe aware that children and young people may feel differently to their parents, carers, or healthcare professionals about how their beliefs and values should influence their care. If there is disagreement, try to make a mutually acceptable care plan, and if necessary involve the chaplaincy service or another facilitator.\n\n# Care of the child or young person who is approaching the end of life\n\nAttempt resuscitation for children and young people with life-limiting conditions, unless there is a 'do not attempt resuscitation' order in place.\n\nBe aware that discussing the Advance Care Plan can be distressing for children and young people who are approaching the end of life and their parents or carers, and they may:\n\nbe reluctant to think about end of life care\n\nhave difficulties discussing end of life care with the professionals or with one another\n\nhave differences of opinion about the care plan.\n\nWhen making or reviewing the Advance Care Plan for a child or young person approaching the end of life, talk to the parents or carers about the care and support they can expect when the child or young person dies. Discuss their personal needs and feelings about this.\n\nWhen a child or young person is approaching the end of life, think about and discuss with them and their parents or carers their specific support needs. Review these needs regularly.\n\nWhen thinking about the possibility of treatment withdrawal for a child or young person who is approaching the end of life, take into account their beliefs, values and wishes and those of their parents or carers.\n\nBe aware of the importance of talking about dying, and if appropriate discuss with children and young people and their parents or carers:\n\nwhether they want and are able to talk about dying\n\nwhether they or their parents or carers would like support in talking to each other about this.\n\nTake account of the beliefs and values of children and young people and their parents or carers when thinking about funeral arrangements and the care of the child or young person's body after death.\n\nWhen a child or young person is approaching the end of life, discuss with their parents or carers what would help them, for example:\n\nimportant rituals\n\nrecording or preserving memories (for example with photographs, hair locks or hand prints)\n\nplans for social media content.\n\n## Preferred place of care and place of death\n\nDiscuss with children and young people with life-limiting conditions and their parents or carers where they would prefer to be cared for and where they would prefer to die.\n\nAgree the preferred place of care and place of death with children and young people and their parents or carers, taking into account:\n\ntheir wishes, which are personal and individual\n\ntheir religious, spiritual and cultural values\n\nthe views of relevant and experienced healthcare professionals\n\nsafety and practicality.\n\nIf possible, services should ensure that children and young people can be cared for at their preferred place of care and die at their preferred place of death.\n\nExplain that the place of care or place of death may change, for example:\n\nif the child or young person and their parents or carers change their minds or\n\nfor clinical reasons or\n\ndue to problems with service provision.\n\nWhen discussing possible places of care or places of death with children and young people and their parents or carers, provide information about:\n\nthe various care settings (for example home, hospice or hospital care)\n\nthe care and support available in each setting\n\npractical and safety issues.\n\nIf the child or young person and their parents or carers prefer care at home, take into account and discuss the practical considerations with them, such as the possible need for:\n\nhome adaptations\n\nchanges to living arrangements\n\nequipment and support.\n\nIf it is suspected that a child or young person may die soon and they are not in their preferred place of death, think about whether rapid transfer is possible and in their best interest. Discuss this with them and their parents or carers.\n\nWhen planning rapid transfer to the preferred place of death, review and if necessary update the Advance Care Plan in discussion with the child or young person and their parents or carers and with the healthcare professionals who will be involved following the transfer. The updated Advance Care Plan should include a record of:\n\nany intended changes to care and when they should happen\n\ncare plans that cover:\n\n\n\nthe final hours or days of life\n\nwhat will happen if the child or young person lives longer than expected\n\nsupport for the family after the child or young person dies\n\ncare of the child's or young person's body after death\n\n\n\nthe professionals who will be involved and their responsibilities\n\nthe professionals who will help with the practical and administrative arrangements after the death.\n\nWhen planning rapid transfer of a child or young person to their intended place of death:\n\nbe aware that the course of their condition may be unpredictable, and that they may die sooner or later than expected\n\ndiscuss any uncertainties about the course of their condition and how this could affect their care with them and their parents or carers\n\nensure that relevant changes to the Advance Care Plan are implemented.\n\nThink about using a rapid transfer process (see recommendation 1.5.8) to allow the child or young person to be in their preferred place of death when withdrawing life-sustaining treatments, such as ventilation.\n\nBefore rapid transfer, agree with the parents or carers where the child's or young person's body will be cared for after their death.\n\n## Managing distressing symptoms\n\nInvolve the specialist paediatric palliative care team if a child or young person has unresolved distressing symptoms as they approach the end of life (see recommendation 1.5.4 for who should be in this team).\n\nWhen assessing and managing pain, be aware that various factors can contribute to it, including:\n\nbiological factors, for example musculoskeletal disorders or constipation\n\nenvironmental factors, such as an uncomfortable or noisy care setting\n\npsychological factors, such as anxiety and depression\n\nsocial, emotional, religious, spiritual or cultural considerations.\n\nWhen assessing pain in children and young people:\n\nuse an age-appropriate approach that takes account of their stage of development and ability to communicate\n\ntry to identify what is causing or contributing to their pain, and be aware that this may not relate to the life-limiting condition\n\ntake into account the following causes of pain and distress that might have been overlooked, particularly in children and young people who cannot communicate:\n\n\n\nneuropathic pain (for example associated with cancer)\n\ngastrointestinal pain (for example associated with diarrhoea or constipation)\n\nbladder pain (for example caused by urinary retention)\n\nbone pain (for example associated with metabolic diseases)\n\npressure ulcers\n\nheadache (for example caused by raised intracranial pressure)\n\nmusculoskeletal pain (particularly if they have neurological disabilities)\n\ndental pain.\n\n\n\nBe aware that pain, discomfort and distress may be caused by a combination of factors, which will need an individualised management approach.\n\nFor children and young people who have pain or have had it before, regularly reassess for its presence and severity even if they are not having treatment for it.\n\nThink about non-pharmacological interventions for pain management, such as:\n\nchanges that may help them to relax, for example:\n\n\n\nenvironmental adjustments (for example reducing noise)\n\nmusic\n\nphysical contact such as touch, holding or massage\n\n\n\nlocal hot or cold applications to the site of pain\n\ncomfort measures, such as sucrose for neonates.\n\nWhen tailoring pain treatment for an individual child or young person, take into account their views and those of their parents or carers on:\n\nthe benefits of pain treatment\n\nthe possible side effects of analgesia for moderate to severe pain (such as opioids), for example:\n\n\n\nunwanted sedation\n\nreduced mobility\n\nconstipation.\n\n\n\nConsider using a stepwise approach to analgesia in children and young people, based on pain severity and persistence:\n\nFor mild pain, consider paracetamol or ibuprofen sequentially, and then in combination if needed\n\nFor moderate to severe pain, consider one of the following options:\n\n\n\nparacetamol or ibuprofen sequentially, and then in combination if needed or\n\nlow-dose oral opioids (such as morphine) or\n\ntransmucosal opioids or\n\nsubcutaneous opioids or\n\nintravenously infused opioids (if a central venous catheter is in place).In December 2016, these uses were off-label: oral paracetamol for children under 2 months, intravenous paracetamol for pre-term infants, concentrated liquid paracetamol (500\xa0mg/5\xa0ml) for children under 16 years, ibuprofen for children under 3 months or weighing under 5\xa0kg, oramorph liquid for children under 1 year, and sevredol tablets for children under 6 years. See NICE's information on prescribing medicines.\n\n\n\nIf treatment with a specific opioid does not give adequate pain relief or if it causes unacceptable side effects, think about trying an alternative opioid preparation.\n\nWhen using opioids, titrate treatment to find the minimal effective dose that will relieve and prevent pain.\n\nTitrate treatment to provide continuous background analgesia, and prescribe additional doses for breakthrough pain if this occurs.\n\nIn addition to background analgesia, consider giving anticipatory doses of analgesia for children and young people who have pain at predictable times (for example when changing dressings, or when moving and handling). Do not include anticipatory doses when calculating the required daily background dose of analgesia.\n\nCalculate opioid dosages for children and young people who are approaching the end of life using weight rather than age, because they may be underweight for their age.\n\nIf you suspect neuropathic pain and standard analgesia is not helping, consider a trial with other medicines, such as:\n\ngabapentin or\n\na low-dose tricyclic antidepressant (for example amitriptyline) or\n\nan anti-NMDA agent (for example ketamine or methadone), used under guidance from a specialist.In December 2016, this was an off-label use of gabapentin, amitriptyline, ketamine and methadone. See NICE's information on prescribing medicines, and the MHRA drug safety update on gabapentin.\n\nBe aware that as children and young people with life-limiting conditions approach the end of life they may:\n\nbecome agitated, shown by restlessness, irritability, aggressive behaviour, crying or other distress\n\nshow signs of delirium, such as confusion, disrupted attention, disordered speech and hallucinations.\n\nIf a child or young person who is approaching the end of life becomes agitated or delirious, make sure that they are safe from physical injury.\n\nIf a child or young person becomes agitated as they are approaching the end of life, look for causes and factors that may be contributing to this, including:\n\nmedical disorders and conditions such as pain, hypoxia, anaemia, dehydration, urinary retention or constipation\n\npsychological factors such as fear, anxiety or depression\n\nadverse effects from medication.\n\nFor children and young people with a neurological disability who are approaching the end of life, be aware that the signs and symptoms of agitation or delirium can be mistaken for the signs and symptoms of seizures or dystonia.\n\nIf a child or young person who is approaching the end of life needs treatment for agitation:\n\nidentify and if possible treat any medical or psychological conditions that may be contributing to it\n\nthink about non-pharmacological interventions, such as:\n\n\n\ncalm speaking, reassurance, distraction, and physical contact such as holding and touch\n\nchanges to the environment to make it more comfortable, calm and reassuring, to reduce noise and lighting, to maintain a comfortable room temperature, and to provide familiar objects and people and relaxing music\n\nreligious and spiritual support if this is wanted and helpful\n\n\n\nthink about pharmacological interventions (beginning with low doses and increasing if necessary). Drugs to think about using include:\n\n\n\nbenzodiazepines, such as midazolam, diazepam or lorazepam\n\nneuroleptics, such as haloperidol or levomepromazine.In December 2016, these uses were off-label: midazolam injections, buccolam, diazepam rectal tubes in children under 1 year, lorazepam, haloperidol, and levomepromazine. See NICE's information on prescribing medicines.\n\n\n\nIf a child or young person is approaching the end of life and has a seizure, look for and if possible treat or remove any potential causes, triggers or contributing factors, for example:\n\nfever\n\nelectrolyte disturbances\n\ndrug reactions\n\nsleep deprivation\n\npain\n\nexcessive environmental stimulation.\n\nIf a child or young person is thought to be at increased risk of seizures (for example because they have had seizures before or because of an existing brain disorder), include seizure management in their Advance Care Plan. Think about the benefits and drawbacks of specific seizure treatments and:\n\ntake into account how any decisions could affect the choices available for place of care and place of death and\n\ndiscuss this with the child or young person and their parents or carers.\n\nFor children and young people who are approaching the end of life, be aware that abnormal movements (such as dystonic spasms) might be mistaken for seizures. If in doubt seek specialist advice.\n\nIf a child or young person is approaching the end of life and is thought to be at increased risk of seizures, explain to them and their parents or carers:\n\nhow likely it is that they may have a seizure\n\nwhat they might notice if a seizure happens\n\nthat seizures can be frightening or upsetting\n\nwhat parents or carers should do if a seizure happens at home (for example placing the child or young person in a safe position).\n\nEnsure that parents or carers who have been provided with anticonvulsive therapy (such as buccal midazolam) know how and when to use it if the child or young person has a seizure at home.\n\nIf a child or young person is approaching the end of life and has respiratory distress, breathlessness or noisy breathing, think about and if possible treat the likely contributing factors or causes. If these are likely to be caused by:\n\nAnxiety:\n\n\n\ndiscuss why they are anxious\n\nreassure them and manage the anxiety accordingly\n\nconsider breathing techniques and guided imagery\n\nconsider anxiolytic agents.\n\n\n\nPhysical discomfort – think about what could be causing the discomfort (for example their position) and help them with it if possible.\n\nEnvironmental factors – think about environmental changes such as changing the temperature.\n\nAccumulated airway secretions – think about repositioning, airway suctioning, physiotherapy or anti-secretory drugs.\n\nMedical disorders (for example pneumonia, heart failure, sepsis or acidosis) – use appropriate interventions such as:\n\n\n\nbronchodilators\n\nnebulised saline\n\nopioids\n\noxygen supplementation.\n\n\n\nFor children and young people who are approaching the end of life and have respiratory distress, breathlessness or noisy breathing that needs further assessment, consider referral to an appropriate specialist (for example a respiratory or cardiac specialist).\n\nIf a child or young person is approaching the end of life and has respiratory distress, breathlessness or noisy breathing:\n\nexplain to them and to their parents or carers that these symptoms are common\n\ndiscuss the likely causes or contributing factors\n\ndiscuss any treatments that may help.\n\n## Managing hydration\n\nIf a child or young person with a life-limiting condition is approaching the end of life or is dying, discuss how to manage their fluid needs with them and their parents or carers.\n\nIf a child or young person is dying, encourage and support them to drink if they want to and are able.\n\nIf a child or young person is dying, continue to provide them with lip and mouth care.\n\nIf a child or young person is dying and cannot drink, discuss with them (as appropriate) and their parents or carers whether starting or continuing enteral tube or intravenous fluids is in their best interests.\n\nBe aware that enteral tube and intravenous fluids may have a significant effect on care, may be a burden for children and young people, and may mean the place of care and place of death need to be changed.\n\nIf a child or young person is given enteral or intravenous fluids, review this decision regularly to make sure it continues to be in their best interests.\n\n## Managing nutrition\n\nIf a child or young person is approaching the end of life or is dying, discuss how to manage their nutritional needs with them and their parents or carers.\n\nIf a child or young person with a life-limiting condition is dying, encourage and support them to eat if they want to and are able.\n\nIf a child or young person is dying and they are receiving enteral tube feeding or intravenous nutrition:\n\ndiscuss with them (as appropriate) and their parents or carers whether continuing this is in their best interest and\n\nreview this decision regularly.\n\n## Recognising that a child or young person is likely to die within hours or days\n\nFor children and young people with life-limiting conditions who are approaching the end of life:\n\nbe aware that there is often uncertainty around when they are likely to die\n\nbe aware that there are various symptoms and signs (individually or in combination) that indicate they are likely to die within hours or days\n\ntake into account the wider clinical context.\n\nWhen assessing whether a child or young person is likely to die within hours or days, be aware that the following signs are common in the last hours or days of life, and monitor these non-invasively as far as possible:\n\na change of breathing pattern (for example noisy, laboured or irregular breathing)\n\nimpaired peripheral perfusion (which can be indicated by a pale or grey appearance, or a prolonged capillary refill time), including temperature instability\n\nloss of interest in or ability to tolerate drinks or food\n\na marked and unexplained fall in urine output\n\nan altered level of awareness (for example reduced consciousness, alertness or responsiveness, excessive sleeping, or confusion)\n\nintractable seizures that keep occurring even with optimal management\n\nnew onset of profound weakness\n\nincreasing pain and need for analgesia.\n\nWhen assessing symptoms and signs to decide whether a child or young person is likely to die within hours or days, take into account the wider clinical context, including:\n\ntheir normal clinical baseline\n\npast clinical events (such as previous episodes of temporary deterioration)\n\nthe overall progression of their condition.\n\nWhen assessing whether a child or young person is likely to die within hours or days, take into account the clinical judgement of healthcare professionals experienced in end of life care.\n\nIf the child or young person or their parents or carers feel that they are likely to die within hours or days:\n\nbe aware that they may be correct\n\ndiscuss their concerns with them.\n\nWhen a child or young person is likely to die within hours or days, support them and their parents or carers by:\n\nlistening to any fears or anxieties they have and\n\nshowing empathy and compassion.\n\nWhen a child or young person is likely to die within hours or days:\n\nbe aware that they or their parents or carers may not express their feelings openly, and may:\n\n\n\nhave intense and varied feelings such as fear, hopelessness or anger or\n\nbecome more accepting of the inevitability of death\n\n\n\ngive them and their parents or carers opportunities to talk.\n\nIf a child or young person is likely to die within hours or days, explain to them and their parents or carers:\n\nwhy you think this is likely, and any uncertainties\n\nwhat clinical changes can be expected\n\nwhether you think the treatment plan should be changed.\n\nWhen children and young people become seriously ill and are likely to die within hours or days, provide care as specified in their Advance Care Plan and review if needed.\n\nBe aware that children and young people may have difficulty asking directly if they are going to die or are dying. Explore and discuss their concerns if you think they want to talk about this.\n\nBe aware that parents or carers may have difficulty asking directly if a child or young person is dying. Explore and discuss their concerns if you think they want to talk about this.\n\nIf a child or young person may be approaching the end of life and they or their parents or carers want to be involved in making decisions about their care, discuss and review their Advance Care Plan with them.\n\nWhen a child or young person is approaching the end of life, discuss with them and their parents or carers and with relevant healthcare professionals:\n\nany available invasive treatments that might be in their best interest\n\nany interventions they are currently receiving that may no longer be in their best interest.\n\nIf withdrawing a treatment for a child or young person who is dying, explain to them and to their parents or carers that it is often difficult to tell if or how this may affect them, or when they will die.\n\nWhen a child or young person is likely to die within hours or days, ensure that they can have private time with their parents or carers.\n\n# Care and support for parents, carers and healthcare professionals in relation to the death of a child or young person\n\nDiscuss with parents or carers the practical arrangements that will be needed after the death of their child, and provide this information in writing. This should cover matters such as:\n\nthe care of the body\n\nrelevant legal considerations, including\n\n\n\nthe involvement of the child death overview panel\n\nthe involvement of the coroner\n\nregistration of the death\n\n\n\nfuneral arrangements\n\npost-mortem examination (if this is to be performed).\n\nWhen a child or young person is approaching the end of life, discuss the bereavement support available with their parents or carers and provide them with written information.\n\nWhen a child or young person is approaching the end of life, talk to their parents or carers about available psychological bereavement support groups.\n\nOffer bereavement support from a professional with appropriate expertise to the parents or carers both before and after the death of a child or young person.\n\nWhen planning bereavement support for parents or carers:\n\ntalk to them about the support that is available and explore with them what they would find helpful and acceptable\n\nthink about what support different professionals could provide, for example:\n\n\n\ntheir GP\n\nhealthcare professionals who know the child or young person and are involved in their care\n\n\n\nthink about the role of individual professionals in providing specific aspects of support\n\ninform the multidisciplinary team about the support plan.\n\nWhen making a bereavement support plan with parents or carers, discuss possible options with them such as:\n\nopportunities to talk to the professionals caring for the child or young person, to:\n\n\n\ndiscuss memories and events\n\nanswer any concerns or questions they may have\n\n\n\nhome visits from the healthcare professionals caring for the child or young person\n\nbereavement support groups.\n\nEnsure that arrangements are in place for professionals to talk about their thoughts and feelings with colleagues when a child or young person they are caring for is approaching the end of life or has died.\n\nFollowing the death of a child or young person, a member of the multidisciplinary team should arrange in a timely manner for all relevant organisations and people to be informed.\n\nUpdate relevant documents and databases after the death of a child or young person (to avoid, for example, clinical appointments being offered by mistake).\n\n# Service delivery\n\n## Multidisciplinary team\n\nChildren and young people with life-limiting conditions should be cared for by a defined multidisciplinary team.\n\nAs the child or young person's circumstances change (for example if they change from having care primarily to manage their condition to having end of life care), the membership of the multidisciplinary team should be adjusted accordingly.\n\nDepending on the needs of the child or young person, the multidisciplinary team may include:\n\nhealthcare professionals from primary, secondary or tertiary services, including specialists in the child's underlying life-limiting condition, hospice professionals and members of the specialist palliative care team (see recommendation 1.5.4)\n\nsocial care practitioners\n\neducation professionals\n\nchaplains\n\nallied health professionals (for example physiotherapists, occupational therapists, and psychological therapists).\n\nThe specialist paediatric palliative care team should include at a minimum:\n\na paediatric palliative care consultant\n\na nurse with expertise in paediatric palliative care\n\na pharmacist with expertise in specialist paediatric palliative care\n\nexperts in child and family support who have experience in end of life care (for example in providing social, practical, emotional, psychological and spiritual support).\n\nExplain to children and young people and their parents or carers:\n\nwho the multidisciplinary team members are and how they are involved in their care\n\nhow the multidisciplinary team membership will change if the care that is needed or the care setting changes.\n\nThink about involving children and young people and their parents or carers in multidisciplinary team meetings (when appropriate).\n\nThink about having a named individual from the multidisciplinary team to act as a first point of contact for the child or young person and their parents or carers.\n\n## Rapid transfer arrangements\n\nIn collaboration with local hospitals, hospices, and community, primary care and ambulance services, ensure there is a rapid transfer process for children and young people with life-limiting conditions to allow urgent transfer to the preferred place (for example from the intensive care unit to their home or to a children's hospice). See recommendations 1.3.15 to 1.3.19 for the planning and practical arrangements of this transfer.\n\n## Care at home\n\nFor children and young people with life-limiting conditions who are approaching the end of life and are being cared for at home, services should provide (when needed):\n\nadvice from a consultant in paediatric palliative care (for example by telephone) at any time (day and night)\n\npaediatric nursing care at any time (day and night)\n\nhome visits by a healthcare professional from the specialist paediatric palliative care team (see recommendation 1.5.4), for example for symptom management\n\npractical support and equipment for interventions including oxygen, enteral nutrition, and subcutaneous and intravenous therapies\n\nanticipatory prescribing for children and young people who are likely to develop symptoms.\n\nServices should have agreed strategies and processes to support children and young people who are approaching the end of life and are being cared for at home. These services should be based on managed clinical networks, and should collaborate on care planning and service delivery.\n\nServices for children and young people who are approaching the end of life and are being cared for at home should be able to support parenteral drug administration (for example continuous subcutaneous opioid or anticonvulsant infusions).\n\n# Terms used in this guideline\n\n## Advance Care Plan\n\nA formal care plan that includes details about the child or young person's condition, decisions made with them and their parents or carers (for example about managing symptoms), and their wishes and ambitions. This plan is a core element of their palliative care.\n\n## Approaching the end of life\n\nThe phase of illness after a change in the person's condition that means they are likely to die within weeks.\n\n## Chaplain\n\nAn expert (with any or no religious beliefs) in religious, spiritual and or pastoral care for patients, families and staff. Chaplains also provide education and advice to organisations or trusts. They work to a nationally recognised code of conduct and a set of standards and competencies.\n\n## Children\n\nAged 0 to 12\xa0years. This includes neonates and infants.\n\n## Dying\n\nWhen the child or young person is likely to die in hours or days.\n\n## End of life care\n\nIn this guideline, end of life care includes the care and support given in the final days, weeks and months of life, and the planning and preparation for this.\n\n## Life-limiting condition\n\nConditions that are expected to result in an early death, either for everyone with the condition or for a specific person.\n\n## Neonates\n\nBabies aged up to 28\xa0days.\n\n## Paediatric palliative care\n\nAn approach to care covering physical, emotional, social and spiritual support. Paediatric palliative care focuses on improving the quality of life for the child or young person and supporting their family members or carers, and includes managing distressing symptoms, providing respite care, and support with death and bereavement.\n\n## Parallel planning\n\nPlanning for end of life care while taking account of the often unpredictable course of life‑limiting conditions. It involves making multiple plans for care, and using the one that best fits the child or young person's circumstances at the time.\n\n## Perinatal palliative care\n\nPerinatal palliative care involves providing integrated ongoing support from the diagnosis of a life-limiting condition in a fetus, and during pregnancy, delivery, postnatal care, and (if needed) bereavement care.\n\n## Young people\n\nAged 13 to 17\xa0years.", 'Context': "The Royal College of Physicians report Why children die: death in infants, children and young people in the UK (2014) noted that, despite improving mortality rates, in 2012 more than 2,000\xa0children and young people aged between 1\xa0and\xa019 died in England and Wales. Approximately 40% of deaths in children and young people under\xa015 are neonatal deaths (Office for National Statistics, 2016). In addition, it is estimated that almost 50,000\xa0children and young people aged 19\xa0or under in the UK (40,000\xa0of these in England) are living with a life-limiting condition and may need palliative care. They may have widely varying needs, as there are over 300\xa0conditions that could be classed as life-limiting or life-threatening in this age group. Some of these children and young people also have severe disabilities and multiple complex health and social care needs.\n\nEnd of life care combines a broad range of health and other care services, including hospitals, hospices, primary care and community professionals, ambulance services, dedicated palliative care teams, and other support providers. Services span the public sector and charities. Because of this, good communication, care coordination, and effective networking are essential. Children and young people are likely to need different services at different stages of their illness and they will get the best care possible when services communicate with and support each other.\n\nPalliative care for adults is a well-established discipline, with evidence that if it starts early it can both enhance and even prolong life. Paediatric palliative and end of life care generally lasts longer and is for a wider range of life-limiting conditions than for adults. It begins when a life-limiting condition is diagnosed (which could be diagnosed during the antenatal period), and continues even if a child is having treatment for the underlying condition (World Health Organization 1998). Young people may continue to have palliative care after they turn\xa018, and it may be part of the transition to adult care (see the NICE guideline on transition from children's to adults' services).\n\nChildren, young people and their parents or carers can have varied ideas about what represents good palliative and end of life care, and they may have differences of opinion with each other. They may also have different priorities at different stages in their lives.\n\nThis guideline covers the physical, emotional, social and spiritual elements of end of life care, and focuses on improving the child's or young person's quality of life and supporting their family. There are for instance recommendations on managing distressing symptoms and providing care and bereavement support after death. It also includes recommendations on how services should be delivered. The guideline is aimed at all providers of paediatric palliative and end of life care (whatever their level of practise), as well as children and young people with life-limiting conditions and their parents and carers.\n\nTo help develop this guideline, a focus group of young people with life-limiting conditions were asked for their views and experiences of care. See the full guideline for the report presenting these findings.\n\nThe guideline covers children and young people with life-limiting conditions. It does not make recommendations for children or young people who die suddenly and unexpectedly (for example accidental death).", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Preferred place of care and place of death\n\nWhen planning and managing end of life care, what factors help children and young people with life-limiting conditions and their parents or carers to decide where they would like end of life care to be provided and where they prefer to die?\n\n## Why this is important\n\nWhen deciding the place of care and place of death, paediatric palliative care services sometimes assume that the main concern of parents and carers is that their child is able to die at home. However, the guideline committee's experience suggests that there are other significant factors for children and young people as well as their parents and carers (in particular, treatment of distressing symptoms) that may affect their choice of care setting. No research has been done to identify these factors, but it is important to recognise any reasons why a care setting might not be suitable. Understanding this would allow services to provide more personalised care, improve planning, and reduce waste and the cost of care.\n\n# Perinatal palliative care\n\nWhat impact does timely perinatal palliative care have on the experience of bereaved parents?\n\n## Why this is important\n\nParents with a baby that is diagnosed antenatally with a life‑limiting condition are increasingly being offered perinatal palliative care before the birth (or very soon afterwards) if they decide to continue with the pregnancy.\n\nPerinatal palliative care should help clinical staff (obstetric, neonatal and specialist palliative care) to deliver consistent high-quality care and ensure that families are offered meaningful and realistic choices for the care of their baby. If it is done well, perinatal palliative care also ensures that everyone involved understands the medical, social and legal frameworks for any decisions on critical care before and after birth.\n\nThere is little evidence on the experience families have of the death of a baby with or without specific support from a perinatal palliative care team. Individual case reports on family experience are very positive about perinatal palliative care, but published evidence is scarce.\n\n# Emotional and psychological support and interventions\n\nWhat emotional support do children and young people with life-limiting conditions and their parents or carers need, and how would they like these needs to be addressed?\n\n## Why this is important\n\nPrevious UK studies, such as The Big Study for Life-Limited Children and their Families from Together for Short Lives, have explored broad themes of psychological support needs. However, no studies have tried to understand psychological difficulties using standardised measures of psychological and relationship distress, or looked at what families want from psychological therapies.\n\nBefore research into effective interventions can be carried out, the following aspects of psychological difficulties need to be better understood:\n\ntheir range (for example low mood, worry, stigma, conflict in family relationships, avoidance, and distress about medical procedures)\n\ntheir severity (from mild long-term low mood to severe depression with suicidal thoughts)\n\ntheir context (for example socioeconomic status, and communication or mobility needs).\n\n# Managing breakthrough pain\n\nWhat is the acceptability, safety, and effectiveness of different types of opioid analgesia for breakthrough pain in children and young people with life-limiting conditions who are having end of life care in the community?\n\n## Why this is important\n\nOpioids (with morphine the most common first-line agent) are effective as background analgesia for children and young people who are having end of life care. However, no evidence was identified on how to provide safe and effective breakthrough analgesia (particularly in community settings). This potentially exposes children and young people who are having end of life care in the community to untreated pain or significant side effects. Studies should aim to provide evidence-based options to help manage breakthrough pain in the community. This would improve the safety and effectiveness of care for breakthrough pain, and would be likely to reduce emergency hospital admissions.\n\n# Recognising that a child or young person may be dying\n\nWhat signs and symptoms indicate that a child or young person with a life-limiting condition is likely to die within hours or days?\n\n## Why this is important\n\nHealthcare professionals are often asked to estimate how close a child or young person may be to death. There is very little evidence on which to base any such estimate. To help predict when a child or young person is in the last hours or days of life, a clearer understanding is needed of which groups of signs and symptoms indicate this most clearly. This would improve healthcare planning, but importantly would also allow families to realistically address their 'hopes and wishes' for their child's care while preparing themselves for the child's or young person's last hours and days of life."}
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https://www.nice.org.uk/guidance/ng61
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This guideline covers the planning and management of end of life and palliative care for infants, children and young people (aged 0 to 17 years) with life-limiting conditions. It aims to involve children, young people and their families in decisions about their care, and improve the support that is available to them throughout their lives.
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30c7105a55e013568580438766d0f4c24d2ea716
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nice
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Transurethral laser ablation for recurrent non-muscle-invasive bladder cancer
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Transurethral laser ablation for recurrent non-muscle-invasive bladder cancer
Evidence-based recommendations on transurethral laser ablation for recurrent non-muscle-invasive bladder cancer in adults. This involves using a laser inserted into the bladder to destroy the cancer cells.
# Recommendations
The evidence on the safety of transurethral laser ablation for recurrent non-muscle-invasive bladder cancer shows that there are no major safety concerns. However, current evidence on its efficacy is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do transurethral laser ablation for recurrent non-muscle-invasive bladder cancer should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having transurethral laser ablation for recurrent non-muscle-invasive bladder cancer. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
Patient selection should be done by a specialist bladder cancer multidisciplinary team.
NICE encourages further research and prospective data collection into transurethral laser ablation for recurrent non-muscle-invasive bladder cancer. Studies should investigate patient selection, types of laser used, tumour recurrence and long-term follow up.# The condition, current treatments and procedure
# The condition
The most common form of bladder cancer is transitional cell carcinoma. Non-muscle-invasive transitional cell carcinoma is classified as stage Ta when it is confined to the uroepithelium and stage T1 when it has spread into the connective tissue layer between the urothelium and the muscle wall. Non-muscle-invasive transitional cell carcinomas usually appear as small growths from the bladder lining. They can be graded from G1 (low grade, least aggressive) to G3 (high grade, most aggressive). Carcinoma in situ consists of aggressive cancer cells that spread within the surface lining of the bladder and appear flat. It is more likely to recur after treatment.
# Current treatments
NICE's guideline on bladder cancer describes its diagnosis and management. Surgical interventions for non-muscle-invasive transitional cell carcinoma include transurethral resection, in which malignant tissue is removed with an electrocautery device during cystoscopy. Bacillus Calmette–Guérin (BCG) vaccine or chemotherapy drugs may be put directly into the bladder, either as treatments in themselves or as adjuvant therapy after transurethral resection. Cystectomy may also be necessary in some patients.
# The procedure
This procedure is most often used for very small, recurrent bladder tumours. It is usually done as day surgery using local anaesthesia. A flexible cystoscope is passed through the urethra into the bladder. The tumours are then ablated using a laser fibre contained in the cystoscope.
If there is a lot of bleeding after the procedure, a urinary catheter may be inserted to allow bladder irrigation.
Adjuvant intravesical chemotherapy may be offered after the procedure.
The aim is to destroy the tumour with less morbidity than is seen with conventional treatments. The suggested benefits over cystodiathermy include less bleeding and reduced pain.
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{'Recommendations': "The evidence on the safety of transurethral laser ablation for recurrent non-muscle-invasive bladder cancer shows that there are no major safety concerns. However, current evidence on its efficacy is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do transurethral laser ablation for recurrent non-muscle-invasive bladder cancer should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having transurethral laser ablation for recurrent non-muscle-invasive bladder cancer. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nPatient selection should be done by a specialist bladder cancer multidisciplinary team.\n\nNICE encourages further research and prospective data collection into transurethral laser ablation for recurrent non-muscle-invasive bladder cancer. Studies should investigate patient selection, types of laser used, tumour recurrence and long-term follow up.", 'The condition, current treatments and procedure': "# The condition\n\nThe most common form of bladder cancer is transitional cell carcinoma. Non-muscle-invasive transitional cell carcinoma is classified as stage\xa0Ta when it is confined to the uroepithelium and stage\xa0T1 when it has spread into the connective tissue layer between the urothelium and the muscle wall. Non-muscle-invasive transitional cell carcinomas usually appear as small growths from the bladder lining. They can be graded from G1 (low grade, least aggressive) to G3 (high grade, most aggressive). Carcinoma in\xa0situ consists of aggressive cancer cells that spread within the surface lining of the bladder and appear flat. It is more likely to recur after treatment.\n\n# Current treatments\n\nNICE's guideline on bladder cancer describes its diagnosis and management. Surgical interventions for non-muscle-invasive transitional cell carcinoma include transurethral resection, in which malignant tissue is removed with an electrocautery device during cystoscopy. Bacillus Calmette–Guérin (BCG) vaccine or chemotherapy drugs may be put directly into the bladder, either as treatments in themselves or as adjuvant therapy after transurethral resection. Cystectomy may also be necessary in some patients.\n\n# The procedure\n\nThis procedure is most often used for very small, recurrent bladder tumours. It is usually done as day surgery using local anaesthesia. A flexible cystoscope is passed through the urethra into the bladder. The tumours are then ablated using a laser fibre contained in the cystoscope.\n\nIf there is a lot of bleeding after the procedure, a urinary catheter may be inserted to allow bladder irrigation.\n\nAdjuvant intravesical chemotherapy may be offered after the procedure.\n\nThe aim is to destroy the tumour with less morbidity than is seen with conventional treatments. The suggested benefits over cystodiathermy include less bleeding and reduced pain."}
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https://www.nice.org.uk/guidance/ipg656
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Evidence-based recommendations on transurethral laser ablation for recurrent non-muscle-invasive bladder cancer in adults. This involves using a laser inserted into the bladder to destroy the cancer cells.
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24f2975da2985e44e3316fffaba2dbf306650d71
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nice
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Ultrasound-guided high-intensity transcutaneous focused ultrasound for symptomatic uterine fibroids
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Ultrasound-guided high-intensity transcutaneous focused ultrasound for symptomatic uterine fibroids
Evidence-based recommendations on ultrasound-guided high-intensity transcutaneous focused ultrasound for symptomatic uterine fibroids in adults. This involves focusing high-intensity ultrasound energy at the fibroids through the skin of the abdomen.
# Recommendations
Current evidence on the safety of ultrasound-guided high‑intensity transcutaneous focused ultrasound for symptomatic uterine fibroids shows there are well-recognised complications including skin burns. The evidence on efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do ultrasound-guided high‑intensity transcutaneous focused ultrasound for symptomatic uterine fibroids should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these and provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having ultrasound-guided high intensity transcutaneous focused ultrasound for symptomatic uterine fibroids. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
During the consent process clinicians should tell patients that their symptoms may not be fully relieved and may return, and that further procedures may be needed. They should also tell patients about the risk of skin burns. Patients considering pregnancy should be told that the effects of the procedure on fertility and future pregnancy are uncertain.
Patient selection should be done by a multidisciplinary team including a gynaecologist and an appropriate imaging specialist.
The procedure should only be done in specialised centres by clinicians with specific training in this technique.
NICE encourages further research and prospective data collection. Studies comparing ultrasound-guided high-intensity focused ultrasound with other therapies such as uterine artery embolisation and MRI-guided high‑intensity transcutaneous focused ultrasound would be useful. Studies should report patient selection (including size, location and number of fibroids), patient-reported outcome measures, long-term outcomes and subsequent pregnancy rates.# The condition, current treatments and procedure
# The condition
Uterine fibroids are benign tumours of the uterine wall. They can be asymptomatic or cause symptoms including menorrhagia, intermenstrual bleeding, pelvic pressure or pain, and urinary incontinence. They can be associated with fertility problems and miscarriage.
# Current treatments
Treatment depends on whether the fibroids cause symptoms, and if the person would like to have children in the future. For symptomatic fibroids, treatment options include medications, interventional radiology and surgery. Interventional radiology treatments include uterine artery embolisation and MRI-guided focused ultrasound. Surgery includes hysterectomy, myomectomy, endometrial ablation techniques and myolysis.
# The procedure
Ultrasound-guided high-intensity transcutaneous focused ultrasound (HIFU) for symptomatic uterine fibroids is done with the patient lying face down, with the abdominal wall immersed in degassed water. Intravenous sedation may be used to help minimise body movement. A urinary catheter is inserted to keep the bladder empty during the procedure. Continuous sonographic imaging is used to identify the fibroid(s) with a real-time diagnostic ultrasound scanner integrated into the centre of a therapeutic ultrasound transducer. After the target fibroid has been confirmed, it is ablated by high-intensity ultrasound energy. The patient may have to lie still for up to 3 hours.
Ultrasound-guided HIFU uses grayscale or echogenicity changes to determine the adequacy of ablation. After treatment, imaging (by ultrasound or MRI scan) is used to evaluate the volume of the fibroid ablated.
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{'Recommendations': "Current evidence on the safety of ultrasound-guided high‑intensity transcutaneous focused ultrasound for symptomatic uterine fibroids shows there are well-recognised complications including skin burns. The evidence on efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do ultrasound-guided high‑intensity transcutaneous focused ultrasound for symptomatic uterine fibroids should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these and provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having ultrasound-guided high intensity transcutaneous focused ultrasound for symptomatic uterine fibroids. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nDuring the consent process clinicians should tell patients that their symptoms may not be fully relieved and may return, and that further procedures may be needed. They should also tell patients about the risk of skin burns. Patients considering pregnancy should be told that the effects of the procedure on fertility and future pregnancy are uncertain.\n\nPatient selection should be done by a multidisciplinary team including a gynaecologist and an appropriate imaging specialist.\n\nThe procedure should only be done in specialised centres by clinicians with specific training in this technique.\n\nNICE encourages further research and prospective data collection. Studies comparing ultrasound-guided high-intensity focused ultrasound with other therapies such as uterine artery embolisation and MRI-guided high‑intensity transcutaneous focused ultrasound would be useful. Studies should report patient selection (including size, location and number of fibroids), patient-reported outcome measures, long-term outcomes and subsequent pregnancy rates.", 'The condition, current treatments and procedure': '# The condition\n\nUterine fibroids are benign tumours of the uterine wall. They can be asymptomatic or cause symptoms including menorrhagia, intermenstrual bleeding, pelvic pressure or pain, and urinary incontinence. They can be associated with fertility problems and miscarriage.\n\n# Current treatments\n\nTreatment depends on whether the fibroids cause symptoms, and if the person would like to have children in the future. For symptomatic fibroids, treatment options include medications, interventional radiology and surgery. Interventional radiology treatments include uterine artery embolisation and MRI-guided focused ultrasound. Surgery includes hysterectomy, myomectomy, endometrial ablation techniques and myolysis.\n\n# The procedure\n\nUltrasound-guided high-intensity transcutaneous focused ultrasound (HIFU) for symptomatic uterine fibroids is done with the patient lying face down, with the abdominal wall immersed in degassed water. Intravenous sedation may be used to help minimise body movement. A urinary catheter is inserted to keep the bladder empty during the procedure. Continuous sonographic imaging is used to identify the fibroid(s) with a real-time diagnostic ultrasound scanner integrated into the centre of a therapeutic ultrasound transducer. After the target fibroid has been confirmed, it is ablated by high-intensity ultrasound energy. The patient may have to lie still for up to 3\xa0hours.\n\nUltrasound-guided HIFU uses grayscale or echogenicity changes to determine the adequacy of ablation. After treatment, imaging (by ultrasound or MRI scan) is used to evaluate the volume of the fibroid ablated.'}
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https://www.nice.org.uk/guidance/ipg657
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Evidence-based recommendations on ultrasound-guided high-intensity transcutaneous focused ultrasound for symptomatic uterine fibroids in adults. This involves focusing high-intensity ultrasound energy at the fibroids through the skin of the abdomen.
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3a64ff20d0e11b7b73c6780be7617597e60170b5
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nice
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Nusinersen for treating spinal muscular atrophy
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Nusinersen for treating spinal muscular atrophy
Evidence-based recommendations on nusinersen (Spinraza) for treating spinal muscular atrophy in children and adults.
# Recommendations
Nusinersen is recommended as an option for treating 5q spinal muscular atrophy (SMA) only if:
people have pre-symptomatic SMA, or SMA types 1, 2 or 3 and
the conditions in the managed access agreement are followed.
Why the committee made these recommendations
SMA is a rare genetic condition, the most severe types of which affect babies and young children. Currently, there is an unmet need for effective treatments that could slow disease progression.
Clinical trial evidence shows that nusinersen improves a range of outcomes that are important to people with early- (type 1) and later-onset (types 2 and 3) SMA. Also, there is some evidence suggesting that nusinersen is effective for pre-symptomatic SMA. However, there is no long-term evidence, so the long-term benefits are highly uncertain. The committee considered that further data collection would help address these uncertainties.
The cost-effectiveness estimates presented are higher than what NICE usually considers a cost-effective use of NHS resources. However, these estimates are difficult to interpret because of the limited evidence base to substantiate longer-term benefits, the difficulty in clearly distinguishing between the SMA subtypes, and the difference in what can be achieved for these various patients without nusinersen.
The proposed managed access agreement details various risk management strategies, including patient selection, starting and stopping rules, data collection, patient consent, exit strategy and commercial offer. Taking these into account, nusinersen is recommended for people with pre-symptomatic SMA, or SMA types 1, 2 or 3 if the conditions in the managed access agreement are followed, including the collection of more data to address the uncertainties. This recommendation will be reviewed based on data collected in the managed access arrangement. The review of the guidance will be published by the end of the fifth year.# Information about nusinersen
Marketing authorisation indication
Nusinersen (Spinraza, Biogen Idec) has a marketing authorisation for 'the treatment of 5q spinal muscular atrophy'.
Dosage in the marketing authorisation
mg, by intrathecal infusion, on days 0, 14, 28 and 63, then every 4 months.
Price
The list price is £75,000 per vial (excluding VAT; BNF, accessed June 2018).
At the list price, the total annual treatment cost is £450,000 for the first year and £225,000 for subsequent years. Over 5 years, the treatment costs per person would be £1.35 million.
The company has a commercial arrangement. This makes nusinersen available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Biogen Idec and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need
## Spinal muscular atrophy is a neuromuscular disorder; the most severe types affect babies and young children
Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease caused by a genetic mutation in the SMN1 gene on chromosome 5q. People with the condition have a range of symptoms, including muscle weakness, and have worsening physical disability, mobility loss and respiratory dysfunction. SMA can be grouped into 5 main types (types 0 to 4), based on the age of onset and the maximum motor function reached. Type 0 SMA, the most severe, affects babies before birth. The babies do not develop any motor skills and often survive for only a few weeks after birth. Babies with SMA type 1 are unable to sit or roll because of severe muscle weakness, which gets worse over time. The muscle weakness also affects swallowing and breathing, and typically results in death within 2 years. In type 2 SMA, the onset of symptoms is between 7 months and 18 months. People with this condition can sit independently at diagnosis. However, progressive loss of motor function means they have a reduced life expectancy compared with the general population. In type 3 SMA, there are varying degrees of muscle weakness, which appear between 18 months and 18 years. People with this condition can have a normal lifespan, and walk or sit unaided at some point, but many lose mobility over time. Type 4 SMA, the least severe, affects adults, who may have only mild motor impairment and live a normal lifespan. The clinical experts suggested that, of all diagnosed cases of SMA, around 60% are type 1 and around 40% are types 2 and 3; types 0 and 4 are rarely diagnosed. The committee acknowledged the extreme challenge that people with SMA experience every day, especially those with type 1. It concluded that the most severe types of SMA affect babies and young children.
## The current SMA classification system is the best system available
The patient experts commented that the SMA classification system is useful but does not always reflect the full extent of the disease: boundaries between the different SMA classifications are blurred and can be subjective. The clinical experts accepted these limitations, but nevertheless acknowledged that the current classification system is the most accurate predictor of severity and prognosis available. The committee acknowledged the difficulties with current SMA classification but concluded that it was the best classification system available.
## SMA severely affects the quality of life of patients, carers and their families
The clinical and patient experts explained that most people with SMA need constant support. This can include full-time care and attention, needing physical effort (such as lifting and carrying) and causing loss of sleep for patients and carers, stress, and fear at loss of abilities. All these factors have a major effect on family members' health-related quality of life. The committee heard from parents and carers that living with the condition involves daily care, exercises and constant vigilance (especially at night, when people with SMA need assistance in bed). SMA also causes anxiety, emotional distress and disruption to work and family finances, as well as straining relationships. Following consultation, the committee heard from patient experts that SMA often has a major impact on the quality of life of multiple members of an extended family, with grandparents, siblings and family friends often severely affected. The committee concluded that SMA has a substantial effect on the quality of life of patients, carers and their families.
# Current treatments
## There is an unmet need for an effective treatment
There are no disease-modifying therapies for SMA. Current treatments are based on symptom control and aim to maintain movement and function for as long as possible and to improve quality of life. This involves a multidisciplinary approach including respiratory, gastroenterology and orthopaedic care, as well as nutritional support, physiotherapy, assistive technologies, occupational therapy and social care. However, the clinical and patient experts emphasised that current treatments do not affect disease progression, so people with SMA will ultimately become totally dependent on their families and carers. The committee recognised that treatment options are limited and there is an unmet need for people with SMA.
# The technology
## Nusinersen has a marketing authorisation for all types of SMA but the company only presented clinical evidence for pre-symptomatic SMA and symptomatic SMA types 1 to 3
Nusinersen has a marketing authorisation for all types of SMA. The clinical experts agreed that it may benefit people with any type of SMA. However, they considered that it may have a relatively greater benefit for those with more severe types of SMA (although using nusinersen in type 0 SMA might be futile because of the degree of established damage at the time treatment could be started). The committee heard that the presence of SMN2 can compensate for the SMN1 deletion to some degree because it is a similar gene, and that the number of SMN2 gene copies is inversely related to the severity of SMA and can be used to predict the course of the disease. However, the clinical experts stated that gene testing may lead to delays in starting treatment. The experts considered that the correlation between copy number and disease severity is much less reliable than the clinical classification system in identifying the likely course of SMA. The committee acknowledged that nusinersen should be considered within its marketing authorisation (that is, for all types of SMA). However, the company only presented clinical evidence for pre-symptomatic SMA and symptomatic SMA types 1, 2 and 3, so restricted its recommendations to these types of SMA (excluding type 0 and type 4).
# Clinical trial evidence
## Evidence from the clinical trials, including ENDEAR and CHERISH, is uncertain but relevant for decision making
The main clinical-effectiveness evidence for nusinersen came from 2 clinical trials:
ENDEAR, a randomised, double-blind, multicentre (including the UK), phase III, sham, procedure-controlled trial. The trial recruited 122 children who developed SMA symptoms between 2 weeks and 6 months, which corresponds to type 1 SMA (described by the company as 'early-onset' SMA).
CHERISH, a randomised, double-blind, multicentre, phase III, sham, procedure-controlled trial. The trial recruited 126 patients who developed SMA symptoms between 6 months and 12 years and who were able to sit independently but never had the ability to walk independently. This corresponds with type 2 SMA and the more severe presentations of type 3 SMA (described by the company as 'later-onset' SMA).There are also 3 ongoing studies: NURTURE, a phase II, single-arm study for pre-symptomatic infants genetically diagnosed with SMA; SHINE, which is a continuation of ENDEAR, CHERISH, CS12 and CS3A; and EMBRACE, for patients with SMA not eligible to participate in the clinical studies ENDEAR and CHERISH. The ERG considered that there were limitations in the clinical evidence. In particular, in ENDEAR, the nusinersen population had a poorer baseline prognosis than the control group and, in CHERISH, the strict entry criteria resulted in a more homogeneous population than would be expected in clinical practice. The ERG also explained that the dose regimen in CHERISH was not consistent with nusinersen's marketing authorisation because the maintenance doses were less frequent. Follow-up periods were relatively short for both ENDEAR and CHERISH, so the long-term benefits of nusinersen are unknown. The committee concluded that although the evidence had uncertainties, it was suitable for decision making.
## Nusinersen improves survival and motor function for people with early‑onset SMA
Results from ENDEAR showed that, compared with sham, nusinersen statistically significantly improved event-free survival, overall survival and motor function in patients with type 1 SMA:
The hazard ratio for event-free survival (defined as time to death or permanent ventilation) was 0.53 (95% confidence interval 0.32 to 0.89; p=0.005).
The hazard ratio for overall survival was 0.37 (95% CI 0.18 to 0.77; p=0.004).
In terms of motor function, 51% of patients in the nusinersen group reached motor milestone responses compared with none in the control group (as measured by a modified version of module 2 of the Hammersmith Infant Neurological Examination ).Based on the strength of the motor benefit shown, ENDEAR was stopped early. The committee agreed that the trial showed a substantial benefit in survival for nusinersen compared with sham. Data from SHINE appeared to show that patients having nusinersen in both ENDEAR and SHINE had improved outcomes in terms of time to death or permanent ventilation compared with patients who started nusinersen in SHINE.
## Other health benefits of nusinersen for early‑onset SMA are less certain
ENDEAR measured other important outcomes at 6 months including:
Overall hospitalisation rate ratio was 0.759 (95% CI 0.55 to 1.05; p=0.965).
Mean treatment difference (measured as least-squares mean) for the proportion of time spent hospitalised for respiratory reasons was −8.638% (95% CI −14.190 to −3.086, p=0.0026).
The odds ratio for infants not needing ventilation started among infants who were not having ventilation support at baseline was 11.6 (95% CI 1.5 to 92.1, p=0.021).
The rate ratio of respiratory events leading to hospitalisation and the mean treatment difference for the number of days needing ventilation support for 16 hours or more per day were not statistically significant.The committee noted that nusinersen appeared to improve respiratory outcomes as measured by the hospitalisation rate. However, the results were not as substantial as those seen for survival, and some of the other respiratory outcomes were not statistically significant (see section 3.7). The committee considered it counterintuitive that an observed substantial survival benefit was not associated with a substantial benefit in other outcomes. The company noted at consultation that the trial was not powered to detect differences between the groups in respiratory outcomes, which would need a much larger cohort. The clinical experts noted that it is difficult to measure respiratory function in infants. They also explained that, although nusinersen would likely improve respiratory function, any improvements in motor function may in turn place greater stress on the respiratory system. Patient experts and consultees emphasised that the benefits of nusinersen seen in the trials and in clinical practice (which were not always measured) were valuable to patients and their families. They emphasised the importance of any stabilisation and even small improvement in symptoms, especially any improvement in motor function. The committee recognised that any improvements would be highly valued by people with SMA, and that nusinersen provides important health benefits for people with early-onset SMA. However, it concluded that the size of some of these benefits remained uncertain.
## Nusinersen substantially improves motor function for people with later‑onset SMA but the effect on survival is unclear
Results from CHERISH showed that, compared with sham, nusinersen statistically significantly improved motor function of children with later‑onset SMA. Motor function as measured by Hammersmith Functional Motor Scale-Expanded (HFMSE) had a least-squares mean difference of 4.9 (95% CI 3.1 to 6.7; p<0.0000001). The committee agreed that nusinersen provides important health benefits for people with later‑onset SMA, but it was unclear how this affects survival because there were no deaths during the CHERISH trial.
## Nusinersen may be more effective if administered early
Subgroup analyses from ENDEAR and CHERISH showed that nusinersen may result in a more prolonged survival and greater motor milestone results in patients with 12 weeks or less disease duration. Also, interim results from the NURTURE trial suggest that nusinersen has a benefit in people with pre-symptomatic SMA. However, the size of the benefit in this patient group has not been established compared with benefits seen in people with symptomatic SMA (that is, in ENDEAR and CHERISH). Also, these results were based on ad-hoc subgroup analyses that may not have been powered sufficiently or on interim study results. The committee also noted that the results on the use of nusinersen in people with pre-symptomatic SMA were not examined in economic analyses. However, it was encouraged by the potential of nusinersen to be used earlier, and suggested that the group of people with pre-symptomatic SMA should be included within the managed access agreement and further data collected.
## Long-term benefits with nusinersen are uncertain
The committee noted that both ENDEAR and CHERISH had short follow-up periods: ENDEAR had a follow-up of only 13 months, 16% of people having nusinersen and 39% of those having sham died; CHERISH had a follow-up of only 15 months, and there were no deaths. It heard from the clinical experts that there was considerable uncertainty surrounding the long-term benefits of nusinersen, although consultation comments indicated that there is no biological mechanism that would suggest that nusinersen would become less effective over time. However, it is possible that some people with SMA may not reach motor function milestones despite having nusinersen, and it is unclear what the relationship is between improvements in motor function and a long-term survival benefit. The ERG considered that this was a source of substantial uncertainty in the clinical evidence base. In addition to the trial evidence, the company submitted interim data from the SHINE extension study for early-onset SMA, which had a follow-up period up to around 2.5 years for a few people. The ERG noted that a few people having nusinersen had a first response at later assessment points, including as late as 2.2 years. This showed that there may be a delayed response to nusinersen for some people. The committee considered that the results from SHINE showed that there are improvements in motor function with nusinersen, which were maintained or improved for up to 2.0 years. It noted that nusinersen is expected to be used for decades for those with later-onset SMA, when life expectancy is likely to be longer than for early-onset SMA, so these results did not show what the long-term survival benefits might be. The committee concluded that, although nusinersen would likely provide long-term benefits, the size and nature of these benefits were uncertain.
## All relevant clinical evidence is considered
Following consultation, the committee heard that there was real-world evidence that would be relevant for the committee's decision making that had not been considered by the company. The company stated that this was because the results were consistent with the clinical data that it had presented and, in comparison, the data were immature, would be from non-UK sources and would only include SMA type 1. The committee stated that it would have liked the company to identify supportive real-world evidence, given the clinical uncertainties identified. However, it considered a wide range of evidence, including:
that presented during consultation (that is, the testimony of parents, carers and clinical experts)
interim results from the NURTURE trial in patients who were pre-symptomatic submitted by the company (see section 3.10)
supplementary evidence on nusinersen use in the UK and Ireland in early-onset SMA as part of the Expanded Access Programme
newly published data on the use of nusinersen in patients with later-onset SMA (from study CS2 and study CS12)
newly published data on the use of nusinersen in patients with early-onset (type 1) SMA (from study CS3A).The committee concluded that it had considered a wide range of clinical evidence and this was taken into consideration within its final decision (see section 3.29 and section 3.30).
# The company's economic model
## The company's economic models are overly complex and cannot reflect the proposed stopping rule
The company presented 2 separate models: an early-onset model, for type 1 SMA (with a cohort age of 5.58 months) and a later-onset model, for types 2 and 3 SMA (with a cohort age of 43.71 months). Both models compared nusinersen with standard care, and transitions through health states were based on assessments of motor milestones using HINE‑2 for early-onset SMA, and HFMSE and World Health Organization criteria for later-onset SMA. Although the model structure was based solely on motor milestones, the ERG explained that motor function was not the only factor affecting health-related quality of life; factors such as participating in activities, respiratory function, pain and physical impairment were also important. There were several iterations of the economic models and the model structures for all of them were overly complex. This led to difficulties in making any structural changes and, for the ERG, in checking the models and in understanding the underlying logic. The committee acknowledged that the model structure was consistent with the main outcomes of the clinical trials, but would have preferred a simpler model. Furthermore, the final versions of the models were structurally unable to accurately reflect the company's proposed stopping rules within their proposed data collection plans (including 2 consecutive 'worsenings'; see section 3.22). The committee concluded that the complexity of the model prevented a thorough understanding of its functioning and added to uncertainty in estimates of cost effectiveness.
## The use of a plateau is clinically plausible but the incremental cost-effectiveness ratio (ICER) is sensitive to the assumptions related to the plateau
Previously, the committee had concluded the company had substantially overestimated the proportion of people who would reach the best health states while on nusinersen because the models assumed that those who remained on treatment would continue to improve indefinitely. The company's final iteration of the early-onset model included an option for patients to plateau while remaining on treatment, resulting in a more plausible proportion of patients who could reach the best health states. This occurred at 2 timepoints: 54 months (4.5 years) and 66 months (5.5 years) for the early-onset model and 15 months and 27 months for the later-onset model. This assumption was based on clinical expert opinion that people taking nusinersen who have not reached the ability to stand by 5 years or 6 years or have not reached the ability to walk before their sixth or seventh birthday would be unlikely to have gained these abilities. The ERG's clinical adviser agreed with the company's clinical adviser. However, the ERG noted that the assumptions related to the plateau (time at which the plateau was applied and whether people who plateau subsequently worsen) were key drivers in the model. The committee concluded that the addition of the plateau submodel and the assumptions about when patients plateau were both clinically plausible. However, it noted the uncertainty around cost-effectiveness estimates related to a lack of robust evidence on these parameters.
## The company's transition probabilities are generally clinically plausible but highly uncertain
The company's final version of both models assumed that patients considered 'improvers' can only lose treatment benefit and stop at the 2 timepoints during which patients were in the plateau state of the model (see section 3.14). The ERG was concerned with the removal of the ability to model worsening at other timepoints because people in clinical practice may worsen at any time. Additionally, the company's models assumed that improvers could worsen but remain as improvers and on treatment. This was because the company noted that some patients in the trial appeared to improve after an episode of worsening. The ERG noted that this assumption was a key driver in the early-onset model. Additionally, the early-onset model was sensitive to the extent to which people walk unaided. However, the ERG noted that there was evidence showing that, very occasionally, people reach this milestone. The ERG noted that the latest version of the later-onset model included an assumption that some patients in the model would lose the ability to sit without support. While the ERG's clinical adviser considered this to be a reasonable assumption, the ERG noted that this was not based on the available trial evidence and that this was a key driver in the model. Despite the complexity of the model, the ERG noted that the latest iteration of the models was, unlike earlier iterations, based on more clinically plausible assumptions. The committee concluded that the company's approach to applying transition probabilities was generally reasonable and clinically plausible, but that there was a high level of uncertainty given the sparsity of evidence.
## The modelled long-term overall survival benefit is highly uncertain
The company presented simpler and more conservative assumptions related to survival for both models than earlier iterations of the models. For both the early- and late-onset models, the company applied a mortality adjustment factor to the nusinersen group. A factor of 0.75, based on clinical opinion, was applied to the best health states so that people in those health states were attributed to 75% of the improved survival probability and 25% of the worst survival probability. However, the ERG noted that the company's clinical advisers had suggested a wide range of adjustment factors (0.5 to 1.0), indicating a high degree of uncertainty. The ERG also noted that the company's approach to estimating the proportion of mortality risk from 2 separate survival functions was unconventional. In the extrapolation period of the early-onset model, the hazard ratio from the trial was tapered for 120 months. The ERG noted that it was not clear why this length of time was chosen, and also noted that the use of a hazard ratio with tapering was inconsistent with the assumption of proportional hazards. The ERG's clinical adviser felt that the overall mean survival estimates from the model for both groups (8.50 years with nusinersen versus 2.14 years with best supportive care in the early-onset model and 38.50 years with nusinersen versus 36.70 years with best supportive care in the later-onset group) were reasonable and may even have been underestimates. The adviser suggested that there may be an initial higher mortality rate but that it may lower and flatten out. Overall, the ERG considered the company's assumptions were more conservative than previous iterations of the models, but were still associated with substantial uncertainty. They noted that the overall survival gain for the early-onset model was a key driver of the results. The committee recalled the overall survival gain with nusinersen for early-onset SMA seen in clinical trials, and heard that this gain had also been seen in clinical practice. The clinical expert explained that nusinersen may help to preserve respiratory muscle function, so it would be reasonable to predict a longer-term survival benefit. The committee concluded that the long-term benefits of nusinersen were highly uncertain (see section 3.11).
## Utility values in the economic model are highly uncertain and may not have captured all the benefits of using nusinersen
The committee recognised that identifying robust utility values in babies and young children is exceptionally challenging. The most recent version of the models used patient utilities that were mainly generated by the company from their clinical advisers. The ERG considered this the most appropriate approach, given the issues with existing preference-based utility estimates, which have limited face validity. However, the ERG noted that the utility estimates should be considered cautiously because they are not based on formal elicitation methods, may be different if other clinicians valued the health states and may not accurately reflect the view of people with SMA or their carers. Patient and clinical experts noted concerns that the health states appeared to be valued based on motor function, but that this may not have captured other benefits of gaining specific motor skills, such as independence or the ability to self-care. The ERG noted that it was difficult to understand what clinicians were valuing without seeing the questions asked to the company's clinical advisers. Patient and clinical experts also commented that the difference in utilities between some health states were small and may not have captured the added benefit of particular motor skills such as learning to write or being able to go through the education system. The committee reiterated that identifying robust utility values in babies and young children is exceptionally challenging and considered that none of the available sources of patient utilities were ideal. It concluded that all utility values in the economic model were therefore highly uncertain. The committee agreed that utilities may not have captured the added benefits of gaining particular motor skills.
## Including carer-related utilities is important but difficult to quantify
The carer-related utilities used by the company assumed that the best health state was associated with general population utility, and the worst health state was the average carer utility from a literature source, with equal transitions between the 2 points for each health state. In addition, the company's early-onset model assumed 3 carers would be affected, whereas the later-onset model assumed 2 carers would be affected (except for the worst health state, which assumed 3 carers). However, the ERG noted that the estimates of carer burden used in the model should be treated with caution because most were driven by assumptions rather than by evidence. The committee noted that the inclusion of carers increased the ICER substantially in the early-onset model but decreased the ICER in the later-onset model. The ERG noted that this effect in the early-onset model was because of improved survival and removal of the quality-adjusted life year (QALY) gain derived by carers when a patient dies and no longer needs caring for (this is not as much of an issue in the later-onset model because patients are assumed to live longer). Patient experts noted that this seemed perverse because it made a life-extending treatment appear to be less cost effective. The committee recalled that SMA has a substantial impact on carers and families as well as patients, and can affect multiple members of the extended family (see section 3.3). It therefore considered that including carer disutility in its decision making was appropriate. However, it considered that it was extremely difficult to estimate the size of any disutility. Carer utility was 1 of the key drivers of the results for both models. The committee concluded that it should consider carer utility in its decision making but that quantifying carer-related utility was extremely difficult.
## The cost of living with SMA is very uncertain
At consultation, many comments were received stating that the costs of living with SMA were substantially underestimated. In response, the company used a substantially higher estimate from a real-world evidence survey that was cited, but not described, in their original submission. The company estimated the cost of living with SMA from a survey of 9 paediatric neurology centres. Because some centres only deliver outpatient care and the standard of care is evolving rapidly, the company chose to include only 2 of the largest centres to more accurately capture the true costs. Although these costs were substantially higher, they only incorporated costs incurred within a hospital and may still have underestimated total care costs. The committee heard many compelling examples of the financial burden of living with SMA from the patient experts, which would not have been captured by the survey. Many of the costs described by the patient experts would be within the NICE reference case and should have been included. The company's expert advisers considered that the company estimates were still a substantial underestimation of the costs of living with SMA, so the company explored doubling the costs in a scenario analysis. The ERG clinical advisers felt that doubling the costs still substantially underestimated the costs, so it explored this further in scenario analyses with higher costs. The committee noted that healthcare costs were a key driver in the later-onset model. It also acknowledged the difficulty of estimating healthcare costs and concluded that the results were very uncertain.
# Results of the cost-effectiveness analysis
## The uncertainty in the cost-effectiveness estimates needs to be considered in the decision making
The cost-effectiveness estimates presented for early-onset and later-onset SMA are above the range normally considered cost effective by NICE. The committee struggled to reconcile the difference in the cost-effectiveness estimates across the 2 populations, in particular when considering the associated QALY gains for each population, and that the models suggested it would be more cost effective to treat the later-onset rather than the early-onset population. The committee agreed it was likely that the existing clinical- and cost-effectiveness evidence may not have fully captured the effects of treatment. The committee could not be certain whether differences in the estimates of cost effectiveness were because of the models or the uncertainties related to the natural history of SMA, or truly represented differences in cost effectiveness between disease subtypes. In addition, the committee heard from the clinical and patient experts that, while the natural history of SMA types 1, 2 and 3 is different, the progression in individual patients cannot be predicted with certainty at diagnosis because the severity and attainment of motor performance in these groups is more on a continuum than distinctly separate in each group. The committee concluded that these uncertainties should be taken into consideration in the decision making.
## Many parameters, when changed, reduce the ICER for 1 population but increase it in the other
The committee recalled that several of the parameters, when changed, fresulted in an opposite impact on the ICER for the 2 populations (early-onset and late-onset SMA; for 1 example, see section 3.18). Additionally, the committee noted that using higher resource costs (see section 3.19) increased the ICER for the early-onset model (because of increased management costs for longer survivors), but it reduced the ICER for the later-onset model (because more patients reached higher milestones that are associated with lower annual management costs). The committee recalled that the resource costs were likely to be underestimated (see section 3.19), and increasing them further made this inconsistency larger. The committee was concerned about the inconsistent results between models because symptoms and motor attainment or ability are on a continuum and it is difficult to divide individual patients into different SMA types distinctly (see section 3.2). The committee recalled that SMA type is defined based on the age of onset and this predicted the maximum motor function reached. It also recalled that the boundaries between the different SMA classification levels are blurred and can be subjective. In addition, individuals may have better or worse clinical courses compared with that predicted based on age of onset of muscle weakness. It was more cautious about relying on the outputs of the models as a robust basis for decision making because of the inconsistent effect of modifying parameters between the 2 models.
# Other factors
## A managed access agreement has been proposed by the company
The committee noted that the company has engaged with NHS England, stakeholders and NICE to develop a managed access agreement for nusinersen. It was proposed that the agreement should last 5 years with at least 3 years' data collected for analysis, and include defined criteria for starting and stopping nusinersen, and for monitoring and data collection requirements:
Eligibility criteria:
people with early- (type 1) or later-onset (types 2 and 3) SMA, and people with pre-symptomatic SMA with homozygous gene deletion or homozygous mutation or compound heterozygous mutation of the SMN1 gene (chromosome 5) found via pre-symptomatic genetic testing
must not have type 4 SMA, that is, must not have symptom onset at or after 19 years of age
must not have type 0 SMA
intrathecal injection must be technically feasible in the opinion of the treating clinician and not contraindicated
no permanent ventilation (16 or more hours per day for 21 consecutive days in the absence of acute reversible infection) or tracheostomy requirement at baseline
must not have had spinal fusion surgery after a diagnosis of scoliosis that, in the opinion of the treating clinician, prohibits safe administration of nusinersen
must not have severe contractures that, in the opinion of the treating clinician, prohibit measurement of motor milestones
if independent ambulation is gained before starting therapy patients must still be independently ambulant, with the exception of paediatric patients who have lost independent ambulation in the previous 12 months.
Stopping criteria:
permanent ventilation (16 or more hours per day for 21 consecutive days in the absence of acute reversible infection) or requirement of insertion of permanent tracheostomy
total worsening in motor function scale scores corroborated by 2 consecutive measures (decline of greater than 2 on horizontal kick or 1 on other HINE scores excluding voluntary grasp, decline of greater than 4 points on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale or decline of greater than 3 points on the Revised Hammersmith Scale)
inability to administer nusinersen by intrathecal administration because of spinal fusion surgery
inability to regain ambulation within 12 months of nusinersen initiation in paediatric patients who have lost ambulation in the previous 12 months and who have been initiated on nusinersen
failure, non-compliance (does not have a maintenance dose without rescheduling) or unforeseen worsening of disease.
Data collection:
clinical data will be collected using the SMA REACH database
patient-reported outcome measures of quality-of-life data, activities of daily living, and indirect resource costs for both patients and carers will be collected using a specially developed tool delivered through a bespoke device
healthcare costs related to treatment of SMA will be collected through surveys annually or biannually.All 3 types of data will be matched using pseudoanonymisation to enable analysis.
## A managed access agreement has the potential to address uncertainties
The committee agreed that data from using nusinersen in clinical practice collected through a managed access agreement may be useful to address uncertainties in the evidence. It also acknowledged the need to manage risks associated with the identified uncertainties. It considered the details of the company's proposed eligibility criteria in the managed access agreement and concluded that they were clinically achievable. Patient and clinical experts considered that the eligibility criteria were broadly appropriate. However, they highlighted that advances in scoliosis surgery mean that people who have had the procedure should not be automatically ineligible for nusinersen, provided administration is technically feasible. The committee was aware that patients with later-onset SMA who had gained independent ambulation would still need to be ambulant to have nusinersen. It noted that there was little trial evidence in patients with later-onset disease who had achieved ambulation because the CHERISH trial required that patients never had the ability to walk independently. The clinical benefit in this group of patients was therefore uncertain and estimates of cost effectiveness not calculated. The committee was aware that the managed access agreement starting and stopping criteria included meeting certain motor milestones. The committee considered this could have an adverse impact on people who had, or developed, a disability unrelated to SMA. The committee concluded that if a disability unrelated to SMA disease impacts the measurement of a starting or stopping criterion, the criterion should be ignored. The committee considered that the data collection proposed by the company would be useful, but was aware that collecting data can be burdensome on patients, family, carers and clinicians. The company highlighted that much of these data are already collected by SMA REACH, a wider clinical neuromuscular network that consists of doctors and physiotherapists working in specialist tertiary centres across the UK. The committee was supportive of adapting existing data collection schemes into a managed access agreement to reduce the potential logistical challenges. It considered that the proposed commercial agreement would reduce the risk to the NHS while the data were being collected. The committee recommended that data should be collected for a minimum 3 years, which could then be analysed and form the evidence for a review published in 5 years. The committee stressed the need for high-quality data to address the evidence gaps, and that the resource implications for data collection would be met by the company. It was also aware that data were being collected in other countries that had provided access to nusinersen, and emphasised that all available data should be provided at the time of a review. In particular, cooperation with other parts of the NHS (Scotland) should be explored to increase the available data.
## Nusinersen is the first disease-modifying therapy for SMA
The committee explored whether nusinersen could be considered innovative. The company explained that nusinersen has been recognised in several countries as the first treatment to address the cause and natural history of motor neurone degeneration in SMA. The committee recognised that nusinersen is an innovative treatment and the first disease-modifying therapy for SMA. However, the committee considered that the data presented did not suggest that there were distinct and substantial benefits relating to the innovative nature of nusinersen that had not been captured in the economic analyses.
## The nature of the eligible population and the disease was considered in the decision making
The committee noted that the population for which nusinersen is indicated includes children and young people. It considered that the fact that children are affected by the condition is reflected in the clinical evidence and model, and in its understanding of the nature of the condition. The committee was aware of the need to consider whether any adjustments to its normal considerations were needed. It discussed the need to balance the importance of improving the lives of children and their families with fairness to people of all ages. It noted NICE's social value judgements: principles for the development of NICE guidance, which emphasise the importance of considering the distribution of health resources fairly within society as a whole, as well as considering factors other than relative costs and benefits. The committee noted that, because of the burden of administration and ongoing nature of the treatment, not all parents and carers would choose to have treatment. The committee also acknowledged that the population eligible for nusinersen has serious disabilities. It acknowledged and considered the nature of the eligible population as part of its decision making and, in particular, the circumstances in which nusinersen could be recommended as a cost-effective treatment.
## The decision making takes into account the rarity and severity of the disease
Although nusinersen has several features that are commonly seen in NICE's highly specialised technologies programme, it was considered as a single technology appraisal. This was because the population covered by the marketing authorisation is larger than what can be considered in highly specialised technologies evaluations, and because SMA is not commissioned through a highly specialised service. The committee acknowledged the difficulty of appraising drugs for very rare conditions. When developing the social value judgements, the Citizens Council considered that rarity alone is not a mitigating factor for accepting high ICERs, and that the committee should consider taking into account other factors such as disease severity in its decision making. The committee was aware that SMA is both rare and a very serious condition. It also reflected on the benefits associated with nusinersen, and how they are highly valued by patients and families. The committee was mindful during its decision making of the need to consider whether any adjustments to its normal considerations were needed to take into account the rarity and severity of the disease.
# End of life
## It is reasonable to accept that nusinersen meets the short life-expectancy criterion for early-onset SMA
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that nusinersen met NICE's criteria for a life-extending treatment at the end of life in the early‑onset SMA population, but did not make a case for meeting the criteria in the later‑onset population. The committee accepted that nusinersen did not meet the end-of-life criteria in the later‑onset population because, although nusinersen may provide a survival benefit, life expectancy in children with later-onset SMA, this is likely to be well over 2 years. For early-onset SMA, the company noted that survival depends on the nature and extent of supportive care, which may vary by country, institution and physician, and the preferences of patients and families. The median age of death or permanent respiratory support in published natural history studies was 9 months to 13 months, and the median event-free survival in the control group of ENDEAR was 22.6 weeks. The ERG commented that low survival rates may not reflect current practice; some people with less severe early‑onset SMA may survive to school age. The ERG also commented that mean survival for people with early-onset SMA in the model having standard care was 2.14 years. The committee recognised that the life expectancy was uncertain, but considered it reasonable to accept that nusinersen could meet the short life-expectancy criterion for early‑onset SMA.
## It is likely that nusinersen extends life by more than 3 months
The committee recalled that the long-term survival is very uncertain (see section 3.16) but concluded it highly likely that nusinersen extends life by more than 3 months.
# Conclusion
## It is appropriate to be flexible when considering uncertainty
The committee carefully considered the advice about the acceptability of the technology as an effective use of NHS resources and factors influencing cost effectiveness in NICE's guide to the methods of technology appraisal. Specifically, it considered:
the degree of certainty around the ICER
whether there are strong reasons indicating that there are substantial benefits not captured by the model, including benefits to families and carers
the likelihood of decision error and its consequences
whether the technology meets criteria for special consideration.The committee recalled the many uncertainties in the clinical trial evidence, particularly concerning long-term benefits (see section 3.16). The very high cost of nusinersen means that there would be a substantial financial risk to the NHS if the committee was to recommend it for routine use when it may not be cost effective. The committee noted that the risk to the NHS is reduced through the proposed managed access agreement. It recalled that there were uncertain benefits, but it was unclear how this affected the cost effectiveness of nusinersen (see section 3.17). The committee was prepared to take into account a wide range of factors in its decision making, including the nature of the population (such as that it included children; see section 3.25), the rarity and severity of the disease (see section 3.26), and the considerable impact on families and carers. The committee concluded that it was willing to be flexible in its considerations around uncertainty, particularly if access could be managed such that the risk to the NHS was reduced.
## Nusinersen is recommended for treating SMA within the managed access agreement
The committee acknowledged that the cost-effectiveness estimates it had been presented with were above the range normally considered cost effective by NICE. However, it was mindful of many other factors it considered important to account for in its decision making. The committee concluded that nusinersen had demonstrated the potential to be cost effective, based on assumptions it considered clinically plausible and acceptable. It also recognised that there is evidence of benefit in early-onset and pre-symptomatic SMA (see section 3.7 and section 3.10). It also acknowledged the difficulty in distinguishing between SMA types (see section 3.2). However, the committee acknowledged that all the clinical- and cost-effectiveness evidence presented was subject to uncertainty, reflecting the lack of data. It accepted that more data were needed, and considered that the commercial agreement sufficiently manages the financial risk to the NHS. The committee took into consideration the consultation responses, views of parents, carers and clinical experts, and full consideration of available evidence. It concluded that nusinersen should be recommended as an option for treating pre-symptomatic and types 1, 2 and 3 SMA, for the duration of and within the conditions set out in the managed access agreement, when the company provides nusinersen with the confidential commercial terms agreed with NHS England. The managed access agreement oversight committee will consider any significant new evidence made available by Biogen in relation to patients with type 3 SMA who are non-ambulant type 3 that may impact the eligibility criteria of the managed access agreement.
|
{'Recommendations': 'Nusinersen is recommended as an option for treating 5q\xa0spinal muscular atrophy (SMA) only if:\n\npeople have pre-symptomatic SMA, or SMA types\xa01, 2\xa0or\xa03 and\n\nthe conditions in the managed access agreement are followed.\n\nWhy the committee made these recommendations\n\nSMA is a rare genetic condition, the most severe types of which affect babies and young children. Currently, there is an unmet need for effective treatments that could slow disease progression.\n\nClinical trial evidence shows that nusinersen improves a range of outcomes that are important to people with early- (type\xa01) and later-onset (types\xa02 and\xa03) SMA. Also, there is some evidence suggesting that nusinersen is effective for pre-symptomatic SMA. However, there is no long-term evidence, so the long-term benefits are highly uncertain. The committee considered that further data collection would help address these uncertainties.\n\nThe cost-effectiveness estimates presented are higher than what NICE usually considers a cost-effective use of NHS resources. However, these estimates are difficult to interpret because of the limited evidence base to substantiate longer-term benefits, the difficulty in clearly distinguishing between the SMA subtypes, and the difference in what can be achieved for these various patients without nusinersen.\n\nThe proposed managed access agreement details various risk management strategies, including patient selection, starting and stopping rules, data collection, patient consent, exit strategy and commercial offer. Taking these into account, nusinersen is recommended for people with pre-symptomatic SMA, or SMA types\xa01, 2\xa0or\xa03 if the conditions in the managed access agreement are followed, including the collection of more data to address the uncertainties. This recommendation will be reviewed based on data collected in the managed access arrangement. The review of the guidance will be published by the end of the fifth year.', 'Information about nusinersen': "Marketing authorisation indication\n\nNusinersen (Spinraza, Biogen Idec) has a marketing authorisation for 'the treatment of 5q\xa0spinal muscular atrophy'.\n\nDosage in the marketing authorisation\n\nmg, by intrathecal infusion, on days 0, 14, 28 and 63, then every 4\xa0months.\n\nPrice\n\nThe list price is £75,000 per vial (excluding VAT; BNF, accessed June 2018).\n\nAt the list price, the total annual treatment cost is £450,000 for the first year and £225,000 for subsequent years. Over 5\xa0years, the treatment costs per person would be £1.35 million.\n\nThe company has a commercial arrangement. This makes nusinersen available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Biogen Idec and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## Spinal muscular atrophy is a neuromuscular disorder; the most severe types affect babies and young children\n\nSpinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease caused by a genetic mutation in the SMN1 gene on chromosome\xa05q. People with the condition have a range of symptoms, including muscle weakness, and have worsening physical disability, mobility loss and respiratory dysfunction. SMA can be grouped into 5\xa0main types (types 0\xa0to\xa04), based on the age of onset and the maximum motor function reached. Type\xa00 SMA, the most severe, affects babies before birth. The babies do not develop any motor skills and often survive for only a few weeks after birth. Babies with SMA type\xa01 are unable to sit or roll because of severe muscle weakness, which gets worse over time. The muscle weakness also affects swallowing and breathing, and typically results in death within 2\xa0years. In type\xa02 SMA, the onset of symptoms is between 7\xa0months and 18\xa0months. People with this condition can sit independently at diagnosis. However, progressive loss of motor function means they have a reduced life expectancy compared with the general population. In type\xa03 SMA, there are varying degrees of muscle weakness, which appear between 18\xa0months and 18\xa0years. People with this condition can have a normal lifespan, and walk or sit unaided at some point, but many lose mobility over time. Type\xa04 SMA, the least severe, affects adults, who may have only mild motor impairment and live a normal lifespan. The clinical experts suggested that, of all diagnosed cases of SMA, around 60% are type\xa01 and around 40% are types\xa02 and\xa03; types\xa00 and\xa04 are rarely diagnosed. The committee acknowledged the extreme challenge that people with SMA experience every day, especially those with type\xa01. It concluded that the most severe types of SMA affect babies and young children.\n\n## The current SMA classification system is the best system available\n\nThe patient experts commented that the SMA classification system is useful but does not always reflect the full extent of the disease: boundaries between the different SMA classifications are blurred and can be subjective. The clinical experts accepted these limitations, but nevertheless acknowledged that the current classification system is the most accurate predictor of severity and prognosis available. The committee acknowledged the difficulties with current SMA classification but concluded that it was the best classification system available.\n\n## SMA severely affects the quality of life of patients, carers and their families\n\nThe clinical and patient experts explained that most people with SMA need constant support. This can include full-time care and attention, needing physical effort (such as lifting and carrying) and causing loss of sleep for patients and carers, stress, and fear at loss of abilities. All these factors have a major effect on family members' health-related quality of life. The committee heard from parents and carers that living with the condition involves daily care, exercises and constant vigilance (especially at night, when people with SMA need assistance in bed). SMA also causes anxiety, emotional distress and disruption to work and family finances, as well as straining relationships. Following consultation, the committee heard from patient experts that SMA often has a major impact on the quality of life of multiple members of an extended family, with grandparents, siblings and family friends often severely affected. The committee concluded that SMA has a substantial effect on the quality of life of patients, carers and their families.\n\n# Current treatments\n\n## There is an unmet need for an effective treatment\n\nThere are no disease-modifying therapies for SMA. Current treatments are based on symptom control and aim to maintain movement and function for as long as possible and to improve quality of life. This involves a multidisciplinary approach including respiratory, gastroenterology and orthopaedic care, as well as nutritional support, physiotherapy, assistive technologies, occupational therapy and social care. However, the clinical and patient experts emphasised that current treatments do not affect disease progression, so people with SMA will ultimately become totally dependent on their families and carers. The committee recognised that treatment options are limited and there is an unmet need for people with SMA.\n\n# The technology\n\n## Nusinersen has a marketing authorisation for all types of SMA but the company only presented clinical evidence for pre-symptomatic SMA and symptomatic SMA types\xa01 to\xa03\n\nNusinersen has a marketing authorisation for all types of SMA. The clinical experts agreed that it may benefit people with any type of SMA. However, they considered that it may have a relatively greater benefit for those with more severe types of SMA (although using nusinersen in type\xa00 SMA might be futile because of the degree of established damage at the time treatment could be started). The committee heard that the presence of SMN2 can compensate for the SMN1 deletion to some degree because it is a similar gene, and that the number of SMN2 gene copies is inversely related to the severity of SMA and can be used to predict the course of the disease. However, the clinical experts stated that gene testing may lead to delays in starting treatment. The experts considered that the correlation between copy number and disease severity is much less reliable than the clinical classification system in identifying the likely course of SMA. The committee acknowledged that nusinersen should be considered within its marketing authorisation (that is, for all types of SMA). However, the company only presented clinical evidence for pre-symptomatic SMA and symptomatic SMA types\xa01,\xa02 and\xa03, so restricted its recommendations to these types of SMA (excluding type\xa00 and type\xa04).\n\n# Clinical trial evidence\n\n## Evidence from the clinical trials, including ENDEAR and CHERISH, is uncertain but relevant for decision making\n\nThe main clinical-effectiveness evidence for nusinersen came from 2\xa0clinical trials:\n\nENDEAR, a randomised, double-blind, multicentre (including the UK), phase\xa0III, sham, procedure-controlled trial. The trial recruited 122\xa0children who developed SMA symptoms between 2\xa0weeks and 6\xa0months, which corresponds to type\xa01 SMA (described by the company as 'early-onset' SMA).\n\nCHERISH, a randomised, double-blind, multicentre, phase III, sham, procedure-controlled trial. The trial recruited 126\xa0patients who developed SMA symptoms between 6\xa0months and 12\xa0years and who were able to sit independently but never had the ability to walk independently. This corresponds with type\xa02 SMA and the more severe presentations of type\xa03 SMA (described by the company as 'later-onset' SMA).There are also 3\xa0ongoing studies: NURTURE, a phase\xa0II, single-arm study for pre-symptomatic infants genetically diagnosed with SMA; SHINE, which is a continuation of ENDEAR, CHERISH, CS12 and CS3A; and EMBRACE, for patients with SMA not eligible to participate in the clinical studies ENDEAR and CHERISH. The ERG considered that there were limitations in the clinical evidence. In particular, in ENDEAR, the nusinersen population had a poorer baseline prognosis than the control group and, in CHERISH, the strict entry criteria resulted in a more homogeneous population than would be expected in clinical practice. The ERG also explained that the dose regimen in CHERISH was not consistent with nusinersen's marketing authorisation because the maintenance doses were less frequent. Follow-up periods were relatively short for both ENDEAR and CHERISH, so the long-term benefits of nusinersen are unknown. The committee concluded that although the evidence had uncertainties, it was suitable for decision making.\n\n## Nusinersen improves survival and motor function for people with early‑onset SMA\n\nResults from ENDEAR showed that, compared with sham, nusinersen statistically significantly improved event-free survival, overall survival and motor function in patients with type\xa01 SMA:\n\nThe hazard ratio for event-free survival (defined as time to death or permanent ventilation) was 0.53 (95% confidence interval [CI] 0.32\xa0to\xa00.89; p=0.005).\n\nThe hazard ratio for overall survival was 0.37 (95%\xa0CI 0.18\xa0to\xa00.77; p=0.004).\n\nIn terms of motor function, 51% of patients in the nusinersen group reached motor milestone responses compared with none in the control group (as measured by a modified version of module\xa02 of the Hammersmith Infant Neurological Examination [HINE‑2]).Based on the strength of the motor benefit shown, ENDEAR was stopped early. The committee agreed that the trial showed a substantial benefit in survival for nusinersen compared with sham. Data from SHINE appeared to show that patients having nusinersen in both ENDEAR and SHINE had improved outcomes in terms of time to death or permanent ventilation compared with patients who started nusinersen in SHINE.\n\n## Other health benefits of nusinersen for early‑onset SMA are less certain\n\nENDEAR measured other important outcomes at 6\xa0months including:\n\nOverall hospitalisation rate ratio was 0.759 (95%\xa0CI 0.55\xa0to\xa01.05; p=0.965).\n\nMean treatment difference (measured as least-squares mean) for the proportion of time spent hospitalised for respiratory reasons was −8.638% (95%\xa0CI −14.190\xa0to\xa0−3.086, p=0.0026).\n\nThe odds ratio for infants not needing ventilation started among infants who were not having ventilation support at baseline was 11.6 (95%\xa0CI 1.5\xa0to\xa092.1, p=0.021).\n\nThe rate ratio of respiratory events leading to hospitalisation and the mean treatment difference for the number of days needing ventilation support for 16\xa0hours or more per day were not statistically significant.The committee noted that nusinersen appeared to improve respiratory outcomes as measured by the hospitalisation rate. However, the results were not as substantial as those seen for survival, and some of the other respiratory outcomes were not statistically significant (see section\xa03.7). The committee considered it counterintuitive that an observed substantial survival benefit was not associated with a substantial benefit in other outcomes. The company noted at consultation that the trial was not powered to detect differences between the groups in respiratory outcomes, which would need a much larger cohort. The clinical experts noted that it is difficult to measure respiratory function in infants. They also explained that, although nusinersen would likely improve respiratory function, any improvements in motor function may in turn place greater stress on the respiratory system. Patient experts and consultees emphasised that the benefits of nusinersen seen in the trials and in clinical practice (which were not always measured) were valuable to patients and their families. They emphasised the importance of any stabilisation and even small improvement in symptoms, especially any improvement in motor function. The committee recognised that any improvements would be highly valued by people with SMA, and that nusinersen provides important health benefits for people with early-onset SMA. However, it concluded that the size of some of these benefits remained uncertain.\n\n## Nusinersen substantially improves motor function for people with later‑onset SMA but the effect on survival is unclear\n\nResults from CHERISH showed that, compared with sham, nusinersen statistically significantly improved motor function of children with later‑onset SMA. Motor function as measured by Hammersmith Functional Motor Scale-Expanded (HFMSE) had a least-squares mean difference of\xa04.9 (95%\xa0CI 3.1\xa0to\xa06.7; p<0.0000001). The committee agreed that nusinersen provides important health benefits for people with later‑onset SMA, but it was unclear how this affects survival because there were no deaths during the CHERISH trial.\n\n## Nusinersen may be more effective if administered early\n\nSubgroup analyses from ENDEAR and CHERISH showed that nusinersen may result in a more prolonged survival and greater motor milestone results in patients with 12\xa0weeks or less disease duration. Also, interim results from the NURTURE trial suggest that nusinersen has a benefit in people with pre-symptomatic SMA. However, the size of the benefit in this patient group has not been established compared with benefits seen in people with symptomatic SMA (that is, in ENDEAR and CHERISH). Also, these results were based on ad-hoc subgroup analyses that may not have been powered sufficiently or on interim study results. The committee also noted that the results on the use of nusinersen in people with pre-symptomatic SMA were not examined in economic analyses. However, it was encouraged by the potential of nusinersen to be used earlier, and suggested that the group of people with pre-symptomatic SMA should be included within the managed access agreement and further data collected.\n\n## Long-term benefits with nusinersen are uncertain\n\nThe committee noted that both ENDEAR and CHERISH had short follow-up periods: ENDEAR had a follow-up of only 13\xa0months, 16% of people having nusinersen and 39% of those having sham died; CHERISH had a follow-up of only 15\xa0months, and there were no deaths. It heard from the clinical experts that there was considerable uncertainty surrounding the long-term benefits of nusinersen, although consultation comments indicated that there is no biological mechanism that would suggest that nusinersen would become less effective over time. However, it is possible that some people with SMA may not reach motor function milestones despite having nusinersen, and it is unclear what the relationship is between improvements in motor function and a long-term survival benefit. The ERG considered that this was a source of substantial uncertainty in the clinical evidence base. In addition to the trial evidence, the company submitted interim data from the SHINE extension study for early-onset SMA, which had a follow-up period up to around 2.5\xa0years for a few people. The ERG noted that a few people having nusinersen had a first response at later assessment points, including as late as 2.2\xa0years. This showed that there may be a delayed response to nusinersen for some people. The committee considered that the results from SHINE showed that there are improvements in motor function with nusinersen, which were maintained or improved for up to 2.0\xa0years. It noted that nusinersen is expected to be used for decades for those with later-onset SMA, when life expectancy is likely to be longer than for early-onset SMA, so these results did not show what the long-term survival benefits might be. The committee concluded that, although nusinersen would likely provide long-term benefits, the size and nature of these benefits were uncertain.\n\n## All relevant clinical evidence is considered\n\nFollowing consultation, the committee heard that there was real-world evidence that would be relevant for the committee's decision making that had not been considered by the company. The company stated that this was because the results were consistent with the clinical data that it had presented and, in comparison, the data were immature, would be from non-UK sources and would only include SMA type\xa01. The committee stated that it would have liked the company to identify supportive real-world evidence, given the clinical uncertainties identified. However, it considered a wide range of evidence, including:\n\nthat presented during consultation (that is, the testimony of parents, carers and clinical experts)\n\ninterim results from the NURTURE trial in patients who were pre-symptomatic submitted by the company (see section\xa03.10)\n\nsupplementary evidence on nusinersen use in the UK and Ireland in early-onset SMA as part of the Expanded Access Programme\n\nnewly published data on the use of nusinersen in patients with later-onset SMA (from study CS2 and study CS12)\n\nnewly published data on the use of nusinersen in patients with early-onset (type\xa01) SMA (from study CS3A).The committee concluded that it had considered a wide range of clinical evidence and this was taken into consideration within its final decision (see section 3.29 and section\xa03.30).\n\n# The company's economic model\n\n## The company's economic models are overly complex and cannot reflect the proposed stopping rule\n\nThe company presented 2\xa0separate models: an early-onset model, for type\xa01 SMA (with a cohort age of 5.58\xa0months) and a later-onset model, for types\xa02 and\xa03 SMA (with a cohort age of 43.71\xa0months). Both models compared nusinersen with standard care, and transitions through health states were based on assessments of motor milestones using HINE‑2 for early-onset SMA, and HFMSE and World Health Organization criteria for later-onset SMA. Although the model structure was based solely on motor milestones, the ERG explained that motor function was not the only factor affecting health-related quality of life; factors such as participating in activities, respiratory function, pain and physical impairment were also important. There were several iterations of the economic models and the model structures for all of them were overly complex. This led to difficulties in making any structural changes and, for the ERG, in checking the models and in understanding the underlying logic. The committee acknowledged that the model structure was consistent with the main outcomes of the clinical trials, but would have preferred a simpler model. Furthermore, the final versions of the models were structurally unable to accurately reflect the company's proposed stopping rules within their proposed data collection plans (including 2\xa0consecutive 'worsenings'; see section\xa03.22). The committee concluded that the complexity of the model prevented a thorough understanding of its functioning and added to uncertainty in estimates of cost effectiveness.\n\n## The use of a plateau is clinically plausible but the incremental cost-effectiveness ratio (ICER) is sensitive to the assumptions related to the plateau\n\nPreviously, the committee had concluded the company had substantially overestimated the proportion of people who would reach the best health states while on nusinersen because the models assumed that those who remained on treatment would continue to improve indefinitely. The company's final iteration of the early-onset model included an option for patients to plateau while remaining on treatment, resulting in a more plausible proportion of patients who could reach the best health states. This occurred at 2\xa0timepoints: 54\xa0months (4.5\xa0years) and 66\xa0months (5.5\xa0years) for the early-onset model and 15\xa0months and 27\xa0months for the later-onset model. This assumption was based on clinical expert opinion that people taking nusinersen who have not reached the ability to stand by 5\xa0years or 6\xa0years or have not reached the ability to walk before their sixth or seventh birthday would be unlikely to have gained these abilities. The ERG's clinical adviser agreed with the company's clinical adviser. However, the ERG noted that the assumptions related to the plateau (time at which the plateau was applied and whether people who plateau subsequently worsen) were key drivers in the model. The committee concluded that the addition of the plateau submodel and the assumptions about when patients plateau were both clinically plausible. However, it noted the uncertainty around cost-effectiveness estimates related to a lack of robust evidence on these parameters.\n\n## The company's transition probabilities are generally clinically plausible but highly uncertain\n\nThe company's final version of both models assumed that patients considered 'improvers' can only lose treatment benefit and stop at the 2\xa0timepoints during which patients were in the plateau state of the model (see section\xa03.14). The ERG was concerned with the removal of the ability to model worsening at other timepoints because people in clinical practice may worsen at any time. Additionally, the company's models assumed that improvers could worsen but remain as improvers and on treatment. This was because the company noted that some patients in the trial appeared to improve after an episode of worsening. The ERG noted that this assumption was a key driver in the early-onset model. Additionally, the early-onset model was sensitive to the extent to which people walk unaided. However, the ERG noted that there was evidence showing that, very occasionally, people reach this milestone. The ERG noted that the latest version of the later-onset model included an assumption that some patients in the model would lose the ability to sit without support. While the ERG's clinical adviser considered this to be a reasonable assumption, the ERG noted that this was not based on the available trial evidence and that this was a key driver in the model. Despite the complexity of the model, the ERG noted that the latest iteration of the models was, unlike earlier iterations, based on more clinically plausible assumptions. The committee concluded that the company's approach to applying transition probabilities was generally reasonable and clinically plausible, but that there was a high level of uncertainty given the sparsity of evidence.\n\n## The modelled long-term overall survival benefit is highly uncertain\n\nThe company presented simpler and more conservative assumptions related to survival for both models than earlier iterations of the models. For both the early- and late-onset models, the company applied a mortality adjustment factor to the nusinersen group. A factor of 0.75, based on clinical opinion, was applied to the best health states so that people in those health states were attributed to 75% of the improved survival probability and 25% of the worst survival probability. However, the ERG noted that the company's clinical advisers had suggested a wide range of adjustment factors (0.5\xa0to\xa01.0), indicating a high degree of uncertainty. The ERG also noted that the company's approach to estimating the proportion of mortality risk from 2\xa0separate survival functions was unconventional. In the extrapolation period of the early-onset model, the hazard ratio from the trial was tapered for 120\xa0months. The ERG noted that it was not clear why this length of time was chosen, and also noted that the use of a hazard ratio with tapering was inconsistent with the assumption of proportional hazards. The ERG's clinical adviser felt that the overall mean survival estimates from the model for both groups (8.50\xa0years with nusinersen versus 2.14\xa0years with best supportive care in the early-onset model and 38.50\xa0years with nusinersen versus 36.70\xa0years with best supportive care in the later-onset group) were reasonable and may even have been underestimates. The adviser suggested that there may be an initial higher mortality rate but that it may lower and flatten out. Overall, the ERG considered the company's assumptions were more conservative than previous iterations of the models, but were still associated with substantial uncertainty. They noted that the overall survival gain for the early-onset model was a key driver of the results. The committee recalled the overall survival gain with nusinersen for early-onset SMA seen in clinical trials, and heard that this gain had also been seen in clinical practice. The clinical expert explained that nusinersen may help to preserve respiratory muscle function, so it would be reasonable to predict a longer-term survival benefit. The committee concluded that the long-term benefits of nusinersen were highly uncertain (see section\xa03.11).\n\n## Utility values in the economic model are highly uncertain and may not have captured all the benefits of using nusinersen\n\nThe committee recognised that identifying robust utility values in babies and young children is exceptionally challenging. The most recent version of the models used patient utilities that were mainly generated by the company from their clinical advisers. The ERG considered this the most appropriate approach, given the issues with existing preference-based utility estimates, which have limited face validity. However, the ERG noted that the utility estimates should be considered cautiously because they are not based on formal elicitation methods, may be different if other clinicians valued the health states and may not accurately reflect the view of people with SMA or their carers. Patient and clinical experts noted concerns that the health states appeared to be valued based on motor function, but that this may not have captured other benefits of gaining specific motor skills, such as independence or the ability to self-care. The ERG noted that it was difficult to understand what clinicians were valuing without seeing the questions asked to the company's clinical advisers. Patient and clinical experts also commented that the difference in utilities between some health states were small and may not have captured the added benefit of particular motor skills such as learning to write or being able to go through the education system. The committee reiterated that identifying robust utility values in babies and young children is exceptionally challenging and considered that none of the available sources of patient utilities were ideal. It concluded that all utility values in the economic model were therefore highly uncertain. The committee agreed that utilities may not have captured the added benefits of gaining particular motor skills.\n\n## Including carer-related utilities is important but difficult to quantify\n\nThe carer-related utilities used by the company assumed that the best health state was associated with general population utility, and the worst health state was the average carer utility from a literature source, with equal transitions between the 2\xa0points for each health state. In addition, the company's early-onset model assumed 3\xa0carers would be affected, whereas the later-onset model assumed 2\xa0carers would be affected (except for the worst health state, which assumed 3\xa0carers). However, the ERG noted that the estimates of carer burden used in the model should be treated with caution because most were driven by assumptions rather than by evidence. The committee noted that the inclusion of carers increased the ICER substantially in the early-onset model but decreased the ICER in the later-onset model. The ERG noted that this effect in the early-onset model was because of improved survival and removal of the quality-adjusted life year (QALY) gain derived by carers when a patient dies and no longer needs caring for (this is not as much of an issue in the later-onset model because patients are assumed to live longer). Patient experts noted that this seemed perverse because it made a life-extending treatment appear to be less cost effective. The committee recalled that SMA has a substantial impact on carers and families as well as patients, and can affect multiple members of the extended family (see section\xa03.3). It therefore considered that including carer disutility in its decision making was appropriate. However, it considered that it was extremely difficult to estimate the size of any disutility. Carer utility was 1\xa0of the key drivers of the results for both models. The committee concluded that it should consider carer utility in its decision making but that quantifying carer-related utility was extremely difficult.\n\n## The cost of living with SMA is very uncertain\n\nAt consultation, many comments were received stating that the costs of living with SMA were substantially underestimated. In response, the company used a substantially higher estimate from a real-world evidence survey that was cited, but not described, in their original submission. The company estimated the cost of living with SMA from a survey of 9\xa0paediatric neurology centres. Because some centres only deliver outpatient care and the standard of care is evolving rapidly, the company chose to include only 2\xa0of the largest centres to more accurately capture the true costs. Although these costs were substantially higher, they only incorporated costs incurred within a hospital and may still have underestimated total care costs. The committee heard many compelling examples of the financial burden of living with SMA from the patient experts, which would not have been captured by the survey. Many of the costs described by the patient experts would be within the NICE reference case and should have been included. The company's expert advisers considered that the company estimates were still a substantial underestimation of the costs of living with SMA, so the company explored doubling the costs in a scenario analysis. The ERG clinical advisers felt that doubling the costs still substantially underestimated the costs, so it explored this further in scenario analyses with higher costs. The committee noted that healthcare costs were a key driver in the later-onset model. It also acknowledged the difficulty of estimating healthcare costs and concluded that the results were very uncertain.\n\n# Results of the cost-effectiveness analysis\n\n## The uncertainty in the cost-effectiveness estimates needs to be considered in the decision making\n\nThe cost-effectiveness estimates presented for early-onset and later-onset SMA are above the range normally considered cost effective by NICE. The committee struggled to reconcile the difference in the cost-effectiveness estimates across the 2\xa0populations, in particular when considering the associated QALY gains for each population, and that the models suggested it would be more cost effective to treat the later-onset rather than the early-onset population. The committee agreed it was likely that the existing clinical- and cost-effectiveness evidence may not have fully captured the effects of treatment. The committee could not be certain whether differences in the estimates of cost effectiveness were because of the models or the uncertainties related to the natural history of SMA, or truly represented differences in cost effectiveness between disease subtypes. In addition, the committee heard from the clinical and patient experts that, while the natural history of SMA types\xa01, 2\xa0and\xa03 is different, the progression in individual patients cannot be predicted with certainty at diagnosis because the severity and attainment of motor performance in these groups is more on a continuum than distinctly separate in each group. The committee concluded that these uncertainties should be taken into consideration in the decision making.\n\n## Many parameters, when changed, reduce the ICER for 1\xa0population but increase it in the other\n\nThe committee recalled that several of the parameters, when changed, fresulted in an opposite impact on the ICER for the 2\xa0populations (early-onset and late-onset SMA; for 1\xa0example, see section\xa03.18). Additionally, the committee noted that using higher resource costs (see section\xa03.19) increased the ICER for the early-onset model (because of increased management costs for longer survivors), but it reduced the ICER for the later-onset model (because more patients reached higher milestones that are associated with lower annual management costs). The committee recalled that the resource costs were likely to be underestimated (see section\xa03.19), and increasing them further made this inconsistency larger. The committee was concerned about the inconsistent results between models because symptoms and motor attainment or ability are on a continuum and it is difficult to divide individual patients into different SMA types distinctly (see section\xa03.2). The committee recalled that SMA type is defined based on the age of onset and this predicted the maximum motor function reached. It also recalled that the boundaries between the different SMA classification levels are blurred and can be subjective. In addition, individuals may have better or worse clinical courses compared with that predicted based on age of onset of muscle weakness. It was more cautious about relying on the outputs of the models as a robust basis for decision making because of the inconsistent effect of modifying parameters between the 2\xa0models.\n\n# Other factors\n\n## A managed access agreement has been proposed by the company\n\nThe committee noted that the company has engaged with NHS England, stakeholders and NICE to develop a managed access agreement for nusinersen. It was proposed that the agreement should last 5\xa0years with at least 3\xa0years' data collected for analysis, and include defined criteria for starting and stopping nusinersen, and for monitoring and data collection requirements:\n\nEligibility criteria:\n\n\n\npeople with early- (type\xa01) or later-onset (types 2\xa0and\xa03) SMA, and people with pre-symptomatic SMA with homozygous gene deletion or homozygous mutation or compound heterozygous mutation of the SMN1 gene (chromosome\xa05) found via pre-symptomatic genetic testing\n\nmust not have type\xa04 SMA, that is, must not have symptom onset at or after 19\xa0years of age\n\nmust not have type\xa00 SMA\n\nintrathecal injection must be technically feasible in the opinion of the treating clinician and not contraindicated\n\nno permanent ventilation (16\xa0or more hours per day for 21\xa0consecutive days in the absence of acute reversible infection) or tracheostomy requirement at baseline\n\nmust not have had spinal fusion surgery after a diagnosis of scoliosis that, in the opinion of the treating clinician, prohibits safe administration of nusinersen\n\nmust not have severe contractures that, in the opinion of the treating clinician, prohibit measurement of motor milestones\n\nif independent ambulation is gained before starting therapy patients must still be independently ambulant, with the exception of paediatric patients who have lost independent ambulation in the previous 12\xa0months.\n\n\n\nStopping criteria:\n\n\n\npermanent ventilation (16\xa0or more hours per day for 21\xa0consecutive days in the absence of acute reversible infection) or requirement of insertion of permanent tracheostomy\n\ntotal worsening in motor function scale scores corroborated by 2\xa0consecutive measures (decline of greater than\xa02 on horizontal kick or 1\xa0on other HINE scores excluding voluntary grasp, decline of greater than\xa04 points on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale or decline of greater than\xa03 points on the Revised Hammersmith Scale)\n\ninability to administer nusinersen by intrathecal administration because of spinal fusion surgery\n\ninability to regain ambulation within 12\xa0months of nusinersen initiation in paediatric patients who have lost ambulation in the previous 12\xa0months and who have been initiated on nusinersen\n\nfailure, non-compliance (does not have a maintenance dose without rescheduling) or unforeseen worsening of disease.\n\n\n\nData collection:\n\n\n\nclinical data will be collected using the SMA REACH database\n\npatient-reported outcome measures of quality-of-life data, activities of daily living, and indirect resource costs for both patients and carers will be collected using a specially developed tool delivered through a bespoke device\n\nhealthcare costs related to treatment of SMA will be collected through surveys annually or biannually.All 3\xa0types of data will be matched using pseudoanonymisation to enable analysis.\n\n\n\n## A managed access agreement has the potential to address uncertainties\n\nThe committee agreed that data from using nusinersen in clinical practice collected through a managed access agreement may be useful to address uncertainties in the evidence. It also acknowledged the need to manage risks associated with the identified uncertainties. It considered the details of the company's proposed eligibility criteria in the managed access agreement and concluded that they were clinically achievable. Patient and clinical experts considered that the eligibility criteria were broadly appropriate. However, they highlighted that advances in scoliosis surgery mean that people who have had the procedure should not be automatically ineligible for nusinersen, provided administration is technically feasible. The committee was aware that patients with later-onset SMA who had gained independent ambulation would still need to be ambulant to have nusinersen. It noted that there was little trial evidence in patients with later-onset disease who had achieved ambulation because the CHERISH trial required that patients never had the ability to walk independently. The clinical benefit in this group of patients was therefore uncertain and estimates of cost effectiveness not calculated. The committee was aware that the managed access agreement starting and stopping criteria included meeting certain motor milestones. The committee considered this could have an adverse impact on people who had, or developed, a disability unrelated to SMA. The committee concluded that if a disability unrelated to SMA disease impacts the measurement of a starting or stopping criterion, the criterion should be ignored. The committee considered that the data collection proposed by the company would be useful, but was aware that collecting data can be burdensome on patients, family, carers and clinicians. The company highlighted that much of these data are already collected by SMA REACH, a wider clinical neuromuscular network that consists of doctors and physiotherapists working in specialist tertiary centres across the UK. The committee was supportive of adapting existing data collection schemes into a managed access agreement to reduce the potential logistical challenges. It considered that the proposed commercial agreement would reduce the risk to the NHS while the data were being collected. The committee recommended that data should be collected for a minimum 3\xa0years, which could then be analysed and form the evidence for a review published in 5\xa0years. The committee stressed the need for high-quality data to address the evidence gaps, and that the resource implications for data collection would be met by the company. It was also aware that data were being collected in other countries that had provided access to nusinersen, and emphasised that all available data should be provided at the time of a review. In particular, cooperation with other parts of the NHS (Scotland) should be explored to increase the available data.\n\n## Nusinersen is the first disease-modifying therapy for SMA\n\nThe committee explored whether nusinersen could be considered innovative. The company explained that nusinersen has been recognised in several countries as the first treatment to address the cause and natural history of motor neurone degeneration in SMA. The committee recognised that nusinersen is an innovative treatment and the first disease-modifying therapy for SMA. However, the committee considered that the data presented did not suggest that there were distinct and substantial benefits relating to the innovative nature of nusinersen that had not been captured in the economic analyses.\n\n## The nature of the eligible population and the disease was considered in the decision making\n\nThe committee noted that the population for which nusinersen is indicated includes children and young people. It considered that the fact that children are affected by the condition is reflected in the clinical evidence and model, and in its understanding of the nature of the condition. The committee was aware of the need to consider whether any adjustments to its normal considerations were needed. It discussed the need to balance the importance of improving the lives of children and their families with fairness to people of all ages. It noted NICE's social value judgements: principles for the development of NICE guidance, which emphasise the importance of considering the distribution of health resources fairly within society as a whole, as well as considering factors other than relative costs and benefits. The committee noted that, because of the burden of administration and ongoing nature of the treatment, not all parents and carers would choose to have treatment. The committee also acknowledged that the population eligible for nusinersen has serious disabilities. It acknowledged and considered the nature of the eligible population as part of its decision making and, in particular, the circumstances in which nusinersen could be recommended as a cost-effective treatment.\n\n## The decision making takes into account the rarity and severity of the disease\n\nAlthough nusinersen has several features that are commonly seen in NICE's highly specialised technologies programme, it was considered as a single technology appraisal. This was because the population covered by the marketing authorisation is larger than what can be considered in highly specialised technologies evaluations, and because SMA is not commissioned through a highly specialised service. The committee acknowledged the difficulty of appraising drugs for very rare conditions. When developing the social value judgements, the Citizens Council considered that rarity alone is not a mitigating factor for accepting high ICERs, and that the committee should consider taking into account other factors such as disease severity in its decision making. The committee was aware that SMA is both rare and a very serious condition. It also reflected on the benefits associated with nusinersen, and how they are highly valued by patients and families. The committee was mindful during its decision making of the need to consider whether any adjustments to its normal considerations were needed to take into account the rarity and severity of the disease.\n\n# End of life\n\n## It is reasonable to accept that nusinersen meets the short life-expectancy criterion for early-onset SMA\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that nusinersen met NICE's criteria for a life-extending treatment at the end of life in the early‑onset SMA population, but did not make a case for meeting the criteria in the later‑onset population. The committee accepted that nusinersen did not meet the end-of-life criteria in the later‑onset population because, although nusinersen may provide a survival benefit, life expectancy in children with later-onset SMA, this is likely to be well over 2\xa0years. For early-onset SMA, the company noted that survival depends on the nature and extent of supportive care, which may vary by country, institution and physician, and the preferences of patients and families. The median age of death or permanent respiratory support in published natural history studies was 9\xa0months to 13\xa0months, and the median event-free survival in the control group of ENDEAR was 22.6\xa0weeks. The ERG commented that low survival rates may not reflect current practice; some people with less severe early‑onset SMA may survive to school age. The ERG also commented that mean survival for people with early-onset SMA in the model having standard care was 2.14\xa0years. The committee recognised that the life expectancy was uncertain, but considered it reasonable to accept that nusinersen could meet the short life-expectancy criterion for early‑onset SMA.\n\n## It is likely that nusinersen extends life by more than 3\xa0months\n\nThe committee recalled that the long-term survival is very uncertain (see section\xa03.16) but concluded it highly likely that nusinersen extends life by more than 3\xa0months.\n\n# Conclusion\n\n## It is appropriate to be flexible when considering uncertainty\n\nThe committee carefully considered the advice about the acceptability of the technology as an effective use of NHS resources and factors influencing cost effectiveness in NICE's guide to the methods of technology appraisal. Specifically, it considered:\n\nthe degree of certainty around the ICER\n\nwhether there are strong reasons indicating that there are substantial benefits not captured by the model, including benefits to families and carers\n\nthe likelihood of decision error and its consequences\n\nwhether the technology meets criteria for special consideration.The committee recalled the many uncertainties in the clinical trial evidence, particularly concerning long-term benefits (see section\xa03.16). The very high cost of nusinersen means that there would be a substantial financial risk to the NHS if the committee was to recommend it for routine use when it may not be cost effective. The committee noted that the risk to the NHS is reduced through the proposed managed access agreement. It recalled that there were uncertain benefits, but it was unclear how this affected the cost effectiveness of nusinersen (see section\xa03.17). The committee was prepared to take into account a wide range of factors in its decision making, including the nature of the population (such as that it included children; see section\xa03.25), the rarity and severity of the disease (see section\xa03.26), and the considerable impact on families and carers. The committee concluded that it was willing to be flexible in its considerations around uncertainty, particularly if access could be managed such that the risk to the NHS was reduced.\n\n## Nusinersen is recommended for treating SMA within the managed access agreement\n\nThe committee acknowledged that the cost-effectiveness estimates it had been presented with were above the range normally considered cost effective by NICE. However, it was mindful of many other factors it considered important to account for in its decision making. The committee concluded that nusinersen had demonstrated the potential to be cost effective, based on assumptions it considered clinically plausible and acceptable. It also recognised that there is evidence of benefit in early-onset and pre-symptomatic SMA (see section\xa03.7 and section\xa03.10). It also acknowledged the difficulty in distinguishing between SMA types (see section\xa03.2). However, the committee acknowledged that all the clinical- and cost-effectiveness evidence presented was subject to uncertainty, reflecting the lack of data. It accepted that more data were needed, and considered that the commercial agreement sufficiently manages the financial risk to the NHS. The committee took into consideration the consultation responses, views of parents, carers and clinical experts, and full consideration of available evidence. It concluded that nusinersen should be recommended as an option for treating pre-symptomatic and types\xa01, 2\xa0and\xa03 SMA, for the duration of and within the conditions set out in the managed access agreement, when the company provides nusinersen with the confidential commercial terms agreed with NHS England. The managed access agreement\xa0oversight committee will consider any significant new evidence made available by Biogen in relation to patients with type\xa03 SMA who are non-ambulant type\xa03 that may impact the eligibility criteria of the managed access agreement."}
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https://www.nice.org.uk/guidance/ta588
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Evidence-based recommendations on nusinersen (Spinraza) for treating spinal muscular atrophy in children and adults.
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fff96709310acffc5f169f12c7e950f0b05c914b
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nice
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Blinatumomab for treating acute lymphoblastic leukaemia in remission with minimal residual disease activity
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Blinatumomab for treating acute lymphoblastic leukaemia in remission with minimal residual disease activity
Evidence-based recommendations on blinatumomab (Blincyto) for treating Philadelphia-chromosome-negative CD19-positive B-precursor acute lymphoblastic leukaemia in remission with minimal residual disease activity in adults.
# Recommendations
Blinatumomab is recommended as an option for treating Philadelphia-chromosome-negative CD19‑positive B‑precursor acute lymphoblastic leukaemia in adults with minimal residual disease (MRD) of at least 0.1%, only if:
the disease is in first complete remission and
the company provides blinatumomab according to the commercial arrangement.
This recommendation is not intended to affect treatment with blinatumomab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current treatment for acute lymphoblastic leukaemia that is in complete remission with MRD of at least 0.1% is continued chemotherapy followed by haematopoietic stem cell transplantation (HSCT) if possible. Some people with MRD can have HSCT without chemotherapy.
Evidence from 2 clinical studies suggests that blinatumomab may help increase the time people have without their disease relapsing and may lead to more disease being cured. But there are no data directly comparing blinatumomab with continued chemotherapy, with or without HSCT. This means that the exact size of the benefit of blinatumomab compared with continued chemotherapy is uncertain.
Blinatumomab meets the extension-to-life criterion, but not the short life-expectancy criterion. Therefore, blinatumomab does not meet NICE's criteria to be considered a life-extending treatment at the end of life.
There is some uncertainty about the cost effectiveness of blinatumomab compared with continued chemotherapy in people with acute lymphoblastic leukaemia with MRD because of the way survival curves are fitted to the clinical data in the new semi-Markov model. Also, there is no evidence presented about the cost effectiveness of blinatumomab in people with acute lymphoblastic leukaemia that is in second complete remission. Because no cost-effectiveness evidence for the second complete remission group is presented, no recommendation for this group can be made. However, all plausible cost-effectiveness estimates of blinatumomab compared with continued chemotherapy are within the range that NICE normally considers a cost-effective use of NHS resources. Therefore, blinatumomab is recommended for routine use in the NHS for people with Philadelphia-chromosome-negative CD19‑positive B‑precursor acute lymphoblastic leukaemia with MRD of at least 0.1% whose disease is in first complete remission.# Information about blinatumomab
Marketing authorisation indication
Blinatumomab (Blincyto, Amgen) is indicated as 'monotherapy for the treatment of adults with Philadelphia-chromosome-negative CD19 positive B‑precursor acute lymphoblastic leukaemia in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%'.
Dosage in the marketing authorisation
Blinatumomab is administered by continuous intravenous infusion delivered at a constant rate using an infusion pump. A single cycle of blinatumomab treatment comprises continuous intravenous infusion at a dose of 28 micrograms/day for 28 days, followed by a 14‑day treatment-free interval.
Price
The list price of blinatumomab is £2,017 per 38.5 microgram vial. The average cost of blinatumomab per cycle at the list price is £56,476 (company submission).
The company has a commercial arrangement. This makes blinatumomab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Amgen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with minimal residual disease B‑precursor acute lymphoblastic leukaemia would welcome a new treatment option to improve symptoms and the chance of survival
People with acute lymphoblastic leukaemia in remission with Philadelphia-chromosome-negative CD19‑positive B‑precursor disease, and with minimal residual disease (MRD) would welcome a new treatment option. MRD in this document refers to detectable MRD of at least 0.1%. Acute lymphoblastic leukaemia is a rare, rapidly progressing form of cancer of the white blood cells. Outcomes for adults with acute lymphoblastic leukaemia are poor. Common symptoms include fatigue, breathlessness, infections, bleeding, bruising, fever and sweating. Although in more than 80% of people with acute lymphoblastic leukaemia, the disease will achieve complete remission, in up to 44% of adults the disease is expected to relapse. Both patient and clinical experts explained that people with MRD experience symptoms, even if their disease is in remission, because they are often having treatment that has a lot of side effects. Although the degree of symptoms varies across patients, overall, they are not well and cannot work. The clinical experts noted that current treatment options (chemotherapy) are difficult for patients to tolerate and they could benefit from novel treatment options. Currently, no approved treatments exist specifically for MRD B‑precursor acute lymphoblastic leukaemia that is in haematological complete remission. The committee concluded that people with MRD B‑precursor acute lymphoblastic leukaemia would welcome a new treatment option that would improve symptoms and the chance of survival.
# Clinical management
## The clinical importance of MRD is clearly established
The committee considered the treatment pathway for B‑precursor acute lymphoblastic leukaemia. In the NHS, patients are monitored regularly for the presence of MRD during the 4 to 8 weeks after starting induction therapy when complete remission is first seen. The clinical experts explained that MRD status is a major predictive factor for patients whose disease is in haematological complete remission. MRD is a marker of chemotherapy resistance and is therefore a predictor of response to subsequent chemotherapy. They noted that there is no current therapy specifically to reduce MRD. The committee acknowledged that MRD is an important factor in predicting future treatment outcomes. It concluded that a treatment for MRD would be a valuable addition to the treatment pathway.
## Haematopoietic stem cell transplantation is important in achieving cure, the main aim of treatment
The clinical experts stated that the main treatment goal for people with acute lymphoblastic leukaemia is to achieve cure through sustained absence of MRD and maintained haematological complete remission. They explained that, in most people whose disease is cured, it is cured after haematopoietic stem cell transplantation (HSCT). However, the use of HSCT may vary based on a patient's fitness, donor availability and their personal preferences. The committee understood that the aim of treatment for B‑precursor acute lymphoblastic leukaemia is a cure. People with MRD may proceed to HSCT, but it is more likely to be successful in the absence of MRD. The committee concluded that HSCT has an important role in achieving a cure in people with acute lymphoblastic leukaemia.
## People with untreated MRD are likely to need subsequent treatment for relapse
The committee noted that people with MRD are at high risk of relapse. The clinical experts explained that, if the disease relapses, the treatment options are continued chemotherapy, inotuzumab ozogamicin or blinatumomab (see NICE technology appraisal guidance on inotuzumab ozogamicin for treating relapsed or refractory B-cell acute lymphoblastic leukaemia and blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia), although continued chemotherapy is now rarely used at this stage. They also said that it is unlikely that people would have blinatumomab for a relapse if they had previously had it for MRD. The committee concluded that people with untreated MRD are likely to need subsequent treatment for relapse, and blinatumomab is a relevant option at this stage.
## The definition and measurement of MRD is standardised
The clinical experts noted that MRD testing is standardised across treatment centres in England. One of the clinical experts stated that MRD presence is established across a quantifiable scale: at least 0.001% is the lowest end of detection possible with current technology. However, they noted that technology is rapidly progressing and there will be more sensitive technologies that will detect even smaller numbers of leukaemic cells in the future. The trial population presented by the company included MRD detected at a level of at least 0.1%. The committee was aware that the marketing authorisation applies to people with MRD of at least 0.1%; this is what is meant by MRD in this document. It agreed that MRD testing is standard practice and was aware it could only make recommendations within the marketing authorisation.
# Clinical evidence
## Blinatumomab is clinically effective but the lack of direct comparative trial data means the size of this benefit is still unclear
The clinical evidence for blinatumomab came from 2 single-arm studies (BLAST and MT103‑202). The committee understood that both studies included patients with acute lymphoblastic leukaemia in complete haematological remission with MRD. The company presented results from 116 patients from BLAST and 20 patients from MT103‑202 (see table 1). All patients had at least 1 blinatumomab infusion. At the August 2015 data cut, the median follow-up in BLAST was 18 months. The survival data were immature. The committee noted a plateau in the Kaplan–Meier curves for overall and relapse-free survival. However, it was aware there were very few patients still at risk in this part of the curves, and no events were recorded after 41 months and 35 months for overall and relapse-free survival respectively. The MT103‑202 study had a follow-up of about 4 years, included only 20 patients and did not record overall survival. The committee was concerned that the single-arm design of the studies meant that the results were potentially biased. It noted that there was no evidence on the effectiveness of blinatumomab directly compared with continued chemotherapy. As requested by the committee, in response to consultation, the company presented updated Kaplan–Meier graphs, using safety data from the latest data cut from June 2017. It presented overall survival data for people with Philadelphia‑chromosome‑negative, B‑precursor acute lymphoblastic leukaemia and presence of MRD whose disease is in first, second or third complete remission. The committee agreed the updated clinical data are more reliable than the original submission. It concluded that blinatumomab is clinically effective, but the lack of direct comparative data means the size of this benefit is still unclear.
Outcome
BLAST (n=116, August 2015 data cut, results presented for primary company analyses, which are not censored at haematopoietic stem cell transplantation)
MT103‑202 (n=20)
Complete minimal residual disease response rate in 1 cycle
n=88 (77.9%)
n=16 (80.0%)
Median overall survival
months (19.2 months, not estimable)
N/A
Overall survival at 18 months
% (95% confidence interval 55 to 73)
N/A
Median relapse-free survival
months (95% CI 12.3 to 35.2)
not estimable (at 1,550 days of follow-up)
Relapse-free survival
% (95% CI 44 to 62) at 18 months
% (N/A) at 5.9 years
## Blinatumomab can only be recommended within its marketing authorisation
Blinatumomab's marketing authorisation includes adult patients with acute lymphoblastic leukaemia in first or second complete remission and which is Philadelphia-chromosome-negative with MRD of at least 0.1%. The study population in BLAST was wider than the population outlined in the marketing authorisation. Although most patients had disease that was in first or second complete remission, it also included patients whose disease was in third complete remission. Also, it included patients with Philadelphia-chromosome-positive and Philadelphia-chromosome-negative disease. In the MT103‑202 study, all patients had disease that was in complete remission, but it also included both Philadelphia-chromosome-positive and negative disease. The committee concluded that it could only make recommendations within the population outlined in the marketing authorisation.
## The indirect comparison is appropriate but is not generalisable to the wider marketing authorisation population
The committee was aware that there were no data directly comparing blinatumomab with continued chemotherapy. The company therefore did an indirect comparison of blinatumomab and continued chemotherapy, which was used in the economic model. The comparator data came from Study 20120148, a retrospective study with data on patients with Philadelphia‑chromosome‑negative B‑precursor acute lymphoblastic leukaemia in complete haematological remission and MRD. The study collected data on overall and relapse-free survival but not on adverse effects. It was used as a matched control for BLAST. Because of differences between the populations in BLAST and the historical comparator, the company used a subset of the original study populations. The committee was aware that the population in the indirect comparison was narrower than the marketing authorisation and excluded the following groups:
patients who could not have HSCT or tolerate chemotherapy
patients whose disease is in second complete remission.The clinical experts suggested that survival outcomes for the excluded groups of people were poor and that they could potentially benefit from treatment with blinatumomab. This was because some patients who had blinatumomab have had good outcomes even without subsequently having HSCT. The committee concluded that the indirect comparison was appropriate, given the absence of randomised controlled trial data, but that the results are not generalisable to the full population outlined in the marketing authorisation.
## The indirect comparison method is appropriate but subject to uncertainty
The company used a propensity score model to compare the primary analysis set from BLAST and the direct comparator Study 20120148. This method produced weights that were applied to the control study (Study 20120148). The aim was to estimate the response to chemotherapy that would be expected in a population with the same characteristics as the population in the BLAST primary analysis set. The ERG noted that the chosen method of applying weights to balance the datasets was appropriate given the lack of randomised controlled trials. The company used 2 different methods to produce weights: 'average treatment effect' and 'average treatment effect on the treated'. For both methods, the company used stabilised and non-stabilised weights. It used stabilised weights to produce the average treatment effect on the treated estimates in the clinical effectiveness analysis. However, non-stabilised weights were used to produce the treatment effect on the treated estimates that were used in the cost-effectiveness analysis. As part of the clarification response, the company provided data to show that there was no substantial difference in the results produced from both methods of applying weights. The results are confidential and cannot be reported here. The committee concluded that the method used to compare the 2 studies was appropriate but subject to uncertainty.
# Cost-effectiveness model
## The company's original model was not suitable for decision making
The company's original model was a partitioned survival model based on relapse-free survival and overall survival, with 3 health states: (1) relapse free; (2) post relapse and (3) dead. The main partitioned survival structure had 2 linked sub-models that were intended to estimate additional costs and utility decrements associated with HSCT received before or after disease has relapsed. The pre-relapse sub-model was not causally related to relapse-free or overall survival, whereas the post-relapse sub-model was partially related to relapse-free survival. The ERG noted that the causal effect of transplant on outcome was not adequately modelled. The clinical experts also explained that MRD status highly correlates with HSCT outcomes: HSCT is less likely to be successful in people with MRD. However, the committee acknowledged that the model did not show how many patients with or without MRD have HSCT. The clinical expert further noted that there is unpublished but more mature and up-to-date data on survival outcomes after HSCT that could be included. The clinical experts highlighted that the original model was not reflective of current practice or the treatment pathway (see section 3.2). They clarified that the treatment pathway has recently changed and now includes NICE technology appraisal guidance on inotuzumab ozogamicin or blinatumomab for treating relapses (see section 3.4). The committee noted that while the model implicitly incorporated HSCT within the relapse-free survival and the overall survival curves, it did not show how many patients had HSCT. Without this direct link, it was not clear what proportion of patients had HSCT, and what their outcomes after HSCT were. Given the importance of HSCT to the likelihood of cure (see section 3.3), the committee was aware that this made it difficult to assess the reliability and clinical plausibility of the original model. At the first committee meeting, it concluded that it would have liked to have seen a cost-effectiveness model including:
a revised cost-effectiveness analysis reflecting the current treatment pathway in the NHS and comparing blinatumomab with continued chemotherapy. The revised economic model should:
include costs, health-related quality-of-life estimates and outcomes associated with the current treatment pathway for people with relapsed or refractory acute lymphoblastic leukaemia
include the proportion of people with and without MRD after blinatumomab treatment and how many have HSCT
incorporate an explicit causal link between the probability of HSCT and relapse-free survival and overall survival in both groups
explicitly model a cure for people whose disease is expected to be cured and include scenario analyses considering different cure fractions and cure points
factor in the different positions in the treatment pathway at which HSCT might be given.
the latest available evidence on survival outcomes after HSCT
the latest trial data cut.In response to consultation, the company submitted a new model (see section 3.13).
## The cure point assumption in the original model should be reconsidered because it is not clinically plausible
The company's original model did not have a fixed cure point. Instead, the model predicted the timepoint at which patients were assumed to be cured and had mortality rates similar to those of the general population with some additional excess mortality risk after a cure. This approach resulted in different cure points between the relapse-free survival and the overall survival extrapolations. The committee concluded that having a large gap between the resulting cure points (company model) is not clinically plausible. It was aware that the assumptions around the cure fraction or cure point were a key driver in the cost-effectiveness analysis. Therefore, at the first committee meeting, the committee concluded they would have liked to have seen a clinically plausible, explicitly modelled cure for the patients whose disease is expected to be cured. In response to consultation, the company submitted a new model with explicitly modelled cure states (see section 3.14).
# Health-related quality of life
## The company's post-relapse utility value is too high
The company used a post-relapse utility value of 0.69 in the model, which was lower than the one seen in the BLAST study (0.819). However, the ERG's clinical experts noted that both values are too high for relapsed patients and were not clinically plausible. The ERG ran exploratory analyses with lower utility values (0.50 and 0.25), which had a small effect on the incremental cost-effectiveness ratio (ICER). The committee concluded that the post-relapse quality-of-life estimates included in the company model were too high but were not a key driver of the results.
# Company's new cost-effectiveness evidence and revised base case
## The company submitted a revised partitioned survival model
In response to consultation, the company submitted a revised partitioned survival model, which used the same structure and parameters as the original model (see section 3.9). It included 3 key changes
inotuzumab ozogamicin is included as a salvage treatment for relapsed disease
the proportions of patients having blinatumomab or inotuzumab ozogamicin as salvage therapy for relapsed disease were estimated based on clinical expert opinion. In the continued chemotherapy arm, patients having first salvage therapy are split equally between blinatumomab and inotuzumab ozogamicin and
the cost calculations for blinatumomab as salvage therapy for relapsed disease have been amended.The revised partitioned survival model did not include the remaining amendments requested by the committee (see section 3.10). Therefore, the committee concluded that the revised partitioned survival model was not suitable for decision making.
## The new semi-Markov model submitted by the company is suitable for decision making
In response to consultation, the company also submitted a semi-Markov model. The model structure was comprised of 4 health states: first complete haematological remission (CR1); pre-relapse HSCT; relapse and dead. The model compares blinatumomab and continued chemotherapy, both followed by pre-relapse HSCT for some patients, followed by post-relapse salvage therapy using inotuzumab ozogamicin for the blinatumomab arm and either inotuzumab ozogamicin or blinatumomab for the continued chemotherapy arm. Most of the parameters used in the new semi-Markov model are the same as the ones used in the updated partitioned survival model. The new semi-Markov model produces outcomes that depend on treatment offered, MRD response and the patient's current health state. This leads to different results compared with the company's partitioned survival model. The ERG explained that the new semi-Markov model incorporates most of the assumptions preferred by the committee (see section 3.9), but it was also subject to certain limitations:
HSCT costs were applied to some patients who relapsed but were not related to downstream salvage treatment
there was a small number of events and patients at risk
the rationale for curve selection was not consistent
concerns about model-predicted relapse-free survival and overall survival (see section 3.17).The committee considered the new semi-Markov model and concluded that it was suitable for decision making.
## The most plausible cure point is likely to be below 5 years
The committee considered how the cure points are modelled in the new semi-Markov model. The ERG explained that the cure point is not fixed but defined in each cure state. People with acute lymphoblastic leukaemia who have pre-relapse HSCT have a cure point later than that applied to the CR1 state. The cure point for CR1 was 5 years. The cure point for patients entering the pre-relapse HSCT state was 5 years after entry into that state (that is, the time spent in CR1 plus 5 years). Patients who experienced relapse and did not die within 5 years of relapse were assumed to be cured 5 years after they entered the relapse state. These patients would have a cure point of more than 5 years but less than 15 years from entering the model. In this way, the model considered patients who remained relapse free and proceed to transplant to be cured at a later timepoint than those who remain relapse free but never proceed to HSCT. The clinical experts said that in clinical practice people with acute lymphoblastic leukaemia are considered cured if their disease has not relapsed within 2 years. The committee concluded that the cure point is likely to be less than 5 years and possibly 3 years would be most plausible.
## The new semi-Markov model uses an inappropriate method for handling competing risks
The company's new semi-Markov model faces an issue with competing risks. Competing risks happen when patients in the model can experience 1 or more events which 'compete' with the event of interest. The new semi-Markov model estimates each transition state by using patient time-to-event data, it then keeps events of interest and removes events not of interest. The ERG explained that this approach does not handle competing risks appropriately. Specifically, the problem with removing events not of interest is that it may lead to a pattern of removal that is not independent anymore. Because of this, the model estimates may be biased and inaccurate. The ERG believes that the company's approach is likely to have increased the risk of each event. The committee concluded that there is uncertainty in the model because of the method used for handling competing risks.
# Overall survival in the new semi-Markov model
## The overall survival extrapolations are subject to uncertainty
The committee considered the overall survival from the new semi-Markov model. The company presented a graph comparing the Kaplan–Meier curves from BLAST and the historical control and the new semi-Markov model predictions for overall survival including blinatumomab and inotuzumab ozogamicin as salvage treatments for relapsed disease. The company used data from the TOWER study (phase III, randomised study of blinatumomab compared with standard care in patients with acute lymphoblastic leukaemia) to inform the post-relapse survival estimation in the new semi-Markov model. The survival curves projected by the model fit the survival curves of the BLAST data and the historical control closely. The parametric curves estimated that the proportion of patients that would be relapse free at 5 years was 40.0% and 18.1% for blinatumomab and standard care, respectively. However, the ERG ran exploratory analyses and presented the same comparison but excluding blinatumomab and inotuzumab ozogamicin as salvage treatments for relapsed disease. The ERG used the restricted Gompertz overall survival function for the standard chemotherapy group after relapse fitted to data from TOWER to model overall survival for patients whose disease had relapsed. The results showed that the new semi-Markov model no longer gives a good fit to the Kaplan–Meier curves in either treatment group. The ERG explained that the predictions from this version of the model should match the Kaplan–Meier curves because both the parametric curves and the Kaplan–Meier data excludes blinatumomab and inotuzumab ozogamicin for treating relapsed disease. Instead, predicted overall survival was underestimated in both treatment groups, but more so in the standard chemotherapy comparator group. The clinical expert pointed out that if there is any benefit because of the newly introduced treatments, there should be an increase in overall survival curves for both blinatumomab and standard care. The committee concluded that the overall survival extrapolations in both arms were subject to uncertainty.
## The new semi-Markov model is appropriate for decision making but results are not generalisable to the full marketing authorisation
The company modelled the cost effectiveness of blinatumomab using data from BLAST, the historical control and TOWER. However, this did not include patients whose disease was in second complete remission. The committee recalled that this was a narrower population than the marketing authorisation (see section 3.9). At consultation, the company stated that there are few people with acute lymphoblastic leukaemia in second complete remission, and the number of people is declining and it should be included in committee's decision making. The committee considered all the evidence within the marketing authorisation. Because the committee did not see cost-effectiveness evidence on acute lymphoblastic leukaemia in second complete remission, it could not make recommendation for this indication. It further concluded that it could only make recommendations based on the evidence presented to it.
# Cost-effectiveness results
## Blinatumomab is cost effective compared with continued chemotherapy
The committee recalled its preferred assumptions (see section 3.9). The committee concluded that its preferred analysis would include a 3-year cure timepoint. Based on the ERG's exploratory analysis, the scenarios with a 3‑year cure point produce an ICER that falls between £21,874 and £25,551 per quality-adjusted life year (QALY) gained, although the committee were aware that there was uncertainty in these estimates. The ERG also reproduced the analyses to include the confidential commercial arrangement for inotuzumab ozogamicin, and the ICERs were within the range that NICE usually considered an acceptable use of NHS resources (the exact ICERs are confidential and cannot be reported here). The committee could make recommendation based only on the evidence presented. Because the committee did not see evidence on people with acute lymphoblastic leukaemia in second complete remission, it was unable to make a recommendation for this indication. Based on the evidence presented to it, the committee concluded the most plausible ICERs were within the range that NICE usually considers an acceptable use of NHS resources.
# Innovation
## Blinatumomab is innovative but there are no benefits not captured by the QALY
The committee considered blinatumomab to be innovative because it represents a step change in the treatment of CD19‑positive B‑precursor acute lymphoblastic leukaemia with presence of MRD. No evidence was presented to suggest that there were additional benefits that were not captured in the QALY calculations. The committee concluded that there were no benefits that would not be captured in the QALY calculations.
# End of life
## Blinatumomab does not meet the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that blinatumomab met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24 months). The company's new evidence was not substantially different from the initial evidence submitted. The committee considered the median and mean survival and the proportion of patients alive at 2 years for the continued chemotherapy arm from the company and the ERG's model. The clinical experts suggested that for patients with MRD, the proportion of people alive at 2 years would be around 20%. The committee noted all the estimates of life expectancy from clinical evidence and the model. It agreed that the mean estimates from the company's model were much longer than the median estimates. The mean and median survival outcomes are confidential and cannot be reported here. The committee concluded that overall the short life-expectancy criterion was not met. The committee also discussed whether a survival benefit of over 3 months can be expected for blinatumomab compared with continued chemotherapy. Based on all the evidence presented to it, the committee concluded that the extension-to-life criterion was met. The committee concluded that blinatumomab did not meet NICE's criteria for being considered a life-extending treatment at the end of life.
# Conclusion
## Blinatumomab is recommended for routine use for people with acute lymphoblastic leukaemia in first complete remission
The committee concluded that the most plausible ICERs for blinatumomab were within the range that NICE usually considers an acceptable use of NHS resources. Blinatumomab could not be considered an end-of-life treatment because the short life-expectancy criterion was not met. It also noted that blinatumomab is clinically effective. However, the committee did not see any evidence to assess cost effectiveness in the second complete remission population. Therefore, the committee recommended blinatumomab as an option for treating Philadelphia-chromosome-negative CD19‑positive B‑precursor acute lymphoblastic leukaemia in adults with MRD of at least 0.1%, only if:
the disease is in first complete remission and
the company provides blinatumomab according to the commercial arrangement.
|
{'Recommendations': "Blinatumomab is recommended as an option for treating Philadelphia-chromosome-negative CD19‑positive B‑precursor acute lymphoblastic leukaemia in adults with minimal residual disease (MRD) of at least 0.1%, only if:\n\nthe disease is in first complete remission and\n\nthe company provides blinatumomab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with blinatumomab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for acute lymphoblastic leukaemia that is in complete remission with MRD of at least 0.1% is continued chemotherapy followed by haematopoietic stem cell transplantation (HSCT) if possible. Some people with MRD can have HSCT without chemotherapy.\n\nEvidence from 2\xa0clinical studies suggests that blinatumomab may help increase the time people have without their disease relapsing and may lead to more disease being cured. But there are no data directly comparing blinatumomab with continued chemotherapy, with or without HSCT. This means that the exact size of the benefit of blinatumomab compared with continued chemotherapy is uncertain.\n\nBlinatumomab meets the extension-to-life criterion, but not the short life-expectancy criterion. Therefore, blinatumomab does not meet NICE's criteria to be considered a life-extending treatment at the end of life.\n\nThere is some uncertainty about the cost effectiveness of blinatumomab compared with continued chemotherapy in people with acute lymphoblastic leukaemia with MRD because of the way survival curves are fitted to the clinical data in the new semi-Markov model. Also, there is no evidence presented about the cost effectiveness of blinatumomab in people with acute lymphoblastic leukaemia that is in second complete remission. Because no cost-effectiveness evidence for the second complete remission group is presented, no recommendation for this group can be made. However, all plausible cost-effectiveness estimates of blinatumomab compared with continued chemotherapy are within the range that NICE normally considers a cost-effective use of NHS resources. Therefore, blinatumomab is recommended for routine use in the NHS for people with Philadelphia-chromosome-negative CD19‑positive B‑precursor acute lymphoblastic leukaemia with MRD of at least 0.1% whose disease is in first complete remission.", 'Information about blinatumomab': "Marketing authorisation indication\n\nBlinatumomab (Blincyto, Amgen) is indicated as 'monotherapy for the treatment of adults with Philadelphia-chromosome-negative CD19\xa0positive B‑precursor acute lymphoblastic leukaemia in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%'.\n\nDosage in the marketing authorisation\n\nBlinatumomab is administered by continuous intravenous infusion delivered at a constant rate using an infusion pump. A single cycle of blinatumomab treatment comprises continuous intravenous infusion at a dose of 28\xa0micrograms/day for 28\xa0days, followed by a 14‑day treatment-free interval.\n\nPrice\n\nThe list price of blinatumomab is £2,017 per 38.5\xa0microgram vial. The average cost of blinatumomab per cycle at the list price is £56,476 (company submission).\n\nThe company has a commercial arrangement. This makes blinatumomab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Amgen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with minimal residual disease B‑precursor acute lymphoblastic leukaemia would welcome a new treatment option to improve symptoms and the chance of survival\n\nPeople with acute lymphoblastic leukaemia in remission with Philadelphia-chromosome-negative CD19‑positive B‑precursor disease, and with minimal residual disease (MRD) would welcome a new treatment option. MRD in this document refers to detectable MRD of at least 0.1%. Acute lymphoblastic leukaemia is a rare, rapidly progressing form of cancer of the white blood cells. Outcomes for adults with acute lymphoblastic leukaemia are poor. Common symptoms include fatigue, breathlessness, infections, bleeding, bruising, fever and sweating. Although in more than 80% of people with acute lymphoblastic leukaemia, the disease will achieve complete remission, in up to 44% of adults the disease is expected to relapse. Both patient and clinical experts explained that people with MRD experience symptoms, even if their disease is in remission, because they are often having treatment that has a lot of side effects. Although the degree of symptoms varies across patients, overall, they are not well and cannot work. The clinical experts noted that current treatment options (chemotherapy) are difficult for patients to tolerate and they could benefit from novel treatment options. Currently, no approved treatments exist specifically for MRD B‑precursor acute lymphoblastic leukaemia that is in haematological complete remission. The committee concluded that people with MRD B‑precursor acute lymphoblastic leukaemia would welcome a new treatment option that would improve symptoms and the chance of survival.\n\n# Clinical management\n\n## The clinical importance of MRD is clearly established\n\nThe committee considered the treatment pathway for B‑precursor acute lymphoblastic leukaemia. In the NHS, patients are monitored regularly for the presence of MRD during the 4 to 8\xa0weeks after starting induction therapy when complete remission is first seen. The clinical experts explained that MRD status is a major predictive factor for patients whose disease is in haematological complete remission. MRD is a marker of chemotherapy resistance and is therefore a predictor of response to subsequent chemotherapy. They noted that there is no current therapy specifically to reduce MRD. The committee acknowledged that MRD is an important factor in predicting future treatment outcomes. It concluded that a treatment for MRD would be a valuable addition to the treatment pathway.\n\n## Haematopoietic stem cell transplantation is important in achieving cure, the main aim of treatment\n\nThe clinical experts stated that the main treatment goal for people with acute lymphoblastic leukaemia is to achieve cure through sustained absence of MRD and maintained haematological complete remission. They explained that, in most people whose disease is cured, it is cured after haematopoietic stem cell transplantation (HSCT). However, the use of HSCT may vary based on a patient's fitness, donor availability and their personal preferences. The committee understood that the aim of treatment for B‑precursor acute lymphoblastic leukaemia is a cure. People with MRD may proceed to HSCT, but it is more likely to be successful in the absence of MRD. The committee concluded that HSCT has an important role in achieving a cure in people with acute lymphoblastic leukaemia.\n\n## People with untreated MRD are likely to need subsequent treatment for relapse\n\nThe committee noted that people with MRD are at high risk of relapse. The clinical experts explained that, if the disease relapses, the treatment options are continued chemotherapy, inotuzumab ozogamicin or blinatumomab (see NICE technology appraisal guidance on inotuzumab ozogamicin for treating relapsed or refractory B-cell acute lymphoblastic leukaemia and blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia), although continued chemotherapy is now rarely used at this stage. They also said that it is unlikely that people would have blinatumomab for a relapse if they had previously had it for MRD. The committee concluded that people with untreated MRD are likely to need subsequent treatment for relapse, and blinatumomab is a relevant option at this stage.\n\n## The definition and measurement of MRD is standardised\n\nThe clinical experts noted that MRD testing is standardised across treatment centres in England. One of the clinical experts stated that MRD presence is established across a quantifiable scale: at least 0.001% is the lowest end of detection possible with current technology. However, they noted that technology is rapidly progressing and there will be more sensitive technologies that will detect even smaller numbers of leukaemic cells in the future. The trial population presented by the company included MRD detected at a level of at least 0.1%. The committee was aware that the marketing authorisation applies to people with MRD of at least 0.1%; this is what is meant by MRD in this document. It agreed that MRD testing is standard practice and was aware it could only make recommendations within the marketing authorisation.\n\n# Clinical evidence\n\n## Blinatumomab is clinically effective but the lack of direct comparative trial data means the size of this benefit is still unclear\n\nThe clinical evidence for blinatumomab came from 2\xa0single-arm studies (BLAST and MT103‑202). The committee understood that both studies included patients with acute lymphoblastic leukaemia in complete haematological remission with MRD. The company presented results from 116\xa0patients from BLAST and 20\xa0patients from MT103‑202 (see table\xa01). All patients had at least 1\xa0blinatumomab infusion. At the August 2015 data cut, the median follow-up in BLAST was 18\xa0months. The survival data were immature. The committee noted a plateau in the Kaplan–Meier curves for overall and relapse-free survival. However, it was aware there were very few patients still at risk in this part of the curves, and no events were recorded after 41\xa0months and 35\xa0months for overall and relapse-free survival respectively. The MT103‑202 study had a follow-up of about 4\xa0years, included only 20\xa0patients and did not record overall survival. The committee was concerned that the single-arm design of the studies meant that the results were potentially biased. It noted that there was no evidence on the effectiveness of blinatumomab directly compared with continued chemotherapy. As requested by the committee, in response to consultation, the company presented updated Kaplan–Meier graphs, using safety data from the latest data cut from June 2017. It presented overall survival data for people with Philadelphia‑chromosome‑negative, B‑precursor acute lymphoblastic leukaemia and presence of MRD whose disease is in first, second or third complete remission. The committee agreed the updated clinical data are more reliable than the original submission. It concluded that blinatumomab is clinically effective, but the lack of direct comparative data means the size of this benefit is still unclear.\n\nOutcome\n\nBLAST (n=116, August 2015 data cut, results presented for primary company analyses, which are not censored at haematopoietic stem cell transplantation)\n\nMT103‑202 (n=20)\n\nComplete minimal residual disease response rate in 1\xa0cycle\n\nn=88 (77.9%)\n\nn=16 (80.0%)\n\nMedian overall survival\n\nmonths (19.2\xa0months, not estimable)\n\nN/A\n\nOverall survival at 18\xa0months\n\n% (95% confidence interval [CI] 55 to 73)\n\nN/A\n\nMedian relapse-free survival\n\nmonths (95% CI 12.3 to 35.2)\n\nnot estimable (at 1,550\xa0days of follow-up)\n\nRelapse-free survival\n\n% (95%\xa0CI 44 to 62) at 18 months\n\n% (N/A) at 5.9\xa0years\n\n## Blinatumomab can only be recommended within its marketing authorisation\n\nBlinatumomab's marketing authorisation includes adult patients with acute lymphoblastic leukaemia in first or second complete remission and which is Philadelphia-chromosome-negative with MRD of at least 0.1%. The study population in BLAST was wider than the population outlined in the marketing authorisation. Although most patients had disease that was in first or second complete remission, it also included patients whose disease was in third complete remission. Also, it included patients with Philadelphia-chromosome-positive and Philadelphia-chromosome-negative disease. In the MT103‑202 study, all patients had disease that was in complete remission, but it also included both Philadelphia-chromosome-positive and negative disease. The committee concluded that it could only make recommendations within the population outlined in the marketing authorisation.\n\n## The indirect comparison is appropriate but is not generalisable to the wider marketing authorisation population\n\nThe committee was aware that there were no data directly comparing blinatumomab with continued chemotherapy. The company therefore did an indirect comparison of blinatumomab and continued chemotherapy, which was used in the economic model. The comparator data came from Study\xa020120148, a retrospective study with data on patients with Philadelphia‑chromosome‑negative B‑precursor acute lymphoblastic leukaemia in complete haematological remission and MRD. The study collected data on overall and relapse-free survival but not on adverse effects. It was used as a matched control for BLAST. Because of differences between the populations in BLAST and the historical comparator, the company used a subset of the original study populations. The committee was aware that the population in the indirect comparison was narrower than the marketing authorisation and excluded the following groups:\n\npatients who could not have HSCT or tolerate chemotherapy\n\npatients whose disease is in second complete remission.The clinical experts suggested that survival outcomes for the excluded groups of people were poor and that they could potentially benefit from treatment with blinatumomab. This was because some patients who had blinatumomab have had good outcomes even without subsequently having HSCT. The committee concluded that the indirect comparison was appropriate, given the absence of randomised controlled trial data, but that the results are not generalisable to the full population outlined in the marketing authorisation.\n\n## The indirect comparison method is appropriate but subject to uncertainty\n\nThe company used a propensity score model to compare the primary analysis set from BLAST and the direct comparator Study\xa020120148. This method produced weights that were applied to the control study (Study\xa020120148). The aim was to estimate the response to chemotherapy that would be expected in a population with the same characteristics as the population in the BLAST primary analysis set. The ERG noted that the chosen method of applying weights to balance the datasets was appropriate given the lack of randomised controlled trials. The company used 2\xa0different methods to produce weights: 'average treatment effect' and 'average treatment effect on the treated'. For both methods, the company used stabilised and non-stabilised weights. It used stabilised weights to produce the average treatment effect on the treated estimates in the clinical effectiveness analysis. However, non-stabilised weights were used to produce the treatment effect on the treated estimates that were used in the cost-effectiveness analysis. As part of the clarification response, the company provided data to show that there was no substantial difference in the results produced from both methods of applying weights. The results are confidential and cannot be reported here. The committee concluded that the method used to compare the 2\xa0studies was appropriate but subject to uncertainty.\n\n# Cost-effectiveness model\n\n## The company's original model was not suitable for decision making\n\nThe company's original model was a partitioned survival model based on relapse-free survival and overall survival, with 3\xa0health states: (1) relapse free; (2) post relapse and (3) dead. The main partitioned survival structure had 2\xa0linked sub-models that were intended to estimate additional costs and utility decrements associated with HSCT received before or after disease has relapsed. The pre-relapse sub-model was not causally related to relapse-free or overall survival, whereas the post-relapse sub-model was partially related to relapse-free survival. The ERG noted that the causal effect of transplant on outcome was not adequately modelled. The clinical experts also explained that MRD status highly correlates with HSCT outcomes: HSCT is less likely to be successful in people with MRD. However, the committee acknowledged that the model did not show how many patients with or without MRD have HSCT. The clinical expert further noted that there is unpublished but more mature and up-to-date data on survival outcomes after HSCT that could be included. The clinical experts highlighted that the original model was not reflective of current practice or the treatment pathway (see section\xa03.2). They clarified that the treatment pathway has recently changed and now includes NICE technology appraisal guidance on inotuzumab ozogamicin or blinatumomab for treating relapses (see section\xa03.4). The committee noted that while the model implicitly incorporated HSCT within the relapse-free survival and the overall survival curves, it did not show how many patients had HSCT. Without this direct link, it was not clear what proportion of patients had HSCT, and what their outcomes after HSCT were. Given the importance of HSCT to the likelihood of cure (see section\xa03.3), the committee was aware that this made it difficult to assess the reliability and clinical plausibility of the original model. At the first committee meeting, it concluded that it would have liked to have seen a cost-effectiveness model including:\n\na revised cost-effectiveness analysis reflecting the current treatment pathway in the NHS and comparing blinatumomab with continued chemotherapy. The revised economic model should:\n\n\n\ninclude costs, health-related quality-of-life estimates and outcomes associated with the current treatment pathway for people with relapsed or refractory acute lymphoblastic leukaemia\n\ninclude the proportion of people with and without MRD after blinatumomab treatment and how many have HSCT\n\nincorporate an explicit causal link between the probability of HSCT and relapse-free survival and overall survival in both groups\n\nexplicitly model a cure for people whose disease is expected to be cured and include scenario analyses considering different cure fractions and cure points\n\nfactor in the different positions in the treatment pathway at which HSCT might be given.\n\n\n\nthe latest available evidence on survival outcomes after HSCT\n\nthe latest trial data cut.In response to consultation, the company submitted a new model (see section\xa03.13).\n\n## The cure point assumption in the original model should be reconsidered because it is not clinically plausible\n\nThe company's original model did not have a fixed cure point. Instead, the model predicted the timepoint at which patients were assumed to be cured and had mortality rates similar to those of the general population with some additional excess mortality risk after a cure. This approach resulted in different cure points between the relapse-free survival and the overall survival extrapolations. The committee concluded that having a large gap between the resulting cure points (company model) is not clinically plausible. It was aware that the assumptions around the cure fraction or cure point were a key driver in the cost-effectiveness analysis. Therefore, at the first committee meeting, the committee concluded they would have liked to have seen a clinically plausible, explicitly modelled cure for the patients whose disease is expected to be cured. In response to consultation, the company submitted a new model with explicitly modelled cure states (see section\xa03.14).\n\n# Health-related quality of life\n\n## The company's post-relapse utility value is too high\n\nThe company used a post-relapse utility value of 0.69 in the model, which was lower than the one seen in the BLAST study (0.819). However, the ERG's clinical experts noted that both values are too high for relapsed patients and were not clinically plausible. The ERG ran exploratory analyses with lower utility values (0.50 and 0.25), which had a small effect on the incremental cost-effectiveness ratio (ICER). The committee concluded that the post-relapse quality-of-life estimates included in the company model were too high but were not a key driver of the results.\n\n# Company's new cost-effectiveness evidence and revised base case\n\n## The company submitted a revised partitioned survival model\n\nIn response to consultation, the company submitted a revised partitioned survival model, which used the same structure and parameters as the original model (see section\xa03.9). It included 3\xa0key changes\n\ninotuzumab ozogamicin is included as a salvage treatment for relapsed disease\n\nthe proportions of patients having blinatumomab or inotuzumab ozogamicin as salvage therapy for relapsed disease were estimated based on clinical expert opinion. In the continued chemotherapy arm, patients having first salvage therapy are split equally between blinatumomab and inotuzumab ozogamicin and\n\nthe cost calculations for blinatumomab as salvage therapy for relapsed disease have been amended.The revised partitioned survival model did not include the remaining amendments requested by the committee (see section\xa03.10). Therefore, the committee concluded that the revised partitioned survival model was not suitable for decision making.\n\n## The new semi-Markov model submitted by the company is suitable for decision making\n\nIn response to consultation, the company also submitted a semi-Markov model. The model structure was comprised of 4\xa0health states: first complete haematological remission (CR1); pre-relapse HSCT; relapse and dead. The model compares blinatumomab and continued chemotherapy, both followed by pre-relapse HSCT for some patients, followed by post-relapse salvage therapy using inotuzumab ozogamicin for the blinatumomab arm and either inotuzumab ozogamicin or blinatumomab for the continued chemotherapy arm. Most of the parameters used in the new semi-Markov model are the same as the ones used in the updated partitioned survival model. The new semi-Markov model produces outcomes that depend on treatment offered, MRD response and the patient's current health state. This leads to different results compared with the company's partitioned survival model. The ERG explained that the new semi-Markov model incorporates most of the assumptions preferred by the committee (see section\xa03.9), but it was also subject to certain limitations:\n\nHSCT costs were applied to some patients who relapsed but were not related to downstream salvage treatment\n\nthere was a small number of events and patients at risk\n\nthe rationale for curve selection was not consistent\n\nconcerns about model-predicted relapse-free survival and overall survival (see section\xa03.17).The committee considered the new semi-Markov model and concluded that it was suitable for decision making.\n\n## The most plausible cure point is likely to be below 5\xa0years\n\nThe committee considered how the cure points are modelled in the new semi-Markov model. The ERG explained that the cure point is not fixed but defined in each cure state. People with acute lymphoblastic leukaemia who have pre-relapse HSCT have a cure point later than that applied to the CR1 state. The cure point for CR1 was 5\xa0years. The cure point for patients entering the pre-relapse HSCT state was 5\xa0years after entry into that state (that is, the time spent in CR1 plus 5\xa0years). Patients who experienced relapse and did not die within 5\xa0years of relapse were assumed to be cured 5\xa0years after they entered the relapse state. These patients would have a cure point of more than 5\xa0years but less than 15\xa0years from entering the model. In this way, the model considered patients who remained relapse free and proceed to transplant to be cured at a later timepoint than those who remain relapse free but never proceed to HSCT. The clinical experts said that in clinical practice people with acute lymphoblastic leukaemia are considered cured if their disease has not relapsed within 2\xa0years. The committee concluded that the cure point is likely to be less than 5\xa0years and possibly 3\xa0years would be most plausible.\n\n## The new semi-Markov model uses an inappropriate method for handling competing risks\n\nThe company's new semi-Markov model faces an issue with competing risks. Competing risks happen when patients in the model can experience 1\xa0or more events which 'compete' with the event of interest. The new semi-Markov model estimates each transition state by using patient time-to-event data, it then keeps events of interest and removes events not of interest. The ERG explained that this approach does not handle competing risks appropriately. Specifically, the problem with removing events not of interest is that it may lead to a pattern of removal that is not independent anymore. Because of this, the model estimates may be biased and inaccurate. The ERG believes that the company's approach is likely to have increased the risk of each event. The committee concluded that there is uncertainty in the model because of the method used for handling competing risks.\n\n# Overall survival in the new semi-Markov model\n\n## The overall survival extrapolations are subject to uncertainty\n\nThe committee considered the overall survival from the new semi-Markov model. The company presented a graph comparing the Kaplan–Meier curves from BLAST and the historical control and the new semi-Markov model predictions for overall survival including blinatumomab and inotuzumab ozogamicin as salvage treatments for relapsed disease. The company used data from the TOWER study (phase\xa0III, randomised study of blinatumomab compared with standard care in patients with acute lymphoblastic leukaemia) to inform the post-relapse survival estimation in the new semi-Markov model. The survival curves projected by the model fit the survival curves of the BLAST data and the historical control closely. The parametric curves estimated that the proportion of patients that would be relapse free at 5\xa0years was 40.0% and 18.1% for blinatumomab and standard care, respectively. However, the ERG ran exploratory analyses and presented the same comparison but excluding blinatumomab and inotuzumab ozogamicin as salvage treatments for relapsed disease. The ERG used the restricted Gompertz overall survival function for the standard chemotherapy group after relapse fitted to data from TOWER to model overall survival for patients whose disease had relapsed. The results showed that the new semi-Markov model no longer gives a good fit to the Kaplan–Meier curves in either treatment group. The ERG explained that the predictions from this version of the model should match the Kaplan–Meier curves because both the parametric curves and the Kaplan–Meier data excludes blinatumomab and inotuzumab ozogamicin for treating relapsed disease. Instead, predicted overall survival was underestimated in both treatment groups, but more so in the standard chemotherapy comparator group. The clinical expert pointed out that if there is any benefit because of the newly introduced treatments, there should be an increase in overall survival curves for both blinatumomab and standard care. The committee concluded that the overall survival extrapolations in both arms were subject to uncertainty.\n\n## The new semi-Markov model is appropriate for decision making but results are not generalisable to the full marketing authorisation\n\nThe company modelled the cost effectiveness of blinatumomab using data from BLAST, the historical control and TOWER. However, this did not include patients whose disease was in second complete remission. The committee recalled that this was a narrower population than the marketing authorisation (see section\xa03.9). At consultation, the company stated that there are few people with acute lymphoblastic leukaemia in second complete remission, and the number of people is declining and it should be included in committee's decision making. The committee considered all the evidence within the marketing authorisation. Because the committee did not see cost-effectiveness evidence on acute lymphoblastic leukaemia in second complete remission, it could not make recommendation for this indication. It further concluded that it could only make recommendations based on the evidence presented to it.\n\n# Cost-effectiveness results\n\n## Blinatumomab is cost effective compared with continued chemotherapy\n\nThe committee recalled its preferred assumptions (see section\xa03.9). The committee concluded that its preferred analysis would include a 3-year cure timepoint. Based on the ERG's exploratory analysis, the scenarios with a 3‑year cure point produce an ICER that falls between £21,874 and £25,551 per quality-adjusted life year (QALY) gained, although the committee were aware that there was uncertainty in these estimates. The ERG also reproduced the analyses to include the confidential commercial arrangement for inotuzumab ozogamicin, and the ICERs were within the range that NICE usually considered an acceptable use of NHS resources (the exact ICERs are confidential and cannot be reported here). The committee could make recommendation based only on the evidence presented. Because the committee did not see evidence on people with acute lymphoblastic leukaemia in second complete remission, it was unable to make a recommendation for this indication. Based on the evidence presented to it, the committee concluded the most plausible ICERs were within the range that NICE usually considers an acceptable use of NHS resources.\n\n# Innovation\n\n## Blinatumomab is innovative but there are no benefits not captured by the QALY\n\nThe committee considered blinatumomab to be innovative because it represents a step change in the treatment of CD19‑positive B‑precursor acute lymphoblastic leukaemia with presence of MRD. No evidence was presented to suggest that there were additional benefits that were not captured in the QALY calculations. The committee concluded that there were no benefits that would not be captured in the QALY calculations.\n\n# End of life\n\n## Blinatumomab does not meet the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that blinatumomab met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24\xa0months). The company's new evidence was not substantially different from the initial evidence submitted. The committee considered the median and mean survival and the proportion of patients alive at 2\xa0years for the continued chemotherapy arm from the company and the ERG's model. The clinical experts suggested that for patients with MRD, the proportion of people alive at 2\xa0years would be around 20%. The committee noted all the estimates of life expectancy from clinical evidence and the model. It agreed that the mean estimates from the company's model were much longer than the median estimates. The mean and median survival outcomes are confidential and cannot be reported here. The committee concluded that overall the short life-expectancy criterion was not met. The committee also discussed whether a survival benefit of over 3\xa0months can be expected for blinatumomab compared with continued chemotherapy. Based on all the evidence presented to it, the committee concluded that the extension-to-life criterion was met. The committee concluded that blinatumomab did not meet NICE's criteria for being considered a life-extending treatment at the end of life.\n\n# Conclusion\n\n## Blinatumomab is recommended for routine use for people with acute lymphoblastic leukaemia in first complete remission\n\nThe committee concluded that the most plausible ICERs for blinatumomab were within the range that NICE usually considers an acceptable use of NHS resources. Blinatumomab could not be considered an end-of-life treatment because the short life-expectancy criterion was not met. It also noted that blinatumomab is clinically effective. However, the committee did not see any evidence to assess cost effectiveness in the second complete remission population. Therefore, the committee recommended blinatumomab as an option for treating Philadelphia-chromosome-negative CD19‑positive B‑precursor acute lymphoblastic leukaemia in adults with MRD of at least 0.1%, only if:\n\nthe disease is in first complete remission and\n\nthe company provides blinatumomab according to the commercial arrangement."}
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https://www.nice.org.uk/guidance/ta589
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Evidence-based recommendations on blinatumomab (Blincyto) for treating Philadelphia-chromosome-negative CD19-positive B-precursor acute lymphoblastic leukaemia in remission with minimal residual disease activity in adults.
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740c1f3f4ed7b0cc502775aa4db0c3f43c068bac
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nice
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Motor neurone disease: assessment and management
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Motor neurone disease: assessment and management
This guideline covers assessing and managing motor neurone disease (MND). It aims to improve care from the time of diagnosis, and covers information and support, organisation of care, managing symptoms and preparing for end of life care.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) or our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Recognition and referral
Ensure that robust protocols and pathways are in place to:
inform healthcare professionals about motor neurone disease (MND) and how it may present
inform healthcare professionals in all settings about local referral arrangements
ensure continued and integrated care for people with MND across all care settings.
Be aware that MND causes progressive muscular weakness that may first present as isolated and unexplained symptoms. These symptoms may include:
functional effects of muscle weakness, such as loss of dexterity, falls or trips
speech or swallowing problems, or tongue fasciculations (this is known as bulbar presentation)
muscle problems, such as weakness, wasting, twitching, cramps and stiffness
breathing problems, such as shortness of breath on exertion or respiratory symptoms that are hard to explain
effects of reduced respiratory function, such as excessive daytime sleepiness, fatigue, early morning headache or shortness of breath when lying down.
Be aware that MND may first present with cognitive features, which may include:
behavioural changes
emotional lability (not related to dementia)
frontotemporal dementia.
If you suspect MND, refer the person without delay and specify the possible diagnosis in the referral letter. Contact the consultant neurologist directly if you think the person needs to be seen urgently.
Provide information and support for people and their family members and/or carers (as appropriate) throughout the diagnostic process, particularly during periods of diagnostic uncertainty or delay.
# Information and support at diagnosis
Please also refer to the recommendations in the NICE guideline on patient experience in adult NHS services, which includes recommendations on communication, information and coordination of care.
Information about the diagnosis, prognosis and management of MND should be given by a consultant neurologist with up‑to‑date knowledge and experience of treating people with MND unless it is clinically necessary to give the diagnosis in an urgent situation. The neurologist should have knowledge and expertise in the following:
Symptoms of MND.
Types and possible causes of MND.
Treatment options.
How MND may progress (including cognitive and behavioural changes) and how progression may affect the treatments offered.
Crisis prevention (for example, if there is an acute hospital admission or a breakdown in care arrangements).
Opportunities for people with MND to be involved in research.
Likely needs and concerns of people with MND and their family members and/or carers (as appropriate).
Advance care planning.
Ask people about how much information they wish to receive about MND, and about their preferences for involving their family members and/or carers (as appropriate).
Ensure people are provided with information about MND and support at diagnosis or when they ask for it. If the person agrees, share the information with their family members and/or carers (as appropriate). Information should be oral and written, and may include the following:
What MND is.
Types and possible causes.
Likely symptoms and how they can be managed.
How MND may progress.
Treatment options.
Where the person's appointments will take place.
Which healthcare professionals and social care practitioners will undertake the person's care.
Expected waiting times for consultations, investigations and treatments.
Local services (including social care and specialist palliative care services) and how to get in touch with them.
Local support groups, online forums and national charities, and how to get in touch with them.
Legal rights, including social care support, employment rights and benefits.
Requirements for disclosure, such as notifying the Driver and Vehicle Licensing Agency (DVLA).
Opportunities for advance care planning.
When MND is diagnosed, provide people with a single point of contact for the specialist MND multidisciplinary team (see section 1.5). Provide information about what to do if there are any concerns between assessments or appointments, during 'out‑of‑hours' or in an emergency, or if there is a problem with equipment.
Offer the person with MND a face‑to‑face, follow‑up appointment with a healthcare professional from the multidisciplinary team, to take place within 4 weeks of diagnosis.
When MND is suspected or confirmed, inform the person's GP without delay and provide information about the likely prognosis.
Set aside enough time to discuss the person's concerns and questions, which may include the following:
What will happen to me?
Are there any treatments available?
Is there a cure?
How long will I live?
What will the impact on my day‑to‑day life be?
What will happen next with my healthcare?
Will my children get MND?
How do I tell my family and friends?
How will I die?
If the person has any social care needs, refer them to social services for an assessment. Be aware that some people with MND may not have informal care available, and may live alone or care for someone else.
Advise carers about their right to carer assessment, and assessment for respite care and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers).
# Cognitive assessments
Please also refer to the recommendations in the NICE guideline on patient experience in adult NHS services.
Be aware that people with MND and frontotemporal dementia may lack mental capacity. Care should be provided in line with the Mental Capacity Act 2005.
At diagnosis, and if there is concern about cognition and behaviour, explore any cognitive or behavioural changes with the person and their family members and/or carers as appropriate. If needed, refer the person for a formal assessment in line with the NICE guideline on dementia.
Tailor all discussions to the person's needs, taking into account their communication ability, cognitive status and mental capacity.
# Prognostic factors
When planning care take into account the following prognostic factors, which are associated with shorter survival if they are present at diagnosis:
Speech and swallowing problems (bulbar presentation).
Weight loss.
Poor respiratory function.
Older age.
Lower Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS or ALSFRS‑R) score.
Shorter time from first developing symptoms to time of diagnosis.
# Organisation of care
Provide coordinated care for people with MND, using a clinic‑based, specialist MND multidisciplinary team approach. The clinic may be community or hospital based.
The multidisciplinary team should:
include healthcare professionals and social care practitioners with expertise in MND, and staff who see people in their home
ensure effective communication and coordination between all healthcare professionals and social care practitioners involved in the person's care and their family members and/or carers (as appropriate)
carry out regular, coordinated assessments at the multidisciplinary team clinic (usually every 2 to 3 months) to assess people's symptoms and needs
provide coordinated care for people who cannot attend the clinic, according to the person's needs.
The multidisciplinary team should assess, manage and review the following areas, including the person's response to treatment:
Weight, diet, nutritional intake and fluid intake, feeding and swallowing (see section 1.10).
Muscle problems, such as weakness, stiffness and cramps (see recommendations 1.8.1 to 1.8.9).
Physical function, including mobility and activities of daily living (see section 1.9).
Saliva problems, such as drooling of saliva (sialorrhoea) and thick, tenacious saliva (see recommendations 1.8.10 to 1.8.15).
Speech and communication (see section 1.11).
Cough effectiveness (see section 1.13).
Respiratory function, respiratory symptoms and non‑invasive ventilation (see section 1.12 and section 1.14).
Pain and other symptoms, such as constipation.
Cognition and behaviour (see section 1.3).
Psychological support needs (see recommendations 1.6.1 to 1.6.4).
Social care needs (see recommendations 1.6.5 and 1.6.6).
End of life care needs (see section 1.7).
Information and support needs for the person and their family members and/or carers (as appropriate) (see section 1.2).
The core multidisciplinary team should consist of healthcare professionals and other professionals with expertise in MND, and should include the following:
Neurologist.
Specialist nurse.
Dietitian.
Physiotherapist.
Occupational therapist.
Respiratory physiologist or a healthcare professional who can assess respiratory function.
Speech and language therapist.
A healthcare professional with expertise in palliative care (MND palliative care expertise may be provided by the neurologist or nurse in the multidisciplinary team, or by a specialist palliative care professional).
The multidisciplinary team should have established relationships with, and prompt access to, the following:
Clinical psychology and neuropsychology.
Social care.
Counselling.
Respiratory ventilation services.
Specialist palliative care.
Gastroenterology.
Orthotics.
Wheelchair services.
Assistive technology services.
Alternative and augmentative communication (AAC) services.
Community neurological care teams.
Tailor the frequency of the multidisciplinary team assessments to the person's symptoms and needs, with more or less frequent assessments as needed.
Ensure arrangements are in place to trigger an earlier multidisciplinary team assessment if there is a significant change in symptoms identified by the person, family members and/or carers (as appropriate), or healthcare professionals.
Tailor the multidisciplinary team assessment to the person's needs, for example, adjust the format if the person has cognitive or behaviour changes or difficulties with communication.
Inform all healthcare professionals and social care practitioners involved in the person's care about key decisions reached with the person and their family members and/or carers (as appropriate).
Ensure that all healthcare professionals and social care practitioners involved in the person's care are aware that MND symptoms may get worse quickly, and that people with MND will need repeated, ongoing assessments. Priority should be given to ensuring continuity of care and avoiding untimely case closure.
Consider referral to a specialist palliative care team for people with current or anticipated significant or complex needs, for example, psychological or social distress, troublesome or rapidly progressing symptoms and complex future care planning needs.
For guidance on the use of riluzole for people with MND, see the NICE technology appraisal guidance on the use of riluzole (Rilutek) for the treatment of motor neurone disease.
# Psychological and social care support
During multidisciplinary team assessments and other appointments, discuss the psychological and emotional impact of MND with the person and ask whether they have any psychological or support care needs. Topics to discuss may include the following:
Their understanding of MND and how it affects daily living.
Accepting and coping with the diagnosis and prognosis, including concerns and fears about dying.
Their ability to continue with current work and usual activities.
Adjusting to changes in their life and their perception of self.
Changes in relationships, familial roles and family dynamics.
Sexuality and intimacy.
Concerns about their family members and/or carers.
Decision-making.
Offer the person information about sources of emotional and psychological support, including support groups and online forums. If needed, refer the person to counselling or psychology services for a specialist assessment and support.
During multidisciplinary team assessments and other appointments, discuss the psychological and emotional impact of MND with family members and/or carers (as appropriate), and ask whether they have any psychological or social care support needs. Topics to discuss may include the following:
Their understanding of MND and how it affects daily living.
Accepting and coping with the diagnosis and prognosis, including concerns and fears about the person with MND dying.
Adjusting to changes in their life.
Changes in relationships, familial roles and family dynamics, including their change to a carer role (if appropriate).
Sexuality and intimacy.
Involvement in decision‑making.
Impact on other family members and/or carers.
Their ability and willingness to provide personal care and operate equipment.See the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers.
Offer family members and/or carers (as appropriate) information about respite care and sources of emotional and psychological support, including support groups, online forums and counselling or psychology services.
A social care practitioner with knowledge of MND or rapidly progressive complex disabilities should discuss the person's needs and preferences for social care, and provide information and support for them to access the following:
Personal care, ensuring there is continuity of care with familiar workers, so that wherever possible, personal care and support is carried out by workers known to the person and their family members and/or carers (as appropriate).
Equipment and practical support (see section 1.9).
Financial support and advice (for example, money management, how to access carers' and disability benefits and grants, continuing healthcare funding and funeral expenses).
Support to engage in work, social activities and hobbies, such as access to social media and physical access to activities outside their home.
Respite care.
Be aware that as MND progresses, people may develop communication problems and have difficulty accessing support or services. For example, they may be unable to access a call centre. Ensure people are given different ways of getting in touch with support or services, and a designated contact if possible.
# Planning for end of life
Offer the person with MND the opportunity to discuss their preferences and concerns about care at the end of life at trigger points such as: at diagnosis, if there is a significant change in respiratory function, or if interventions such as gastrostomy or non‑invasive ventilation are needed. Be sensitive about the timing of discussions and take into account the person's current communication ability, cognitive status and mental capacity.
Be prepared to discuss end of life issues whenever people wish to do so.
Provide support and advice on advance care planning for end of life. Topics to discuss may include:
What could happen at the end of life, for example, how death may occur.
Providing anticipatory medicines in the home.
Advance care planning, including Advance Decisions to Refuse Treatment (ADRT) and Do Not Attempt Resuscitation (DNACPR) orders, and Lasting Power of Attorney.
How to ensure advance care plans will be available when needed, for example, including the information on the person's Summary Care Record.
When to involve specialist palliative care.
Areas that people might wish to plan for, such as:
what they want to happen (for example, their preferred place of death)
what they do not want to happen (for example, being admitted to hospital)
who will represent their decisions, if necessary
what should happen if they develop an intercurrent illness.
Think about discussing advance care planning with people at an earlier opportunity if you expect their communication ability, cognitive status or mental capacity to get worse.
Offer people the opportunity to talk about, and review any existing, ADRT, DNACPR orders and Lasting Power of Attorney when interventions such as gastrostomy and non‑invasive ventilation are planned.
Provide additional support as the end of life approaches, for example, additional social or nursing care to enable informal carers and family to reduce their carer responsibilities and spend time with the person with MND.
Towards the end of life, ensure there is prompt access to the following, if not already provided:
A method of communication that meets the person's needs, such as an AAC system.
Specialist palliative care.
Equipment, if needed, such as syringe drivers, suction machines, riser–recliner chair, hospital bed, commode and hoist.
Anticipatory medicines, including opioids and benzodiazepines to treat breathlessness, and antimuscarinic medicines to treat problematic saliva and respiratory secretions.
Offer bereavement support to family members and/or carers (as appropriate).
# Managing symptoms
## Pharmacological treatments for muscle problems
Discuss the available treatment options for muscle problems. Take into account the person's needs and preferences, and whether they have any difficulties taking medicine (for example, if they have problems swallowing).
Consider quinine as first‑line treatment for muscle cramps in people with MND. If quinine is not effective, not tolerated or contraindicated, consider baclofen instead as second‑line treatment. If baclofen is not effective, not tolerated or contraindicated, consider tizanidine, dantrolene or gabapentin.In February 2016 this was an off-label use of quinine, baclofen, tizanidine, and dantrolene. See NICE's information on prescribing medicines and the MHRA safety advice on prescribing gabapentin.
Consider baclofen, tizanidine, dantrolene or gabapentin to treat muscle stiffness, spasticity or increased tone in people with MND. If these treatments are not effective, not tolerated or contraindicated, consider referral to a specialist service for the treatment of severe spasticity.In February 2016 this was an off-label use of dantrolene. See NICE's information on prescribing medicines and the MHRA safety advice on prescribing gabapentin.
Review the treatments for muscle problems during multidisciplinary team assessments, ask about how the person is finding the treatment, whether it is working and whether they have any adverse side effects.
## Exercise programmes
Consider an exercise programme for people with MND to:
maintain joint range of movement
prevent contractures
reduce stiffness and discomfort
-ptimise function and quality of life.
Choose a programme that is appropriate to the person's level of function and tailored to their needs, abilities and preferences. Take into account factors such as postural needs and fatigue. The programme might be a resistance programme, an active‑assisted programme or a passive programme.
Check that family members and/or carers (as appropriate) are willing and able to help with exercise programmes.
Give advice to the person and their family members and/or carers (as appropriate) about safe manual handling.
If a person needs orthoses to help with muscle problems, they should be referred to orthotics services without delay, and the orthoses should be provided without delay.
## Saliva problems
If a person with MND has problems with saliva, assess the volume and viscosity of the saliva and the person's respiratory function, swallowing, diet, posture and oral care.
If a person with MND has problems with drooling of saliva (sialorrhoea), provide advice on swallowing, diet, posture, positioning, oral care and suctioning.
Consider a trial of antimuscarinic medicine as the first‑line treatment for sialorrhoea in people with MND.In February 2016 this was an off-label use of antimuscarinic medicine. See NICE's information on prescribing medicines.
Consider glycopyrrolate as the first‑line treatment for sialorrhoea in people with MND who have cognitive impairment, because it has fewer central nervous system side effects.In February 2016 this was an off-label use of glycopyrrolate. See NICE's information on prescribing medicines.
If first-line treatment for sialorrhoea is not effective, not tolerated or contraindicated, consider referral to a specialist service for Botulinum toxin A. In September 2019 Xeomin was the only Botulinium toxin A with a UK marketing authorisation for this indication.
If a person with MND has thick, tenacious saliva:
review all current medicines, especially any treatments for sialorrhoea
provide advice on swallowing, diet, posture, positioning, oral care, suctioning and hydration
consider treatment with humidification, nebulisers and carbocisteine.
# Equipment and adaptations to aid activities of daily living and mobility
Healthcare professionals and social care practitioners, which will include physiotherapists and occupational therapists, should assess and anticipate changes in the person's daily living needs, taking into account the following:
Activities of daily living, including personal care, dressing and bathing, housework, shopping, food preparation, eating and drinking, and ability to continue with current work and usual activities.
Mobility and avoiding falls and problems from loss of dexterity.
The home environment and the need for adaptations.
The need for assistive technology, such as environmental control systems.
Provide equipment and adaptations that meet the person's needs without delay, so that people can participate in activities of daily living and maintain their quality of life as much as possible.
Refer people to specialist services without delay if assistive technology such as environmental control systems is needed. People should be assessed and assistive technology provided without delay.
Refer people to wheelchair services without delay if needed. Wheelchair needs should be assessed and a manual and/or powered wheelchair that meets the person's needs should be provided without delay.
Ensure that equipment, adaptations, daily living aids, assistive technology and wheelchairs meet the changing needs of the person and their family and/or carers (as appropriate) to maximise mobility and participation in activities of daily living.
Ensure regular, ongoing monitoring of the person's mobility and daily life needs and abilities as MND progresses. Regularly review their ability to use equipment and to adapt equipment as necessary.
Healthcare professionals, social care practitioners and other services providing equipment should liaise to ensure that all equipment provided can be integrated, for example, integrating AAC aids and devices and environmental control systems with wheelchairs.
Enable prompt access and assessment for funding for home adaptation. If the person is not eligible for funding, continue to offer information and support in arranging home environment adaptations.
# Nutrition and gastrostomy
Please also refer to the recommendations in the NICE guideline on nutrition support for adults.
At diagnosis and at multidisciplinary team assessments, or if there are any concerns about weight, nutrition or swallowing, assess the person's weight, diet, nutritional intake, fluid intake, hydration, oral health, feeding, drinking and swallowing, and offer support, advice and interventions as needed.
Assess the person's diet, hydration, nutritional intake and fluid intake by taking into account:
fluids and food intake versus nutritional and hydration needs
nutritional supplements, if needed
appetite and thirst
gastrointestinal symptoms, such as nausea or constipation
causes of reduced oral intake (for example, swallowing difficulties, limb weakness or the possibility of low mood or depression causing loss of appetite).
Assess the person's ability to eat and drink by taking into account:
the need for eating and drinking aids and altered utensils to help them take food from the plate to their mouth
the need for help with food and drink preparation
advice and aids for positioning, seating and posture while eating and drinking
dealing with social situations (for example, eating out).
Arrange for a clinical swallowing assessment if swallowing problems are suspected.
Assess and manage factors that may contribute to problems with swallowing, such as:
positioning
seating
the need to modify food and drink consistency and palatability
respiratory symptoms and risk of aspiration and/or choking
fear of choking and psychological considerations (for example, wanting to eat and drink without assistance in social situations).
Discuss gastrostomy at an early stage, and at regular intervals as MND progresses, taking into account the person's preferences and issues, such as ability to swallow, weight loss, respiratory function, effort of feeding and drinking and risk of choking. Be aware that some people will not want to have a gastrostomy.
Explain the benefits of early placement of a gastrostomy, and the possible risks of a late gastrostomy (for example, low critical body mass, respiratory complications, risk of dehydration, different methods of insertion, and a higher risk of mortality and procedural complications).
If a person is referred for a gastrostomy, it should take place without unnecessary delay.
Pay particular attention to the nutritional and hydration needs of people with MND who have frontotemporal dementia and who lack mental capacity. The multidisciplinary team assessment should include the support they need from carers, and their ability to understand the risks of swallowing difficulties.
Before a decision is made on the use of gastrostomy for a person with MND who has frontotemporal dementia, the neurologist from the multidisciplinary team should assess the following:
The person's ability to make decisions and to give consent (see Mental Capacity Act 2005).
The severity of frontotemporal dementia and cognitive problems.
Whether the person is likely to accept and cope with treatment.Discuss with the person's family members and/or carers (as appropriate; with the person's consent if they have the ability to give it).
# Communication
When assessing speech and communication needs during multidisciplinary team assessments and other appointments, discuss face‑to‑face and remote communication, for example, using the telephone, email, the Internet and social media. Ensure that the assessment and review is carried out by a speech and language therapist without delay.
Provide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life. The use of both low‑level technologies, for example, alphabet, word or picture boards and high‑level technologies, for example, PC or tablet‑based voice output communication aids may be helpful. Review the person's communication needs during multidisciplinary team assessments.
Liaise with, or refer the person with MND to, a specialised NHS AAC hub if complex high technology AAC equipment (for example, eye gaze access) is needed or is likely to be needed.
Involve other healthcare professionals, such as occupational therapists, to ensure that AAC equipment is integrated with other assistive technologies, such as environmental control systems and personal computers or tablets.
Ensure regular, ongoing monitoring of the person's communication needs and abilities as MND progresses, and review their ability to use AAC equipment. Reassess and liaise with a specialised NHS AAC hub if needed.
Provide ongoing support and training for the person with MND, and their family members and/or carers (as appropriate), in using AAC equipment and other communication strategies.
# Respiratory function and respiratory symptoms
Assess and monitor the person's respiratory function and symptoms. Treat people with MND and worsening respiratory impairment for reversible causes (for example, respiratory tract infections or secretion problems) before considering other treatments.
Offer non-invasive ventilation as treatment for people with respiratory impairment (see section 1.14). Decisions to offer non‑invasive ventilation should be made by the multidisciplinary team in conjunction with the respiratory ventilation service, and the person (see recommendations 1.5.1 to 1.5.5).
Consider urgent introduction of non‑invasive ventilation for people with MND who develop worsening respiratory impairment and are not already using non‑invasive ventilation.
Consider opioids as an option to relieve symptoms of breathlessness. Take into account the route of administration and acquisition cost of medicines.In February 2016 this was an off-label use of opioids. See NICE's information on prescribing medicines for more information.
Consider benzodiazepines to manage breathlessness that is exacerbated by anxiety. Take into account the route of administration and acquisition cost of medicines.In February 2016 this was an off-label use of benzodiazepines. See NICE's information on prescribing medicines.
# Cough effectiveness
Offer cough augmentation techniques such as manual assisted cough to people with MND who cannot cough effectively.
Consider unassisted breath stacking and/or manual assisted cough as the first‑line treatment for people with MND who have an ineffective cough.
For people with bulbar dysfunction, or whose cough is ineffective with unassisted breath stacking, consider assisted breath stacking (for example, using a lung volume recruitment bag).
Consider a mechanical cough assist device if assisted breath stacking is not effective, and/or during a respiratory tract infection.
# Non-invasive ventilation
## Information and support about non‑invasive ventilation
Offer to discuss the possible use of non‑invasive ventilation with the person and (if the person agrees) their family and carers, at an appropriate time and in a sensitive manner. This may be at one or more of the following times:
soon after MND is first diagnosed
when monitoring respiratory function
when respiratory function deteriorates
if the person asks for information.
Discussions about non‑invasive ventilation should be appropriate to the stage of the person's illness, carried out in a sensitive manner and include information on:
the possible symptoms and signs of respiratory impairment (see table 1)
the purpose, nature and timing of respiratory function tests, and explanations of the test results
how non‑invasive ventilation (as a treatment option) can improve symptoms associated with respiratory impairment and can be life prolonging, but does not stop progression of the underlying disease.
When discussing non‑invasive ventilation, explain the different ways that people can manage their breathlessness symptoms. This should include:
non-invasive ventilation, and its advantages and disadvantages
using non-invasive ventilation at different points in the course of the person's lifetime
the possibility of the person becoming dependent on non‑invasive ventilation
-ptions for treating any infections
support and information on how to recognise and cope with a distressing situation
the role of medication for breathing problems
psychological techniques and support.
Check that the person thinking about non‑invasive ventilation:
understands what non‑invasive ventilation is and what it can achieve
recognises the need for regular review
has enough information about non‑invasive ventilation and other options for breathing problems to make decisions about how and when to use it.
understands possible problems with compatibility with other equipment, for example, eye gaze access systems.
Explain that non-invasive ventilation can be stopped at any time. Reassure people that they can ask for help and advice if they need it, especially if they are dependent on non‑invasive ventilation for 24 hours a day, or become distressed when attempting to stop it. Inform people that medicines can be used to alleviate symptoms (see recommendation 1.14.29).
Ensure that families and carers:
have an initial assessment if the person they care for decides to use non‑invasive ventilation, which should include:
their ability and willingness to assist in providing non‑invasive ventilation
their training needs
have the opportunity to discuss any concerns they may have with members of the multidisciplinary team, the respiratory ventilation service and/or other healthcare professionals.
## Identification and assessment of respiratory impairment
Monitor the symptoms and signs listed in table 1 to detect potential respiratory impairment.
Symptoms
Signs
Breathlessness
Increased respiratory rate
Orthopnoea
Shallow breathing
Recurrent chest infections
Weak cough
Disturbed sleep
Weak sniff
Non-refreshing sleep
Abdominal paradox (inward movement of the abdomen during inspiration)
Nightmares
Use of accessory muscles of respiration
Daytime sleepiness
Reduced chest expansion on maximal inspiration
Poor concentration and/or memory
Confusion
Hallucinations
Morning headaches
Fatigue
Poor appetite
Weak cough could be assessed by measuring peak cough flow.
As part of the initial assessment to diagnose MND, or soon after diagnosis, a healthcare professional from the multidisciplinary team who has appropriate competencies should perform the following tests (or arrange for them to be performed) to establish the person's baseline respiratory function:
-xygen saturation measured by pulse oximetry (SpO2):
this should be a single measurement of SpO2 with the person at rest and breathing room air
if it is not possible to perform pulse oximetry locally, refer the person to a respiratory ventilation service.Then one or both of the following:
forced vital capacity (FVC) or vital capacity (VC)
sniff nasal inspiratory pressure (SNIP) and/or maximal inspiratory pressure (MIP). Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
If the person has severe bulbar impairment or severe cognitive problems that may be related to respiratory impairment:
ensure that SpO2 is measured (at rest and breathing room air)
do not perform the other respiratory function tests (FVC, VC, SNIP and MIP) if interfaces are not suitable for the person.
A healthcare professional with appropriate competencies should perform the respiratory function tests every 2 to 3 months, although tests may be performed more or less often depending on:
whether there are any symptoms and signs of respiratory impairment (see table 1)
the rate of progression of MND
the person's preference and circumstances.
Perform arterial or capillary blood gas analysis if the person's SpO2 (measured at rest and breathing room air):
is less than or equal to 92% if they have known lung disease
is less than or equal to 94% if they do not have lung disease.If it is not possible to perform arterial or capillary blood gas analysis locally, refer the person to a respiratory ventilation service.
If the person's SpO2 (measured at rest and breathing room air) is greater than 94%, or 92% for those with lung disease, but they have sleep‑related respiratory symptoms:
consider referring them to a respiratory ventilation service for continuous nocturnal (overnight) oximetry and/or a limited sleep study and
discuss both the impact of respiratory impairment and treatment options with the patient and (if the person agrees) their family and carers.
If the person's arterial partial pressure of carbon dioxide (PaCO2) is greater than 6 kPa:
refer them urgently to a respiratory ventilation service (to be seen within 1 week) and
explain the reasons for and implications of the urgent referral to the person and (if the person agrees) their family and carers.
If the person's PaCO2 is less than or equal to 6 kPa but they have any symptoms or signs of respiratory impairment, particularly orthopnoea (see recommendation 1.14.15):
refer them to a respiratory ventilation service for nocturnal (overnight) oximetry and/or a limited sleep study and
discuss both the impact of respiratory impairment and treatment options with the person and (if the person agrees) their family and/or carers (as appropriate).
If any of the results listed in table 2 is obtained, discuss with the person and (if appropriate) their family and carers:
their respiratory impairment
their treatment options
possible referral to a respiratory ventilation service for further assessment based on discussion with the person, and their wishes.
Forced vital capacity (FVC) or vital capacity (VC)
Sniff nasal inspiratory pressure (SNIP) and/or maximal inspiratory pressure (MIP)
(if both tests are performed, base the assessment on the better respiratory function reading)
FVC or VC less than 50% of predicted value
SNIP or MIP less than 40 cmH2O
FVC or VC less than 80% of predicted value plus any symptoms or signs of respiratory impairment (see recommendation 1.14.7), particularly orthopnoea
SNIP or MIP less than 65 cmH2O for men or 55 cmH2O for women plus any symptoms or signs of respiratory impairment (see recommendation 1.14.7), particularly orthopnoea
Repeated regular tests show a rate of decrease of SNIP or MIP of more than 10 cm H2O per 3 months
Base decisions on respiratory function tests for a person with a diagnosis of frontotemporal dementia on considerations specific to their needs and circumstances, such as:
their ability to give consent
their understanding of the tests
their tolerance of the tests and willingness to undertake them
the impact on their family and carers
whether they are capable of receiving non‑invasive ventilation.
## Non-invasive ventilation for treatment of respiratory impairment in people with MND
Offer a trial of non-invasive ventilation if the person's symptoms and signs and the results of the respiratory function tests indicate that the person is likely to benefit from the treatment.
Consider a trial of non‑invasive ventilation for a person who has severe bulbar impairment or severe cognitive problems that may be related to respiratory impairment only if they may benefit from an improvement in sleep‑related symptoms or correction of hypoventilation.
Before starting non-invasive ventilation, the multidisciplinary team together with the respiratory ventilation service should carry out and coordinate a patient‑centred risk assessment, after discussion with the person and their family and carers. This should consider:
the most appropriate type of non‑invasive ventilator and interfaces, based on the person's needs and lifestyle factors and safety
the person's tolerance of the treatment
the risk, and possible consequences, of ventilator failure
the power supply required, including battery back‑up
how easily the person can get to hospital
risks associated with travelling away from home (especially abroad)
whether a humidifier is required
issues relating to secretion management
the availability of carers.
Before starting non-invasive ventilation, the multidisciplinary team together with the respiratory ventilation service should prepare a comprehensive care plan, after discussion with the person and their family and carers (who should be offered a copy of the plan). This should cover:
long-term support provided by the multidisciplinary team
the initial frequency of respiratory function tests and monitoring of respiratory impairment
the frequency of clinical reviews of symptomatic and physiological changes
the provision of carers
arrangements for device maintenance and 24‑hour emergency clinical and technical support
secretion management and respiratory physiotherapy assessment, including cough augmentation (if required)
training in and support for the use of non-invasive ventilation for the person and their family and carers
regular opportunities to discuss the person's wishes in relation to continuing or withdrawing non‑invasive ventilation.
When starting non‑invasive ventilation:
perform initial acclimatisation during the day when the person is awake
usually start regular treatment at night, before and during sleep
gradually build up the person's hours of use as necessary.
Continue non-invasive ventilation if the clinical reviews show:
symptomatic and/or physiological improvements for a person without severe bulbar impairment and without severe cognitive problems
an improvement in sleep‑related symptoms for a person with severe bulbar impairment or with severe cognitive problems that may be related to respiratory impairment.
Provide the person and their family and/or carers (as appropriate) with support and assistance to manage non‑invasive ventilation. This should include:
training on using non‑invasive ventilation and ventilator interfaces, for example:
emergency procedures
night-time assistance if the person is unable to use the equipment independently (for example, emergency removal or replacement of interfaces)
how to use the equipment with a wheelchair or other mobility aids if required
what to do if the equipment fails
assistance with secretion management
information on general palliative strategies
an offer of ongoing emotional and psychological support for the person and their family and carers.
Discuss all decisions to continue or withdraw non‑invasive ventilation with the person and (if the person agrees) their family and carers.
Before a decision is made on the use of non‑invasive ventilation for a person with a diagnosis of frontotemporal dementia, the multidisciplinary team together with the respiratory ventilation service should carry out an assessment that includes:
the person's capacity to make decisions and to give consent (see Mental Capacity Act 2005)
the severity of dementia and cognitive problems
whether the person is likely to accept treatment
whether the person is likely to achieve improvements in sleep‑related symptoms and/or behavioural improvements
a discussion with the person's family and/or carers (with the person's consent if they have the capacity to give it).
Consider prescribing medicines to help ease breathlessness that people using non‑invasive ventilation can take on an 'as‑needed' basis at home, for example, opioids or benzodiazepines.In February 2016 this was an off-label use of opioids and benzodiazepines. See NICE's information on prescribing medicines.
Inform services that may see the person in crisis situations, such as their GP and services that provide emergency or urgent care, that the person is using non‑invasive ventilation.
## Stopping non-invasive ventilation
The healthcare professionals responsible for starting non‑invasive ventilation treatment in people with MND should ensure that support is available for other healthcare professionals who may be involved if there is a plan to stop non‑invasive ventilation, including the legal and ethical implications.
If a person on continuous non‑invasive ventilation wishes to stop treatment, ensure that they have support from healthcare professionals with knowledge and expertise of:
stopping non‑invasive ventilation
the ventilator machine
palliative medicines (see the NICE guideline on care of dying adults in the last days of life)
supporting the person, family members and/or carers (as appropriate)
supponad rting other healthcare professionals involved with the person's care
legal and ethical frameworks and responsibilities.
If a person on continuous non‑invasive ventilation wishes to stop treatment, seek advice from healthcare professionals who have knowledge and experience of stopping non‑invasive ventilation.
Healthcare professionals involved in stopping non‑invasive ventilation should have up‑to‑date knowledge of the law regarding the Mental Capacity Act, DNACPR, ADRT orders, and Lasting Power of Attorney. # Context
Motor neurone disease (MND) is a neurodegenerative condition that affects the brain and spinal cord. MND is characterised by the degeneration of primarily motor neurones, leading to muscle weakness.
The presentation of the disease varies and can be as muscle weakness, wasting, cramps and stiffness of arms and/or legs; problems with speech and/or swallowing or, more rarely, with breathing problems. As the disease progresses, the pattern of symptoms and signs becomes similar, with increasing muscle weakness in the person's arms and legs, problems swallowing and communicating and weakness of the muscles used for breathing, which ultimately leads to death. Most people die within 2 to 3 years of developing symptoms, but 25% are alive at 5 years and 5% to 10% at 10 years. The most common type of MND is amyotrophic lateral sclerosis (ALS). There are rarer forms of MND such as progressive muscular atrophy or primary lateral sclerosis, which may have a slower rate of progression.
Every person with MND has an individual progression of the disease. About 10% to 15% of people with MND will show signs of frontotemporal dementia, which causes cognitive dysfunction and issues in decision‑making. A further 35% of people with MND show signs of mild cognitive change, which may affect their ability to make decisions and plan ahead.
MND is a disorder which can affect adults of any age. It is most common in people aged 55 to 79 years, and onset below the age of 40 years is uncommon. There are approximately 4,000 people living with MND in England and Wales at any one time. The cause of MND is unknown. About 5% to 10% of people with MND have a family history of the disease and several abnormal genes have been identified.
As there is no cure for MND, care focuses on maintaining functional ability and enabling people with MND and their family members to live as full a life as possible. Early diagnosis, without delay after investigation, may be helpful, as it allows medication and the provision of aids, as well as communication about the disease and advance care planning to be undertaken appropriately.
Care of people with MND varies across England and Wales, with MND care centres and networks providing coordinated multidisciplinary care. However, some people with MND are left isolated and their care is less than ideal. This guideline aims to consider the clinical and cost‑effectiveness evidence for the care of people with MND from the time of diagnosis, including communication of the diagnosis, monitoring of disease progression, management of symptoms (in particular muscle weakness, excess secretions, breathing and nutrition problems), ongoing support and services available, mobility, emotional and psychological changes, and the preparation for end of life care. Particular emphasis is placed on the importance of a multidisciplinary team approach to the care and management of people with MND.# Recommendations for research
The Guideline Committee has made the following recommendations for research. The Committee's full set of recommendations for research is detailed in the full guideline.
# Organisation of care
Is a network‑based model as effective as a clinic‑based model to deliver multidisciplinary care to people with motor neurone disease (MND)?
## Why this is important
Multidisciplinary care improves survival in patients with MND. The evidence is drawn from models of multidisciplinary care that use a clinic based approach. However there are other models of care delivery in practice including care networks. Often these alternative models of care have arisen out of necessity in large geographical regions with low density populations. These alternative models may have similar survival advantages to patients with MND and this needs to be established.
# Cognitive assessment
What is the impact of assessing for cognitive and behaviour change in people with MND on clinical practice, the person and their family and carers? Does repeated assessment provide more benefit than assessment at a single point at diagnosis?
## Why this is important
Clinic‑based and population‑based studies demonstrate that up to 15% of people with MND have frontotemporal dementia. A further third of people with MND have changes in behaviour and cognition. These impairments are present at diagnosis. Their course during the disease has shown varying patterns between studies although several studies have shown that cognitive and behavioural impairments predict poorer survival and increased carer burden. A randomised controlled trial is needed to assess whether formal assessment at diagnosis and/or repeated assessment improves clinical practice, subsequent care of the person and quality of life for the person, their family and carers.
# Prognostic tools
Is the ALS Prognostic Index an accurate predictor of survival in people with MND under NHS care in England and/or Wales?
## Why this is important
Accurate predictions of survival in people with MND would be of great use to clinicians and to the person with MND, their family and carers. Accurate predictions would enable people with MND to be clearer about their prognosis, make plans for the rest of their life and have a well‑prepared and dignified transition into the end of life phase. Family members would similarly benefit in being more aware of the likely progression and prepare themselves for the death of their loved one.
Accurate predictions of survival would enable professionals to create and deliver more effective management and care plans and access services when it is most appropriate, for example specialist palliative care.
The ALS Prognostic Index (ALS‑PI) was developed in a cohort of people with ALS in the Republic of Ireland and externally validated in a cohort in Italy. However, it has not been validated in people with ALS, primary lateral sclerosis or progressive muscular atrophy in the NHS in England or Wales. The tool needs to be validated in a UK population using a simplified measure of executive function.
# Saliva
How is excessive drooling of saliva (sialorrhoea) managed in people with MND?
## Why this is important
Sialorrhoea affects up to 50% of people with MND and in 42% of these individuals the symptom is poorly controlled. There is no evidence base for clinicians to make decisions with regards to the treatment options available. Antimuscarinics are used first‑line but there is no evidence to inform which antimuscarinic and at what dose. Botulinum toxin is used second- or third‑line although there is little evidence to guide dosing, which salivary glands to inject and which type of botulinum toxin to use. Currently there is no baseline information about how specialists are using these treatments and this information is required to inform comparative studies.
# Nutrition
Does a high calorific diet prolong survival of people with MND if initiated following diagnosis or following initiation of feeding using a gastrostomy?
## Why this is important
There is little specific guidance on the optimal calorie intake for people with MND. There is growing evidence that people with MND have a hypercatabolic state and have high energy requirements. A large cohort study in the UK has demonstrated that nearly half of people continue to lose weight following gastrostomy and most show no improvement in their weight. A small study has demonstrated that high fat and high carbohydrate feeding may prolong survival in gastrostomy‑fed people. A larger randomised trial is needed to inform clinical practice.
# Augmentative and alternative communication
What is the current pattern of provision and use of augmentative and alternative communication (AAC) by people with MND in England?
## Why this is important
Appropriate AAC equipment can have a significant effect on quality of life for people with MND. While the NHS has a responsibility to provide equipment and ongoing support in its use, there are no reliable data on the types of equipment found most useful at different stages of the disease process, or the number of people with MND who may benefit from AAC. A prospective census study of people with MND presenting with early onset of speech problems is needed to establish the current baseline provision and needs of this population and how best to utilise AAC equipment. The programme will begin with the collection and analysis of basic data. It will then progress to patient‑related outcomes.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) or our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Recognition and referral\n\nEnsure that robust protocols and pathways are in place to:\n\ninform healthcare professionals about motor neurone disease (MND) and how it may present\n\ninform healthcare professionals in all settings about local referral arrangements\n\nensure continued and integrated care for people with MND across all care settings. \n\nBe aware that MND causes progressive muscular weakness that may first present as isolated and unexplained symptoms. These symptoms may include:\n\nfunctional effects of muscle weakness, such as loss of dexterity, falls or trips\n\nspeech or swallowing problems, or tongue fasciculations (this is known as bulbar presentation)\n\nmuscle problems, such as weakness, wasting, twitching, cramps and stiffness\n\nbreathing problems, such as shortness of breath on exertion or respiratory symptoms that are hard to explain\n\neffects of reduced respiratory function, such as excessive daytime sleepiness, fatigue, early morning headache or shortness of breath when lying down. \n\nBe aware that MND may first present with cognitive features, which may include:\n\nbehavioural changes\n\nemotional lability (not related to dementia)\n\nfrontotemporal dementia. \n\nIf you suspect MND, refer the person without delay and specify the possible diagnosis in the referral letter. Contact the consultant neurologist directly if you think the person needs to be seen urgently. \n\nProvide information and support for people and their family members and/or carers (as appropriate) throughout the diagnostic process, particularly during periods of diagnostic uncertainty or delay. \n\n# Information and support at diagnosis\n\nPlease also refer to the recommendations in the NICE guideline on patient experience in adult NHS services, which includes recommendations on communication, information and coordination of care.\n\nInformation about the diagnosis, prognosis and management of MND should be given by a consultant neurologist with up‑to‑date knowledge and experience of treating people with MND unless it is clinically necessary to give the diagnosis in an urgent situation. The neurologist should have knowledge and expertise in the following:\n\nSymptoms of MND.\n\nTypes and possible causes of MND.\n\nTreatment options.\n\nHow MND may progress (including cognitive and behavioural changes) and how progression may affect the treatments offered.\n\nCrisis prevention (for example, if there is an acute hospital admission or a breakdown in care arrangements).\n\nOpportunities for people with MND to be involved in research.\n\nLikely needs and concerns of people with MND and their family members and/or carers (as appropriate).\n\nAdvance care planning. \n\nAsk people about how much information they wish to receive about MND, and about their preferences for involving their family members and/or carers (as appropriate). \n\nEnsure people are provided with information about MND and support at diagnosis or when they ask for it. If the person agrees, share the information with their family members and/or carers (as appropriate). Information should be oral and written, and may include the following:\n\nWhat MND is.\n\nTypes and possible causes.\n\nLikely symptoms and how they can be managed.\n\nHow MND may progress.\n\nTreatment options.\n\nWhere the person's appointments will take place.\n\nWhich healthcare professionals and social care practitioners will undertake the person's care.\n\nExpected waiting times for consultations, investigations and treatments.\n\nLocal services (including social care and specialist palliative care services) and how to get in touch with them.\n\nLocal support groups, online forums and national charities, and how to get in touch with them.\n\nLegal rights, including social care support, employment rights and benefits.\n\nRequirements for disclosure, such as notifying the Driver and Vehicle Licensing Agency (DVLA).\n\nOpportunities for advance care planning. \n\nWhen MND is diagnosed, provide people with a single point of contact for the specialist MND multidisciplinary team (see section 1.5). Provide information about what to do if there are any concerns between assessments or appointments, during 'out‑of‑hours' or in an emergency, or if there is a problem with equipment. \n\nOffer the person with MND a face‑to‑face, follow‑up appointment with a healthcare professional from the multidisciplinary team, to take place within 4\xa0weeks of diagnosis. \n\nWhen MND is suspected or confirmed, inform the person's GP without delay and provide information about the likely prognosis. \n\nSet aside enough time to discuss the person's concerns and questions, which may include the following:\n\nWhat will happen to me?\n\nAre there any treatments available?\n\nIs there a cure?\n\nHow long will I live?\n\nWhat will the impact on my day‑to‑day life be?\n\nWhat will happen next with my healthcare?\n\nWill my children get MND?\n\nHow do I tell my family and friends?\n\nHow will I die? \n\nIf the person has any social care needs, refer them to social services for an assessment. Be aware that some people with MND may not have informal care available, and may live alone or care for someone else. \n\nAdvise carers about their right to carer assessment, and assessment for respite care and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers). \n\n# Cognitive assessments\n\nPlease also refer to the recommendations in the NICE guideline on patient experience in adult NHS services.\n\nBe aware that people with MND and frontotemporal dementia may lack mental capacity. Care should be provided in line with the Mental Capacity Act 2005. \n\nAt diagnosis, and if there is concern about cognition and behaviour, explore any cognitive or behavioural changes with the person and their family members and/or carers as appropriate. If needed, refer the person for a formal assessment in line with the NICE guideline on dementia. \n\nTailor all discussions to the person's needs, taking into account their communication ability, cognitive status and mental capacity. \n\n# Prognostic factors\n\nWhen planning care take into account the following prognostic factors, which are associated with shorter survival if they are present at diagnosis:\n\nSpeech and swallowing problems (bulbar presentation).\n\nWeight loss.\n\nPoor respiratory function.\n\nOlder age.\n\nLower Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS or ALSFRS‑R) score.\n\nShorter time from first developing symptoms to time of diagnosis. \n\n# Organisation of care\n\nProvide coordinated care for people with MND, using a clinic‑based, specialist MND multidisciplinary team approach. The clinic may be community or hospital based. \n\nThe multidisciplinary team should:\n\ninclude healthcare professionals and social care practitioners with expertise in MND, and staff who see people in their home\n\nensure effective communication and coordination between all healthcare professionals and social care practitioners involved in the person's care and their family members and/or carers (as appropriate)\n\ncarry out regular, coordinated assessments at the multidisciplinary team clinic (usually every 2 to 3\xa0months) to assess people's symptoms and needs\n\nprovide coordinated care for people who cannot attend the clinic, according to the person's needs. \n\nThe multidisciplinary team should assess, manage and review the following areas, including the person's response to treatment:\n\nWeight, diet, nutritional intake and fluid intake, feeding and swallowing (see section 1.10).\n\nMuscle problems, such as weakness, stiffness and cramps (see recommendations 1.8.1 to 1.8.9).\n\nPhysical function, including mobility and activities of daily living (see section 1.9).\n\nSaliva problems, such as drooling of saliva (sialorrhoea) and thick, tenacious saliva (see recommendations 1.8.10 to 1.8.15).\n\nSpeech and communication (see section 1.11).\n\nCough effectiveness (see section 1.13).\n\nRespiratory function, respiratory symptoms and non‑invasive ventilation (see section 1.12 and section 1.14).\n\nPain and other symptoms, such as constipation.\n\nCognition and behaviour (see section 1.3).\n\nPsychological support needs (see recommendations 1.6.1 to 1.6.4).\n\nSocial care needs (see recommendations 1.6.5 and 1.6.6).\n\nEnd of life care needs (see section 1.7).\n\nInformation and support needs for the person and their family members and/or carers (as appropriate) (see section 1.2). \n\nThe core multidisciplinary team should consist of healthcare professionals and other professionals with expertise in MND, and should include the following:\n\nNeurologist.\n\nSpecialist nurse.\n\nDietitian.\n\nPhysiotherapist.\n\nOccupational therapist.\n\nRespiratory physiologist or a healthcare professional who can assess respiratory function.\n\nSpeech and language therapist.\n\nA healthcare professional with expertise in palliative care (MND palliative care expertise may be provided by the neurologist or nurse in the multidisciplinary team, or by a specialist palliative care professional). \n\nThe multidisciplinary team should have established relationships with, and prompt access to, the following:\n\nClinical psychology and neuropsychology.\n\nSocial care.\n\nCounselling.\n\nRespiratory ventilation services.\n\nSpecialist palliative care.\n\nGastroenterology.\n\nOrthotics.\n\nWheelchair services.\n\nAssistive technology services.\n\nAlternative and augmentative communication (AAC) services.\n\nCommunity neurological care teams. \n\nTailor the frequency of the multidisciplinary team assessments to the person's symptoms and needs, with more or less frequent assessments as needed. \n\nEnsure arrangements are in place to trigger an earlier multidisciplinary team assessment if there is a significant change in symptoms identified by the person, family members and/or carers (as appropriate), or healthcare professionals. \n\nTailor the multidisciplinary team assessment to the person's needs, for example, adjust the format if the person has cognitive or behaviour changes or difficulties with communication. \n\nInform all healthcare professionals and social care practitioners involved in the person's care about key decisions reached with the person and their family members and/or carers (as appropriate). \n\nEnsure that all healthcare professionals and social care practitioners involved in the person's care are aware that MND symptoms may get worse quickly, and that people with MND will need repeated, ongoing assessments. Priority should be given to ensuring continuity of care and avoiding untimely case closure. \n\nConsider referral to a specialist palliative care team for people with current or anticipated significant or complex needs, for example, psychological or social distress, troublesome or rapidly progressing symptoms and complex future care planning needs. \n\nFor guidance on the use of riluzole for people with MND, see the NICE technology appraisal guidance on the use of riluzole (Rilutek) for the treatment of motor neurone disease. \n\n# Psychological and social care support\n\nDuring multidisciplinary team assessments and other appointments, discuss the psychological and emotional impact of MND with the person and ask whether they have any psychological or support care needs. Topics to discuss may include the following:\n\nTheir understanding of MND and how it affects daily living.\n\nAccepting and coping with the diagnosis and prognosis, including concerns and fears about dying.\n\nTheir ability to continue with current work and usual activities.\n\nAdjusting to changes in their life and their perception of self.\n\nChanges in relationships, familial roles and family dynamics.\n\nSexuality and intimacy.\n\nConcerns about their family members and/or carers.\n\nDecision-making. \n\nOffer the person information about sources of emotional and psychological support, including support groups and online forums. If needed, refer the person to counselling or psychology services for a specialist assessment and support. \n\nDuring multidisciplinary team assessments and other appointments, discuss the psychological and emotional impact of MND with family members and/or carers (as appropriate), and ask whether they have any psychological or social care support needs. Topics to discuss may include the following:\n\nTheir understanding of MND and how it affects daily living.\n\nAccepting and coping with the diagnosis and prognosis, including concerns and fears about the person with MND dying.\n\nAdjusting to changes in their life.\n\nChanges in relationships, familial roles and family dynamics, including their change to a carer role (if appropriate).\n\nSexuality and intimacy.\n\nInvolvement in decision‑making.\n\nImpact on other family members and/or carers.\n\nTheir ability and willingness to provide personal care and operate equipment.See the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers. \n\nOffer family members and/or carers (as appropriate) information about respite care and sources of emotional and psychological support, including support groups, online forums and counselling or psychology services. \n\nA social care practitioner with knowledge of MND or rapidly progressive complex disabilities should discuss the person's needs and preferences for social care, and provide information and support for them to access the following:\n\nPersonal care, ensuring there is continuity of care with familiar workers, so that wherever possible, personal care and support is carried out by workers known to the person and their family members and/or carers (as appropriate).\n\nEquipment and practical support (see section 1.9).\n\nFinancial support and advice (for example, money management, how to access carers' and disability benefits and grants, continuing healthcare funding and funeral expenses).\n\nSupport to engage in work, social activities and hobbies, such as access to social media and physical access to activities outside their home.\n\nRespite care. \n\nBe aware that as MND progresses, people may develop communication problems and have difficulty accessing support or services. For example, they may be unable to access a call centre. Ensure people are given different ways of getting in touch with support or services, and a designated contact if possible. \n\n# Planning for end of life\n\nOffer the person with MND the opportunity to discuss their preferences and concerns about care at the end of life at trigger points such as: at diagnosis, if there is a significant change in respiratory function, or if interventions such as gastrostomy or non‑invasive ventilation are needed. Be sensitive about the timing of discussions and take into account the person's current communication ability, cognitive status and mental capacity. \n\nBe prepared to discuss end of life issues whenever people wish to do so. \n\nProvide support and advice on advance care planning for end of life. Topics to discuss may include:\n\nWhat could happen at the end of life, for example, how death may occur.\n\nProviding anticipatory medicines in the home.\n\nAdvance care planning, including Advance Decisions to Refuse Treatment (ADRT) and Do Not Attempt Resuscitation (DNACPR) orders, and Lasting Power of Attorney.\n\nHow to ensure advance care plans will be available when needed, for example, including the information on the person's Summary Care Record.\n\nWhen to involve specialist palliative care.\n\nAreas that people might wish to plan for, such as:\n\n\n\nwhat they want to happen (for example, their preferred place of death)\n\nwhat they do not want to happen (for example, being admitted to hospital)\n\nwho will represent their decisions, if necessary\n\nwhat should happen if they develop an intercurrent illness. \n\n\n\nThink about discussing advance care planning with people at an earlier opportunity if you expect their communication ability, cognitive status or mental capacity to get worse. \n\nOffer people the opportunity to talk about, and review any existing, ADRT, DNACPR orders and Lasting Power of Attorney when interventions such as gastrostomy and non‑invasive ventilation are planned. \n\nProvide additional support as the end of life approaches, for example, additional social or nursing care to enable informal carers and family to reduce their carer responsibilities and spend time with the person with MND. \n\nTowards the end of life, ensure there is prompt access to the following, if not already provided:\n\nA method of communication that meets the person's needs, such as an AAC system.\n\nSpecialist palliative care.\n\nEquipment, if needed, such as syringe drivers, suction machines, riser–recliner chair, hospital bed, commode and hoist.\n\nAnticipatory medicines, including opioids and benzodiazepines to treat breathlessness, and antimuscarinic medicines to treat problematic saliva and respiratory secretions. \n\nOffer bereavement support to family members and/or carers (as appropriate). \n\n# Managing symptoms\n\n## Pharmacological treatments for muscle problems\n\nDiscuss the available treatment options for muscle problems. Take into account the person's needs and preferences, and whether they have any difficulties taking medicine (for example, if they have problems swallowing). \n\nConsider quinine as first‑line treatment for muscle cramps in people with MND. If quinine is not effective, not tolerated or contraindicated, consider baclofen instead as second‑line treatment. If baclofen is not effective, not tolerated or contraindicated, consider tizanidine, dantrolene or gabapentin.In February 2016 this was an off-label use of quinine, baclofen, tizanidine, and dantrolene. See NICE's information on prescribing medicines and the MHRA safety advice on prescribing gabapentin. \n\nConsider baclofen, tizanidine, dantrolene or gabapentin to treat muscle stiffness, spasticity or increased tone in people with MND. If these treatments are not effective, not tolerated or contraindicated, consider referral to a specialist service for the treatment of severe spasticity.In February 2016 this was an off-label use of dantrolene. See NICE's information on prescribing medicines and the MHRA safety advice on prescribing gabapentin. \n\nReview the treatments for muscle problems during multidisciplinary team assessments, ask about how the person is finding the treatment, whether it is working and whether they have any adverse side effects. \n\n## Exercise programmes\n\nConsider an exercise programme for people with MND to:\n\nmaintain joint range of movement\n\nprevent contractures\n\nreduce stiffness and discomfort\n\noptimise function and quality of life. \n\nChoose a programme that is appropriate to the person's level of function and tailored to their needs, abilities and preferences. Take into account factors such as postural needs and fatigue. The programme might be a resistance programme, an active‑assisted programme or a passive programme. \n\nCheck that family members and/or carers (as appropriate) are willing and able to help with exercise programmes. \n\nGive advice to the person and their family members and/or carers (as appropriate) about safe manual handling. \n\nIf a person needs orthoses to help with muscle problems, they should be referred to orthotics services without delay, and the orthoses should be provided without delay. \n\n## Saliva problems\n\nIf a person with MND has problems with saliva, assess the volume and viscosity of the saliva and the person's respiratory function, swallowing, diet, posture and oral care. \n\nIf a person with MND has problems with drooling of saliva (sialorrhoea), provide advice on swallowing, diet, posture, positioning, oral care and suctioning. \n\nConsider a trial of antimuscarinic medicine as the first‑line treatment for sialorrhoea in people with MND.In February 2016 this was an off-label use of antimuscarinic medicine. See NICE's information on prescribing medicines. \n\nConsider glycopyrrolate as the first‑line treatment for sialorrhoea in people with MND who have cognitive impairment, because it has fewer central nervous system side effects.In February 2016 this was an off-label use of glycopyrrolate. See NICE's information on prescribing medicines. \n\nIf first-line treatment for sialorrhoea is not effective, not tolerated or contraindicated, consider referral to a specialist service for Botulinum toxin\xa0A. In September 2019 Xeomin was the only Botulinium toxin\xa0A with a UK marketing authorisation for this indication.\n\nIf a person with MND has thick, tenacious saliva:\n\nreview all current medicines, especially any treatments for sialorrhoea\n\nprovide advice on swallowing, diet, posture, positioning, oral care, suctioning and hydration\n\nconsider treatment with humidification, nebulisers and carbocisteine. \n\n# Equipment and adaptations to aid activities of daily living and mobility\n\nHealthcare professionals and social care practitioners, which will include physiotherapists and occupational therapists, should assess and anticipate changes in the person's daily living needs, taking into account the following:\n\nActivities of daily living, including personal care, dressing and bathing, housework, shopping, food preparation, eating and drinking, and ability to continue with current work and usual activities.\n\nMobility and avoiding falls and problems from loss of dexterity.\n\nThe home environment and the need for adaptations.\n\nThe need for assistive technology, such as environmental control systems. \n\nProvide equipment and adaptations that meet the person's needs without delay, so that people can participate in activities of daily living and maintain their quality of life as much as possible. \n\nRefer people to specialist services without delay if assistive technology such as environmental control systems is needed. People should be assessed and assistive technology provided without delay. \n\nRefer people to wheelchair services without delay if needed. Wheelchair needs should be assessed and a manual and/or powered wheelchair that meets the person's needs should be provided without delay. \n\nEnsure that equipment, adaptations, daily living aids, assistive technology and wheelchairs meet the changing needs of the person and their family and/or carers (as appropriate) to maximise mobility and participation in activities of daily living. \n\nEnsure regular, ongoing monitoring of the person's mobility and daily life needs and abilities as MND progresses. Regularly review their ability to use equipment and to adapt equipment as necessary. \n\nHealthcare professionals, social care practitioners and other services providing equipment should liaise to ensure that all equipment provided can be integrated, for example, integrating AAC aids and devices and environmental control systems with wheelchairs. \n\nEnable prompt access and assessment for funding for home adaptation. If the person is not eligible for funding, continue to offer information and support in arranging home environment adaptations. \n\n# Nutrition and gastrostomy\n\nPlease also refer to the recommendations in the NICE guideline on nutrition support for adults.\n\nAt diagnosis and at multidisciplinary team assessments, or if there are any concerns about weight, nutrition or swallowing, assess the person's weight, diet, nutritional intake, fluid intake, hydration, oral health, feeding, drinking and swallowing, and offer support, advice and interventions as needed. \n\nAssess the person's diet, hydration, nutritional intake and fluid intake by taking into account:\n\nfluids and food intake versus nutritional and hydration needs\n\nnutritional supplements, if needed\n\nappetite and thirst\n\ngastrointestinal symptoms, such as nausea or constipation\n\ncauses of reduced oral intake (for example, swallowing difficulties, limb weakness or the possibility of low mood or depression causing loss of appetite). \n\nAssess the person's ability to eat and drink by taking into account:\n\nthe need for eating and drinking aids and altered utensils to help them take food from the plate to their mouth\n\nthe need for help with food and drink preparation\n\nadvice and aids for positioning, seating and posture while eating and drinking\n\ndealing with social situations (for example, eating out). \n\nArrange for a clinical swallowing assessment if swallowing problems are suspected. \n\nAssess and manage factors that may contribute to problems with swallowing, such as:\n\npositioning\n\nseating\n\nthe need to modify food and drink consistency and palatability\n\nrespiratory symptoms and risk of aspiration and/or choking\n\nfear of choking and psychological considerations (for example, wanting to eat and drink without assistance in social situations). \n\nDiscuss gastrostomy at an early stage, and at regular intervals as MND progresses, taking into account the person's preferences and issues, such as ability to swallow, weight loss, respiratory function, effort of feeding and drinking and risk of choking. Be aware that some people will not want to have a gastrostomy. \n\nExplain the benefits of early placement of a gastrostomy, and the possible risks of a late gastrostomy (for example, low critical body mass, respiratory complications, risk of dehydration, different methods of insertion, and a higher risk of mortality and procedural complications). \n\nIf a person is referred for a gastrostomy, it should take place without unnecessary delay. \n\nPay particular attention to the nutritional and hydration needs of people with MND who have frontotemporal dementia and who lack mental capacity. The multidisciplinary team assessment should include the support they need from carers, and their ability to understand the risks of swallowing difficulties. \n\nBefore a decision is made on the use of gastrostomy for a person with MND who has frontotemporal dementia, the neurologist from the multidisciplinary team should assess the following:\n\nThe person's ability to make decisions and to give consent (see Mental Capacity Act 2005).\n\nThe severity of frontotemporal dementia and cognitive problems.\n\nWhether the person is likely to accept and cope with treatment.Discuss with the person's family members and/or carers (as appropriate; with the person's consent if they have the ability to give it). \n\n# Communication\n\nWhen assessing speech and communication needs during multidisciplinary team assessments and other appointments, discuss face‑to‑face and remote communication, for example, using the telephone, email, the Internet and social media. Ensure that the assessment and review is carried out by a speech and language therapist without delay. \n\nProvide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life. The use of both low‑level technologies, for example, alphabet, word or picture boards and high‑level technologies, for example, PC or tablet‑based voice output communication aids may be helpful. Review the person's communication needs during multidisciplinary team assessments. \n\nLiaise with, or refer the person with MND to, a specialised NHS AAC hub if complex high technology AAC equipment (for example, eye gaze access) is needed or is likely to be needed. \n\nInvolve other healthcare professionals, such as occupational therapists, to ensure that AAC equipment is integrated with other assistive technologies, such as environmental control systems and personal computers or tablets. \n\nEnsure regular, ongoing monitoring of the person's communication needs and abilities as MND progresses, and review their ability to use AAC equipment. Reassess and liaise with a specialised NHS AAC hub if needed. \n\nProvide ongoing support and training for the person with MND, and their family members and/or carers (as appropriate), in using AAC equipment and other communication strategies. \n\n# Respiratory function and respiratory symptoms\n\nAssess and monitor the person's respiratory function and symptoms. Treat people with MND and worsening respiratory impairment for reversible causes (for example, respiratory tract infections or secretion problems) before considering other treatments. \n\nOffer non-invasive ventilation as treatment for people with respiratory impairment (see section 1.14). Decisions to offer non‑invasive ventilation should be made by the multidisciplinary team in conjunction with the respiratory ventilation service, and the person (see recommendations 1.5.1 to 1.5.5). \n\nConsider urgent introduction of non‑invasive ventilation for people with MND who develop worsening respiratory impairment and are not already using non‑invasive ventilation. \n\nConsider opioids as an option to relieve symptoms of breathlessness. Take into account the route of administration and acquisition cost of medicines.In February 2016 this was an off-label use of opioids. See NICE's information on prescribing medicines for more information. \n\nConsider benzodiazepines to manage breathlessness that is exacerbated by anxiety. Take into account the route of administration and acquisition cost of medicines.In February 2016 this was an off-label use of benzodiazepines. See NICE's information on prescribing medicines. \n\n# Cough effectiveness\n\nOffer cough augmentation techniques such as manual assisted cough to people with MND who cannot cough effectively. \n\nConsider unassisted breath stacking and/or manual assisted cough as the first‑line treatment for people with MND who have an ineffective cough. \n\nFor people with bulbar dysfunction, or whose cough is ineffective with unassisted breath stacking, consider assisted breath stacking (for example, using a lung volume recruitment bag). \n\nConsider a mechanical cough assist device if assisted breath stacking is not effective, and/or during a respiratory tract infection. \n\n# Non-invasive ventilation\n\n## Information and support about non‑invasive ventilation\n\nOffer to discuss the possible use of non‑invasive ventilation with the person and (if the person agrees) their family and carers, at an appropriate time and in a sensitive manner. This may be at one or more of the following times:\n\nsoon after MND is first diagnosed\n\nwhen monitoring respiratory function\n\nwhen respiratory function deteriorates\n\nif the person asks for information. \n\nDiscussions about non‑invasive ventilation should be appropriate to the stage of the person's illness, carried out in a sensitive manner and include information on:\n\nthe possible symptoms and signs of respiratory impairment (see table 1)\n\nthe purpose, nature and timing of respiratory function tests, and explanations of the test results\n\nhow non‑invasive ventilation (as a treatment option) can improve symptoms associated with respiratory impairment and can be life prolonging, but does not stop progression of the underlying disease. [2010, amended 2016]\n\nWhen discussing non‑invasive ventilation, explain the different ways that people can manage their breathlessness symptoms. This should include:\n\nnon-invasive ventilation, and its advantages and disadvantages\n\nusing non-invasive ventilation at different points in the course of the person's lifetime\n\nthe possibility of the person becoming dependent on non‑invasive ventilation\n\noptions for treating any infections\n\nsupport and information on how to recognise and cope with a distressing situation\n\nthe role of medication for breathing problems\n\npsychological techniques and support. \n\nCheck that the person thinking about non‑invasive ventilation:\n\nunderstands what non‑invasive ventilation is and what it can achieve\n\nrecognises the need for regular review\n\nhas enough information about non‑invasive ventilation and other options for breathing problems to make decisions about how and when to use it.\n\nunderstands possible problems with compatibility with other equipment, for example, eye gaze access systems. \n\nExplain that non-invasive ventilation can be stopped at any time. Reassure people that they can ask for help and advice if they need it, especially if they are dependent on non‑invasive ventilation for 24\xa0hours a day, or become distressed when attempting to stop it. Inform people that medicines can be used to alleviate symptoms (see recommendation\xa01.14.29). \n\nEnsure that families and carers:\n\nhave an initial assessment if the person they care for decides to use non‑invasive ventilation, which should include:\n\n\n\ntheir ability and willingness to assist in providing non‑invasive ventilation\n\ntheir training needs\n\n\n\nhave the opportunity to discuss any concerns they may have with members of the multidisciplinary team, the respiratory ventilation service and/or other healthcare professionals. \n\n## Identification and assessment of respiratory impairment\n\nMonitor the symptoms and signs listed in table\xa01 to detect potential respiratory impairment. [2010, amended 2016]\n\nSymptoms\n\nSigns\n\nBreathlessness\n\nIncreased respiratory rate\n\nOrthopnoea\n\nShallow breathing\n\nRecurrent chest infections\n\nWeak cough\n\nDisturbed sleep\n\nWeak sniff\n\nNon-refreshing sleep\n\nAbdominal paradox (inward movement of the abdomen during inspiration)\n\nNightmares\n\nUse of accessory muscles of respiration\n\nDaytime sleepiness\n\nReduced chest expansion on maximal inspiration\n\nPoor concentration and/or memory\n\n–\n\nConfusion\n\n–\n\nHallucinations\n\n–\n\nMorning headaches\n\n–\n\nFatigue\n\n–\n\nPoor appetite\n\n–\n\nWeak cough could be assessed by measuring peak cough flow.\n\nAs part of the initial assessment to diagnose MND, or soon after diagnosis, a healthcare professional from the multidisciplinary team who has appropriate competencies should perform the following tests (or arrange for them to be performed) to establish the person's baseline respiratory function:\n\noxygen saturation measured by pulse oximetry (SpO2):\n\n\n\nthis should be a single measurement of SpO2 with the person at rest and breathing room air\n\nif it is not possible to perform pulse oximetry locally, refer the person to a respiratory ventilation service.Then one or both of the following:\n\n\n\nforced vital capacity (FVC) or vital capacity (VC)\n\nsniff nasal inspiratory pressure (SNIP) and/or maximal inspiratory pressure (MIP). Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nIf the person has severe bulbar impairment or severe cognitive problems that may be related to respiratory impairment:\n\nensure that SpO2 is measured (at rest and breathing room air)\n\ndo not perform the other respiratory function tests (FVC, VC, SNIP and MIP) if interfaces are not suitable for the person. \n\nA healthcare professional with appropriate competencies should perform the respiratory function tests every 2 to 3\xa0months, although tests may be performed more or less often depending on:\n\nwhether there are any symptoms and signs of respiratory impairment (see table 1)\n\nthe rate of progression of MND\n\nthe person's preference and circumstances. [2010, amended 2016]\n\nPerform arterial or capillary blood gas analysis if the person's SpO2 (measured at rest and breathing room air):\n\nis less than or equal to 92% if they have known lung disease\n\nis less than or equal to 94% if they do not have lung disease.If it is not possible to perform arterial or capillary blood gas analysis locally, refer the person to a respiratory ventilation service. \n\nIf the person's SpO2 (measured at rest and breathing room air) is greater than 94%, or 92% for those with lung disease, but they have sleep‑related respiratory symptoms:\n\nconsider referring them to a respiratory ventilation service for continuous nocturnal (overnight) oximetry and/or a limited sleep study and\n\ndiscuss both the impact of respiratory impairment and treatment options with the patient and (if the person agrees) their family and carers. \n\nIf the person's arterial partial pressure of carbon dioxide (PaCO2) is greater than 6\xa0kPa:\n\nrefer them urgently to a respiratory ventilation service (to be seen within 1\xa0week) and\n\nexplain the reasons for and implications of the urgent referral to the person and (if the person agrees) their family and carers. \n\nIf the person's PaCO2 is less than or equal to 6\xa0kPa but they have any symptoms or signs of respiratory impairment, particularly orthopnoea (see recommendation 1.14.15):\n\nrefer them to a respiratory ventilation service for nocturnal (overnight) oximetry and/or a limited sleep study and\n\ndiscuss both the impact of respiratory impairment and treatment options with the person and (if the person agrees) their family and/or carers (as appropriate). \n\nIf any of the results listed in table 2 is obtained, discuss with the person and (if appropriate) their family and carers:\n\ntheir respiratory impairment\n\ntheir treatment options\n\npossible referral to a respiratory ventilation service for further assessment based on discussion with the person, and their wishes. [2010, amended 2016]\n\nForced vital capacity (FVC) or vital capacity (VC)\n\nSniff nasal inspiratory pressure (SNIP) and/or maximal inspiratory pressure (MIP)\n\n(if both tests are performed, base the assessment on the better respiratory function reading)\n\nFVC or VC less than 50% of predicted value\n\nSNIP or MIP less than 40\xa0cmH2O\n\nFVC or VC less than 80% of predicted value plus any symptoms or signs of respiratory impairment (see recommendation 1.14.7), particularly orthopnoea\n\nSNIP or MIP less than 65\xa0cmH2O for men or 55\xa0cmH2O for women plus any symptoms or signs of respiratory impairment (see recommendation 1.14.7), particularly orthopnoea\n\n–\n\nRepeated regular tests show a rate of decrease of SNIP or MIP of more than 10\xa0cm\xa0H2O per 3\xa0months\n\nBase decisions on respiratory function tests for a person with a diagnosis of frontotemporal dementia on considerations specific to their needs and circumstances, such as:\n\ntheir ability to give consent\n\ntheir understanding of the tests\n\ntheir tolerance of the tests and willingness to undertake them\n\nthe impact on their family and carers\n\nwhether they are capable of receiving non‑invasive ventilation. [2010, amended 2016]\n\n## Non-invasive ventilation for treatment of respiratory impairment in people with MND\n\nOffer a trial of non-invasive ventilation if the person's symptoms and signs and the results of the respiratory function tests indicate that the person is likely to benefit from the treatment. [2010, amended 2016]\n\nConsider a trial of non‑invasive ventilation for a person who has severe bulbar impairment or severe cognitive problems that may be related to respiratory impairment only if they may benefit from an improvement in sleep‑related symptoms or correction of hypoventilation. [2010, amended 2016]\n\nBefore starting non-invasive ventilation, the multidisciplinary team together with the respiratory ventilation service should carry out and coordinate a patient‑centred risk assessment, after discussion with the person and their family and carers. This should consider:\n\nthe most appropriate type of non‑invasive ventilator and interfaces, based on the person's needs and lifestyle factors and safety\n\nthe person's tolerance of the treatment\n\nthe risk, and possible consequences, of ventilator failure\n\nthe power supply required, including battery back‑up\n\nhow easily the person can get to hospital\n\nrisks associated with travelling away from home (especially abroad)\n\nwhether a humidifier is required\n\nissues relating to secretion management\n\nthe availability of carers. \n\nBefore starting non-invasive ventilation, the multidisciplinary team together with the respiratory ventilation service should prepare a comprehensive care plan, after discussion with the person and their family and carers (who should be offered a copy of the plan). This should cover:\n\nlong-term support provided by the multidisciplinary team\n\nthe initial frequency of respiratory function tests and monitoring of respiratory impairment\n\nthe frequency of clinical reviews of symptomatic and physiological changes\n\nthe provision of carers\n\narrangements for device maintenance and 24‑hour emergency clinical and technical support\n\nsecretion management and respiratory physiotherapy assessment, including cough augmentation (if required)\n\ntraining in and support for the use of non-invasive ventilation for the person and their family and carers\n\nregular opportunities to discuss the person's wishes in relation to continuing or withdrawing non‑invasive ventilation. [2010, amended 2016]\n\nWhen starting non‑invasive ventilation:\n\nperform initial acclimatisation during the day when the person is awake\n\nusually start regular treatment at night, before and during sleep\n\ngradually build up the person's hours of use as necessary. \n\nContinue non-invasive ventilation if the clinical reviews show:\n\nsymptomatic and/or physiological improvements for a person without severe bulbar impairment and without severe cognitive problems\n\nan improvement in sleep‑related symptoms for a person with severe bulbar impairment or with severe cognitive problems that may be related to respiratory impairment. \n\nProvide the person and their family and/or carers (as appropriate) with support and assistance to manage non‑invasive ventilation. This should include:\n\ntraining on using non‑invasive ventilation and ventilator interfaces, for example:\n\n\n\nemergency procedures\n\nnight-time assistance if the person is unable to use the equipment independently (for example, emergency removal or replacement of interfaces)\n\nhow to use the equipment with a wheelchair or other mobility aids if required\n\nwhat to do if the equipment fails\n\n\n\nassistance with secretion management\n\ninformation on general palliative strategies\n\nan offer of ongoing emotional and psychological support for the person and their family and carers. [2010, amended 2016]\n\nDiscuss all decisions to continue or withdraw non‑invasive ventilation with the person and (if the person agrees) their family and carers. \n\nBefore a decision is made on the use of non‑invasive ventilation for a person with a diagnosis of frontotemporal dementia, the multidisciplinary team together with the respiratory ventilation service should carry out an assessment that includes:\n\nthe person's capacity to make decisions and to give consent (see Mental Capacity Act 2005)\n\nthe severity of dementia and cognitive problems\n\nwhether the person is likely to accept treatment\n\nwhether the person is likely to achieve improvements in sleep‑related symptoms and/or behavioural improvements\n\na discussion with the person's family and/or carers (with the person's consent if they have the capacity to give it). [2010, amended 2016]\n\nConsider prescribing medicines to help ease breathlessness that people using non‑invasive ventilation can take on an 'as‑needed' basis at home, for example, opioids or benzodiazepines.In February 2016 this was an off-label use of opioids and benzodiazepines. See NICE's information on prescribing medicines. \n\nInform services that may see the person in crisis situations, such as their GP and services that provide emergency or urgent care, that the person is using non‑invasive ventilation. \n\n## Stopping non-invasive ventilation\n\nThe healthcare professionals responsible for starting non‑invasive ventilation treatment in people with MND should ensure that support is available for other healthcare professionals who may be involved if there is a plan to stop non‑invasive ventilation, including the legal and ethical implications. \n\nIf a person on continuous non‑invasive ventilation wishes to stop treatment, ensure that they have support from healthcare professionals with knowledge and expertise of:\n\nstopping non‑invasive ventilation\n\nthe ventilator machine\n\npalliative medicines (see the NICE guideline on care of dying adults in the last days of life)\n\nsupporting the person, family members and/or carers (as appropriate)\n\nsupponad rting other healthcare professionals involved with the person's care\n\nlegal and ethical frameworks and responsibilities. \n\nIf a person on continuous non‑invasive ventilation wishes to stop treatment, seek advice from healthcare professionals who have knowledge and experience of stopping non‑invasive ventilation. \n\nHealthcare professionals involved in stopping non‑invasive ventilation should have up‑to‑date knowledge of the law regarding the Mental Capacity Act, DNACPR, ADRT orders, and Lasting Power of Attorney. ", 'Context': "Motor neurone disease (MND) is a neurodegenerative condition that affects the brain and spinal cord. MND is characterised by the degeneration of primarily motor neurones, leading to muscle weakness.\n\nThe presentation of the disease varies and can be as muscle weakness, wasting, cramps and stiffness of arms and/or legs; problems with speech and/or swallowing or, more rarely, with breathing problems. As the disease progresses, the pattern of symptoms and signs becomes similar, with increasing muscle weakness in the person's arms and legs, problems swallowing and communicating and weakness of the muscles used for breathing, which ultimately leads to death. Most people die within 2 to 3\xa0years of developing symptoms, but 25% are alive at 5\xa0years and 5% to 10% at 10\xa0years. The most common type of MND is amyotrophic lateral sclerosis (ALS). There are rarer forms of MND such as progressive muscular atrophy or primary lateral sclerosis, which may have a slower rate of progression.\n\nEvery person with MND has an individual progression of the disease. About 10% to 15% of people with MND will show signs of frontotemporal dementia, which causes cognitive dysfunction and issues in decision‑making. A further 35% of people with MND show signs of mild cognitive change, which may affect their ability to make decisions and plan ahead.\n\nMND is a disorder which can affect adults of any age. It is most common in people aged 55 to 79\xa0years, and onset below the age of 40\xa0years is uncommon. There are approximately 4,000\xa0people living with MND in England and Wales at any one time. The cause of MND is unknown. About 5% to 10% of people with MND have a family history of the disease and several abnormal genes have been identified.\n\nAs there is no cure for MND, care focuses on maintaining functional ability and enabling people with MND and their family members to live as full a life as possible. Early diagnosis, without delay after investigation, may be helpful, as it allows medication and the provision of aids, as well as communication about the disease and advance care planning to be undertaken appropriately.\n\nCare of people with MND varies across England and Wales, with MND care centres and networks providing coordinated multidisciplinary care. However, some people with MND are left isolated and their care is less than ideal. This guideline aims to consider the clinical and cost‑effectiveness evidence for the care of people with MND from the time of diagnosis, including communication of the diagnosis, monitoring of disease progression, management of symptoms (in particular muscle weakness, excess secretions, breathing and nutrition problems), ongoing support and services available, mobility, emotional and psychological changes, and the preparation for end of life care. Particular emphasis is placed on the importance of a multidisciplinary team approach to the care and management of people with MND.", 'Recommendations for research': "The Guideline Committee has made the following recommendations for research. The Committee's full set of recommendations for research is detailed in the full guideline.\n\n# Organisation of care\n\nIs a network‑based model as effective as a clinic‑based model to deliver multidisciplinary care to people with motor neurone disease (MND)?\n\n## Why this is important\n\nMultidisciplinary care improves survival in patients with MND. The evidence is drawn from models of multidisciplinary care that use a clinic based approach. However there are other models of care delivery in practice including care networks. Often these alternative models of care have arisen out of necessity in large geographical regions with low density populations. These alternative models may have similar survival advantages to patients with MND and this needs to be established.\n\n# Cognitive assessment\n\nWhat is the impact of assessing for cognitive and behaviour change in people with MND on clinical practice, the person and their family and carers? Does repeated assessment provide more benefit than assessment at a single point at diagnosis?\n\n## Why this is important\n\nClinic‑based and population‑based studies demonstrate that up to 15% of people with MND have frontotemporal dementia. A further third of people with MND have changes in behaviour and cognition. These impairments are present at diagnosis. Their course during the disease has shown varying patterns between studies although several studies have shown that cognitive and behavioural impairments predict poorer survival and increased carer burden. A randomised controlled trial is needed to assess whether formal assessment at diagnosis and/or repeated assessment improves clinical practice, subsequent care of the person and quality of life for the person, their family and carers.\n\n# Prognostic tools\n\nIs the ALS Prognostic Index an accurate predictor of survival in people with MND under NHS care in England and/or Wales?\n\n## Why this is important\n\nAccurate predictions of survival in people with MND would be of great use to clinicians and to the person with MND, their family and carers. Accurate predictions would enable people with MND to be clearer about their prognosis, make plans for the rest of their life and have a well‑prepared and dignified transition into the end of life phase. Family members would similarly benefit in being more aware of the likely progression and prepare themselves for the death of their loved one.\n\nAccurate predictions of survival would enable professionals to create and deliver more effective management and care plans and access services when it is most appropriate, for example specialist palliative care.\n\nThe ALS Prognostic Index (ALS‑PI) was developed in a cohort of people with ALS in the Republic of Ireland and externally validated in a cohort in Italy. However, it has not been validated in people with ALS, primary lateral sclerosis or progressive muscular atrophy in the NHS in England or Wales. The tool needs to be validated in a UK population using a simplified measure of executive function.\n\n# Saliva\n\nHow is excessive drooling of saliva (sialorrhoea) managed in people with MND?\n\n## Why this is important\n\nSialorrhoea affects up to 50% of people with MND and in 42% of these individuals the symptom is poorly controlled. There is no evidence base for clinicians to make decisions with regards to the treatment options available. Antimuscarinics are used first‑line but there is no evidence to inform which antimuscarinic and at what dose. Botulinum toxin is used second- or third‑line although there is little evidence to guide dosing, which salivary glands to inject and which type of botulinum toxin to use. Currently there is no baseline information about how specialists are using these treatments and this information is required to inform comparative studies.\n\n# Nutrition\n\nDoes a high calorific diet prolong survival of people with MND if initiated following diagnosis or following initiation of feeding using a gastrostomy?\n\n## Why this is important\n\nThere is little specific guidance on the optimal calorie intake for people with MND. There is growing evidence that people with MND have a hypercatabolic state and have high energy requirements. A large cohort study in the UK has demonstrated that nearly half of people continue to lose weight following gastrostomy and most show no improvement in their weight. A small study has demonstrated that high fat and high carbohydrate feeding may prolong survival in gastrostomy‑fed people. A larger randomised trial is needed to inform clinical practice.\n\n# Augmentative and alternative communication\n\nWhat is the current pattern of provision and use of augmentative and alternative communication (AAC) by people with MND in England?\n\n## Why this is important\n\nAppropriate AAC equipment can have a significant effect on quality of life for people with MND. While the NHS has a responsibility to provide equipment and ongoing support in its use, there are no reliable data on the types of equipment found most useful at different stages of the disease process, or the number of people with MND who may benefit from AAC. A prospective census study of people with MND presenting with early onset of speech problems is needed to establish the current baseline provision and needs of this population and how best to utilise AAC equipment. The programme will begin with the collection and analysis of basic data. It will then progress to patient‑related outcomes."}
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https://www.nice.org.uk/guidance/ng42
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This guideline covers assessing and managing motor neurone disease (MND). It aims to improve care from the time of diagnosis, and covers information and support, organisation of care, managing symptoms and preparing for end of life care.
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ed89f10129c8de0b2b79d3d2467af160b42cf85c
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nice
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Therapeutic monitoring of TNF-alpha inhibitors in rheumatoid arthritis
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Therapeutic monitoring of TNF-alpha inhibitors in rheumatoid arthritis
Evidence-based recommendations on enzyme-linked immunosorbent assay (ELISA) tests for therapeutic monitoring of tumour necrosis factor (TNF)-alpha inhibitors in rheumatoid arthritis. The tests are Promonitor, IDKmonitor, LISA‑tracker, RIDASCREEN, MabTrack, and those used by Sanquin Diagnostic Services.
# Recommendations
Enzyme-linked immunosorbent assay (ELISA) tests for therapeutic monitoring of tumour necrosis factor (TNF)-alpha inhibitors (drug serum levels and antidrug antibodies) show promise but there is currently insufficient evidence to recommend their routine adoption in rheumatoid arthritis. The ELISA tests covered by this guidance are Promonitor, IDKmonitor, LISA-TRACKER, RIDASCREEN, MabTrack, and tests used by Sanquin Diagnostic Services.
Laboratories currently using ELISA tests for therapeutic monitoring of TNF-alpha inhibitors in rheumatoid arthritis should do so as part of research and further data collection (see section 5.22).
Further research is recommended on the clinical effectiveness of using ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in rheumatoid arthritis (see sections 5.23, and 6.1 and 6.2).
Why the committee made these recommendations
TNF-alpha inhibitors can be an effective treatment option for severe rheumatoid arthritis that does not respond to conventional therapy. Therapeutic monitoring of TNF‑alpha inhibitors could help to optimise their use, improving management of the condition and outcomes that are important for people with rheumatoid arthritis. These include how long their disease is in remission, the rate of flares and relapse, and health-related quality of life.
The clinical-effectiveness evidence for ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in rheumatoid arthritis is not robust, although there are some positive trends. The key INGEBIO study is of poor quality and is not generalisable to NHS practice.
Results of the economic modelling based on INGEBIO are uncertain. So, although the tests show some promise, they are not recommended for routine use in the NHS. Further research would be valuable.# Clinical need and practice
# The problem addressed
Tumour necrosis factor (TNF)‑alpha inhibitors are recommended as treatment options for people with severe rheumatoid arthritis (disease activity score greater than 5.1) whose disease does not respond to intensive conventional therapy (a combination of conventional disease-modifying antirheumatic drugs ).
In some people, the disease does not respond to treatment with TNF‑alpha inhibitors or stops responding over time. This can be related to the formation of antibodies to TNF‑alpha inhibitors and fluctuations in circulating TNF‑alpha inhibitor levels. Therefore, laboratory tests that measure the levels of these antibodies and the circulating drug could help clinicians understand the reasons for non-response (for example, to exclude poor adherence). This information could guide decisions on which treatment to offer next. Currently, although there is considerable interest in therapeutic drug monitoring, treatment decisions are usually based on clinical judgement alone.
Therapeutic monitoring of TNF-alpha inhibitors could also potentially benefit people whose rheumatoid arthritis has a sustained response to these drugs and who could be considered for dose reduction. Reducing the dose of TNF‑alpha inhibitor is expected to lower the risk of unnecessary side effects such as serious infections, and lower the cost of treatment, without negatively affecting outcomes. Currently, dose reduction is not routine NHS practice and if carried out, it is usually based only on clinical assessment and patient history.
The purpose of this assessment is to evaluate the clinical effectiveness and cost effectiveness of using enzyme-linked immunosorbent assay (ELISA) tests (Promonitor, IDKmonitor, LISA-TRACKER, RIDASCREEN, MabTrack, and tests used by Sanquin Diagnostic Services). These are used to measure circulating drug levels and antidrug antibodies to monitor response to TNF‑alpha inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol and golimumab) in people with rheumatoid arthritis who:
have reached their treatment target (remission or low disease activity)
have disease that has not responded to TNF‑alpha inhibitors (primary non-response)
have disease that has stopped responding to TNF‑alpha inhibitors (secondary non-response).
# The condition
Rheumatoid arthritis is a chronic systemic autoimmune disease, primarily causing inflammation, pain and stiffness (synovitis) in the joints. It affects approximately 0.8% of the population (around 500,000 people in the UK; Symmons et al. 2002). The disease affects about 2 to 3 times more women than men.
The course of rheumatoid arthritis varies considerably from person to person, but often results in substantial morbidity, impaired physical activity, poor quality of life, and reduced life expectancy. It is marked by relapses (when the disease flares up) and remission (when there are few or no signs or symptoms). Rheumatoid arthritis is currently incurable, and people will remain on treatment for the rest of their lives.
# The care pathways
Initial diagnosis and management of rheumatoid arthritis, including monitoring of treatment response, are covered in NICE's guideline on rheumatoid arthritis.
People with active rheumatoid arthritis should have treatment with the aim of disease remission or low disease activity. Monitoring treatment response allows treatment adjustments to be made. In current clinical practice, the DAS28 and the European League Against Rheumatism (EULAR) response classification system (which is based on the DAS28) are most commonly used to monitor disease activity.
People with rheumatoid arthritis whose disease does not respond to intensive conventional therapy (a combination of conventional DMARDs), and whose disease is severe (DAS28 greater than 5.1), may have treatment with biological therapy. This includes the TNF‑alpha inhibitors adalimumab, etanercept, infliximab, certolizumab pegol and golimumab.
Treatment with a TNF‑alpha inhibitor should only be continued if there is an adequate response (using EULAR criteria) 6 months after starting therapy. Treatment should be withdrawn if an adequate EULAR response is not maintained.
Currently, monitoring response to TNF‑alpha inhibitors is usually based only on clinical assessment and patient history. A monitoring review appointment generally takes place 6 months after reaching the treatment target (remission or low disease activity) to ensure it has been maintained. Monitoring should continue every 6 to 12 months to assess disease activity, treatment response, functioning, quality of life, comorbidities, complications and the need for surgery, and to arrange multidisciplinary referrals.
Treatment options for people whose disease does not respond to treatment with TNF-alpha inhibitors or stops responding over time include switching to another TNF‑alpha inhibitor or switching to treatment with a different mechanism of action.
Currently, dose reduction of TNF‑alpha inhibitors in people whose disease is in sustained remission or has low disease activity is not part of routine NHS practice in England and is not covered in NICE guidance. However, dose reduction is already being done in some centres, and there is interest in developing local treatment protocols for dose reduction in the UK. Also, the EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological DMARDs recommend reducing the dose of biological DMARDs if a person's disease is in persistent remission after reducing their dose of glucocorticoids, especially if this treatment is combined with a conventional DMARD.
Adding therapeutic monitoring of circulating TNF‑alpha inhibitor levels and antidrug antibodies to the current monitoring of response to TNF‑alpha inhibitors could help inform treatment decisions for people with rheumatoid arthritis.# The diagnostic tests
The assessment compared 6 intervention tests (enzyme-linked immunosorbent assay tests: Promonitor, IDKmonitor, LISA‑TRACKER, RIDASCREEN, MabTrack, and in-house tests used by Sanquin Diagnostic Services) with 1 comparator (standard care). These ELISA tests are intended to be used for measuring the levels of tumour necrosis factor (TNF)‑alpha inhibitors and antibodies to TNF‑alpha inhibitors in the blood of people having TNF‑alpha inhibitor treatment for rheumatoid arthritis.
Single or duplicate ELISA tests may be done. Testing can be concurrent or reflex, and can include testing of free or total antibody levels:
Concurrent testing: tests for TNF‑alpha inhibitor drug levels and antibodies to TNF‑alpha inhibitors are done at the same time.
Reflex testing: the test for TNF‑alpha inhibitor drug levels is done first. If the drug is undetectable, testing for antibodies to the TNF‑alpha inhibitor would be done without a further request from the treating clinician. If TNF‑alpha inhibitor is present in the sample, then testing for antibodies would not be done.
Testing of free antibody levels: the test measures the levels of antidrug antibodies that are unbound to drug.
Testing of total antidrug antibody levels: the test measures levels of both unbound (free) antidrug antibodies and those bound to TNF‑alpha inhibitor.
# The interventions
The ELISA tests are all similar and consist of strips of pre-coated microtitre plate (96 wells), reagents, buffers, standards or calibrators, and controls (see table 1). The tests are done either manually or on an automated ELISA processor in a laboratory.
ELISA kits and tests relevant to this assessment
Manufacturer and UK distributor
Promonitor; 8 CE-marked ELISA kits, 4 measuring the levels of circulating TNF‑alpha inhibitor (adalimumab, etanercept, infliximab or golimumab) and 4 measuring the levels of corresponding free antidrug antibodies.
Proteomika, distributed by Grifols UK
IDKmonitor; 10 CE-marked ELISA kits, 4 measuring the levels of free TNF‑alpha inhibitor (adalimumab, etanercept, infliximab or golimumab), 4 measuring corresponding levels of free antidrug antibodies and 2 measuring the levels of total antidrug antibodies (against adalimumab or infliximab).
Immundiagnostik, distributed by BioHit Healthcare Ltd
LISA-TRACKER; 10 CE-marked ELISA kits, 5 measuring the levels of free TNF‑alpha inhibitor (adalimumab, certolizumab pegol, etanercept, infliximab or golimumab) and 5 measuring the corresponding levels of free antidrug antibodies. LISA-TRACKER Duo kits are also available that include assays to measure the levels of both free antidrug antibodies and TNF‑alpha inhibitor.
Theradiag, distributed by Cambridge Life Sciences Ltd
RIDASCREEN; 4 CE-marked ELISA kits, 2 measuring the levels of free TNF‑alpha inhibitor (adalimumab or infliximab) and 2 measuring the corresponding levels of free antidrug antibodies. They are commercial versions of the KU Leuven in-house ELISAs, and are marketed as apDia ELISA kits in Belgium, the Netherlands, and Luxembourg.
R-Biopharm
MabTrack; 4 CE-marked ELISA kits; 2 measuring the levels of free TNF‑alpha inhibitor (adalimumab and infliximab) and 2 measuring the corresponding levels of free antidrug antibodies. They are commercial versions of the Sanquin in-house ELISAs.
Sanquin
Sanquin Diagnostic Services ELISA tests. Validated ELISAs are available for adalimumab, infliximab, golimumab, etanercept and certolizumab and their corresponding antidrug antibodies.
Test service provided by Sanquin Diagnostic Services, a laboratory in the Netherlands
Abbreviations: ELISA, enzyme-linked immunosorbent assay; TNF, tumour necrosis factor.
# The comparator
The comparator for this assessment is treatment decisions based on clinical judgement only, without measuring the levels of TNF‑alpha inhibitor or antibodies to TNF‑alpha inhibitor. Clinical judgement usually includes assessing disease activity, treatment response, functioning, quality of life, comorbidities, complications and the need for surgery.# Evidence
The diagnostics advisory committee (section 8) considered evidence on enzyme-linked immunosorbent assay (ELISA) tests (Promonitor, IDKmonitor, LISA‑TRACKER, RIDASCREEN, MabTrack, and tests used by Sanquin Diagnostic Services) for therapeutic monitoring of tumour necrosis factor (TNF)‑alpha inhibitors in rheumatoid arthritis from several sources. Full details of all the evidence are in the diagnostics advisory committee papers.
# Clinical effectiveness
The external assessment group (EAG) did a systematic review of the evidence on ELISA tests to monitor the levels of TNF‑alpha inhibitors and antibodies to TNF‑alpha inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol and golimumab) in people with rheumatoid arthritis who:
have reached their treatment target (remission or low disease activity)
have disease that has not responded to TNF‑alpha inhibitors (primary non-response)
have disease that has stopped responding to TNF‑alpha inhibitors (secondary non-response).
Evidence on the following outcomes was of interest in the clinical-effectiveness review:
Decision impact – how the test influences decision making in terms of the proportion of people having treatment modifications such as TNF‑alpha inhibitor dose reduction or switching to another treatment.
Clinical utility – the ability of the prospective use of the test (through treatment modification) to affect outcomes for people with rheumatoid arthritis such as duration of time in remission, rate of flares, relapse, or health-related quality of life.
The EAG included only studies in which at least 70% of people had rheumatoid arthritis, but this inclusion criterion was subsequently relaxed because of the low number of studies retrieved. The EAG found no studies that met the initial criterion, and 2 studies (reported in 4 sources) that met the relaxed inclusion criterion, that is, the 2 studies were done in a mixed population of people with rheumatic diseases, rather than specifically in rheumatoid arthritis. Both studies were done in Spain, in people whose rheumatoid arthritis had reached the treatment target (remission or low disease activity). One was a non-randomised controlled study (INGEBIO; Gorostiza et al. 2016, Arango et al. 2017, Ucar et al. 2017) and the other an observational cohort study (Pascual-Salcedo et al. 2013; Pascual-Salcedo et al. 2015).
The EAG also considered a study by l'Ami et al. (2017), in people with rheumatoid arthritis. It did not meet the inclusion criteria of the systematic review because it did not specify that people were in remission or had low disease activity at study enrolment. But from the description of the inclusion and exclusion criteria, most people had disease that met this criterion.
The EAG found 1 ongoing Norwegian multicentre randomised controlled trial (NOR‑DRUM) that is evaluating the effect of therapeutic monitoring of infliximab in people with different inflammatory diseases, including rheumatoid arthritis, compared with standard care. Enrolment for NOR‑DRUM started in March 2017, with an expected primary completion date of March 2020 and study completion date of March 2022.
## INGEBIO non-randomised controlled study
INGEBIO was a prospective, non-randomised, non-inferiority, multicentre pragmatic study. It assessed the efficacy and cost of implementing therapeutic monitoring to guide treatment decisions in people with different rheumatic diseases taking adalimumab. The comparator was standard care in Spain, where treatment decisions (including dose reduction) are based on clinical judgement only.
It recruited a mixed population of 169 people with rheumatoid arthritis (n=63; 37%), psoriatic arthritis (n=54; 32%) and ankylosing spondylitis (n=52; 31%). They had treatment with adalimumab and had remained clinically stable for at least 6 months (Ucar et al. 2017).
In the study, everyone had therapeutic monitoring using Promonitor adalimumab and anti-adalimumab antibody kits, but test results were only revealed to clinicians in the intervention arm. They were not obliged to follow any therapeutic algorithm based on the test results but could use it to inform their judgement on treatment. In contrast, therapeutic monitoring test results were not revealed to clinicians in the control arm. This reflected standard care in Spain where treatment decisions are based on clinical judgement only, without knowing the drug levels and antidrug antibodies of people with rheumatoid arthritis.
The frequency of testing was once every 2 to 3 months. People were assessed for up to 18 months for change in disease response and health-related quality-of-life outcomes.
Results were reported in 3 conference abstracts. During consultation on the draft guidance, Grifols provided the full study report (commercial in confidence). Table 2A and B show the baseline characteristics and 18‑month clinical outcomes reported in INGEBIO. Ucar et al. (2017) reported intention-to-treat analysis, whereas Arango et al. (2017) reported per-protocol analysis, which excluded 19 people who were lost to follow up. The full study report provided further details on the per-protocol analysis. In the intention-to-treat analysis:
A total of 35.8% of people in the intervention group and 36.7% in the control arm (standard care) had their adalimumab doses reduced.
The mean duration of remission was 344 days in the intervention group and 329 days in the control group.
The rate of flares per patient-year was 0.463 in the intervention group and 0.639 for the control group, with a rate difference of −0.176 (95% confidence interval −0.379 to 0.0289).
There was a non-statistically significant reduction in the risk of flares in the intervention group compared with the control group (incidence rate ratio 0.7252, 95% CI 0.4997 to 1.0578).
Median time to the first flare was 145 days in the intervention group and 136.5 days in the control group.
Quality of life (EQ‑5D‑5L) was statistically significantly better in the intervention group at visits 2 (p=0.001) and 3 (p=0.035) compared with the control group; EQ‑5D‑5L remained higher in the intervention group throughout the 18‑month follow-up period, although the difference was not statistically significant at other visits.
Outcome
Intervention arm (n=109)
Control arm (n=60)
Baseline characteristics
Proportion of people in remission (%)
Proportion of people with low disease activity (%)
Median trough adalimumab levels (mg/litre)
Clinical outcomes
Mean follow up (days)
Proportion of people on reduced dose % (number)
Rate of flares per patient-year
Mean duration of remission (days)
Mean duration of remission or low disease activity (days)
NR
NR
Median time to first flare (days)
Outcome
Intervention arm (n=98)
Control arm (n=52)
Baseline characteristics
Proportion of people in remission (%)
Proportion of people with low disease activity (%)
Median trough adalimumab levels (mg/litre)
Clinical outcomes
Mean follow up (days)
Proportion of people on reduced dose % (number)
Rate of flares per patient-year
Mean duration of remission (days)
Mean duration of remission or low disease activity (days)
Median time to first flare (days)
Notes: The rate of flares per patient-year reported in Ucar et al. (2017) is the same as in Arango et al. (2017) even though these sources reported outcomes for different numbers of people and different follow-up periods. This could be because of an error in 1 of the abstracts.
The difference in duration of follow up between the 2 abstracts is most likely because of the exclusion of 19 people who were lost to follow up (and so had a shorter follow-up time) rather than a longer data collection period.
Abbreviations: NR, not reported.
Using ROBINS-I criteria, INGEBIO was judged to be at serious risk of bias, because of baseline imbalance in disease activity between the intervention and control groups. The full study report highlighted additional important differences in baseline characteristics between the 2 study groups. Also, the findings may not be generalisable to the UK rheumatoid arthritis population because:
the study was done in Spain (dose reduction of TNF‑alpha inhibitors is part of standard care in Spain but not in the UK)
it enrolled a mixed population of people with rheumatic diseases.
## Observational study by Pascual-Salcedo et al.
The study was initially identified as a conference abstract (Pascual-Salcedo et al. 2013). However, during consultation Sanquin provided a full-text article (Pascual-Salcedo et al. 2015) that was not indexed in any database and therefore not identified in the systematic literature review. Although results were presented for slightly different populations, the 2 sources were generally in line.
This was a single-centre observational study of daily clinical practice comparing clinical outcomes. The conference abstract included 88 people (43 with rheumatoid arthritis and 45 with spondyloarthritis) and the full-text publication included 77 people (36 with rheumatoid arthritis and 41 with spondyloarthritis). They had treatment with TNF‑alpha inhibitors (infliximab, adalimumab and etanercept) before and after introducing therapeutic monitoring of TNF‑alpha inhibitors (capture ELISA by Sanquin). Inclusion and exclusion criteria were reported only in the full-text publication.
The study compared outcomes in the same cohort of people in 2 periods: before introducing therapeutic monitoring, from 2006 to 2009 (full-text publication: 2007 to 2009) and after introducing therapeutic monitoring, from 2010 to 2012. Everyone was in sustained remission or had low disease activity for at least 6 months (defined in rheumatoid arthritis as disease activity score less than 3.2), and had treatment with the same TNF inhibitor throughout the entire study.
There were statistically significant changes after introducing therapeutic monitoring of TNF‑alpha inhibitors for all 3 drugs (reported in the conference abstract and the full-text publication):
the mean drug administration interval was longer (p<0.001)
the mean weekly dose was lower (approximately 20% reduction; p<0.001).
Everyone had stable clinical activity in both periods. In people with rheumatoid arthritis, the mean (± standard deviation ) DAS28 was 2.31±0.52 after introducing therapeutic monitoring of TNF‑alpha inhibitors compared with 2.51±0.85 before (p=0.061). In the full-text publication the mean DAS28 was 2.37±0.50 and 2.28±0.47, respectively (p=0.2).
## Additional study by l'Ami et al. (2017)
The study was an open-label, randomised, parallel-group, non-inferiority trial done in the Netherlands. It assessed clinical outcomes in people with rheumatoid arthritis with high serum adalimumab concentrations (above 8 mg/litre) who had dose-interval prolongation, compared with people who continued standard dosing.
The trial considered people with rheumatoid arthritis who had treatment for at least 28 weeks and had no indication for adjustment of adalimumab treatment, discontinuation or a scheduled surgery in the next 6 months. A total of 55 people were randomised and 54 included for analyses.
The mean DAS28 after 28 weeks decreased by 0.14 (SD 0.61) in the interval prolongation group and increased by 0.30 (SD 0.52) in the continuation group. The difference in the mean change in DAS28 was 0.44 (95% CI 0.12 to 0.76; p=0.01) in favour of the prolongation group.
The authors concluded that the frequency of adalimumab dosing can be safely extended without loss of disease control. However, because of the small sample size and comparable median adalimumab doses at week 28 in both groups, the EAG did not include this study in the economic assessment.
# Cost effectiveness
## Systematic review of cost-effectiveness evidence
The EAG identified 5 studies investigating the cost effectiveness of ELISA tests used to measure drug levels and antidrug antibodies for monitoring response to TNF‑alpha inhibitors. There were 3 studies that were model-based economic evaluations (cost-effectiveness models) and 2 were observational (Pascual-Salcedo et al. 2013 reported costs and Arango et al. 2017 reported costs and quality-adjusted life years ).
In INGEBIO (see sections 4.6 to 4.11 for study details), the mean QALYs during the 18‑month follow-up period were 1.076 in the control (standard care) group and 1.145 in the intervention group (therapeutic monitoring of TNF‑alpha inhibitors). This was a gain of 0.069 QALYs compared with control (Arango et al. 2017). The average per patient-year costs of adalimumab were €10,665 in the control group and €9,856 in the intervention group. This was a cost saving of €808 (8% of cost). Other healthcare costs were not reported. Data in the full study report (commercial in confidence) were generally in line with the findings in the conference abstract.
In the observational study by Pascual-Salcedo et al. (2013; see sections 4.12 to 4.16 for study details), introducing therapeutic monitoring of TNF‑alpha inhibitors resulted in lower monthly acquisition costs of TNF‑alpha inhibitors, compared with the monthly costs of the drugs before monitoring. The monthly cost saving was €92 per person on infliximab (assuming a mean weight of 70 kg), €324 per person on adalimumab, and €257 per person on etanercept. In the full-text publication the monthly cost saving was €143, €215, and €136 per person, respectively (Pascual-Salcedo et al. 2015).
Krieckaert et al. (2015) considered the cost effectiveness of a personalised treatment algorithm in people with rheumatoid arthritis taking adalimumab in the Netherlands. This was based on clinical response and drug levels (in-house ELISA tests, Sanquin) at 6 months of treatment, compared with standard care. The study population included all people who had treatment for 6 months, regardless of disease response. For 272 people starting adalimumab treatment over the period of 3 years, a test-based treatment strategy would:
add 3.84 QALYs
save €2.5 million in total healthcare costs (including €2.3 million in drug costs) and
save approximately €15,000 in productivity costs.
Laine et al. (2016) assessed the cost effectiveness of routine monitoring of serum drug concentrations and antidrug antibodies in people with rheumatoid arthritis who had TNF‑alpha inhibitors (adalimumab and infliximab), compared with standard care in Finland. Routine monitoring of both drug and antibody levels was estimated to be cost saving, assuming that it would improve treatment decisions for 2.5% to 5% of people who would otherwise have non-optimal treatment for 3 to 6 months in the standard care scenario.
Gavan (PhD thesis 2017; personal communication with the EAG) assessed the cost effectiveness of using ELISA testing (no test specified) for monitoring people with rheumatoid arthritis taking adalimumab. The analysis considered 10 different testing scenarios and 2 scenarios in which adalimumab doses were halved without previous testing. Routine adalimumab testing (either drug levels alone or drug levels plus antidrug antibodies) was generally cost effective compared with current practice. But it was unlikely to be cost effective relative to dose reduction (without testing) for people in remission.
## Economic analysis
The EAG developed a de novo economic model designed to estimate the health and economic outcomes of adding therapeutic monitoring of TNF‑alpha inhibitors to usual practice to guide treatment decisions in people with rheumatoid arthritis who had reached treatment target (remission or low disease activity). The model was based on the INGEBIO results, so it considered Promonitor tests for measuring adalimumab drug and antibody levels. Several analyses were done:
The first primary analysis, based on the intention-to-treat INGEBIO results reported in a conference abstract by Ucar et al. (2017).
The second primary analysis, based on the INGEBIO results reported in a conference abstract by Arango et al. (2017), which excluded 19 people who were lost to follow up.
There were 2 additional analyses based on the INGEBIO full study report (commercial in confidence; excluding 19 people who were lost to follow up, as in Arango et al. 2017).The 2 primary analyses were considered during the first committee meeting and the 2 additional analyses were considered during the second committee meeting.
Exploratory analyses were done to assess the health and economic outcomes of the Promonitor tests to measure drug levels and antidrug antibodies for TNF‑alpha inhibitors other than adalimumab (that is, infliximab and etanercept). These assumed similar clinical effectiveness across the TNF‑alpha inhibitors and similar performance of the Promonitor tests used for measuring the drug and antibody levels of all TNF‑alpha inhibitors.
Economic analyses for ELISA tests other than Promonitor were not done because of the lack of evidence to inform the models.
Economic assessment for the population with primary or secondary non-response was not possible because of the lack of evidence.
The time horizon was 18 months, as defined by the observational period in INGEBIO. Cost and health outcomes were not extrapolated into the future because of the lack of long-term evidence, so external validation of extrapolated outcomes was not feasible. Therefore, no discounting was applied to estimated costs and QALYs, and mortality was not modelled.
Because of the short time horizon, a simple model was created. It was assumed that people could be in 1 of 2 health states. However, definitions of health states in each analysis differed because different outcomes were reported in each data source:
Ucar et al. (2017) reported time in remission; the model assumed that people would be in the remission health state or the active disease health state (low to high disease activity).
Arango et al. (2017) reported time in remission or low disease activity; the model assumed that people would be in the remission or low disease activity health state, or the active disease health state (moderate to high disease activity).
The INGEBIO full study report reported both time in remission and time in remission or low disease activity. This meant that 2 separate analyses based on these 2 alternative health state descriptions were done.The duration of time in each health state was based on the INGEBIO results.
At the beginning of the model time horizon, a proportion of people had their doses reduced in both intervention and control groups, as in INGEBIO. This was based either on clinical assessment only (control group) or clinical assessment and therapeutic monitoring (intervention group).
The dose of adalimumab was reduced by increasing the interval between doses from 2 to 3 weeks (that is, by spacing doses).
A proportion of people in both the intervention and control groups had flares, as reported in INGEBIO. In INGEBIO, flare rates in the intervention and control arms were not stratified further according to the dose (full or reduced). Therefore, within each arm, the EAG applied the same flare rate for everyone, regardless of their dose.
The full dose of adalimumab was restored for everyone on reduced doses when their disease flared (based on the mean time to first flare derived from INGEBIO).
Everyone who was switched back to the full dose continued on it for the rest of the model time horizon. The disutility of the flare and the cost of managing the flare were applied for the duration of the flare (7 days in the primary analyses; 3 months in the additional analyses).
The rates of serious adverse events in people on full and tapered doses were 3 per 100 and 2 per 100 patient-years, respectively.
The model was populated with data from INGEBIO and supplemented with information from secondary sources.
Costs considered in the economic evaluation included the costs of testing, the costs of treatments taken by people with rheumatoid arthritis, and healthcare costs, from the perspective of the NHS and personal social services.
The costs of testing comprised those of the test kits, staff time to perform the test and staff training, the cost of the testing service and sample transport. Based on the information submitted by Grifols, the assay cost was £8.75 per test per sample. In the primary analyses, it was assumed that tests for trough drug and antibody levels would be done at the same time (concurrent testing), each sample would be tested once (single testing), and testing would be done once a year. In the additional analyses, it was assumed that reflex testing would be done (see section 3.2), with single testing per sample. The number of tests per year was based on the INGEBIO full study report (commercial in confidence).
Adalimumab acquisition costs were based on the Humira list price in the British national formulary (BNF; £9,187). However, biosimilar versions of adalimumab are available in the UK. Because the actual prices paid by the NHS are confidential and subject to regional tendering processes, the EAG assumed a hypothetical minimum cost of adalimumab of £1,000 in the threshold analysis. Also, the EAG did one-way deterministic sensitivity analyses to explore the effect of an up to 80% discount on the adalimumab BNF list price on the incremental cost-effectiveness ratio (ICER).
Treatment wastage was assumed to be £370 per patient-year in people on a full dose; it was reduced proportionally to the reduction in dose.
Adalimumab is self-administered (usually at home), and, therefore, the administration cost was assumed to be zero.
The annual per-patient costs of managing health states used in the primary analyses were found to be incorrect after the first committee meeting. Health state costs used in the additional analyses were: remission, £902; remission or low disease activity, £1,089; active disease (low to high activity), £1,483; active disease (medium to high activity), £1,827.
The costs associated with flare management were £423 per flare for diagnostic investigations and £68 per month for treatment (excluding the cost of biological disease-modifying antirheumatic drugs ).
The cost of managing an adverse event was £1,622.
QALYs were estimated from the duration of time in each of the 2 health states, the rates and duration of flares and adverse events, and the corresponding utility values from published literature (see table 3).
Assumption
Estimate
Source
Remission
Estimated from health assessment questionnaire scores for different health assessment questionnaire bands reported by Radner et al. (2014).
Low disease activity or active disease
Estimated from health assessment questionnaire scores for different health assessment questionnaire bands reported by Radner et al. (2014).
Remission or low disease activity
Estimated from health assessment questionnaire scores for different health assessment questionnaire bands reported by Radner et al. (2014).
Active disease
Estimated from health assessment questionnaire scores for different health assessment questionnaire bands reported by Radner et al. (2014).
Disutility of flare
Markusse et al. 2015.
Disutility of adverse events*
NICE technology appraisal guidance 375, Oppong et al. (2013).
- Computed from a weighted average health assessment questionnaire score for the low, moderate and high disease activity health states reported by Radner et al. (2014) and mapped to EQ-5D values following Malottki et al. (2011).
Rates of flares were based on the INGEBIO study. In the primary analyses, duration of flare was assumed to be 7 days.
* In the primary analyses, the rates of adverse events in people on full and reduced doses were 3 per 100 and 2 per 100 patient-years, respectively. Duration of adverse events was assumed to be 28 days.
The results of the primary analyses were discussed during the first committee meeting, but because of the error in the health state costs, they were superseded by results from the additional analyses.
In the additional analyses based on the INGEBIO full study report and corrected health state costs, the ICERs were:
£51,929 per QALY gained when the analysis was based on time in remission
£125,272 per QALY gained when the analysis was based on time in remission or low disease activity.
Sensitivity analyses were done to explore the effect of the following parametric and structural uncertainties on the model outcomes from the additional analyses:
differences in costs and QALYs are related to differences in rates of flares only (that is, when the effect of health states and adverse events is not considered)
the tapering strategy (dose halving: adalimumab 40 mg every 4 weeks rather than every 3 weeks assumed in primary analyses )
the total cost of treatment wastage (£0 rather than £370 assumed in the primary analyses)
the proportion of people with flares who increase their TNF‑alpha inhibitor dose (55% or 0% instead of 100%)
the frequency of testing (once or twice per year rather than the number of tests based on INGEBIO)
the cost of testing (including the effect of excluding the cost of the initial phlebotomy appointment, the effect of testing in duplicate, and the effect of concurrent testing or the effect of reflex testing assuming 35.8% have low drug levels).
In the additional analyses based on the INGEBIO full study report (commercial in confidence), in all except 2 scenarios, the ICERs ranged from £12,035 to £68,693 per QALY gained when analysis was based on time in remission, and from £33,082 to £164,009 per QALY gained when analysis was based on time in remission or low disease activity. When the frequency of testing was assumed to be 1 test per year, or when it was assumed that no additional phlebotomy appointment was needed, testing dominated standard care in both analyses (that is, testing was more clinically effective and cheaper than standard care).
Sensitivity analyses on the cost of adalimumab (20% to 80% discount) had little effect on the results of the additional analyses. In all analyses based on the INGEBIO full study report, the ICERs ranged from:
£55,249 to £65,207 per QALY gained when the analysis was based on time in remission
£132,942 to £155,954 per QALY gained when the analysis was based on time in remission or low disease activity.# Committee discussion
# Clinical need and practice
A clinical expert explained that rheumatoid arthritis has a devastating effect on a person's quality of life and almost 1 in 3 people stop work within 2 years of diagnosis. The patient experts commented that active disease and flares have the biggest effect on their lives and they constantly fear their recurrence. The committee noted that there is no standard definition of flare. Further research to better define it would be beneficial but may be challenging because of the variability in disease presentation. The committee also heard that 'low disease activity' covers a wide range of disease presentations, and people with rheumatoid arthritis can continue to have pain even when their joints are not visibly swollen.
The committee heard that tumour necrosis factor (TNF)‑alpha inhibitors can be an effective treatment option for severe rheumatoid arthritis that has not responded to conventional therapy. But some people have disease that does not respond or loses response to TNF‑alpha inhibitors. Based on British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR‑RA) data, approximately 50% of people who have TNF‑alpha inhibitors stop within the first 4 years because of lack of efficacy and adverse events such as severe infections. The committee concluded that managing rheumatoid arthritis is complex. New tests to optimise the use of TNF‑alpha inhibitors could improve management of the condition and so improve outcomes and quality of life for people with rheumatoid arthritis.
The committee noted that therapeutic monitoring of TNF‑alpha inhibitors is more established in inflammatory bowel disease. It was informed that companies who make TNF‑alpha inhibitors may offer to cover the cost of the enzyme-linked immunosorbent assay (ELISA) kits if a trust switches to their drug. The committee concluded that because testing is already being done and may be provided free of charge, clinicians may potentially have access. Therefore, it was important to consider whether testing in rheumatoid arthritis is appropriate.
The committee discussed treatment options for people with rheumatoid arthritis whose treatment target (remission or low disease activity) with TNF‑alpha inhibitors had been reached. The clinical experts explained that, in the UK, most people continue their treatment at the standard dose, that is, their dose is not reduced. But the committee was also informed that an increasing number of trusts do reduce the dose of TNF‑alpha inhibitor (based on clinical judgement) for these people. These trusts would have quick access policies in place for people reducing their dose, so they can return to clinic should their disease need to be reassessed or treatment adjusted.
The committee considered the potential value of therapeutic monitoring of TNF‑alpha inhibitors in people with rheumatoid arthritis whose treatment target (remission or low disease activity) had been reached. The committee noted that compared with no dose reduction, therapeutic monitoring could help inform clinicians who could reduce their dose of TNF‑alpha inhibitor without loss of efficacy. Lower doses could mean a lower risk of side effects, such as serious infections, and lower costs for TNF‑alpha inhibitors. The committee noted that compared with dose reduction based on clinical judgement only, therapeutic monitoring may have a limited effect on the average dose of TNF‑alpha inhibitor and rates of adverse events. However, helping to better inform clinicians who can reduce their dose without loss of efficacy could lead to a lower rate of relapse and flares.
A patient expert explained that therapeutic monitoring of TNF‑alpha inhibitors can reassure people with rheumatoid arthritis who wish to consider reducing their dose. People may be uneasy about reducing their dose, fearing they may have disease recurrence or a flare as a result. The committee concluded that therapeutic monitoring of TNF‑alpha inhibitors could potentially reassure people with rheumatoid arthritis about reducing their dose more than when their dose is reduced based on clinical judgement alone.
The committee noted that therapeutic monitoring of TNF‑alpha inhibitors could improve adherence to TNF‑alpha inhibitors by helping to identify people for whom this could be a problem. The importance of adherence could then be discussed with them. However, clinical experts commented that concerns about adherence would not be the main reason for using therapeutic monitoring of TNF‑alpha inhibitors.
# Clinical effectiveness
The committee reviewed the available evidence on the clinical effectiveness of using ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in people with rheumatoid arthritis. The committee noted that there was no evidence available for people with disease that has not responded to TNF‑alpha inhibitors or has stopped responding to TNF‑alpha inhibitors. It also noted that the evidence for people whose treatment target had been reached was limited and of poor quality. The committee was aware that no UK studies had been identified and there was no evidence for the IDKmonitor, LISA‑TRACKER and RIDASCREEN ELISA tests.
The committee was concerned that the results of the INGEBIO study may not be generalisable to the NHS. This was because of differences in the healthcare settings between Spain and the UK, and the lack of an explicit algorithm for guiding clinicians in how the test results should be interpreted and how they affect treatment. A patient expert explained that a warm climate has a favourable effect on symptoms, so there could be some differences in disease presentation between Spain and the UK. The committee noted that, because both treatment groups were enrolled at the same study sites, climate should not affect the results. Also, the committee was aware that the rate of dose reduction of TNF‑alpha inhibitors based on clinical judgement alone (standard care) and the rate of dose reduction based on clinical judgement plus therapeutic monitoring of TNF‑alpha inhibitors was similar in both study arms. The committee recalled that dose reduction based on clinical judgement is not routine practice in the NHS (see section 5.4). It concluded that INGEBIO may not be generalisable to clinical practice in the NHS.
The committee considered other limitations of INGEBIO. It noted that the study findings were presented as abstracts only, but the full study report had now been provided as commercial in confidence by Grifols. A full-text publication is being prepared. The committee was aware that the study had a non-randomised design and that baseline imbalances reported in the full study report were concerning. The external assessment group (EAG) explained that there was no adjustment for baseline imbalance in disease activity between groups. Also, there were unclear differences in clinical outcomes between the intention-to-treat analysis and the analysis that excluded 19 people who were lost to follow up. The committee noted that the study enrolled a mixed population of people with different rheumatic diseases, with only 37% of people having rheumatoid arthritis. The clinical experts explained that rheumatic diseases have different rates of immunogenicity and therapeutic ranges but algorithms to interpret test results should be similar across these diseases. The committee noted a trend towards a reduced rate of flares with therapeutic monitoring, but the difference was not statistically significant. Also, the committee noted that the rates of flares were not stratified by dose and so did not provide information as to whether doses of TNF‑alpha inhibitors can be reduced without loss of efficacy. The committee noted that without this dose-relationship information, the differences seen in INGEBIO could simply be caused by chance. The committee concluded that the clinical outcomes reported were uncertain.
The committee considered the single-centre observational study by Pascual-Salcedo et al. (2013) and the small randomised controlled trial by l'Ami et al. (2017). It discussed its doubts about the generalisability of the Spanish observational study to the NHS because of differences in healthcare setting, the lack of a control group and enrolling people with mixed rheumatic diseases. The committee noted that l'Ami et al. enrolled a small number of people, had a short follow-up time, and the median doses of TNF‑alpha inhibitor (adalimumab) in both treatment groups were not statistically significantly different at the end of the study. The committee also noted that l'Ami et al. only randomised people with high blood levels of TNF‑alpha inhibitor. It did not provide any information on treatment choices and outcomes for people with lower levels of TNF‑alpha inhibitor. The committee concluded that the 2 studies had important limitations, but they provided some support that therapeutic monitoring could help reduce doses of TNF‑alpha inhibitors without negatively affecting clinical outcomes (that is, without a subsequent increase in disease activity).
The committee considered the analytical validity of the tests. A clinical expert explained that there is no formal external quality assurance scheme for measuring levels of TNF‑alpha inhibitors and antibodies to TNF‑alpha inhibitors, but some laboratories take part in sample-exchange schemes as a form of quality assurance. Work on assuring the quality of ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors is ongoing and is most advanced for infliximab, for which World Health Organization international calibration standards have been developed. These calibration standards were shown to improve the consistency of results between different laboratories. A clinical expert explained that there is variability between results generated by the different ELISA tests, especially for TNF‑alpha inhibitors other than infliximab. The committee concluded that there is still potential uncertainty in the analytical performance of the ELISAs.
The committee noted that studies on the clinical validity of measuring levels of TNF‑alpha inhibitors (that is, studies looking at correlation between test results and health states such as remission or active disease) were not included in the assessment. It concluded that considering the very limited and poor-quality direct evidence on the clinical utility of ELISA tests (that is, information showing how treatment decisions informed by ELISA test results affect outcomes for people with rheumatoid arthritis), information on the clinical validity of ELISA tests could be beneficial. However, this information would not be able to confirm their clinical utility.
# Cost effectiveness
The committee considered the choice of model structure. It recalled the uncertainties associated with INGEBIO (see sections 5.9 and 5.10), which provided the main clinical inputs for the model. Because of this, the committee agreed with the choice of a simple modelling approach. It concluded that the model results were of limited value because of a lack of robust clinical data.
At the first meeting, the committee discussed the primary analyses based on the Ucar et al. and Arango et al. conference abstracts (see section 5.16). It noted that the costs of managing health states appeared to be high. At the second meeting, the committee considered the additional analyses based on the INGEBIO full study report and updated health state costs. The committee concluded that because of the error in the health state costs, the results of the primary analyses were inaccurate. It noted that none of the analyses adjusted for the baseline imbalances between the 2 study arms in INGEBIO. Therefore, the costs and quality-adjusted life years (QALYs) estimated from the model are likely to be flawed. The committee also agreed that the degree of uncertainty in the current clinical evidence was too high to use the model for decision making.
At the first meeting, the committee discussed differences between the 2 sources of clinical data from INGEBIO for the 2 primary analyses and noted both were conference abstracts. It was aware that the Ucar et al. intention-to-treat analysis reported time in remission, whereas Arango et al. excluded people lost to follow up and reported time in remission or low disease activity pooled together. As a result, health states were defined differently in the 2 primary analyses: remission compared with active disease (low to high disease activity) in the first analysis, and remission or low disease activity compared with active disease (moderate to high disease activity) in the second analysis. The committee agreed that in the EAG's model based on INGEBIO, the time spent in each health state was a key driver of the cost-effectiveness results. The committee also noted that if the comparator in the model was no dose reduction it would be likely that the amount of drug would be a key driver of the cost-effectiveness results, and not the time spent in each health state.
The committee noted that the rates of adalimumab dose reduction in INGEBIO were similar in the 2 treatment groups. As a result, the model did not provide information on whether therapeutic monitoring could offer savings to the NHS on the costs of adalimumab compared with the current practice of no dose reduction (see sections 5.4 and 5.5). The committee also noted that the similar rates of dose reduction in both groups explained why the results were not sensitive to changes in the price of adalimumab, even when discounts of up to 80% were considered. The committee agreed that in the NHS, rates of dose reduction and biosimilar prices are expected to affect the cost effectiveness of therapeutic monitoring of TNF‑alpha inhibitors. The committee was aware that in Gavan's cost-effectiveness modelling, based on the BSRBR‑RA data, therapeutic monitoring of TNF‑alpha inhibitors was generally cost effective compared with no dose reduction. But it was unlikely to be cost effective relative to dose reduction based on clinical judgement. The committee concluded that the EAG model may not be representative of NHS practice, in which dose reduction of TNF‑alpha inhibitors is not routinely done.
The committee acknowledged that the rates of flares in INGEBIO were not stratified by dose and so the relationship between adalimumab dose and the rate of flares was not captured in the model. It concluded therefore, that the model may not accurately reflect the experience of people with rheumatoid arthritis in the NHS whose dose of TNF‑alpha inhibitors is reduced.
The committee noted that the cost of a phlebotomy appointment appeared to be high but clinical experts explained that it likely represents the true cost of an outpatient phlebotomy appointment. They commented that although people with rheumatoid arthritis taking TNF‑alpha inhibitors (especially those also taking methotrexate) have frequent monitoring, an additional phlebotomy appointment may be needed to measure trough drug levels. This additional appointment would not be needed if drug levels of TNF‑alpha inhibitors could be measured at any time in the administration cycle. This was explored in sensitivity analyses.
The committee discussed the limitations of the economic model. It considered that although the clinical studies for therapeutic monitoring of TNF‑alpha inhibitors show promising results, the degree of uncertainty in the clinical evidence was too high for it to be able to use the incremental cost-effectiveness ratios (ICERs) for decision making. It concluded that the scope of any further changes to the modelling assumptions would be limited without more robust clinical data. The committee noted other evidence gaps such as:
the lack of clinical evidence on rheumatoid arthritis that has not responded to TNF-alpha inhibitors or has stopped responding
the lack of evidence for tests other than Promonitor and the Sanquin tests for therapeutic monitoring of adalimumab
the lack of data correlating test results and health states such as remission or active disease (which was out of scope for the EAG assessment).The committee noted that the last limitation could be addressed by further secondary research. Without robust clinical outcomes data, the committee was not able to recommend ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in rheumatoid arthritis for routine use in the NHS.
## Research considerations
The committee noted the ongoing NOR‑DRUM trial in Norway, which will assess the efficacy of therapeutic monitoring of infliximab in a broad range of inflammatory diseases. The clinical experts advised that infliximab is rarely offered to people with rheumatoid arthritis in the UK. According to recent UK registry data, only about 5% of people with rheumatoid arthritis in the UK have infliximab. Therefore the committee concluded that this study may be of limited relevance to the NHS, but some findings could potentially be extrapolated to represent the likely value of therapeutic monitoring of TNF-alpha inhibitors as a class.
The committee expressed concern that because therapeutic monitoring of TNF‑alpha inhibitors is already used in inflammatory bowel disease and may be provided free of charge by companies that make TNF‑alpha inhibitors, the tests could be adopted inappropriately in rheumatoid arthritis, without proof of clinical and cost effectiveness. The committee concluded that if therapeutic monitoring of TNF‑alpha inhibitors is currently done in rheumatoid arthritis, audit data should be collected.
The committee noted that further primary research comparing therapeutic monitoring of TNF‑alpha inhibitors with current clinical practice in the NHS in people with rheumatoid arthritis is needed. However, because of the high level of uncertainty about the potential value to the NHS, it is not clear if this would be considered a priority by research funding bodies.
Further research is also needed into:
the analytical and clinical validity of the ELISA tests
clinically meaningful thresholds for interpreting test results
the most appropriate test-based treatment algorithms and
which groups of people with rheumatoid arthritis are likely to benefit most from therapeutic monitoring of TNF‑alpha inhibitors.# Recommendations for further research
Further secondary research is recommended to understand:
the clinical validity of enzyme-linked immunosorbent assay (ELISA) tests, that is the correlation between ELISA test results and health outcomes or states, such as remission, response, low or high disease activity or flares in rheumatoid arthritis
the comparative performance of different ELISA tests for therapeutic monitoring of tumour necrosis factor (TNF)‑alpha inhibitors in rheumatoid arthritis.
Further primary research is recommended on the clinical effectiveness of using ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in people with rheumatoid arthritis.
|
{'Recommendations': 'Enzyme-linked immunosorbent assay (ELISA) tests for therapeutic monitoring of tumour necrosis factor (TNF)-alpha inhibitors (drug serum levels and antidrug antibodies) show promise but there is currently insufficient evidence to recommend their routine adoption in rheumatoid arthritis. The ELISA tests covered by this guidance are Promonitor, IDKmonitor, LISA-TRACKER, RIDASCREEN, MabTrack, and tests used by Sanquin Diagnostic Services.\n\nLaboratories currently using ELISA tests for therapeutic monitoring of TNF-alpha inhibitors in rheumatoid arthritis should do so as part of research and further data collection (see section 5.22).\n\nFurther research is recommended on the clinical effectiveness of using ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in rheumatoid arthritis (see sections 5.23, and 6.1 and 6.2).\n\nWhy the committee made these recommendations\n\nTNF-alpha inhibitors can be an effective treatment option for severe rheumatoid arthritis that does not respond to conventional therapy. Therapeutic monitoring of TNF‑alpha inhibitors could help to optimise their use, improving management of the condition and outcomes that are important for people with rheumatoid arthritis. These include how long their disease is in remission, the rate of flares and relapse, and health-related quality of life.\n\nThe clinical-effectiveness evidence for ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in rheumatoid arthritis is not robust, although there are some positive trends. The key INGEBIO study is of poor quality and is not generalisable to NHS practice.\n\nResults of the economic modelling based on INGEBIO are uncertain. So, although the tests show some promise, they are not recommended for routine use in the NHS. Further research would be valuable.', 'Clinical need and practice': "# The problem addressed\n\nTumour necrosis factor (TNF)‑alpha inhibitors are recommended as treatment options for people with severe rheumatoid arthritis (disease activity score [DAS28] greater than\xa05.1) whose disease does not respond to intensive conventional therapy (a combination of conventional disease-modifying antirheumatic drugs [DMARDs]).\n\nIn some people, the disease does not respond to treatment with TNF‑alpha inhibitors or stops responding over time. This can be related to the formation of antibodies to TNF‑alpha inhibitors and fluctuations in circulating TNF‑alpha inhibitor levels. Therefore, laboratory tests that measure the levels of these antibodies and the circulating drug could help clinicians understand the reasons for non-response (for example, to exclude poor adherence). This information could guide decisions on which treatment to offer next. Currently, although there is considerable interest in therapeutic drug monitoring, treatment decisions are usually based on clinical judgement alone.\n\nTherapeutic monitoring of TNF-alpha inhibitors could also potentially benefit people whose rheumatoid arthritis has a sustained response to these drugs and who could be considered for dose reduction. Reducing the dose of TNF‑alpha inhibitor is expected to lower the risk of unnecessary side effects such as serious infections, and lower the cost of treatment, without negatively affecting outcomes. Currently, dose reduction is not routine NHS practice and if carried out, it is usually based only on clinical assessment and patient history.\n\nThe purpose of this assessment is to evaluate the clinical effectiveness and cost effectiveness of using enzyme-linked immunosorbent assay (ELISA) tests (Promonitor, IDKmonitor, LISA-TRACKER, RIDASCREEN, MabTrack, and tests used by Sanquin Diagnostic Services). These are used to measure circulating drug levels and antidrug antibodies to monitor response to TNF‑alpha inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol and golimumab) in people with rheumatoid arthritis who:\n\nhave reached their treatment target (remission or low disease activity)\n\nhave disease that has not responded to TNF‑alpha inhibitors (primary non-response)\n\nhave disease that has stopped responding to TNF‑alpha inhibitors (secondary non-response).\n\n# The condition\n\nRheumatoid arthritis is a chronic systemic autoimmune disease, primarily causing inflammation, pain and stiffness (synovitis) in the joints. It affects approximately 0.8% of the population (around 500,000\xa0people in the UK; Symmons et al. 2002). The disease affects about 2\xa0to 3\xa0times more women than men.\n\nThe course of rheumatoid arthritis varies considerably from person to person, but often results in substantial morbidity, impaired physical activity, poor quality of life, and reduced life expectancy. It is marked by relapses (when the disease flares up) and remission (when there are few or no signs or symptoms). Rheumatoid arthritis is currently incurable, and people will remain on treatment for the rest of their lives.\n\n# The care pathways\n\nInitial diagnosis and management of rheumatoid arthritis, including monitoring of treatment response, are covered in NICE's guideline on rheumatoid arthritis.\n\nPeople with active rheumatoid arthritis should have treatment with the aim of disease remission or low disease activity. Monitoring treatment response allows treatment adjustments to be made. In current clinical practice, the DAS28 and the European League Against Rheumatism (EULAR) response classification system (which is based on the DAS28) are most commonly used to monitor disease activity.\n\nPeople with rheumatoid arthritis whose disease does not respond to intensive conventional therapy (a combination of conventional DMARDs), and whose disease is severe (DAS28 greater than\xa05.1), may have treatment with biological therapy. This includes the TNF‑alpha inhibitors adalimumab, etanercept, infliximab, certolizumab pegol and golimumab.\n\nTreatment with a TNF‑alpha inhibitor should only be continued if there is an adequate response (using EULAR criteria) 6\xa0months after starting therapy. Treatment should be withdrawn if an adequate EULAR response is not maintained.\n\nCurrently, monitoring response to TNF‑alpha inhibitors is usually based only on clinical assessment and patient history. A monitoring review appointment generally takes place 6\xa0months after reaching the treatment target (remission or low disease activity) to ensure it has been maintained. Monitoring should continue every 6\xa0to 12\xa0months to assess disease activity, treatment response, functioning, quality of life, comorbidities, complications and the need for surgery, and to arrange multidisciplinary referrals.\n\nTreatment options for people whose disease does not respond to treatment with TNF-alpha inhibitors or stops responding over time include switching to another TNF‑alpha inhibitor or switching to treatment with a different mechanism of action.\n\nCurrently, dose reduction of TNF‑alpha inhibitors in people whose disease is in sustained remission or has low disease activity is not part of routine NHS practice in England and is not covered in NICE guidance. However, dose reduction is already being done in some centres, and there is interest in developing local treatment protocols for dose reduction in the UK. Also, the EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological DMARDs recommend reducing the dose of biological DMARDs if a person's disease is in persistent remission after reducing their dose of glucocorticoids, especially if this treatment is combined with a conventional DMARD.\n\nAdding therapeutic monitoring of circulating TNF‑alpha inhibitor levels and antidrug antibodies to the current monitoring of response to TNF‑alpha inhibitors could help inform treatment decisions for people with rheumatoid arthritis.", 'The diagnostic tests': 'The assessment compared 6\xa0intervention tests (enzyme-linked immunosorbent assay [ELISA] tests: Promonitor, IDKmonitor, LISA‑TRACKER, RIDASCREEN, MabTrack, and in-house tests used by Sanquin Diagnostic Services) with 1\xa0comparator (standard care). These ELISA tests are intended to be used for measuring the levels of tumour necrosis factor (TNF)‑alpha inhibitors and antibodies to TNF‑alpha inhibitors in the blood of people having TNF‑alpha inhibitor treatment for rheumatoid arthritis.\n\nSingle or duplicate ELISA tests may be done. Testing can be concurrent or reflex, and can include testing of free or total antibody levels:\n\nConcurrent testing: tests for TNF‑alpha inhibitor drug levels and antibodies to TNF‑alpha inhibitors are done at the same time.\n\nReflex testing: the test for TNF‑alpha inhibitor drug levels is done first. If the drug is undetectable, testing for antibodies to the TNF‑alpha inhibitor would be done without a further request from the treating clinician. If TNF‑alpha inhibitor is present in the sample, then testing for antibodies would not be done.\n\nTesting of free antibody levels: the test measures the levels of antidrug antibodies that are unbound to drug.\n\nTesting of total antidrug antibody levels: the test measures levels of both unbound (free) antidrug antibodies and those bound to TNF‑alpha inhibitor.\n\n# The interventions\n\nThe ELISA tests are all similar and consist of strips of pre-coated microtitre plate (96\xa0wells), reagents, buffers, standards or calibrators, and controls (see table\xa01). The tests are done either manually or on an automated ELISA processor in a laboratory.\n\nELISA kits and tests relevant to this assessment\n\nManufacturer and UK distributor\n\nPromonitor; 8\xa0CE-marked ELISA kits, 4\xa0measuring the levels of circulating TNF‑alpha inhibitor (adalimumab, etanercept, infliximab or golimumab) and 4\xa0measuring the levels of corresponding free antidrug antibodies.\n\nProteomika, distributed by Grifols UK\n\nIDKmonitor; 10 CE-marked ELISA kits, 4 measuring the levels of free TNF‑alpha inhibitor (adalimumab, etanercept, infliximab or golimumab), 4 measuring corresponding levels of free antidrug antibodies and 2 measuring the levels of total antidrug antibodies (against adalimumab or infliximab).\n\nImmundiagnostik, distributed by BioHit Healthcare Ltd\n\nLISA-TRACKER; 10\xa0CE-marked ELISA kits, 5\xa0measuring the levels of free TNF‑alpha inhibitor (adalimumab, certolizumab pegol, etanercept, infliximab or golimumab) and 5\xa0measuring the corresponding levels of free antidrug antibodies. LISA-TRACKER Duo kits are also available that include assays to measure the levels of both free antidrug antibodies and TNF‑alpha inhibitor.\n\nTheradiag, distributed by Cambridge Life Sciences Ltd\n\nRIDASCREEN; 4\xa0CE-marked ELISA kits, 2 measuring the levels of free TNF‑alpha inhibitor (adalimumab or infliximab) and 2 measuring the corresponding levels of free antidrug antibodies. They are commercial versions of the KU Leuven in-house ELISAs, and are marketed as apDia ELISA kits in Belgium, the Netherlands, and Luxembourg.\n\nR-Biopharm\n\nMabTrack; 4 CE-marked ELISA kits; 2 measuring the levels of free TNF‑alpha inhibitor (adalimumab and infliximab) and 2 measuring the corresponding levels of free antidrug antibodies. They are commercial versions of the Sanquin in-house ELISAs.\n\nSanquin\n\nSanquin Diagnostic Services ELISA tests. Validated ELISAs are available for adalimumab, infliximab, golimumab, etanercept and certolizumab and their corresponding antidrug antibodies.\n\nTest service provided by Sanquin Diagnostic Services, a laboratory in the Netherlands\n\nAbbreviations: ELISA, enzyme-linked immunosorbent assay; TNF, tumour necrosis factor.\n\n# The comparator\n\nThe comparator for this assessment is treatment decisions based on clinical judgement only, without measuring the levels of TNF‑alpha inhibitor or antibodies to TNF‑alpha inhibitor. Clinical judgement usually includes assessing disease activity, treatment response, functioning, quality of life, comorbidities, complications and the need for surgery.', 'Evidence': "The diagnostics advisory committee (section 8) considered evidence on enzyme-linked immunosorbent assay (ELISA) tests (Promonitor, IDKmonitor, LISA‑TRACKER, RIDASCREEN, MabTrack, and tests used by Sanquin Diagnostic Services) for therapeutic monitoring of tumour necrosis factor (TNF)‑alpha inhibitors in rheumatoid arthritis from several sources. Full details of all the evidence are in the diagnostics advisory committee papers.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) did a systematic review of the evidence on ELISA tests to monitor the levels of TNF‑alpha inhibitors and antibodies to TNF‑alpha inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol and golimumab) in people with rheumatoid arthritis who:\n\nhave reached their treatment target (remission or low disease activity)\n\nhave disease that has not responded to TNF‑alpha inhibitors (primary non-response)\n\nhave disease that has stopped responding to TNF‑alpha inhibitors (secondary non-response).\n\nEvidence on the following outcomes was of interest in the clinical-effectiveness review:\n\nDecision impact – how the test influences decision making in terms of the proportion of people having treatment modifications such as TNF‑alpha inhibitor dose reduction or switching to another treatment.\n\nClinical utility – the ability of the prospective use of the test (through treatment modification) to affect outcomes for people with rheumatoid arthritis such as duration of time in remission, rate of flares, relapse, or health-related quality of life.\n\nThe EAG included only studies in which at least 70% of people had rheumatoid arthritis, but this inclusion criterion was subsequently relaxed because of the low number of studies retrieved. The EAG found no studies that met the initial criterion, and 2\xa0studies (reported in 4\xa0sources) that met the relaxed inclusion criterion, that is, the 2\xa0studies were done in a mixed population of people with rheumatic diseases, rather than specifically in rheumatoid arthritis. Both studies were done in Spain, in people whose rheumatoid arthritis had reached the treatment target (remission or low disease activity). One was a non-randomised controlled study (INGEBIO; Gorostiza et al. 2016, Arango et al. 2017, Ucar et al. 2017) and the other an observational cohort study (Pascual-Salcedo et al. 2013; Pascual-Salcedo et al. 2015).\n\nThe EAG also considered a study by l'Ami et al. (2017), in people with rheumatoid arthritis. It did not meet the inclusion criteria of the systematic review because it did not specify that people were in remission or had low disease activity at study enrolment. But from the description of the inclusion and exclusion criteria, most people had disease that met this criterion.\n\nThe EAG found 1\xa0ongoing Norwegian multicentre randomised controlled trial (NOR‑DRUM) that is evaluating the effect of therapeutic monitoring of infliximab in people with different inflammatory diseases, including rheumatoid arthritis, compared with standard care. Enrolment for NOR‑DRUM started in March 2017, with an expected primary completion date of March 2020 and study completion date of March 2022.\n\n## INGEBIO non-randomised controlled study\n\nINGEBIO was a prospective, non-randomised, non-inferiority, multicentre pragmatic study. It assessed the efficacy and cost of implementing therapeutic monitoring to guide treatment decisions in people with different rheumatic diseases taking adalimumab. The comparator was standard care in Spain, where treatment decisions (including dose reduction) are based on clinical judgement only.\n\nIt recruited a mixed population of 169\xa0people with rheumatoid arthritis (n=63; 37%), psoriatic arthritis (n=54; 32%) and ankylosing spondylitis (n=52; 31%). They had treatment with adalimumab and had remained clinically stable for at least 6\xa0months (Ucar et al. 2017).\n\nIn the study, everyone had therapeutic monitoring using Promonitor adalimumab and anti-adalimumab antibody kits, but test results were only revealed to clinicians in the intervention arm. They were not obliged to follow any therapeutic algorithm based on the test results but could use it to inform their judgement on treatment. In contrast, therapeutic monitoring test results were not revealed to clinicians in the control arm. This reflected standard care in Spain where treatment decisions are based on clinical judgement only, without knowing the drug levels and antidrug antibodies of people with rheumatoid arthritis.\n\nThe frequency of testing was once every 2\xa0to 3\xa0months. People were assessed for up to 18\xa0months for change in disease response and health-related quality-of-life outcomes.\n\nResults were reported in 3\xa0conference abstracts. During consultation on the draft guidance, Grifols provided the full study report (commercial in confidence). Table 2A and B show the baseline characteristics and 18‑month clinical outcomes reported in INGEBIO. Ucar et al. (2017) reported intention-to-treat analysis, whereas Arango et al. (2017) reported per-protocol analysis, which excluded 19\xa0people who were lost to follow up. The full study report provided further details on the per-protocol analysis. In the intention-to-treat analysis:\n\nA total of 35.8% of people in the intervention group and 36.7% in the control arm (standard care) had their adalimumab doses reduced.\n\nThe mean duration of remission was 344\xa0days in the intervention group and 329\xa0days in the control group.\n\nThe rate of flares per patient-year was 0.463 in the intervention group and 0.639 for the control group, with a rate difference of −0.176 (95% confidence interval [CI] −0.379 to 0.0289).\n\nThere was a non-statistically significant reduction in the risk of flares in the intervention group compared with the control group (incidence rate ratio 0.7252, 95% CI 0.4997 to 1.0578).\n\nMedian time to the first flare was 145\xa0days in the intervention group and 136.5\xa0days in the control group.\n\nQuality of life (EQ‑5D‑5L) was statistically significantly better in the intervention group at visits 2 (p=0.001) and 3 (p=0.035) compared with the control group; EQ‑5D‑5L remained higher in the intervention group throughout the 18‑month follow-up period, although the difference was not statistically significant at other visits.\n\nOutcome\n\nIntervention arm (n=109)\n\nControl arm (n=60)\n\nBaseline characteristics\n\n–\n\n–\n\nProportion of people in remission (%)\n\n\n\n\n\nProportion of people with low disease activity (%)\n\n\n\n\n\nMedian trough adalimumab levels (mg/litre)\n\n\n\n\n\nClinical outcomes\n\n–\n\n–\n\nMean follow up (days)\n\n\n\n\n\nProportion of people on reduced dose % (number)\n\n(39/109)\n\n(22/60)\n\nRate of flares per patient-year\n\n\n\n\n\nMean duration of remission (days)\n\n\n\n\n\nMean duration of remission or low disease activity (days)\n\nNR\n\nNR\n\nMedian time to first flare (days)\n\n\n\n\n\nOutcome\n\nIntervention arm (n=98)\n\nControl arm (n=52)\n\nBaseline characteristics\n\n–\n\n–\n\nProportion of people in remission (%)\n\n\n\n\n\nProportion of people with low disease activity (%)\n\n\n\n\n\nMedian trough adalimumab levels (mg/litre)\n\n\n\n\n\nClinical outcomes\n\n–\n\n–\n\nMean follow up (days)\n\n\n\n\n\nProportion of people on reduced dose % (number)\n\n(35/98)\n\n(18/52)\n\nRate of flares per patient-year\n\n\n\n\n\nMean duration of remission (days)\n\n\n\n\n\nMean duration of remission or low disease activity (days)\n\n\n\n\n\nMedian time to first flare (days)\n\n\n\n\n\nNotes: The rate of flares per patient-year reported in Ucar et al. (2017) is the same as in Arango et al. (2017) even though these sources reported outcomes for different numbers of people and different follow-up periods. This could be because of an error in 1 of the abstracts.\n\nThe difference in duration of follow up between the 2 abstracts is most likely because of the exclusion of 19\xa0people who were lost to follow up (and so had a shorter follow-up time) rather than a longer data collection period.\n\nAbbreviations: NR, not reported.\n\nUsing ROBINS-I criteria, INGEBIO was judged to be at serious risk of bias, because of baseline imbalance in disease activity between the intervention and control groups. The full study report highlighted additional important differences in baseline characteristics between the 2\xa0study groups. Also, the findings may not be generalisable to the UK rheumatoid arthritis population because:\n\nthe study was done in Spain (dose reduction of TNF‑alpha inhibitors is part of standard care in Spain but not in the UK)\n\nit enrolled a mixed population of people with rheumatic diseases.\n\n## Observational study by Pascual-Salcedo et al.\n\nThe study was initially identified as a conference abstract (Pascual-Salcedo et al. 2013). However, during consultation Sanquin provided a full-text article (Pascual-Salcedo et al. 2015) that was not indexed in any database and therefore not identified in the systematic literature review. Although results were presented for slightly different populations, the 2\xa0sources were generally in line.\n\nThis was a single-centre observational study of daily clinical practice comparing clinical outcomes. The conference abstract included 88\xa0people (43\xa0with rheumatoid arthritis and 45\xa0with spondyloarthritis) and the full-text publication included 77\xa0people (36\xa0with rheumatoid arthritis and 41 with spondyloarthritis). They had treatment with TNF‑alpha inhibitors (infliximab, adalimumab and etanercept) before and after introducing therapeutic monitoring of TNF‑alpha inhibitors (capture ELISA by Sanquin). Inclusion and exclusion criteria were reported only in the full-text publication.\n\nThe study compared outcomes in the same cohort of people in 2\xa0periods: before introducing therapeutic monitoring, from 2006 to 2009 (full-text publication: 2007 to 2009) and after introducing therapeutic monitoring, from 2010 to 2012. Everyone was in sustained remission or had low disease activity for at least 6\xa0months (defined in rheumatoid arthritis as disease activity score [DAS28] less than 3.2), and had treatment with the same TNF inhibitor throughout the entire study.\n\nThere were statistically significant changes after introducing therapeutic monitoring of TNF‑alpha inhibitors for all 3\xa0drugs (reported in the conference abstract and the full-text publication):\n\nthe mean drug administration interval was longer (p<0.001)\n\nthe mean weekly dose was lower (approximately 20% reduction; p<0.001).\n\nEveryone had stable clinical activity in both periods. In people with rheumatoid arthritis, the mean (±\xa0standard deviation [SD]) DAS28 was 2.31±0.52 after introducing therapeutic monitoring of TNF‑alpha inhibitors compared with 2.51±0.85 before (p=0.061). In the full-text publication the mean DAS28 was 2.37±0.50 and 2.28±0.47, respectively (p=0.2).\n\n## Additional study by l'Ami et al. (2017)\n\nThe study was an open-label, randomised, parallel-group, non-inferiority trial done in the Netherlands. It assessed clinical outcomes in people with rheumatoid arthritis with high serum adalimumab concentrations (above 8\xa0mg/litre) who had dose-interval prolongation, compared with people who continued standard dosing.\n\nThe trial considered people with rheumatoid arthritis who had treatment for at least 28\xa0weeks and had no indication for adjustment of adalimumab treatment, discontinuation or a scheduled surgery in the next 6\xa0months. A total of 55\xa0people were randomised and 54 included for analyses.\n\nThe mean DAS28 after 28\xa0weeks decreased by 0.14 (SD 0.61) in the interval prolongation group and increased by 0.30 (SD 0.52) in the continuation group. The difference in the mean change in DAS28 was 0.44 (95% CI 0.12 to 0.76; p=0.01) in favour of the prolongation group.\n\nThe authors concluded that the frequency of adalimumab dosing can be safely extended without loss of disease control. However, because of the small sample size and comparable median adalimumab doses at week\xa028 in both groups, the EAG did not include this study in the economic assessment.\n\n# Cost effectiveness\n\n## Systematic review of cost-effectiveness evidence\n\nThe EAG identified 5\xa0studies investigating the cost effectiveness of ELISA tests used to measure drug levels and antidrug antibodies for monitoring response to TNF‑alpha inhibitors. There were 3\xa0studies that were model-based economic evaluations (cost-effectiveness models) and 2 were observational (Pascual-Salcedo et al. 2013 reported costs and Arango et al. 2017 reported costs and quality-adjusted life years [QALYs]).\n\nIn INGEBIO (see sections 4.6 to 4.11 for study details), the mean QALYs during the 18‑month follow-up period were 1.076 in the control (standard care) group and 1.145 in the intervention group (therapeutic monitoring of TNF‑alpha inhibitors). This was a gain of 0.069 QALYs compared with control (Arango et al. 2017). The average per patient-year costs of adalimumab were €10,665 in the control group and €9,856 in the intervention group. This was a cost saving of €808 (8% of cost). Other healthcare costs were not reported. Data in the full study report (commercial in confidence) were generally in line with the findings in the conference abstract.\n\nIn the observational study by Pascual-Salcedo et al. (2013; see sections 4.12 to 4.16 for study details), introducing therapeutic monitoring of TNF‑alpha inhibitors resulted in lower monthly acquisition costs of TNF‑alpha inhibitors, compared with the monthly costs of the drugs before monitoring. The monthly cost saving was €92 per person on infliximab (assuming a mean weight of 70\xa0kg), €324 per person on adalimumab, and €257 per person on etanercept. In the full-text publication the monthly cost saving was €143, €215, and €136 per person, respectively (Pascual-Salcedo et al. 2015).\n\nKrieckaert et al. (2015) considered the cost effectiveness of a personalised treatment algorithm in people with rheumatoid arthritis taking adalimumab in the Netherlands. This was based on clinical response and drug levels (in-house ELISA tests, Sanquin) at 6\xa0months of treatment, compared with standard care. The study population included all people who had treatment for 6\xa0months, regardless of disease response. For 272\xa0people starting adalimumab treatment over the period of 3\xa0years, a test-based treatment strategy would:\n\nadd 3.84\xa0QALYs\n\nsave €2.5\xa0million in total healthcare costs (including €2.3\xa0million in drug costs) and\n\nsave approximately €15,000 in productivity costs.\n\nLaine et al. (2016) assessed the cost effectiveness of routine monitoring of serum drug concentrations and antidrug antibodies in people with rheumatoid arthritis who had TNF‑alpha inhibitors (adalimumab and infliximab), compared with standard care in Finland. Routine monitoring of both drug and antibody levels was estimated to be cost saving, assuming that it would improve treatment decisions for 2.5% to 5% of people who would otherwise have non-optimal treatment for 3\xa0to 6\xa0months in the standard care scenario.\n\nGavan (PhD thesis 2017; personal communication with the EAG) assessed the cost effectiveness of using ELISA testing (no test specified) for monitoring people with rheumatoid arthritis taking adalimumab. The analysis considered 10\xa0different testing scenarios and 2\xa0scenarios in which adalimumab doses were halved without previous testing. Routine adalimumab testing (either drug levels alone or drug levels plus antidrug antibodies) was generally cost effective compared with current practice. But it was unlikely to be cost effective relative to dose reduction (without testing) for people in remission.\n\n## Economic analysis\n\nThe EAG developed a de novo economic model designed to estimate the health and economic outcomes of adding therapeutic monitoring of TNF‑alpha inhibitors to usual practice to guide treatment decisions in people with rheumatoid arthritis who had reached treatment target (remission or low disease activity). The model was based on the INGEBIO results, so it considered Promonitor tests for measuring adalimumab drug and antibody levels. Several analyses were done:\n\nThe first primary analysis, based on the intention-to-treat INGEBIO results reported in a conference abstract by Ucar et al. (2017).\n\nThe second primary analysis, based on the INGEBIO results reported in a conference abstract by Arango et al. (2017), which excluded 19\xa0people who were lost to follow up.\n\nThere were 2\xa0additional analyses based on the INGEBIO full study report (commercial in confidence; excluding 19\xa0people who were lost to follow up, as in Arango et al. 2017).The 2\xa0primary analyses were considered during the first committee meeting and the 2\xa0additional analyses were considered during the second committee meeting.\n\nExploratory analyses were done to assess the health and economic outcomes of the Promonitor tests to measure drug levels and antidrug antibodies for TNF‑alpha inhibitors other than adalimumab (that is, infliximab and etanercept). These assumed similar clinical effectiveness across the TNF‑alpha inhibitors and similar performance of the Promonitor tests used for measuring the drug and antibody levels of all TNF‑alpha inhibitors.\n\nEconomic analyses for ELISA tests other than Promonitor were not done because of the lack of evidence to inform the models.\n\nEconomic assessment for the population with primary or secondary non-response was not possible because of the lack of evidence.\n\nThe time horizon was 18\xa0months, as defined by the observational period in INGEBIO. Cost and health outcomes were not extrapolated into the future because of the lack of long-term evidence, so external validation of extrapolated outcomes was not feasible. Therefore, no discounting was applied to estimated costs and QALYs, and mortality was not modelled.\n\nBecause of the short time horizon, a simple model was created. It was assumed that people could be in 1\xa0of\xa02 health states. However, definitions of health states in each analysis differed because different outcomes were reported in each data source:\n\nUcar et al. (2017) reported time in remission; the model assumed that people would be in the remission health state or the active disease health state (low to high disease activity).\n\nArango et al. (2017) reported time in remission or low disease activity; the model assumed that people would be in the remission or low disease activity health state, or the active disease health state (moderate to high disease activity).\n\nThe INGEBIO full study report reported both time in remission and time in remission or low disease activity. This meant that 2\xa0separate analyses based on these 2\xa0alternative health state descriptions were done.The duration of time in each health state was based on the INGEBIO results.\n\nAt the beginning of the model time horizon, a proportion of people had their doses reduced in both intervention and control groups, as in INGEBIO. This was based either on clinical assessment only (control group) or clinical assessment and therapeutic monitoring (intervention group).\n\nThe dose of adalimumab was reduced by increasing the interval between doses from 2\xa0to 3\xa0weeks (that is, by spacing doses).\n\nA proportion of people in both the intervention and control groups had flares, as reported in INGEBIO. In INGEBIO, flare rates in the intervention and control arms were not stratified further according to the dose (full or reduced). Therefore, within each arm, the EAG applied the same flare rate for everyone, regardless of their dose.\n\nThe full dose of adalimumab was restored for everyone on reduced doses when their disease flared (based on the mean time to first flare derived from INGEBIO).\n\nEveryone who was switched back to the full dose continued on it for the rest of the model time horizon. The disutility of the flare and the cost of managing the flare were applied for the duration of the flare (7\xa0days in the primary analyses; 3\xa0months in the additional analyses).\n\nThe rates of serious adverse events in people on full and tapered doses were 3\xa0per\xa0100 and 2\xa0per 100\xa0patient-years, respectively.\n\nThe model was populated with data from INGEBIO and supplemented with information from secondary sources.\n\nCosts considered in the economic evaluation included the costs of testing, the costs of treatments taken by people with rheumatoid arthritis, and healthcare costs, from the perspective of the NHS and personal social services.\n\nThe costs of testing comprised those of the test kits, staff time to perform the test and staff training, the cost of the testing service and sample transport. Based on the information submitted by Grifols, the assay cost was £8.75 per test per sample. In the primary analyses, it was assumed that tests for trough drug and antibody levels would be done at the same time (concurrent testing), each sample would be tested once (single testing), and testing would be done once a year. In the additional analyses, it was assumed that reflex testing would be done (see section 3.2), with single testing per sample. The number of tests per year was based on the INGEBIO full study report (commercial in confidence).\n\nAdalimumab acquisition costs were based on the Humira list price in the British national formulary (BNF; £9,187). However, biosimilar versions of adalimumab are available in the UK. Because the actual prices paid by the NHS are confidential and subject to regional tendering processes, the EAG assumed a hypothetical minimum cost of adalimumab of £1,000 in the threshold analysis. Also, the EAG did one-way deterministic sensitivity analyses to explore the effect of an up to 80% discount on the adalimumab BNF list price on the incremental cost-effectiveness ratio (ICER).\n\nTreatment wastage was assumed to be £370 per patient-year in people on a full dose; it was reduced proportionally to the reduction in dose.\n\nAdalimumab is self-administered (usually at home), and, therefore, the administration cost was assumed to be zero.\n\nThe annual per-patient costs of managing health states used in the primary analyses were found to be incorrect after the first committee meeting. Health state costs used in the additional analyses were: remission, £902; remission or low disease activity, £1,089; active disease (low to high activity), £1,483; active disease (medium to high activity), £1,827.\n\nThe costs associated with flare management were £423 per flare for diagnostic investigations and £68 per month for treatment (excluding the cost of biological disease-modifying antirheumatic drugs [DMARDs]).\n\nThe cost of managing an adverse event was £1,622.\n\nQALYs were estimated from the duration of time in each of the 2\xa0health states, the rates and duration of flares and adverse events, and the corresponding utility values from published literature (see table\xa03).\n\nAssumption\n\nEstimate\n\nSource\n\nRemission\n\n\n\nEstimated from health assessment questionnaire scores for different health assessment questionnaire bands reported by Radner et al. (2014).\n\nLow\xa0disease\xa0activity or active disease\n\n*\n\nEstimated from health assessment questionnaire scores for different health assessment questionnaire bands reported by Radner et al. (2014).\n\nRemission or low disease activity\n\n*\n\nEstimated from health assessment questionnaire scores for different health assessment questionnaire bands reported by Radner et al. (2014).\n\nActive disease\n\n\n\nEstimated from health assessment questionnaire scores for different health assessment questionnaire bands reported by Radner et al. (2014).\n\nDisutility of flare**\n\n\n\nMarkusse et al. 2015.\n\nDisutility of adverse events***\n\n\n\nNICE technology appraisal guidance 375, Oppong et al. (2013).\n\n* Computed from a weighted average health assessment questionnaire score for the low, moderate and high disease activity health states reported by Radner et al. (2014) and mapped to EQ-5D values following Malottki et al. (2011).\n\n** Rates of flares were based on the INGEBIO study. In the primary analyses, duration of flare was assumed to be 7\xa0days.\n\n*** In the primary analyses, the rates of adverse events in people on full and reduced doses were 3 per 100 and 2 per 100 patient-years, respectively. Duration of adverse events was assumed to be 28\xa0days.\n\nThe results of the primary analyses were discussed during the first committee meeting, but because of the error in the health state costs, they were superseded by results from the additional analyses.\n\nIn the additional analyses based on the INGEBIO full study report and corrected health state costs, the ICERs were:\n\n£51,929 per QALY gained when the analysis was based on time in remission\n\n£125,272 per QALY gained when the analysis was based on time in remission or low disease activity.\n\nSensitivity analyses were done to explore the effect of the following parametric and structural uncertainties on the model outcomes from the additional analyses:\n\ndifferences in costs and QALYs are related to differences in rates of flares only (that is, when the effect of health states and adverse events is not considered)\n\nthe tapering strategy (dose halving: adalimumab 40\xa0mg every 4\xa0weeks rather than every 3\xa0weeks assumed in primary analyses [and compared with every 2\xa0weeks for standard dosing])\n\nthe total cost of treatment wastage (£0 rather than £370 assumed in the primary analyses)\n\nthe proportion of people with flares who increase their TNF‑alpha inhibitor dose (55% or 0% instead of 100%)\n\nthe frequency of testing (once or twice per year rather than the number of tests based on INGEBIO)\n\nthe cost of testing (including the effect of excluding the cost of the initial phlebotomy appointment, the effect of testing in duplicate, and the effect of concurrent testing or the effect of reflex testing assuming 35.8% have low drug levels).\n\nIn the additional analyses based on the INGEBIO full study report (commercial in confidence), in all except 2\xa0scenarios, the ICERs ranged from £12,035 to £68,693 per QALY gained when analysis was based on time in remission, and from £33,082 to £164,009 per QALY gained when analysis was based on time in remission or low disease activity. When the frequency of testing was assumed to be 1\xa0test per year, or when it was assumed that no additional phlebotomy appointment was needed, testing dominated standard care in both analyses (that is, testing was more clinically effective and cheaper than standard care).\n\nSensitivity analyses on the cost of adalimumab (20% to 80% discount) had little effect on the results of the additional analyses. In all analyses based on the INGEBIO full study report, the ICERs ranged from:\n\n£55,249 to £65,207 per QALY gained when the analysis was based on time in remission\n\n£132,942 to £155,954 per QALY gained when the analysis was based on time in remission or low disease activity.", 'Committee discussion': "# Clinical need and practice\n\nA clinical expert explained that rheumatoid arthritis has a devastating effect on a person's quality of life and almost 1\xa0in 3\xa0people stop work within 2\xa0years of diagnosis. The patient experts commented that active disease and flares have the biggest effect on their lives and they constantly fear their recurrence. The committee noted that there is no standard definition of flare. Further research to better define it would be beneficial but may be challenging because of the variability in disease presentation. The committee also heard that 'low disease activity' covers a wide range of disease presentations, and people with rheumatoid arthritis can continue to have pain even when their joints are not visibly swollen.\n\nThe committee heard that tumour necrosis factor (TNF)‑alpha inhibitors can be an effective treatment option for severe rheumatoid arthritis that has not responded to conventional therapy. But some people have disease that does not respond or loses response to TNF‑alpha inhibitors. Based on British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR‑RA) data, approximately 50% of people who have TNF‑alpha inhibitors stop within the first 4\xa0years because of lack of efficacy and adverse events such as severe infections. The committee concluded that managing rheumatoid arthritis is complex. New tests to optimise the use of TNF‑alpha inhibitors could improve management of the condition and so improve outcomes and quality of life for people with rheumatoid arthritis.\n\nThe committee noted that therapeutic monitoring of TNF‑alpha inhibitors is more established in inflammatory bowel disease. It was informed that companies who make TNF‑alpha inhibitors may offer to cover the cost of the enzyme-linked immunosorbent assay (ELISA) kits if a trust switches to their drug. The committee concluded that because testing is already being done and may be provided free of charge, clinicians may potentially have access. Therefore, it was important to consider whether testing in rheumatoid arthritis is appropriate.\n\nThe committee discussed treatment options for people with rheumatoid arthritis whose treatment target (remission or low disease activity) with TNF‑alpha inhibitors had been reached. The clinical experts explained that, in the UK, most people continue their treatment at the standard dose, that is, their dose is not reduced. But the committee was also informed that an increasing number of trusts do reduce the dose of TNF‑alpha inhibitor (based on clinical judgement) for these people. These trusts would have quick access policies in place for people reducing their dose, so they can return to clinic should their disease need to be reassessed or treatment adjusted.\n\nThe committee considered the potential value of therapeutic monitoring of TNF‑alpha inhibitors in people with rheumatoid arthritis whose treatment target (remission or low disease activity) had been reached. The committee noted that compared with no dose reduction, therapeutic monitoring could help inform clinicians who could reduce their dose of TNF‑alpha inhibitor without loss of efficacy. Lower doses could mean a lower risk of side effects, such as serious infections, and lower costs for TNF‑alpha inhibitors. The committee noted that compared with dose reduction based on clinical judgement only, therapeutic monitoring may have a limited effect on the average dose of TNF‑alpha inhibitor and rates of adverse events. However, helping to better inform clinicians who can reduce their dose without loss of efficacy could lead to a lower rate of relapse and flares.\n\nA patient expert explained that therapeutic monitoring of TNF‑alpha inhibitors can reassure people with rheumatoid arthritis who wish to consider reducing their dose. People may be uneasy about reducing their dose, fearing they may have disease recurrence or a flare as a result. The committee concluded that therapeutic monitoring of TNF‑alpha inhibitors could potentially reassure people with rheumatoid arthritis about reducing their dose more than when their dose is reduced based on clinical judgement alone.\n\nThe committee noted that therapeutic monitoring of TNF‑alpha inhibitors could improve adherence to TNF‑alpha inhibitors by helping to identify people for whom this could be a problem. The importance of adherence could then be discussed with them. However, clinical experts commented that concerns about adherence would not be the main reason for using therapeutic monitoring of TNF‑alpha inhibitors.\n\n# Clinical effectiveness\n\nThe committee reviewed the available evidence on the clinical effectiveness of using ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in people with rheumatoid arthritis. The committee noted that there was no evidence available for people with disease that has not responded to TNF‑alpha inhibitors or has stopped responding to TNF‑alpha inhibitors. It also noted that the evidence for people whose treatment target had been reached was limited and of poor quality. The committee was aware that no UK studies had been identified and there was no evidence for the IDKmonitor, LISA‑TRACKER and RIDASCREEN ELISA tests.\n\nThe committee was concerned that the results of the INGEBIO study may not be generalisable to the NHS. This was because of differences in the healthcare settings between Spain and the UK, and the lack of an explicit algorithm for guiding clinicians in how the test results should be interpreted and how they affect treatment. A patient expert explained that a warm climate has a favourable effect on symptoms, so there could be some differences in disease presentation between Spain and the UK. The committee noted that, because both treatment groups were enrolled at the same study sites, climate should not affect the results. Also, the committee was aware that the rate of dose reduction of TNF‑alpha inhibitors based on clinical judgement alone (standard care) and the rate of dose reduction based on clinical judgement plus therapeutic monitoring of TNF‑alpha inhibitors was similar in both study arms. The committee recalled that dose reduction based on clinical judgement is not routine practice in the NHS (see section\xa05.4). It concluded that INGEBIO may not be generalisable to clinical practice in the NHS.\n\nThe committee considered other limitations of INGEBIO. It noted that the study findings were presented as abstracts only, but the full study report had now been provided as commercial in confidence by Grifols. A full-text publication is being prepared. The committee was aware that the study had a non-randomised design and that baseline imbalances reported in the full study report were concerning. The external assessment group (EAG) explained that there was no adjustment for baseline imbalance in disease activity between groups. Also, there were unclear differences in clinical outcomes between the intention-to-treat analysis and the analysis that excluded 19\xa0people who were lost to follow up. The committee noted that the study enrolled a mixed population of people with different rheumatic diseases, with only 37% of people having rheumatoid arthritis. The clinical experts explained that rheumatic diseases have different rates of immunogenicity and therapeutic ranges but algorithms to interpret test results should be similar across these diseases. The committee noted a trend towards a reduced rate of flares with therapeutic monitoring, but the difference was not statistically significant. Also, the committee noted that the rates of flares were not stratified by dose and so did not provide information as to whether doses of TNF‑alpha inhibitors can be reduced without loss of efficacy. The committee noted that without this dose-relationship information, the differences seen in INGEBIO could simply be caused by chance. The committee concluded that the clinical outcomes reported were uncertain.\n\nThe committee considered the single-centre observational study by Pascual-Salcedo et al. (2013) and the small randomised controlled trial by l'Ami et al. (2017). It discussed its doubts about the generalisability of the Spanish observational study to the NHS because of differences in healthcare setting, the lack of a control group and enrolling people with mixed rheumatic diseases. The committee noted that l'Ami et al. enrolled a small number of people, had a short follow-up time, and the median doses of TNF‑alpha inhibitor (adalimumab) in both treatment groups were not statistically significantly different at the end of the study. The committee also noted that l'Ami et al. only randomised people with high blood levels of TNF‑alpha inhibitor. It did not provide any information on treatment choices and outcomes for people with lower levels of TNF‑alpha inhibitor. The committee concluded that the 2\xa0studies had important limitations, but they provided some support that therapeutic monitoring could help reduce doses of TNF‑alpha inhibitors without negatively affecting clinical outcomes (that is, without a subsequent increase in disease activity).\n\nThe committee considered the analytical validity of the tests. A clinical expert explained that there is no formal external quality assurance scheme for measuring levels of TNF‑alpha inhibitors and antibodies to TNF‑alpha inhibitors, but some laboratories take part in sample-exchange schemes as a form of quality assurance. Work on assuring the quality of ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors is ongoing and is most advanced for infliximab, for which World Health Organization international calibration standards have been developed. These calibration standards were shown to improve the consistency of results between different laboratories. A clinical expert explained that there is variability between results generated by the different ELISA tests, especially for TNF‑alpha inhibitors other than infliximab. The committee concluded that there is still potential uncertainty in the analytical performance of the ELISAs.\n\nThe committee noted that studies on the clinical validity of measuring levels of TNF‑alpha inhibitors (that is, studies looking at correlation between test results and health states such as remission or active disease) were not included in the assessment. It concluded that considering the very limited and poor-quality direct evidence on the clinical utility of ELISA tests (that is, information showing how treatment decisions informed by ELISA test results affect outcomes for people with rheumatoid arthritis), information on the clinical validity of ELISA tests could be beneficial. However, this information would not be able to confirm their clinical utility.\n\n# Cost effectiveness\n\nThe committee considered the choice of model structure. It recalled the uncertainties associated with INGEBIO (see sections 5.9 and 5.10), which provided the main clinical inputs for the model. Because of this, the committee agreed with the choice of a simple modelling approach. It concluded that the model results were of limited value because of a lack of robust clinical data.\n\nAt the first meeting, the committee discussed the primary analyses based on the Ucar et al. and Arango et al. conference abstracts (see section\xa05.16). It noted that the costs of managing health states appeared to be high. At the second meeting, the committee considered the additional analyses based on the INGEBIO full study report and updated health state costs. The committee concluded that because of the error in the health state costs, the results of the primary analyses were inaccurate. It noted that none of the analyses adjusted for the baseline imbalances between the 2\xa0study arms in INGEBIO. Therefore, the costs and quality-adjusted life years (QALYs) estimated from the model are likely to be flawed. The committee also agreed that the degree of uncertainty in the current clinical evidence was too high to use the model for decision making.\n\nAt the first meeting, the committee discussed differences between the 2\xa0sources of clinical data from INGEBIO for the 2\xa0primary analyses and noted both were conference abstracts. It was aware that the Ucar et al. intention-to-treat analysis reported time in remission, whereas Arango et al. excluded people lost to follow up and reported time in remission or low disease activity pooled together. As a result, health states were defined differently in the 2\xa0primary analyses: remission compared with active disease (low to high disease activity) in the first analysis, and remission or low disease activity compared with active disease (moderate to high disease activity) in the second analysis. The committee agreed that in the EAG's model based on INGEBIO, the time spent in each health state was a key driver of the cost-effectiveness results. The committee also noted that if the comparator in the model was no dose reduction it would be likely that the amount of drug would be a key driver of the cost-effectiveness results, and not the time spent in each health state.\n\nThe committee noted that the rates of adalimumab dose reduction in INGEBIO were similar in the 2\xa0treatment groups. As a result, the model did not provide information on whether therapeutic monitoring could offer savings to the NHS on the costs of adalimumab compared with the current practice of no dose reduction (see sections 5.4 and 5.5). The committee also noted that the similar rates of dose reduction in both groups explained why the results were not sensitive to changes in the price of adalimumab, even when discounts of up to 80% were considered. The committee agreed that in the NHS, rates of dose reduction and biosimilar prices are expected to affect the cost effectiveness of therapeutic monitoring of TNF‑alpha inhibitors. The committee was aware that in Gavan's cost-effectiveness modelling, based on the BSRBR‑RA data, therapeutic monitoring of TNF‑alpha inhibitors was generally cost effective compared with no dose reduction. But it was unlikely to be cost effective relative to dose reduction based on clinical judgement. The committee concluded that the EAG model may not be representative of NHS practice, in which dose reduction of TNF‑alpha inhibitors is not routinely done.\n\nThe committee acknowledged that the rates of flares in INGEBIO were not stratified by dose and so the relationship between adalimumab dose and the rate of flares was not captured in the model. It concluded therefore, that the model may not accurately reflect the experience of people with rheumatoid arthritis in the NHS whose dose of TNF‑alpha inhibitors is reduced.\n\nThe committee noted that the cost of a phlebotomy appointment appeared to be high but clinical experts explained that it likely represents the true cost of an outpatient phlebotomy appointment. They commented that although people with rheumatoid arthritis taking TNF‑alpha inhibitors (especially those also taking methotrexate) have frequent monitoring, an additional phlebotomy appointment may be needed to measure trough drug levels. This additional appointment would not be needed if drug levels of TNF‑alpha inhibitors could be measured at any time in the administration cycle. This was explored in sensitivity analyses.\n\nThe committee discussed the limitations of the economic model. It considered that although the clinical studies for therapeutic monitoring of TNF‑alpha inhibitors show promising results, the degree of uncertainty in the clinical evidence was too high for it to be able to use the incremental cost-effectiveness ratios (ICERs) for decision making. It concluded that the scope of any further changes to the modelling assumptions would be limited without more robust clinical data. The committee noted other evidence gaps such as:\n\nthe lack of clinical evidence on rheumatoid arthritis that has not responded to TNF-alpha inhibitors or has stopped responding\n\nthe lack of evidence for tests other than Promonitor and the Sanquin tests for therapeutic monitoring of adalimumab\n\nthe lack of data correlating test results and health states such as remission or active disease (which was out of scope for the EAG assessment).The committee noted that the last limitation could be addressed by further secondary research. Without robust clinical outcomes data, the committee was not able to recommend ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in rheumatoid arthritis for routine use in the NHS.\n\n## Research considerations\n\nThe committee noted the ongoing NOR‑DRUM trial in Norway, which will assess the efficacy of therapeutic monitoring of infliximab in a broad range of inflammatory diseases. The clinical experts advised that infliximab is rarely offered to people with rheumatoid arthritis in the UK. According to recent UK registry data, only about 5% of people with rheumatoid arthritis in the UK have infliximab. Therefore the committee concluded that this study may be of limited relevance to the NHS, but some findings could potentially be extrapolated to represent the likely value of therapeutic monitoring of TNF-alpha inhibitors as a class.\n\nThe committee expressed concern that because therapeutic monitoring of TNF‑alpha inhibitors is already used in inflammatory bowel disease and may be provided free of charge by companies that make TNF‑alpha inhibitors, the tests could be adopted inappropriately in rheumatoid arthritis, without proof of clinical and cost effectiveness. The committee concluded that if therapeutic monitoring of TNF‑alpha inhibitors is currently done in rheumatoid arthritis, audit data should be collected.\n\nThe committee noted that further primary research comparing therapeutic monitoring of TNF‑alpha inhibitors with current clinical practice in the NHS in people with rheumatoid arthritis is needed. However, because of the high level of uncertainty about the potential value to the NHS, it is not clear if this would be considered a priority by research funding bodies.\n\nFurther research is also needed into:\n\nthe analytical and clinical validity of the ELISA tests\n\nclinically meaningful thresholds for interpreting test results\n\nthe most appropriate test-based treatment algorithms and\n\nwhich groups of people with rheumatoid arthritis are likely to benefit most from therapeutic monitoring of TNF‑alpha inhibitors.", 'Recommendations for further research': 'Further secondary research is recommended to understand:\n\nthe clinical validity of enzyme-linked immunosorbent assay (ELISA) tests, that is the correlation between ELISA test results and health outcomes or states, such as remission, response, low or high disease activity or flares in rheumatoid arthritis\n\nthe comparative performance of different ELISA tests for therapeutic monitoring of tumour necrosis factor (TNF)‑alpha inhibitors in rheumatoid arthritis.\n\nFurther primary research is recommended on the clinical effectiveness of using ELISA tests for therapeutic monitoring of TNF‑alpha inhibitors in people with rheumatoid arthritis.'}
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https://www.nice.org.uk/guidance/dg36
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Evidence-based recommendations on enzyme-linked immunosorbent assay (ELISA) tests for therapeutic monitoring of tumour necrosis factor (TNF)-alpha inhibitors in rheumatoid arthritis. The tests are Promonitor, IDKmonitor, LISA‑tracker, RIDASCREEN, MabTrack, and those used by Sanquin Diagnostic Services.
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336c5d6139fbfd77c59c995861b5136d241aa869
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nice
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Bisphosphonates for treating osteoporosis
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Bisphosphonates for treating osteoporosis
Evidence-based recommendations on the bisphosphonates alendronic acid, ibandronic acid, risedronate sodium and zoledronic acid for treating osteoporosis.
# Recommendations
Oral bisphosphonates (alendronic acid, ibandronic acid and risedronate sodium) and intravenous bisphosphonates (ibandronic acid and zoledronic acid) are recommended, within their marketing authorisations, as options for treating osteoporosis in adults:
who are eligible for risk assessment as defined in NICE's guideline on osteoporosis (recommendations 1.1 and 1.2) and NICE's quality standard on osteoporosis and
who have been assessed as being at higher risk of osteoporotic fragility fracture using the methods recommended in NICE's guideline on osteoporosis (recommendations 1.3 to 1.12) and NICE's quality standard on osteoporosis and
when bisphosphonate treatment is appropriate, taking into account their risk of fracture, their risk of adverse effects from bisphosphonates, and their clinical circumstances and preferences.
The choice of treatment should be made on an individual basis after discussion between the responsible clinician and the patient, or their carers, about the advantages and disadvantages of the treatments available. If generic products are available, start treatment with the least expensive formulation, taking into account administration costs, the dose needed and the cost per dose.
These recommendations are not intended to affect treatment with alendronic acid, ibandronic acid, risedronate sodium and zoledronic acid that was started in the NHS before this guidance was published. Adults having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Alendronic acid, ibandronic acid, risedronate sodium and zoledronic acid are bisphosphonates, licensed for treating osteoporosis. Currently clinicians offer bisphosphonates to people with osteoporosis who are eligible for risk assessment and who have a high fracture risk.
To simplify the criteria for treatment and bring the guidance into line with NICE's guideline on osteoporosis, the evidence on bisphosphonates has been reviewed. A new network meta-analysis confirms that bisphosphonates are more effective at reducing the risk of fracture than placebo.
Risk assessment tools are used in clinical practice (FRAX and QFracture), in line with NICE's guideline on osteoporosis. These tools measure risk differently and can give different levels of risk in the same person.
Oral and intravenous bisphosphonates are recommended because new analyses show they are cost effective for people who have been assessed as being at higher risk of osteoporotic fragility fracture using the methods recommended in NICE's guideline on osteoporosis and NICE's quality standard on osteoporosis.# The technologies
The technologies being considered in this appraisal can be used at any point in the treatment pathway, within their marketing authorisations. Costs may vary in different settings because of negotiated procurement discounts.
Drug, dosage form and dosage
Indication
Price
Alendronic acid (generic) tablets, 10 mg once a day
Treating postmenopausal osteoporosis
Preventing and treating corticosteroid-induced osteoporosis in postmenopausal women not receiving hormone replacement therapy
Treating osteoporosis in men
‑tablet pack = £1.69
Alendronic acid (generic) tablets, 70 mg once a week
Treating postmenopausal osteoporosis
‑tablet pack = £0.72
Alendronic acid (generic) oral solution, 70 mg/100 ml once a week
Treating postmenopausal osteoporosis
× 100 ml = £27.36
Ibandronic acid (generic) tablets, 150 mg once a month
Treating postmenopausal osteoporosis
‑tablet pack = £1.13
Ibandronic acid (generic) injection, 3 mg/3 ml once every 3 months
Treating postmenopausal osteoporosis
‑ml prefilled syringe = £10.27*
Risedronate sodium (generic) tablets, 5 mg once a day
Treating postmenopausal osteoporosis to reduce risk of vertebral or hip fractures
Preventing osteoporosis (including corticosteroid-induced osteoporosis) in postmenopausal women
‑tablet pack = £8.60*
Risedronate sodium (generic) tablets, 35 mg once a week
Treating postmenopausal osteoporosis to reduce risk of vertebral or hip fractures
Treating osteoporosis in men at high risk of fractures
‑tablet pack = £0.85
Zoledronic acid
(generic) intravenous infusion, 50 micrograms/ml once a year
Treating postmenopausal osteoporosis and osteoporosis in men (including corticosteroid-induced osteoporosis)
‑ml solution for infusion bag = £7.36*
Prices based on national drug tariff
- Price based on eMIT database (data from 12-month period to end December 2015).# Committee discussion
The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Nature of the condition
## Osteoporosis can have a significant impact on a person's quality of life
Osteoporosis is a progressive skeletal disorder. It is characterised by low bone mass and deterioration of the structure of bone tissue leading to an increase in bone fragility and risk of fracture. The patient experts explained that fractures can be painful, have a significant impact on a person's independence and increase mortality. The clinical experts emphasised that it is important to prevent fragility fractures, particularly in people at the highest risk of fracture. The committee concluded that osteoporotic fragility fractures are debilitating, also affecting family and friends, and that preventing these would preserve the quality of life of the person and their carers.
# Clinical management of the condition
## Bisphosphonates are offered to people with the highest risk of osteoporotic fragility fractures
The clinical experts explained that bisphosphonates are generally well tolerated and are an important option in treating osteoporosis. The committee understood that bisphosphonates are usually offered to people with high fracture risk who typically have several risk factors, such as parental history of hip fracture, alcohol intake of 4 or more units per day and rheumatoid arthritis (see NICE's technology appraisal guidance on primary prevention of osteoporotic fragility fractures and secondary prevention of osteoporotic fragility fractures). Sometimes they are offered to people with comorbidities that can lead to osteoporotic fractures. The committee noted consultation comments on the assessment report that intravenous treatment needs to be available for people who are unable to take or tolerate oral bisphosphonates (such as those with impaired cognitive function). The committee concluded that bisphosphonates are an important treatment option, which clinicians prescribe for people at the highest risk of having osteoporotic fractures.
## The technology appraisal guidance on osteoporosis needs to be simplified and aligned with the clinical guideline
The committee was aware of the guidance on using bisphosphonates.
Alendronic acid was recommended as an option for primary prevention of osteoporotic fragility fractures in postmenopausal women with a high risk of fracture; and risedronate and etidronate for those at higher fracture risk.
Alendronic acid was recommended as an option for secondary prevention of osteoporotic fragility fractures in postmenopausal women with a high risk of fracture; and risedronate and etidronate for those at higher fracture risk.
The committee understood from the clinical experts that they have concerns about NICE's technology appraisal guidance because:
It is based on assessing the risk of osteoporotic fragility fractures taking into account a number of specific clinical factors, which may not be readily known.
It is difficult to implement because the criteria for using each treatment are complex.
It is not linked to NICE's guideline on osteoporosis, which refers to a treatment threshold associated with risk assessment rather than clinical factors.
It does not include recommendations for men.
There are now more bisphosphonate treatments available, such as ibandronic acid and zoledronic acid, which are not covered by the guidance.
Since publication a number of bisphosphonates have generic versions and as a result their price has dropped significantly.The committee concluded that there is a need to align the NICE guideline and NICE technology appraisal guidance, to simplify the guidance, to include recommendations for men, and to reflect the current price of bisphosphonates.
# Assessing fracture risk
## QFracture and FRAX assess risk in different ways; the recommendations should be based on using either tool
The committee recognised that assessing fracture risk is important to guide treatment. It noted that the absolute risk of an osteoporotic fracture over 10 years is usually assessed using tools such as FRAX or QFracture, which are both recommended in the NICE guideline. The committee noted comments from consultees and heard from clinical experts that the 2 tools have important differences in their approach to calculating fracture risk. The committee heard that each tool includes different risk factors, and that only FRAX accounts for the competing risk of mortality. The committee further noted that FRAX can be used with or without bone mineral density but that QFracture does not incorporate bone mineral density. It heard from clinical experts that FRAX is used more often than QFracture, possibly because FRAX is included in the National Osteoporosis Guideline Group's guideline. However, it noted that QFracture is also widely used in clinical practice. The committee understood that the risk level for an individual person from each tool could be very different and the 2 tools were not interchangeable. The committee agreed that the risk assessment tools were different and that it was not possible to determine which, if either, provided a more accurate and comprehensive risk assessment of fracture. It concluded that NICE guidance needed to account for the variation in practice and differences between the tools, and therefore agreed that its recommendations should be based on a level of risk determined by either tool.
# National Osteoporosis Guideline Group
## The National Osteoporosis Guideline Group's guideline provides a treatment threshold for clinicians
The committee was aware of the recent publication of a NICE accredited guideline by the National Osteoporosis Guideline Group for preventing and treating osteoporosis. The committee understood that the guideline recommended:
treatment for people with a high risk of fragility fracture
measuring bone mineral density and then assessing the risk of osteoporotic fragility fractures in people with intermediate risk.The committee noted that the guideline recommended treatment thresholds, which the recent NICE quality standard on osteoporosis reflected. The committee acknowledged that the thresholds may be used to determine when to offer treatment in clinical practice. However, it recognised that the recommendations to use these thresholds did not take cost effectiveness into account.
# Clinical effectiveness
## Using a class-effect network meta-analysis model to assess clinical effectiveness is appropriate
The committee considered the assessment group's network meta-analysis to determine the effectiveness of the bisphosphonates compared with placebo. It noted that 27 studies providing fracture data and 35 studies providing bone mineral density data were included in the network meta-analysis designed to develop a class-effect model, that is, the treatment effects are assumed to come from a common distribution based on the class of drug. The network meta-analysis assessed clinical effectiveness for:
vertebral fracture
hip fracture
wrist fracture and
femoral neck: bone mineral density only.The committee concluded that the methods used for the meta-analysis were appropriate.
## Pooling the efficacy results for bisphosphonates is appropriate, but cost effectiveness needs to be assessed for each treatment
The committee noted that the assessment group presented the network meta-analysis results for each treatment individually and for all bisphosphonates as a class. The committee discussed whether the bisphosphonates could be considered as a class. It heard that in clinical practice the treatments were considered to be interchangeable. It acknowledged comments from consultees that the efficacy estimates of the oral and intravenous bisphosphonates should be pooled for each fracture site. The committee noted that there were differences between the bisphosphonates in administration methods, persistence and adverse events. It therefore concluded that the efficacy estimates should be pooled, but the cost effectiveness for each treatment would need to be considered individually.
## Bisphosphonates are more effective than placebo in reducing fracture risk
The committee considered the pooled efficacy estimates in the network meta-analyses, which suggest that:
All treatments are associated with a statistically significant reduced risk of vertebral fracture compared with placebo (hazard ratio 0.45; credible interval 0.31 to 0.65).
All treatments are associated with a statistically significant reduced risk of hip fracture compared with placebo (HR 0.67; CrI 0.48 to 0.96).
None of the treatments are associated with a statistically significant reduced risk of wrist fracture compared with placebo (HR 0.81; CrI 0.46 to 1.44).
None of the treatments are associated with a statistically significant reduced risk of proximal humerus fracture compared with placebo (HR 0.79; CrI 0.58 to 1.11).The committee concluded that all bisphosphonates (oral and intravenous) are more clinically effective than placebo in reducing fracture risk.
# Assessment group's economic model
## The model structure is appropriate for decision-making
The committee was aware that the assessment group developed a de novo economic model to compare the cost effectiveness of oral bisphosphonates (alendronic acid, risedronate sodium, ibandronic acid) and intravenous bisphosphonates (ibandronic acid and zoledronic acid) and no treatment. The model was a discrete event simulation model that simulates patients with different characteristics, and calculates the costs and benefits after each event, such as fractures or death. The clinical events included in the model were hip fracture, wrist fracture, vertebral fracture, proximal humerus fracture and death. Time to event estimates were calculated using the FRAX and QFracture assessment tools. The committee concluded the model structure was appropriate for decision-making.
# Population in the economic model
## The model includes adults assessed for risk of osteoporotic fragility fracture
The committee noted that, in line with the final scope, the assessment group modelled a population of adults assessed for risk of osteoporotic fragility fracture, according to the recommendations in NICE's guideline on osteoporosis. These state that assessment of fracture risk should be considered:
in all women aged 65 years and over and all men aged 75 years and over
in women aged under 65 years and men aged under 75 years in the presence of risk factors, for example:
previous fragility fracture
current use or frequent recent use of oral or systemic glucocorticoids
history of falls
family history of hip fracture
-ther causes of secondary osteoporosis
low BMI (less than 18.5 kg/m2)
smoking
alcohol intake of more than 14 units per week for women and more than 21 units per week for men.
Fracture risk should not be routinely assessed in people aged under 50 years unless they have major risk factors (for example, current or frequent recent use of oral or systemic glucocorticoids, untreated premature menopause or previous fragility fracture), because they are unlikely to be at high risk.
## The modelled population is appropriate because it includes men and women
The committee recalled that one of the objectives of this technology appraisal was to make recommendations for men (see section 3.5), and it was assured by the assessment group that the modelled population included both men and women. The committee concluded that the modelled population was appropriate because it matched the final scope and included both men and women.
# Duration of treatment in the economic model
## The duration of treatment in clinical practice is uncertain
The clinical experts explained that there is uncertainty about the recommended treatment duration for someone prescribed a bisphosphonate. Depending on the person's fracture risk, treatment for up to 60 months may be recommended. However, the treatment duration assumed in the model (based on studies reporting mean duration of treatment) was lower than this; 6 months for oral bisphosphonates, 13 months for intravenous ibandronic acid and 14 months for zoledronic acid. The committee understood that there are factors that may influence the person adhering to treatment. For example, the initial discussion between the clinician and the patient about the aim of treatment and the correct method of administration, the regular telephone follow-up to encourage patients to adhere to treatment, and help the person has in managing any adverse effects during the initial treatment period. The committee recognised that this support varies across England, which would affect how long the person stays on treatment. The committee concluded that the model may have underestimated the duration of treatment in clinical practice. But given the relatively low acquisition cost of bisphosphonates, this is likely to affect the effectiveness of treatment more than its cost, and modelling longer treatment duration would improve the cost effectiveness of bisphosphonates.
# Survival estimates in the economic model
## It is plausible that the survival curve for FRAX is similar to that for QFracture
The committee was aware of the assumptions made by the assessment group about the fracture-free survival curve for FRAX. The assessment group noted that the parametric curve for fracture-free survival in QFracture was a Gompertz curve, and it had assumed that the fracture-free survival curve for FRAX would also follow a Gompertz curve with the same shape but a different rate of fracture. The committee acknowledged that the assessment group made this assumption because it did not have access to the underlying data for FRAX. The committee considered whether it was reasonable to assume that the 2 survival curves would be similar, particularly considering that the algorithm for FRAX takes mortality risk into account whereas QFracture does not. The committee concluded that there were limitations of this method, but agreed it was an appropriate approach given the lack of information on FRAX.
# Utilities in the economic model
## The model appropriately captures the impact on health-related quality of life of a fracture or entering a nursing home
The committee was aware that the utility values used in the model for those who have not had a fracture, or moved to a nursing home, depended on age and sex, and were based on EQ-5D data for the UK general population. It noted:
Disutility associated with fractures was accounted for by applying a fracture disutility multiplier (rather than a decrement) to the pre-fracture utility value. Values for hip, wrist and spine fractures were based on the KOFOR/ICUROS study because this was the only study to provide pre- and post-fracture EQ-5D values for these fractures. It also had the largest sample size and reported similar results to other studies. Values from Zethraeus et al. (2002) were used for proximal humerus fractures because no other studies reported a value for this fracture site.
Disutility associated with moving into a nursing home was accounted for by applying a utility multiplier of 0.625 to the pre-fracture utility value. This was based on a prospective cohort study that collected EQ-5D values from 90 patients with hip fractures, a proportion of whom moved into a nursing home after fracture. Several publications report a lower multiplier of 0.4. However, this was based on expert opinion rather than EQ-5D scores.The committee concluded that it was satisfied that the impact of a fracture or of moving to a nursing home on health-related quality of life had been adequately captured in the model.
# Cost of bisphosphonates in the economic model
## Using the lowest cost for each bisphosphonate is appropriate
The committee was aware that generic versions of the bisphosphonates are available, and it heard from clinical experts that these are regarded as being the same as the branded drug in clinical practice. The clinical experts explained that the most appropriate bisphosphonate would be prescribed at the lowest available cost, and that sometimes this would be outside of that formulation's marketing authorisation. The committee heard that the assessment group used the lowest available cost for each bisphosphonate in the model. However, since the model was run some prices have decreased slightly, which the committee acknowledged should be taken into account in the cost-effectiveness results. The committee concluded that using the lowest available cost for each bisphosphonate in the cost-effectiveness modelling reflected clinical practice and was appropriate.
# Nursing home costs
## The costs of nursing homes and residential care are captured in the model
The committee noted that the initial assessment group report had considered nursing home and residential care together, and applied the costs of residential care to both. The patient expert explained that nursing home costs are much greater than residential home costs. Additionally, the level of care provided in nursing homes and in residential care is very different. Nursing homes provide medical care for people who can no longer care for themselves and residential care provides independent living with limited support. The committee acknowledged that many people moving into residential care or nursing homes do so for reasons other than a fragility fracture. Therefore they may already be in a nursing home or residential care before fracture. The committee considered that given the differences between nursing homes and residential care, the costs of each setting should be considered individually. In the revised analyses, the assessment group separated nursing home and residential care costs. The revisions resulted in the annual cost of new admission to long-term care reducing from £36,600 to £23,500. The committee concluded that on balance the costs of nursing care and residential care in the model were appropriately captured.
# Adverse events in the economic model
## The model reflected the range of adverse events associated with treatment
The economic model captured some adverse events including gastrointestinal symptoms, which are associated with oral bisphosphonates (alendronic acid, risedronate sodium, ibandronic acid) and flu-like symptoms, which are associated with intravenous bisphosphonates (zoledronic acid and ibandronic acid). The committee was concerned that osteonecrosis of the jaw was not included in the model. The assessment group explained that there was not enough evidence for it to be included. Although not all adverse events have been included the committee was satisfied that the model reflected an adequate range of adverse effects associated with treatment.
# Cost-effectiveness results
## Conclusions on cost effectiveness should not be made, irrespective of the fracture risk tool used
The assessment group presented separate results based on using FRAX or QFracture to assess fracture risk. The committee was aware that both tools are widely used in clinical practice. It was also aware that they can provide a different probability of fracture risk for the same person, which means that the cost-effectiveness estimates could vary depending on which tool was used to determine risk. Because of this, the committee considered that it was appropriate to estimate cost effectiveness using each risk assessment tool separately. However, the committee also recalled the need to simplify the recommendations on preventing osteoporotic fragility fractures, and link them to existing NICE guidance in this disease area. Because of this, the committee concluded that if feasible, it was appropriate to recommend treatment at a level of fracture risk irrespective of the tool used, to complement other NICE guidance on preventing osteoporotic fragility fractures.
## Oral bisphosphonates are cost effective for people with at least a 1% fracture risk
The committee was aware that the assessment group provided results as incremental net benefits to allow cost effectiveness to be assessed across different 10‑year fracture risk probabilities. It noted that the results were provided when valuing a quality-adjusted life year (QALY) at £20,000 per QALY gained and at £30,000 per QALY gained. At £20,000 per QALY gained oral bisphosphonates were cost effective (that is, the incremental net benefit of bisphosphonates was positive) at:
around 1% probability of fracture risk when using QFracture and
any treatment threshold when using FRAX.The committee concluded that oral bisphosphonates were cost effective for people with at least a 1% fracture risk.
## Intravenous bisphosphonates are cost effective for people with at least a 10% fracture risk
The committee considered the incremental net benefits of intravenous ibandronic acid and intravenous zoledronic acid. It noted the risk level at which the treatments were cost effective (that is, at which the incremental net benefit of bisphosphonates was positive):
ibandronic acid:
QFracture: at 13.7% and 10.1% (at £20,000 and £30,000 per QALY gained respectively)
FRAX: at 10.3% and 6.8% (at £20,000 and £30,000 per QALY gained respectively).
zoledronic acid:
QFracture: at 15.9% and 10.9% (at £20,000 and £30,000 per QALY gained respectively)
FRAX: at 10.1% and 6.4% (at £20,000 and £30,000 per QALY gained respectively).
The committee noted that the prices of zoledronic acid and ibandronic acid are now lower than those used in the cost-effectiveness model and reasoned that this would lower the risk level at which treatments became cost effective. Therefore the committee concluded that intravenous bisphosphonates were cost effective for those with at least a 10% fracture risk.
# Equality issues
## Consideration should be given to people who cannot take oral bisphosphonates
The committee noted the potential equality issue raised during scoping; some people will have difficulty adhering to the complex instructions for taking oral bisphosphonates, which will affect treatment benefit. For example, people with dementia, learning disabilities, those unable to remain upright for the specified time period, and people for whom oral bisphosphonates might be contraindicated such as those with oesophageal stricture. The committee agreed that consideration should be given to this group and people who are unable to tolerate the recommended treatment.
# Conclusion
## Oral and intravenous bisphosphonates are recommended for some people
The committee noted its earlier conclusion that oral bisphosphonates were cost effective for people with at least a 1% fracture risk and that intravenous bisphosphonates were cost effective for those with at least a 10% fracture risk. It recommended oral and intravenous bisphosphonates as options for treating osteoporosis at these risk levels in people eligible for risk assessment. The committee considered those who are unable to tolerate oral bisphosphonates and agreed that for this group, intravenous bisphosphonates would be a cost-effective use of NHS resources.
# Other factors
The Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of any of the technologies in this appraisal.
|
{'Recommendations': "Oral bisphosphonates (alendronic acid, ibandronic acid and risedronate sodium) and intravenous bisphosphonates (ibandronic acid and zoledronic acid) are recommended, within their marketing authorisations, as options for treating osteoporosis in adults:\n\nwho are eligible for risk assessment as defined in NICE's guideline on osteoporosis (recommendations\xa01.1 and\xa01.2) and NICE's quality standard on osteoporosis and\n\nwho have been assessed as being at higher risk of osteoporotic fragility fracture using the methods recommended in NICE's guideline on osteoporosis (recommendations\xa01.3 to\xa01.12) and NICE's quality standard on osteoporosis and\n\nwhen bisphosphonate treatment is appropriate, taking into account their risk of fracture, their risk of adverse effects from bisphosphonates, and their clinical circumstances and preferences.\n\nThe choice of treatment should be made on an individual basis after discussion between the responsible clinician and the patient, or their carers, about the advantages and disadvantages of the treatments available. If generic products are available, start treatment with the least expensive formulation, taking into account administration costs, the dose needed and the cost per dose.\n\nThese recommendations are not intended to affect treatment with alendronic acid, ibandronic acid, risedronate sodium and zoledronic acid that was started in the NHS before this guidance was published. Adults having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nAlendronic acid, ibandronic acid, risedronate sodium and zoledronic acid are bisphosphonates, licensed for treating osteoporosis. Currently clinicians offer bisphosphonates to people with osteoporosis who are eligible for risk assessment and who have a high fracture risk.\n\nTo simplify the criteria for treatment and bring the guidance into line with NICE's guideline on osteoporosis, the evidence on bisphosphonates has been reviewed. A new network meta-analysis confirms that bisphosphonates are more effective at reducing the risk of fracture than placebo.\n\nRisk assessment tools are used in clinical practice (FRAX and QFracture), in line with NICE's guideline on osteoporosis. These tools measure risk differently and can give different levels of risk in the same person.\n\nOral and intravenous bisphosphonates are recommended because new analyses show they are cost effective for people who have been assessed as being at higher risk of osteoporotic fragility fracture using the methods recommended in NICE's guideline on osteoporosis and NICE's quality standard on osteoporosis.", 'The technologies': 'The technologies being considered in this appraisal can be used at any point in the treatment pathway, within their marketing authorisations. Costs may vary in different settings because of negotiated procurement discounts.\n\nDrug, dosage form and dosage\n\nIndication\n\nPrice\n\nAlendronic acid (generic) tablets, 10\xa0mg once a day\n\nTreating postmenopausal osteoporosis\n\nPreventing and treating corticosteroid-induced osteoporosis in postmenopausal women not receiving hormone replacement therapy\n\nTreating osteoporosis in men\n\n‑tablet pack = £1.69\n\nAlendronic acid (generic) tablets, 70\xa0mg once a week\n\nTreating postmenopausal osteoporosis\n\n‑tablet pack = £0.72\n\nAlendronic acid (generic) oral solution, 70\xa0mg/100\xa0ml once a week\n\nTreating postmenopausal osteoporosis\n\n×\xa0100\xa0ml = £27.36\n\nIbandronic acid (generic) tablets, 150\xa0mg once a month\n\nTreating postmenopausal osteoporosis\n\n‑tablet pack = £1.13\n\nIbandronic acid (generic) injection, 3\xa0mg/3\xa0ml once every 3\xa0months\n\nTreating postmenopausal osteoporosis\n\n‑ml prefilled syringe = £10.27*\n\nRisedronate sodium (generic) tablets, 5\xa0mg once a day\n\nTreating postmenopausal osteoporosis to reduce risk of vertebral or hip fractures\n\nPreventing osteoporosis (including corticosteroid-induced osteoporosis) in postmenopausal women\n\n‑tablet pack = £8.60*\n\nRisedronate sodium (generic) tablets, 35\xa0mg once a week\n\nTreating postmenopausal osteoporosis to reduce risk of vertebral or hip fractures\n\nTreating osteoporosis in men at high risk of fractures\n\n‑tablet pack = £0.85\n\nZoledronic acid\n\n(generic) intravenous infusion, 50\xa0micrograms/ml once a year\n\nTreating postmenopausal osteoporosis and osteoporosis in men (including corticosteroid-induced osteoporosis)\n\n‑ml solution for infusion bag = £7.36*\n\nPrices based on national drug tariff\n\n* Price based on eMIT database (data from 12-month period to end December 2015).', 'Committee discussion': "The appraisal committee (section\xa05) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Nature of the condition\n\n## Osteoporosis can have a significant impact on a person's quality of life\n\nOsteoporosis is a progressive skeletal disorder. It is characterised by low bone mass and deterioration of the structure of bone tissue leading to an increase in bone fragility and risk of fracture. The patient experts explained that fractures can be painful, have a significant impact on a person's independence and increase mortality. The clinical experts emphasised that it is important to prevent fragility fractures, particularly in people at the highest risk of fracture. The committee concluded that osteoporotic fragility fractures are debilitating, also affecting family and friends, and that preventing these would preserve the quality of life of the person and their carers.\n\n# Clinical management of the condition\n\n## Bisphosphonates are offered to people with the highest risk of osteoporotic fragility fractures\n\nThe clinical experts explained that bisphosphonates are generally well tolerated and are an important option in treating osteoporosis. The committee understood that bisphosphonates are usually offered to people with high fracture risk who typically have several risk factors, such as parental history of hip fracture, alcohol intake of 4\xa0or more units per day and rheumatoid arthritis (see NICE's technology appraisal guidance on primary prevention of osteoporotic fragility fractures and secondary prevention of osteoporotic fragility fractures). Sometimes they are offered to people with comorbidities that can lead to osteoporotic fractures. The committee noted consultation comments on the assessment report that intravenous treatment needs to be available for people who are unable to take or tolerate oral bisphosphonates (such as those with impaired cognitive function). The committee concluded that bisphosphonates are an important treatment option, which clinicians prescribe for people at the highest risk of having osteoporotic fractures.\n\n## The technology appraisal guidance on osteoporosis needs to be simplified and aligned with the clinical guideline\n\nThe committee was aware of the guidance on using bisphosphonates.\n\nAlendronic acid was recommended as an option for primary prevention of osteoporotic fragility fractures in postmenopausal women with a high risk of fracture; and risedronate and etidronate for those at higher fracture risk.\n\nAlendronic acid was recommended as an option for secondary prevention of osteoporotic fragility fractures in postmenopausal women with a high risk of fracture; and risedronate and etidronate for those at higher fracture risk.\n\nThe committee understood from the clinical experts that they have concerns about NICE's technology appraisal guidance because:\n\nIt is based on assessing the risk of osteoporotic fragility fractures taking into account a number of specific clinical factors, which may not be readily known.\n\nIt is difficult to implement because the criteria for using each treatment are complex.\n\nIt is not linked to NICE's guideline on osteoporosis, which refers to a treatment threshold associated with risk assessment rather than clinical factors.\n\nIt does not include recommendations for men.\n\nThere are now more bisphosphonate treatments available, such as ibandronic acid and zoledronic acid, which are not covered by the guidance.\n\nSince publication a number of bisphosphonates have generic versions and as a result their price has dropped significantly.The committee concluded that there is a need to align the NICE guideline and NICE technology appraisal guidance, to simplify the guidance, to include recommendations for men, and to reflect the current price of bisphosphonates.\n\n# Assessing fracture risk\n\n## QFracture and FRAX assess risk in different ways; the recommendations should be based on using either tool\n\nThe committee recognised that assessing fracture risk is important to guide treatment. It noted that the absolute risk of an osteoporotic fracture over 10\xa0years is usually assessed using tools such as FRAX or QFracture, which are both recommended in the NICE guideline. The committee noted comments from consultees and heard from clinical experts that the 2\xa0tools have important differences in their approach to calculating fracture risk. The committee heard that each tool includes different risk factors, and that only FRAX accounts for the competing risk of mortality. The committee further noted that FRAX can be used with or without bone mineral density but that QFracture does not incorporate bone mineral density. It heard from clinical experts that FRAX is used more often than QFracture, possibly because FRAX is included in the National Osteoporosis Guideline Group's guideline. However, it noted that QFracture is also widely used in clinical practice. The committee understood that the risk level for an individual person from each tool could be very different and the 2\xa0tools were not interchangeable. The committee agreed that the risk assessment tools were different and that it was not possible to determine which, if either, provided a more accurate and comprehensive risk assessment of fracture. It concluded that NICE guidance needed to account for the variation in practice and differences between the tools, and therefore agreed that its recommendations should be based on a level of risk determined by either tool.\n\n# National Osteoporosis Guideline Group\n\n## The National Osteoporosis Guideline Group's guideline provides a treatment threshold for clinicians\n\nThe committee was aware of the recent publication of a NICE accredited guideline by the National Osteoporosis Guideline Group for preventing and treating osteoporosis. The committee understood that the guideline recommended:\n\ntreatment for people with a high risk of fragility fracture\n\nmeasuring bone mineral density and then assessing the risk of osteoporotic fragility fractures in people with intermediate risk.The committee noted that the guideline recommended treatment thresholds, which the recent NICE quality standard on osteoporosis reflected. The committee acknowledged that the thresholds may be used to determine when to offer treatment in clinical practice. However, it recognised that the recommendations to use these thresholds did not take cost effectiveness into account.\n\n# Clinical effectiveness\n\n## Using a class-effect network meta-analysis model to assess clinical effectiveness is appropriate\n\nThe committee considered the assessment group's network meta-analysis to determine the effectiveness of the bisphosphonates compared with placebo. It noted that 27\xa0studies providing fracture data and 35\xa0studies providing bone mineral density data were included in the network meta-analysis designed to develop a class-effect model, that is, the treatment effects are assumed to come from a common distribution based on the class of drug. The network meta-analysis assessed clinical effectiveness for:\n\nvertebral fracture\n\nhip fracture\n\nwrist fracture and\n\nfemoral neck: bone mineral density only.The committee concluded that the methods used for the meta-analysis were appropriate.\n\n## Pooling the efficacy results for bisphosphonates is appropriate, but cost effectiveness needs to be assessed for each treatment\n\nThe committee noted that the assessment group presented the network meta-analysis results for each treatment individually and for all bisphosphonates as a class. The committee discussed whether the bisphosphonates could be considered as a class. It heard that in clinical practice the treatments were considered to be interchangeable. It acknowledged comments from consultees that the efficacy estimates of the oral and intravenous bisphosphonates should be pooled for each fracture site. The committee noted that there were differences between the bisphosphonates in administration methods, persistence and adverse events. It therefore concluded that the efficacy estimates should be pooled, but the cost effectiveness for each treatment would need to be considered individually.\n\n## Bisphosphonates are more effective than placebo in reducing fracture risk\n\nThe committee considered the pooled efficacy estimates in the network meta-analyses, which suggest that:\n\nAll treatments are associated with a statistically significant reduced risk of vertebral fracture compared with placebo (hazard ratio [HR] 0.45; credible interval [CrI] 0.31 to 0.65).\n\nAll treatments are associated with a statistically significant reduced risk of hip fracture compared with placebo (HR\xa00.67; CrI\xa00.48 to\xa00.96).\n\nNone of the treatments are associated with a statistically significant reduced risk of wrist fracture compared with placebo (HR\xa00.81; CrI\xa00.46 to\xa01.44).\n\nNone of the treatments are associated with a statistically significant reduced risk of proximal humerus fracture compared with placebo (HR\xa00.79; CrI\xa00.58 to\xa01.11).The committee concluded that all bisphosphonates (oral and intravenous) are more clinically effective than placebo in reducing fracture risk.\n\n# Assessment group's economic model\n\n## The model structure is appropriate for decision-making\n\nThe committee was aware that the assessment group developed a de novo economic model to compare the cost effectiveness of oral bisphosphonates (alendronic acid, risedronate sodium, ibandronic acid) and intravenous bisphosphonates (ibandronic acid and zoledronic acid) and no treatment. The model was a discrete event simulation model that simulates patients with different characteristics, and calculates the costs and benefits after each event, such as fractures or death. The clinical events included in the model were hip fracture, wrist fracture, vertebral fracture, proximal humerus fracture and death. Time to event estimates were calculated using the FRAX and QFracture assessment tools. The committee concluded the model structure was appropriate for decision-making.\n\n# Population in the economic model\n\n## The model includes adults assessed for risk of osteoporotic fragility fracture\n\nThe committee noted that, in line with the final scope, the assessment group modelled a population of adults assessed for risk of osteoporotic fragility fracture, according to the recommendations in NICE's guideline on osteoporosis. These state that assessment of fracture risk should be considered:\n\nin all women aged 65\xa0years and over and all men aged 75\xa0years and over\n\nin women aged under 65\xa0years and men aged under 75\xa0years in the presence of risk factors, for example:\n\n\n\nprevious fragility fracture\n\ncurrent use or frequent recent use of oral or systemic glucocorticoids\n\nhistory of falls\n\nfamily history of hip fracture\n\nother causes of secondary osteoporosis\n\nlow BMI (less than 18.5\xa0kg/m2)\n\nsmoking\n\nalcohol intake of more than 14\xa0units per week for women and more than 21\xa0units per week for men.\n\n\n\nFracture risk should not be routinely assessed in people aged under 50\xa0years unless they have major risk factors (for example, current or frequent recent use of oral or systemic glucocorticoids, untreated premature menopause or previous fragility fracture), because they are unlikely to be at high risk.\n\n## The modelled population is appropriate because it includes men and women\n\nThe committee recalled that one of the objectives of this technology appraisal was to make recommendations for men (see section\xa03.5), and it was assured by the assessment group that the modelled population included both men and women. The committee concluded that the modelled population was appropriate because it matched the final scope and included both men and women.\n\n# Duration of treatment in the economic model\n\n## The duration of treatment in clinical practice is uncertain\n\nThe clinical experts explained that there is uncertainty about the recommended treatment duration for someone prescribed a bisphosphonate. Depending on the person's fracture risk, treatment for up to 60\xa0months may be recommended. However, the treatment duration assumed in the model (based on studies reporting mean duration of treatment) was lower than this; 6\xa0months for oral bisphosphonates, 13\xa0months for intravenous ibandronic acid and 14\xa0months for zoledronic acid. The committee understood that there are factors that may influence the person adhering to treatment. For example, the initial discussion between the clinician and the patient about the aim of treatment and the correct method of administration, the regular telephone follow-up to encourage patients to adhere to treatment, and help the person has in managing any adverse effects during the initial treatment period. The committee recognised that this support varies across England, which would affect how long the person stays on treatment. The committee concluded that the model may have underestimated the duration of treatment in clinical practice. But given the relatively low acquisition cost of bisphosphonates, this is likely to affect the effectiveness of treatment more than its cost, and modelling longer treatment duration would improve the cost effectiveness of bisphosphonates.\n\n# Survival estimates in the economic model\n\n## It is plausible that the survival curve for FRAX is similar to that for QFracture\n\nThe committee was aware of the assumptions made by the assessment group about the fracture-free survival curve for FRAX. The assessment group noted that the parametric curve for fracture-free survival in QFracture was a Gompertz curve, and it had assumed that the fracture-free survival curve for FRAX would also follow a Gompertz curve with the same shape but a different rate of fracture. The committee acknowledged that the assessment group made this assumption because it did not have access to the underlying data for FRAX. The committee considered whether it was reasonable to assume that the 2\xa0survival curves would be similar, particularly considering that the algorithm for FRAX takes mortality risk into account whereas QFracture does not. The committee concluded that there were limitations of this method, but agreed it was an appropriate approach given the lack of information on FRAX.\n\n# Utilities in the economic model\n\n## The model appropriately captures the impact on health-related quality of life of a fracture or entering a nursing home\n\nThe committee was aware that the utility values used in the model for those who have not had a fracture, or moved to a nursing home, depended on age and sex, and were based on EQ-5D data for the UK general population. It noted:\n\nDisutility associated with fractures was accounted for by applying a fracture disutility multiplier (rather than a decrement) to the pre-fracture utility value. Values for hip, wrist and spine fractures were based on the KOFOR/ICUROS study because this was the only study to provide pre- and post-fracture EQ-5D values for these fractures. It also had the largest sample size and reported similar results to other studies. Values from Zethraeus et al. (2002) were used for proximal humerus fractures because no other studies reported a value for this fracture site.\n\nDisutility associated with moving into a nursing home was accounted for by applying a utility multiplier of 0.625 to the pre-fracture utility value. This was based on a prospective cohort study that collected EQ-5D values from 90\xa0patients with hip fractures, a proportion of whom moved into a nursing home after fracture. Several publications report a lower multiplier of 0.4. However, this was based on expert opinion rather than EQ-5D scores.The committee concluded that it was satisfied that the impact of a fracture or of moving to a nursing home on health-related quality of life had been adequately captured in the model.\n\n# Cost of bisphosphonates in the economic model\n\n## Using the lowest cost for each bisphosphonate is appropriate\n\nThe committee was aware that generic versions of the bisphosphonates are available, and it heard from clinical experts that these are regarded as being the same as the branded drug in clinical practice. The clinical experts explained that the most appropriate bisphosphonate would be prescribed at the lowest available cost, and that sometimes this would be outside of that formulation's marketing authorisation. The committee heard that the assessment group used the lowest available cost for each bisphosphonate in the model. However, since the model was run some prices have decreased slightly, which the committee acknowledged should be taken into account in the cost-effectiveness results. The committee concluded that using the lowest available cost for each bisphosphonate in the cost-effectiveness modelling reflected clinical practice and was appropriate.\n\n# Nursing home costs\n\n## The costs of nursing homes and residential care are captured in the model\n\nThe committee noted that the initial assessment group report had considered nursing home and residential care together, and applied the costs of residential care to both. The patient expert explained that nursing home costs are much greater than residential home costs. Additionally, the level of care provided in nursing homes and in residential care is very different. Nursing homes provide medical care for people who can no longer care for themselves and residential care provides independent living with limited support. The committee acknowledged that many people moving into residential care or nursing homes do so for reasons other than a fragility fracture. Therefore they may already be in a nursing home or residential care before fracture. The committee considered that given the differences between nursing homes and residential care, the costs of each setting should be considered individually. In the revised analyses, the assessment group separated nursing home and residential care costs. The revisions resulted in the annual cost of new admission to long-term care reducing from £36,600 to £23,500. The committee concluded that on balance the costs of nursing care and residential care in the model were appropriately captured.\n\n# Adverse events in the economic model\n\n## The model reflected the range of adverse events associated with treatment\n\nThe economic model captured some adverse events including gastrointestinal symptoms, which are associated with oral bisphosphonates (alendronic acid, risedronate sodium, ibandronic acid) and flu-like symptoms, which are associated with intravenous bisphosphonates (zoledronic acid and ibandronic acid). The committee was concerned that osteonecrosis of the jaw was not included in the model. The assessment group explained that there was not enough evidence for it to be included. Although not all adverse events have been included the committee was satisfied that the model reflected an adequate range of adverse effects associated with treatment.\n\n# Cost-effectiveness results\n\n## Conclusions on cost effectiveness should not be made, irrespective of the fracture risk tool used\n\nThe assessment group presented separate results based on using FRAX or QFracture to assess fracture risk. The committee was aware that both tools are widely used in clinical practice. It was also aware that they can provide a different probability of fracture risk for the same person, which means that the cost-effectiveness estimates could vary depending on which tool was used to determine risk. Because of this, the committee considered that it was appropriate to estimate cost effectiveness using each risk assessment tool separately. However, the committee also recalled the need to simplify the recommendations on preventing osteoporotic fragility fractures, and link them to existing NICE guidance in this disease area. Because of this, the committee concluded that if feasible, it was appropriate to recommend treatment at a level of fracture risk irrespective of the tool used, to complement other NICE guidance on preventing osteoporotic fragility fractures.\n\n## Oral bisphosphonates are cost effective for people with at least a 1%\xa0fracture risk\n\nThe committee was aware that the assessment group provided results as incremental net benefits to allow cost effectiveness to be assessed across different 10‑year fracture risk probabilities. It noted that the results were provided when valuing a quality-adjusted life year (QALY) at £20,000 per QALY gained and at £30,000 per QALY gained. At £20,000 per QALY gained oral bisphosphonates were cost effective (that is, the incremental net benefit of bisphosphonates was positive) at:\n\naround 1%\xa0probability of fracture risk when using QFracture and\n\nany treatment threshold when using FRAX.The committee concluded that oral bisphosphonates were cost effective for people with at least a 1%\xa0fracture risk.\n\n## Intravenous bisphosphonates are cost effective for people with at least a 10%\xa0fracture risk\n\nThe committee considered the incremental net benefits of intravenous ibandronic acid and intravenous zoledronic acid. It noted the risk level at which the treatments were cost effective (that is, at which the incremental net benefit of bisphosphonates was positive):\n\nibandronic acid:\n\n\n\nQFracture: at 13.7% and 10.1% (at £20,000 and £30,000 per QALY gained respectively)\n\nFRAX: at 10.3% and 6.8% (at £20,000 and £30,000 per QALY gained respectively).\n\n\n\nzoledronic acid:\n\n\n\nQFracture: at 15.9% and 10.9% (at £20,000 and £30,000 per QALY gained respectively)\n\nFRAX: at 10.1% and 6.4% (at £20,000 and £30,000 per QALY gained respectively).\n\n\n\nThe committee noted that the prices of zoledronic acid and ibandronic acid are now lower than those used in the cost-effectiveness model and reasoned that this would lower the risk level at which treatments became cost effective. Therefore the committee concluded that intravenous bisphosphonates were cost effective for those with at least a 10%\xa0fracture risk.\n\n# Equality issues\n\n## Consideration should be given to people who cannot take oral bisphosphonates\n\nThe committee noted the potential equality issue raised during scoping; some people will have difficulty adhering to the complex instructions for taking oral bisphosphonates, which will affect treatment benefit. For example, people with dementia, learning disabilities, those unable to remain upright for the specified time period, and people for whom oral bisphosphonates might be contraindicated such as those with oesophageal stricture. The committee agreed that consideration should be given to this group and people who are unable to tolerate the recommended treatment.\n\n# Conclusion\n\n## Oral and intravenous bisphosphonates are recommended for some people\n\nThe committee noted its earlier conclusion that oral bisphosphonates were cost effective for people with at least a 1%\xa0fracture risk and that intravenous bisphosphonates were cost effective for those with at least a 10%\xa0fracture risk. It recommended oral and intravenous bisphosphonates as options for treating osteoporosis at these risk levels in people eligible for risk assessment. The committee considered those who are unable to tolerate oral bisphosphonates and agreed that for this group, intravenous bisphosphonates would be a cost-effective use of NHS resources.\n\n# Other factors\n\nThe Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of any of the technologies in this appraisal."}
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https://www.nice.org.uk/guidance/ta464
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Evidence-based recommendations on the bisphosphonates alendronic acid, ibandronic acid, risedronate sodium and zoledronic acid for treating osteoporosis.
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9b1a630de8fc139787b80fd16bd248c425dc7e57
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nice
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Suspected neurological conditions: recognition and referral
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Suspected neurological conditions: recognition and referral
This guideline covers the initial assessment of symptoms and signs that might indicate a neurological condition. It helps non-specialist healthcare professionals to identify people who should be offered referral for specialist investigation.
# Recommendations for adults aged over 16
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Blackouts in adults
Refer urgently adults with new-onset blackouts (transient loss of consciousness), accompanied by features that are strongly suggestive of epileptic seizures, for neurological assessment in line with the recommendation for people with suspected epilepsy in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s.
Do not routinely refer adults with blackouts if there are clear features of vasovagal syncope, even if associated with brief jerking of the limbs. See the recommendation on diagnosing uncomplicated faint in the section on no further immediate management required in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on blackouts in adults .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Dizziness and vertigo in adults
## Sudden-onset dizziness with a focal neurological deficit
For adults with sudden-onset dizziness and a focal neurological deficit such as vertical or rotatory nystagmus, new-onset unsteadiness or new‑onset deafness:
if the person has diabetes, check for and treat hypoglycaemia
if the person does not have diabetes, or treating hypoglycaemia does not resolve the symptoms, and benign paroxysmal positional vertigo or postural hypotension do not account for the presentation, refer immediately to exclude posterior circulation stroke, in line with the NICE guideline on stroke and transient ischaemic attack in over 16s.
## Sudden-onset acute vestibular syndrome
For adults with sudden-onset acute vestibular syndrome (vertigo, nausea or vomiting and gait unsteadiness), a HINTS (head-impulse–nystagmus–test-of-skew) test should be performed if a healthcare professional with training and experience in the use of this test is available.
For adults with sudden-onset acute vestibular syndrome who have had a HINTS test:
be aware that a negative HINTS test makes a diagnosis of stroke very unlikely
refer immediately for neuroimaging if the HINTS test shows indications of stroke (a normal head impulse test, direction-changing nystagmus or skew deviation).
Refer immediately adults with sudden-onset acute vestibular syndrome in whom benign paroxysmal positional vertigo or postural hypotension do not account for the presentation, in line with local stroke pathways, if a healthcare professional with training and experience in the use of the HINTS test is not available.
## Sudden-onset dizziness with no imbalance or focal neurological deficit
Be aware that dizziness in adults with no imbalance or other focal neurological deficit is unlikely to indicate a serious neurological condition.
## Vertigo on head movement
For adults with transient rotational vertigo on head movement:
Offer the Hallpike manoeuvre to check for benign paroxysmal positional vertigo (BPPV) if a healthcare professional trained in its use is available. If there is no healthcare professional trained in the Hallpike manoeuvre available, refer in accordance with local pathways.
If BPPV is diagnosed, offer a canalith repositioning manoeuvre (such as the Epley manoeuvre) if a healthcare professional trained in its use is available and if the person does not have unstable cervical spine disease. If there is no healthcare professional trained in a canalith repositioning manoeuvre available, or the person has unstable cervical spine disease, refer in accordance with local pathways.
Be aware that BPPV is common after a head injury or labyrinthitis.
## Vestibular migraine
Be alert to the possibility of vestibular migraine (migraine-associated vertigo) in adults who have episodes of dizziness that last between 5 minutes and 72 hours and a history of recurrent headache.
## Recurrent dizziness as part of a functional neurological disorder
Be aware that, for adults who have been diagnosed with a functional neurological disorder by a specialist, recurrent dizziness might be part of the disorder and the person might not need re‑referral if there are no new neurological signs. New symptoms or signs in adults who have been diagnosed with a functional neurological disorder by a specialist should be assessed as described in the relevant sections of this guideline.
Advise adults with recurrent dizziness and a diagnosed functional neurological disorder that their dizziness will fluctuate and might increase during times of stress.
## Dizziness with altered consciousness
Refer adults with recurrent fixed-pattern dizziness associated with alteration of consciousness to have an assessment for epilepsy in line with the NICE guideline on epilepsies.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on dizziness and vertigo in adults .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Facial pain, atraumatic
## Facial pain with persistent facial numbness or abnormal neurological signs
Refer urgently adults with facial pain associated with persistent facial numbness or abnormal neurological signs for neuroimaging.
## Unilateral facial pain triggered by touching the face (trigeminal neuralgia)
Refer adults with unilateral facial pain that is triggered by touching the affected part of the face (trigeminal neuralgia) and is refractory to treatment, in line with the NICE guideline on neuropathic pain in adults.
## Scalp tenderness or jaw claudication suggestive of temporal arteritis
For adults with scalp tenderness or jaw claudication suggestive of temporal arteritis, consider blood tests and follow local pathways for suspected giant cell (temporal) arteritis. Be aware that a normal ESR (erythrocyte sedimentation rate) does not exclude a diagnosis of giant cell arteritis.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on atraumatic facial pain .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Gait unsteadiness
## Sudden-onset unsteady gait
For recommendations on assessing sudden-onset unsteady gait in adults, see the NICE guideline on stroke and transient ischaemic attack in over 16s.
## Rapidly progressive unsteady gait (gait ataxia)
Refer urgently adults with rapidly (within days to weeks) progressive unsteady gait (gait ataxia) for neurological assessment.
## Gradually progressive unsteady gait (gait ataxia)
Refer adults with gradually progressive unsteady gait (gait ataxia) for neurological assessment and:
take an alcohol history and follow the recommendations in the NICE guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence
check thyroid function
check for vitamin B12 and folate deficiency
consider serological testing for gluten sensitivity as recommended in the NICE guideline on coeliac disease.
## Difficulty initiating and coordinating walking (gait apraxia)
Refer adults who have difficulty initiating and coordinating walking (gait apraxia) to neurology or an elderly care clinic to exclude normal pressure hydrocephalus.
For adults with unsteadiness of gait who are at risk of falling, follow the recommendations on multifactorial falls risk assessment in the NICE guideline on falls in older people, and consider referring to a falls prevention team.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on gait unsteadiness .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Handwriting difficulties
Refer adults who have sudden-onset difficulty with handwriting that has no obvious musculoskeletal cause for a neurological assessment according to local stroke pathways.
Ask adults who have difficulty with handwriting that has no obvious musculoskeletal cause to demonstrate their handwriting and:
if they have a problem with generating language rather than hand function, refer for neurological assessment
if their handwriting is small and slow, consider referring for possible Parkinson's disease
if their difficulty is specific to the task of handwriting and examination shows no other abnormalities, consider referring for possible focal dystonia.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on handwriting difficulties .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Headaches in adults
For advice on referral for headaches in adults, see the NICE guideline on headaches in over 12s.
# Limb or facial weakness in adults
## Sudden-onset limb weakness
Be aware that sudden-onset weakness, even in restricted distribution (for example, sudden hand weakness), may be caused by a stroke or transient ischaemic attack. See the NICE guideline on stroke and transient ischaemic attack in over 16s for recommendations on assessing sudden-onset limb or facial weakness in adults.
## Rapidly progressive symmetrical limb weakness
Refer immediately adults with rapidly (within 4 weeks) progressive symmetrical limb weakness for neurological assessment and assessment of bulbar and respiratory function.
## Severe low back pain together with other symptoms
Refer immediately, in line with local pathways, adults who have severe low back pain radiating into the leg and new-onset disturbance of bladder, bowel or sexual function, or new-onset perineal numbness, to have an assessment for cauda equina syndrome.
## Rapidly progressive weakness of a single limb or hemiparesis
Refer urgently adults with very rapidly (within hours to days) progressive weakness of a single limb or hemiparesis for investigation, including neuroimaging, in line with the recommendation on brain and central nervous system cancers in adults in the NICE guideline on suspected cancer.
## Slowly progressive limb or neck weakness
For adults with slowly (within weeks to months) progressive limb or neck weakness:
refer for an assessment for neuromuscular disorders, in line with the recommendations on recognition and referral in the NICE guideline on motor neurone disease
refer urgently if there is any evidence of swallowing impairment
refer immediately if there is breathlessness at rest or when lying flat.
## Lower limb claudication symptoms
Be aware that lower limb claudication symptoms in adults with adequate peripheral circulation might be caused by lumbar canal stenosis and need specialist assessment and imaging.
## Recurrent limb or facial weakness as part of a functional neurological disorder
Be aware that, for adults who have been diagnosed with a functional neurological disorder by a specialist, recurrent limb weakness might be part of the disorder and the person might not need re‑referral if there are no new neurological signs. New symptoms or signs in adults who have been diagnosed with a functional neurological disorder by a specialist should be assessed as described in the relevant sections of this guideline.
Advise adults with limb or facial weakness ascribed to a functional neurological disorder that their limb or facial weakness might fluctuate and evolve over time and might increase during times of stress.
## Compression neuropathy
For adults with clear features of compression neuropathy of the radial nerve, common peroneal nerve or ulnar nerve and no features of a nerve root lesion (radiculopathy):
refer to orthotic services for a splint
review the symptoms after 6 weeks, and refer for neurological assessment if there is no evidence of improvement.For adults with features of radiculopathy, see the section on cervical or lumbar radiculopathy.
Advise adults with compression neuropathy to avoid any activity that might lead to further pressure on the affected nerve.
## Bell's palsy
Do not routinely refer adults with an uncomplicated episode of Bell's palsy (unilateral lower motor neurone pattern facial weakness affecting all parts of the face and including weakness of eye closure) and no evidence of another medical condition such as middle ear disease.
Advise adults with Bell's palsy about eye care, and explain that Bell's palsy improves at different rates and maximum recovery can take several months.
Consider referring adults with Bell's palsy who have developed symptoms of aberrant reinnervation (including gustatory sweating or jaw-winking) 5 months or more after the onset of Bell's palsy for neurological assessment and possible treatment.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on limb or facial weakness in adults .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Memory failure and cognitive deterioration
## Memory problems in adults aged under 50
For adults aged under 50 with memory problems and no other neurological signs:
do not routinely refer if brief testing shows memory function to be normal and symptoms are consistent with concentration difficulties
be aware that memory problems or concentration difficulties can be caused by:
recreational, and some prescription, drugs
alcohol
affective disorders
stress. For more information, see initial assessment in non-specialist settings in the NICE guideline on dementia.
## Memory problems as part of an anxiety disorder or a functional neurological disorder
Be aware that, for adults who have an anxiety disorder or have been diagnosed with a functional neurological disorder by a specialist, memory problems and concentration difficulties might be part of the disorder and the person might not need re‑referral if there are no new neurological signs. New symptoms or signs in adults who have been diagnosed with a functional neurological disorder by a specialist should be assessed as described in the relevant sections of this guideline.
## Concentration difficulties associated with myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome or fibromyalgia
Do not routinely refer adults for neurological assessment if they have concentration difficulties associated with myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome or fibromyalgia.
## Progressive memory problems
For guidance on referring adults with progressive memory problems, see initial assessment in non-specialist settings in the NICE guideline on dementia.
## Dense amnesia
Do not routinely refer adults with a single episode of dense amnesia (inability to recall the recent past or form new memories) if:
the episode lasts less than 8 hours and
there is complete recovery and
there are no features suggestive of an epileptic seizure (see seizure markers for suspected epilepsy in the NICE guideline on transient loss of consciousness in over 16s).Advise the person that they have probably had an episode of transient global amnesia and that the recurrence rate is low.
Refer adults with recurrent episodes of dense amnesia to have an assessment for epileptic amnesia.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on memory failure and cognitive deterioration .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Posture distortion in adults
## Dystonia
Suspect cervical dystonia in adults who have persistent abnormalities of head or neck posture, with or without head tremor, especially if the symptom improves when the person touches their chin with their hand.
Do not offer cervical imaging to evaluate suspected cervical dystonia in adults.
Be aware that dystonia in adults can affect other parts of the body (for example, it can cause writer's cramp or in‑turned posture of the foot).
Refer adults with suspected dystonia to have an assessment for diagnosis and possible botulinum toxin treatment.
## Dystonia as a side effect of medications
Be aware that antipsychotic and antiemetic medicines can trigger or exacerbate dystonia in adults.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on posture distortion in adults .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Sensory symptoms including tingling or numbness in adults
## Numbness and weakness
Assess sudden-onset transient unilateral numbness in adults in line with the NICE guideline on stroke and transient ischaemic attack in over 16s.
Refer immediately adults with rapidly progressive (within hours to days) symmetrical numbness and weakness or imbalance to have a neurological assessment.
## Sensory disturbances
Refer urgently adults with recurrent, brief (less than 2 minutes), fixed-pattern disturbances of sensation to have an assessment for epilepsy.
Refer adults with persistent, distally predominant altered sensation in the limbs, and brisk deep tendon reflexes, to have an assessment for possible brain or spine disease.
Suspect migraine with aura in adults who have sensory symptoms that occur with or without headache and:
are fully reversible and
develop over at least 5 minutes and
last between 5 and 60 minutes.For recommendations on diagnosing and managing migraine with aura, see the NICE guideline on headaches in over 12s.
For adults with persistent, distally predominant ('stocking' or 'glove and stocking') altered sensation in the limbs and depressed deep tendon reflexes:
be alert to the possibility of peripheral neuropathy and consider checking:
vitamin B12 deficiency
thyroid function
for evidence of coeliac disease in line with the NICE guideline on coeliac disease
renal function
blood glucose
ESR (erythrocyte sedimentation rate)
alcohol consumption, using a tool such as AUDIT (Alcohol Use Disorders Identification Test), in line with the NICE guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence
if no causes of peripheral neuropathy are found, refer for neurological assessment.
## Numbness and tingling as part of a functional neurological disorder
Be aware that, for adults who have been diagnosed with a functional neurological disorder by a specialist, recurrent numbness and tingling might be part of the disorder and the person might not need re‑referral if there are no new neurological signs. New symptoms or signs in adults who have been diagnosed with a functional neurological disorder by a specialist should be assessed as described in the relevant sections of this guideline.
Advise adults with tingling and a diagnosis of functional neurological disorder that the tingling might fluctuate and evolve over time and could increase at times of stress.
## Carpal tunnel syndrome
Refer in line with local pathways if symptoms of carpal tunnel syndrome are severe or persistent after initial management.
## Numbness, tingling or pain in the outer thigh
Reassure adults with unilateral or bilateral numbness, tingling or pain in the distribution of the lateral cutaneous nerve of the thigh (meralgia paraesthetica) that the condition is benign and might improve spontaneously. Consider referring for pain management only if the symptoms are severe.
## Cervical or lumbar radiculopathy
Do not routinely refer adults with symptoms of cervical radiculopathy that have remained stable for 6 weeks or more unless:
pain is not controlled with analgesics or
the symptoms are disabling or
-ne of the following factors is present:
age under 20
gait disturbance
clumsy or weak hands or legs
brisk deep tendon reflexes (triceps and lower limbs)
extensor plantar responses
new-onset disturbance of bladder or bowel function.
Do not routinely refer adults with symptoms of lumbar radiculopathy that have remained stable for 6 weeks or more unless pain is not controlled with analgesics or symptoms are disabling, in line with the NICE guideline on low back pain and sciatica in over 16s.
## Tingling or sensory disturbances on waking from sleep
Do not routinely refer adults with recurrent episodes of tingling or sensory disturbance in the limbs that are present on waking from sleep and last less than 10 minutes.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on sensory symptoms including tingling or numbness in adults .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Sleep disorders in adults
## Insomnia
Offer advice on sleep hygiene to adults with insomnia.
Do not routinely refer adults with insomnia, jerks on falling asleep or isolated brief episodes of sleep paralysis.
## Symptoms that suggest new-onset epileptic seizures
Refer urgently adults with symptoms suggestive of new-onset epileptic seizures in sleep for neurological assessment in line with the NICE guideline on epilepsies.
## Excessive sleepiness and narcolepsy
For adults with excessive sleepiness:
use the Epworth score together with history of obstructive symptoms in sleep to assess the likelihood of sleep apnoea
refer in accordance with local policy
if appropriate, offer advice on weight reduction, alcohol consumption and smoking cessation, in line with NICE guidance on obesity, alcohol-use disorders and smoking and tobacco.
Refer adults with narcolepsy, with or without cataplexy, for neurological assessment.
## Sleep behaviour disorders
Consider referring adults with persistent symptoms suggestive of sleep behaviour disorders (such as agitated or violent movements that are more complex than a simple jerking motion) for neurological assessment.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on sleep disorders in adults .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Smell or taste problems
## Distorted sense of smell or taste
Be aware that sudden-onset distortion of sense of smell or taste in adults is rarely associated with structural neurological abnormality and usually resolves within a few months.
## Smell or taste hallucinations
Refer adults with transient, repetitive smell or taste hallucinations to have a neurological assessment for epilepsy.
## Loss of sense of smell or taste
Consider neuroimaging for adults with unexplained loss of sense of smell or taste that lasts more than 3 months.
Do not routinely refer adults with loss of sense of smell or taste and normal neuroimaging.
Do not routinely refer adults who lose their sense of smell or taste immediately after a head injury.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on smell or taste problems .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Speech, swallowing and language problems in adults
## Sudden-onset speech or language disturbance
Refer immediately adults with sudden-onset speech or language disturbance to have an assessment for a vascular event, in line with local stroke pathways and following the recommendations in the NICE guideline on stroke and transient ischaemic attack in over 16s.
## Progressive slurred or disrupted speech
For adults with progressive slurred or disrupted speech:
refer for an assessment for neuromuscular disorders, in line with the recommendations on recognition and referral in the NICE guideline on motor neurone disease
refer urgently if there is any evidence of swallowing impairment
refer immediately if there is breathlessness at rest or when lying flat.
## Dysphonia
Consider referring adults with isolated and unexplained persistent dysphonia (a quiet, hoarse or wobbly voice) to have an assessment for laryngeal dystonia (involuntary contractions of the vocal cords) if hoarseness caused by structural abnormality or malignancy has been excluded by ear, nose and throat examination.
Be aware that persistent dysphonia in adults may be a presenting symptom of a neurological condition such as Parkinson's disease. For recommendations on the diagnosis and management of Parkinson's disease, see the NICE guideline on Parkinson's disease in adults.
## Word-finding difficulties as part of an anxiety disorder or a functional neurological disorder
Be aware that anxiety disorder and functional neurological disorders are the most common causes of minor word-finding difficulties in adults, and people with a diagnosis of anxiety disorder or functional neurological disorder made by a specialist might not need a referral.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on speech, swallowing and language problems in adults .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Tics and involuntary movements in adults
## Tics
Do not routinely refer adults with tics (involuntary movements that can be temporarily suppressed at the expense of mounting inner tension) unless the tics are troublesome or accompanied by additional progressive neurological symptoms.
Consider referring adults with a tic disorder for psychological therapy if the disorder distresses them.
Consider referring adults who have completed psychological therapy for a tic disorder to have a neurological assessment if their symptoms are severe and the disorder continues to distress them, but tell the person that:
there are not many medicines available to treat a tic disorder
the medicines that are available don't always work well and can have serious side effects.
## Involuntary movements
Do not routinely refer adults with isolated involuntary movements of the eyelid unless the movements:
cause involuntary tight eye closure of both eyes (blepharospasm) or
have persisted for more than 3 months.
In adults with involuntary movements of the face, neck, limbs or trunk that cannot be temporarily suppressed by mental concentration:
refer for neurological assessment or
refer to neurology or an eye clinic, according to local provision, if the person has involuntary tight eye closure of both eyes (blepharospasm).
Do not routinely refer adults with small involuntary muscular twitches (fasciculations) unless these are associated with muscle wasting and weakness or muscle rigidity.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on tics and involuntary movements in adults .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Tremor in adults
## Tremor suggesting Parkinson's disease
Refer adults with suspected parkinsonian tremor, other asymmetric tremor, or tremor associated with stiffness, slowness, balance problems or gait disorders for neurological assessment before treatment, in line with the NICE guideline on Parkinson's disease in adults.
## Essential tremor
Suspect essential tremor in an adult with symmetrical postural tremor and no symptoms of parkinsonism.
In adults with suspected essential tremor:
review regular medication
check thyroid function
assess alcohol consumption using a tool such as AUDIT (Alcohol Use Disorders Identification Test), in line with the NICE guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence.Refer for neurological assessment only if the symptoms are disabling and first-line treatment as specified in the BNF is ineffective or not tolerated.
Consider referring adults with troublesome tremor of the head to a movement disorder clinic.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on tremor in adults .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Information and support
Follow the principles in the NICE guidelines on patient experience in adult NHS services and shared decision making in relation to communication (including different formats and languages), information, shared decision making and continuity of care.
Advise adults with suspected neurological conditions to:
check the government's information on driving with medical conditions to find out whether they might have a condition that needs to be notified to the DVLA (Driver and Vehicle Licensing Agency)
consider telling their employer, school or college if their symptoms might affect their ability to work or study.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on information and support .
Full details of the evidence and the committee's discussion are in the full guideline.
Loading. Please wait.# Recommendations for children aged under 16
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Attention, concentration and memory problems
## Attention, concentration and memory problems related to epilepsy
Refer urgently children who present with discrete episodes of loss of awareness (mid-activity vacant spells) or of attention and concentration difficulty, in line with the NICE guideline on epilepsies.
Be aware that medicines commonly used to treat epilepsy in children can adversely affect concentration and memory.
## Concentration or memory difficulties that interfere with learning or behaviour
Refer children with concentration or memory difficulties that interfere with learning, school progress or behaviour to community paediatric or paediatric neurodevelopmental services for assessment.
Be aware that some children with attention and concentration difficulties do not have hyperactivity.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on attention, concentration and memory problems .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Blackouts and other paroxysmal events
## Blackouts and vacant spells
Refer urgently children with new-onset blackouts (transient loss of consciousness) accompanied by seizure markers for neurological assessment, in line with the recommendation for people with suspected epilepsy in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s.The committee agreed that the recommendation for people with suspected epilepsy in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s is applicable to children aged under 16.
Refer urgently children with mid-activity vacant spells or behavioural outbursts associated with altered consciousness or amnesia for the events to have a paediatric assessment.
## Blackouts in children under 12 years
Refer urgently all children aged under 12 years with blackouts for paediatric assessment.
## Vasovagal syncope
Do not routinely refer children aged over 12 years with blackouts if there are clear features of vasovagal syncope, even if associated with brief jerking of the limbs, in line with the recommendation on diagnosing uncomplicated faint in the section on no further immediate management required in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s.
## Blackouts, seizures or amnesia after a head injury
For children who have blackouts, seizures or amnesia for events after a head injury, follow the recommendations on pre-hospital assessment, advice and referral to hospital in the NICE guideline on head injury.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on blackouts and other paroxysmal events .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Confusion, acute
For children with unexplained acute confusion:
arrange an emergency transfer to hospital and
measure blood glucose.
Be aware that acute confusion in children can be a symptom of meningitis, encephalitis or poisoning. If infection is suspected, follow the recommendations in the NICE guideline on sepsis for identifying people with suspected sepsis and face-to-face assessment of people with suspected sepsis.
For children with acute confusion who have a non-blanching rash or other signs or symptoms suggestive of meningococcal septicaemia, follow the recommendations on suspected meningococcal disease (meningitis with non-blanching rash or meningococcal septicaemia) in the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s. For other signs and symptoms of meningococcal septicaemia, see bacterial meningitis and meningococcal septicaemia in children and young people – symptoms, signs and initial assessment in the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on acute confusion .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Dizziness and vertigo in children
## Dizziness with no accompanying symptoms or signs
Be aware that isolated dizziness in children is unlikely to be a symptom of a brain tumour if there are no accompanying symptoms or signs.
Be aware that dizziness in children is often a symptom of migraine and may be the predominant feature.
## Dizziness in older children
Be aware that in older children (usually aged over 8 years), dizziness related to change in posture is often caused by postural hypotension.
## Dizziness caused by middle ear infection or effusion
In children with dizziness, examine the ears for any signs of infection, inflammation or eardrum perforation.
## Recurrent dizziness
For children with recurrent episodes of dizziness:
consider referring for cardiological assessment if there are any factors that might suggest a cardiac cause, such as blackouts (transient loss of consciousness), a family history of cardiomyopathy or unexplained sudden death, or palpitations
if there are episodes of dizziness with a fixed symptom pattern, be alert to the possibility of epilepsy as the cause and follow the recommendations in the NICE guideline on epilepsies.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on dizziness and vertigo in children .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Headaches in children
For recommendations on headaches or migraine in children aged over 12 years, see the NICE guideline on headaches in over 12s.
## Headaches in children under 12 years
Refer immediately children aged under 12 years with headache for same-day assessment, according to local pathways, if they have any one of the following:
headache that wakes them at night
headache that is present on awakening in the morning
headache that progressively worsens
headache triggered or aggravated by coughing, sneezing or bending down
headache with fever and features of meningism
headache associated with vomiting
headache associated with ataxia
headache associated with change in conscious level or pervasive lethargy
headache occurring within 5 days of a head injury
headache associated with squint or failure of upward gaze ('sunsetting').
## Headaches in children under 4 years
Refer urgently all children aged under 4 years with headache for neurological assessment.
## Recurrent headaches and migraines
Perform or request fundoscopy for all children with recurrent headache and refer urgently for neurological assessment if there are abnormalities.
For all children with recurrent headache:
be aware that hypertension might be the cause
measure the child's blood pressure and check the measurement against blood pressure reference ranges adjusted for age and height
refer children if headaches are consistently worsened by upright posture and relieved by lying down.
Do not routinely refer children with migraine unless it is affecting their school life, social life or family activities, or they have one of the features listed in recommendation 1.21.1.
Be aware that emotional stress is a strong trigger of migraine and chronic, daily headache in children. Ask the child and their parent or carer about specific learning problems, bullying at school and stress in the family.
Ask about analgesic use in children with recurrent headache to ensure that medicine use is not excessive and to assess the likelihood of medication overuse headache. See the NICE guideline on headaches in over 12s for more information on medication overuse headache.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on headaches in children .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Head shape or size abnormalities
## Children with dysmorphic features and developmental delay
Refer urgently to paediatric services children with dysmorphic features and developmental delay.
## Children aged under 4 years
For all children aged under 4 years with suspected abnormal head shape or size:
take 3 consecutive measurements of the child's head circumference at the same appointment, using a disposable paper tape measure
plot the longest of the 3 measurements on a standardised growth chart, corrected for gestational age
if the child's head circumference is below the 2nd centile, refer for paediatric assessment.Offer follow-up measurements if needed, according to clinical judgement and taking the child's age into account.
For children with a head circumference measurement that differs by 2 or more centile lines from a previous measurement on a standardised growth chart (for example, an increase from the 25th to the 75th centile, or a decrease from the 50th to the 9th centile):
refer to paediatric services for assessment and cranial imaging to exclude progressive hydrocephalus or microcephaly or
refer immediately to paediatric services if the child also has any of the following signs or symptoms of raised intracranial pressure:
tense fontanelle
sixth nerve palsy
failure of upward gaze ('sunsetting')
vomiting
unsteadiness (ataxia)
headache.
For children with a head circumference above the 98th centile that has not changed by more than 2 centile lines from the previous measurement on a standardised growth chart, who are developing normally and who have no symptoms of raised intracranial pressure:
note the head size of the biological parents, if possible, to check for familial macrocephaly
if familial macrocephaly is likely, do not routinely refer the child in the absence of any other problem.
## Babies aged under 1 year with plagiocephaly
For babies aged under 1 year whose head is flattened on one side (plagiocephaly):
be aware that positional plagiocephaly (plagiocephaly caused by pressure outside the skull before or after birth) is the most common cause of asymmetric head shape
measure the distance between the outer canthus of the baby's eye and the tragus of their ear on each side
if the measurements differ, confirm positional plagiocephaly and do not routinely refer if the baby is developing normally
if the measurements are the same, suspect unilateral premature closure of lambdoid suture and refer to paediatric services.
Advise parents or carers of babies with positional plagiocephaly that it is usually caused by the baby sleeping in one position and can be improved by changing the baby's position when they are lying, encouraging the baby to sit up when awake, and giving the baby time on their tummy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on head shape or size abnormalities .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Hypotonia ('floppiness')
For babies aged under 1 year with acute-onset hypotonia (floppiness), examine the baby for signs of cardiac failure, enlargement of the liver or kidneys, pyrexia or an altered level of consciousness, and refer immediately to paediatric services.
For babies aged under 1 year with hypotonia (floppiness) that has been present for weeks or months:
if the baby is weak (for example, with feeding and breathing difficulties), refer urgently to paediatric services or
if the baby is not weak and has no signs of intercurrent illness, consider referring in line with the recommendations on looking for signs of cerebral palsy in the NICE guideline on cerebral palsy under 25s.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on hypotonia ('floppiness') .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Limb or facial weakness in children
## Sudden-onset or progressive limb or facial weakness
Refer immediately children with sudden-onset or rapidly progressive (hours to days) limb or facial weakness for neurological assessment.
Refer urgently children with progressive limb weakness for neurological assessment.
## Limb weakness as part of a developmental disorder
Refer children with limb weakness that is part of a developmental disorder to paediatric services, in line with the recommendations on looking for signs of cerebral palsy in the NICE guideline on cerebral palsy under 25s.
## Boys with limb weakness
For boys with limb weakness, see the recommendations on boys with motor development delay and motor development regression.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on limb or facial weakness in children .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Motor development delay or regression, and unsteadiness
## New-onset gait abnormality
Refer immediately children with new-onset gait abnormality to acute paediatric services.
## Motor development delay
Refer children to a child development service, and consider referring for physiotherapy or occupational therapy, in line with the recommendations in the NICE guideline on cerebral palsy in under 25s, if they:
are not sitting unsupported by 8 months (corrected for gestational age) or
are not walking independently by 15 months (girls) or 18 months (boys) (corrected for gestational age) or
show early asymmetry of hand function (hand preference) before 1 year (corrected for gestational age).
If the child is a boy, consider measuring creatinine kinase level to exclude Duchenne muscular dystrophy before the boy has had a specialist review.
## Motor development regression
Refer children with motor development regression to a paediatric neurodevelopmental service or paediatric neurology depending on locally agreed pathways.
If the child is a boy, consider measuring creatinine kinase level to exclude Duchenne muscular dystrophy before the boy has had a specialist review.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on motor development delay and unsteadiness .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Posture distortion in children
## Children with a recent head or neck trauma
Refer immediately children with abnormal neck posture and a recent head or neck trauma to an emergency department for assessment, and follow the recommendations on cervical spine immobilisation in the section on initial assessment and care in the NICE guideline on head injury, and the recommendation on spinal immobilisation in the section on assessment for spinal injury in the NICE guideline on spinal injury.
## Children with no recent trauma
In children with abnormal neck posture, check whether painful cervical lymphadenopathy is the cause.
Refer children who develop abnormal limb posture that has no apparent musculoskeletal cause for neurological assessment.
Be aware that abnormal head tilt in children can be a symptom of posterior fossa tumour.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on posture distortion in children .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Sensory symptoms such as tingling or numbness in children
## Tingling together with other symptoms
Refer urgently children who have tingling accompanied by other peripheral nervous system symptoms such as weakness, bladder dysfunction or bowel dysfunction for neurological assessment.
Be aware that tingling in children may be the first symptom of an acute polyneuropathy (Guillain–Barré syndrome) or other neuro-inflammatory conditions. If the child has features suggesting motor impairment, refer urgently for neurological assessment.
## Isolated tingling, altered sensation or paraesthesia
Refer children with isolated tingling, altered sensation or paraesthesia for neurological assessment if the symptoms are episodic and are not associated with compression of a nerve. For more information, see the recommendations on diagnosis and investigations in the NICE guideline on epilepsies.
## Temporary tingling caused by nerve compression or hyperventilation
Do not routinely refer children for neurological assessment of temporary tingling or numbness if there is a clear history of the symptom being triggered by activities known to cause nerve compression, such as carrying a heavy backpack or sitting with crossed legs.
Be aware that in children, hyperventilation is a common cause of transient tingling in the limbs.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on sensory symptoms such as tingling or numbness in children .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Sleep disorders in children
## Symptoms suggesting possible respiratory failure
Refer urgently children with neuromuscular disorders who have early-morning headaches or new-onset sleep disturbance for a respiratory assessment.
## Sleep disorders suggesting nocturnal seizures
Refer urgently children who have symptoms suggestive of new-onset epileptic seizures in sleep for neurological assessment.
## Narcolepsy
Refer children with symptoms suggestive of narcolepsy, with or without cataplexy, for neurological assessment or a sleep clinic assessment according to local pathways.
## Sleep disorders suggesting sleep apnoea
Refer children with symptoms of sleep apnoea to ear, nose and throat or paediatric respiratory services, as appropriate, and offer advice on weight loss if the child is obese.
## Night terrors in children aged over 5 years
Refer children aged over 5 years with new-onset night terrors and children with night terrors that persist after age 12.
## Night terrors and other sleep disturbances in children aged under 5 years
Reassure parents or carers of children aged under 5 years who have night terrors, repetitive movements, sleep talking or sleep walking that these are common in healthy children and rarely indicate a neurological condition.
Offer advice on sleep hygiene to parents or carers of children with insomnia, and consider referring to a health visitor if the child is aged under 5 years.
## Sleep disorders in children with neurodevelopmental disorders or learning disabilities
Consider referring children with sleep disorders associated with neurodevelopmental disorders or learning disabilities to community paediatric services.
## Sleep disorders as a result of gastro-oesophageal reflux or constipation
Be aware that sleep disorders in children may be a symptom of gastro-oesophageal reflux or constipation. See the recommendations on diagnosing and investigating gastro-oesophageal reflux disease in the NICE guideline on gastro-oesophageal reflux disease in children and young people, and the NICE guideline on constipation in children and young people.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on sleep disorders in children .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Speech problems in children
## New-onset slurred or disrupted speech
Refer urgently children with new-onset slurred or disrupted speech that is not attributable to prescribed medicines, recreational drugs or alcohol for neurological assessment.
## Problems with speech development in children aged over 2 years
Consider referring children aged over 2 years with abnormal speech development to speech and language services.
Be aware that delay or regression in speech and language in children can be a symptom of autism. Follow the recommendations in the NICE guideline on recognition, referral and diagnosis of autism spectrum disorder in under 19s for recognising children and young people with possible autism and referring children and young people to the autism team.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on speech problems in children .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Squint
## New-onset squint with loss of red reflex
Refer immediately children with new-onset squint that occurs together with loss of red reflex in one or both eyes to ophthalmology services. (Also see recommendations on childhood cancers in NICE's guideline on suspected cancer.)
## New-onset squint with ataxia, vomiting or headache
Refer immediately children with new-onset squint that occurs together with ataxia, vomiting or headache to acute paediatric services.
## Paralytic squint
Refer urgently children with paralytic squint for neurological assessment, even in the absence of other signs and symptoms of raised intracranial pressure.
## Non-paralytic squint
Refer children with non-paralytic squint to ophthalmology services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on squint .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Tics and involuntary movements in children
## Sudden-onset involuntary movements
Refer immediately children who have sudden-onset chorea, ataxia or dystonia for neurological assessment.
## Tics
Do not routinely refer children with simple motor tics that are not troublesome to the child.
Advise parents or carers of children with a tic disorder to discuss the disorder with the child's school, emphasising that the tic is an involuntary movement and the child should not be reprimanded for it.
Do not offer medicine for motor tics in children without specialist referral and advice (see recommendation 1.31.6).
Be aware that tics and stereotypies (repetitive or ritualistic movements such as body rocking) are more common in children with autism or a learning (intellectual) disability.
For children with a tic disorder that has a significant impact on their quality of life, consider referring according to local pathways, as follows:
referral to mental health services if the tic disorder is associated with symptoms of anxiety or obsessive compulsive behaviour
referral to the neurodevelopmental team if the tic disorder is associated with symptoms suggestive of autism or attention deficit hyperactivity disorder
referral for neurological assessment if the tic disorder is severe.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on tics and involuntary movements in children .
Full details of the evidence and the committee's discussion are in the full guideline.
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# Tremor in children
## Tremor of sudden onset or with accompanying neurological signs or symptoms
Refer urgently children presenting with tremor for neurological assessment if:
they have additional neurological signs or symptoms such as unsteadiness or
the onset of the tremor was sudden.
## Postural tremor
Be aware that isolated postural tremor in children may be a side effect of sodium valproate or a beta-adrenergic agonist.
Consider thyroid function tests for children with postural tremor and other symptoms or signs suggestive of thyroid overactivity.
Refer children with postural tremor for occupational therapy only if the tremor is affecting activities of daily living such as writing, eating or dressing.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on tremor in children .
Full details of the evidence and the committee's discussion are in the full guideline.
Loading. Please wait.# Terms used in this guideline
# Refer immediately
To be seen by the specialist service within a few hours, or even more quickly if necessary.
# Refer urgently
To be seen by the specialist service within 2 weeks.
# Refer
A routine referral.
# Consider referring
Consider a routine referral.
# Dizziness
A subjective sensation of spinning (vertigo) or a more vague sensation of unsteadiness, and sometimes a feeling of light-headedness or pre-syncope.
# Functional neurological disorder
A condition in which people experience neurological symptoms in the absence of any identifiable causative physical or structural abnormality.
# Radiculopathy
Irritation or damage to a nerve root as it exits the spinal canal. It is most commonly caused by mechanical compression from a prolapsed intervertebral disc or degenerative arthritis of the spine. Less frequently, an infection such as herpes zoster or Lyme disease is the cause. Symptoms include neck or low back pain radiating into a limb, tingling (paraesthesia), reduced or absent deep tendon reflex(es) and weakness in the distribution of the nerve root.# Rationale: recommendations for adults aged over 16
These sections briefly explain why the committee made the recommendations for adults. They link to details of the evidence and a full description of the committee's discussion.
# Blackouts in adults
Recommendations 1.1.1 and 1.1.2
## Why the committee made the recommendations
The committee agreed that the NICE guideline on transient loss of consciousness ('blackouts') in over 16s provides comprehensive recommendations on recognition and referral.
Return to recommendations
# Dizziness and vertigo in adults
Recommendations 1.2.1 to 1.2.10
## Why the committee made the recommendations
The committee used their knowledge and experience, together with evidence, to develop the recommendations on dizziness and vertigo in adults.
Evidence showed that sudden-onset dizziness is more likely to indicate a serious neurological condition if it is accompanied by imbalance and a focal abnormality. The committee confirmed that this is in line with their own clinical experience. They noted that these symptoms can also be caused by hypoglycaemia, and that prompt treatment of hypoglycaemia can reduce neurological damage.
The committee acknowledged the difficulty in differentiating between benign peripheral vertigo and the potentially more serious central vertigo that indicates a possible posterior circulation stroke. They agreed that a rapid bedside test would be a valuable addition to practice and could reduce unnecessary scans.
There is evidence showing that the accuracy of the bedside HINTS (head-impulse–nystagmus–test-of-skew) test is broadly similar to that of MRI in identifying people who have had a stroke and ruling out stroke in those who haven't. However, this accuracy is achieved only if the test is carried out by someone who has training and expertise in its use and interpretation. The committee noted that the HINTS test is non-invasive and would avoid the need for scans in people with a negative HINTS examination. To ensure that all people with stroke are identified promptly, the committee agreed that an immediate referral should be made if there is no healthcare professional with training in the HINTS test available.
Evidence showed that dizziness on its own is less likely to indicate a serious neurological condition than dizziness accompanied by other symptoms or signs. The committee confirmed that this is in line with their own clinical experience. They agreed that dizziness is a common and often self-limiting symptom and that this recommendation will help to reduce unnecessary referrals.
The committee's clinical experience has shown that for many people, positional vertigo is rapidly relieved by a canalith repositioning manoeuvre such as the Epley manoeuvre. The committee agreed that this is a simple, low-risk and effective intervention that can be offered in primary care.
The committee agreed that the diagnostic criteria for vestibular migraine (vertigo associated with migraine) issued by the International Headache Society would be useful to aid recognition of this condition in primary care.
In the committee's experience, symptoms caused by a functional neurological disorder can mimic symptoms caused by a physical neurological disorder. Dizziness is a common example of such a symptom. The committee thought it important to make a recommendation highlighting this to enable non-specialists to recognise when recurrent dizziness can be managed as part of a functional neurological disorder, rather than a symptom needing referral for neurological investigation.
The committee noted that epilepsy can sometimes present as recurrent fixed-pattern dizziness associated with alteration of consciousness.
Return to recommendations
# Facial pain, atraumatic
Recommendations 1.3.1 to 1.3.3
## Why the committee made the recommendations
Although atraumatic facial pain is a common symptom, no evidence on associated features that might indicate a need for referral was identified. The committee used their knowledge and experience to highlight signs and symptoms that might indicate a need for referral.
The committee agreed that facial pain together with persistent numbness or abnormal neurological signs should be referred urgently for neuroimaging to exclude a possible infiltrative or intracranial mass lesion.
The committee agreed that trigeminal neuralgia can be managed in primary care, following the recommendations in the NICE guideline on neuropathic pain in adults. A lack of response indicates that specialist review of the diagnosis and treatment is needed.
The committee noted that temporal arteritis can be difficult to diagnose. Left untreated, it can lead to permanent neurological damage, so the committee thought it important that temporal arteritis is always considered as a possible cause of facial pain and headache in older people.
Return to recommendations
# Gait unsteadiness
Recommendations 1.4.1 to 1.4.5
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on gait unsteadiness.
The committee agreed that sudden onset of an unsteady gait could indicate a vascular event such as a stroke, and therefore people with this symptom should be referred urgently, in line with the NICE guideline on stroke and transient ischaemic attack in over 16s.
The committee noted that this is an unusual symptom that could indicate a number of underlying conditions, including a brain tumour, an infection or a paraneoplastic presentation of an ovarian, lung or breast cancer. Because of the seriousness of these conditions, the committee agreed that people with this symptom should be referred urgently for specialist investigation.
The committee agreed that referral is important to identify treatable causes of a gradually progressive unsteady gait. The committee also agreed that it would be useful to highlight simple measures that can be taken while waiting for an appointment in secondary care. Checking and addressing alcohol consumption, gluten sensitivity and thyroid function can aid management of associated conditions and help to inform diagnosis.
The committee agreed that raising awareness of normal pressure hydrocephalus as a possible cause of gait apraxia is important because it is easily overlooked and can sometimes be treated.
Return to recommendations
# Handwriting difficulties
Recommendations 1.5.1 and 1.5.2
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on handwriting difficulties.
Although the committee thought that isolated handwriting difficulty is an unusual stroke presentation, they agreed that it is important to consider the possibility of stroke if handwriting difficulty occurs very suddenly.
The committee noted that difficulties with handwriting are not a common presentation in primary care and it can be difficult for non-specialists to recognise when they indicate an underlying neurological disorder.
Return to recommendations
# Limb or facial weakness in adults
Recommendations 1.7.1 to 1.7.13
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on limb or facial weakness in adults.
In the committee's experience, sudden-onset weakness that is restricted to a single limb is sometimes incorrectly attributed to a compression neuropathy or a musculoskeletal cause. They agreed that stroke or transient ischaemic attack should be suspected in all cases of sudden-onset limb or facial weakness.
The committee agreed that rapidly progressive symmetrical limb weakness can indicate a potentially life-threatening neuromuscular disorder or cervical myelopathy. These disorders can affect the respiratory muscles and cause respiratory failure. Their presenting features can be difficult to recognise in the early stages of the disorder.
The committee agreed that these symptoms can indicate cauda equina syndrome, which is a medical emergency.
The committee agreed that this symptom can indicate potentially serious neurological disease and needs to be assessed urgently.
The committee agreed that recognition and referral of slowly progressive limb or neck weakness is covered in the NICE guideline on motor neurone disease. If the weakness is accompanied by symptoms such as problems with swallowing or breathing, an urgent referral is needed.
The committee agreed that lower limb discomfort that comes on after walking and improves with rest (claudication), and that has no vascular cause, might indicate lumbar canal stenosis. If the pain is severe or disabling, a specialist assessment is indicated and this may be carried out by an extended scope practitioner, neurosurgeon or orthopaedic surgeon.
The committee noted that recurrent episodes of limb weakness are not uncommon in people with functional neurological disorders. They agreed that in these cases, referral after each episode of limb weakness is not necessary.
The committee agreed that reassuring adults about the nature of the underlying condition will help to allay their concerns and reduce requests for referrals.
In the committee's experience, compression neuropathies can be recognised on the basis of a history of prolonged pressure on the nerve and the pattern of weakness and numbness. They usually resolve spontaneously within 6 weeks, although a splint might be needed for support during recovery. Reducing recurrent pressure or trauma on the affected nerve aids recovery.
The committee agreed that uncomplicated Bell's palsy can be diagnosed and managed in primary care. They thought it important that people with this condition know that recovery time can vary and that recovery might not be complete. Referral for specialist treatment can be beneficial for people who develop troublesome symptoms after recovering from Bell's palsy.
Return to recommendations
# Memory failure and cognitive deterioration
Recommendations 1.8.1 to 1.8.6
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on memory failure and cognitive deterioration. They reviewed evidence on specific tools for brief memory testing but no evidence to support a recommendation on specific tools was identified.
The committee agreed that, although difficulties with memory are common in people aged under 50, neurodegenerative disorders affecting memory are rare. Brief memory testing and knowledge of common causes of memory difficulties can reassure the clinician that referral is not needed. No evidence on the diagnostic accuracy of different tools for brief memory testing was identified so the committee agreed not to recommend any specific tests.
The committee noted that difficulty concentrating is a common symptom in people with an anxiety disorder or a functional neurological disorder. It often presents as a problem with memory.
The committee pointed out that difficulties with memory and concentration are common in myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome or fibromyalgia, and that these symptoms can be managed as part of the management of those conditions.
The committee agreed that the NICE guideline on dementia provides advice on referring adults with progressive memory problems.
The committee thought it important to raise awareness of transient global amnesia, which presents as a single episode of dense amnesia with complete recovery and no features of epilepsy, and has a very low recurrence rate. The committee wanted to help non-specialists differentiate this from transient epileptic amnesia, which is recurrent and needs further investigation.
Return to recommendations
# Posture distortion in adults
Recommendations 1.9.1 to 1.9.5
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on posture distortion in adults.
The committee wanted non-specialists to be aware that cervical dystonia is diagnosed on the basis of clinical features, and that imaging is unnecessary and can delay treatment. They also wanted to raise awareness of the wide range of ways in which dystonia can present, such as only during the performance of certain tasks or in certain parts of the body.
The committee discussed the possible misinterpretation of dystonia affecting neck and foot posture as an orthopaedic problem, leading to unnecessary orthopaedic referrals. They made a specific recommendation for neurological referral to ensure that dystonia caused by an underlying neurodegenerative condition, or by medication, is identified and managed. If the dystonia is idiopathic, treatment can be offered.
The committee wanted to point out that dystonia is a side effect of some widely used antipsychotic and antiemetic medicines. It typically occurs within a few days of starting the medicine. In these cases, the prescriber of the medicine should review it.
Return to recommendations
# Sensory symptoms including tingling or numbness in adults
Recommendations 1.10.1 to 1.10.13
## Why the committee made the recommendations
The committee used their knowledge and experience to develop the recommendations on sensory symptoms including tingling or numbness in adults. Although evidence was reviewed, none that could support recommendations was identified.
The committee agreed that transient unilateral numbness of sudden onset should be managed in line with the NICE guideline on stroke and transient ischaemic attack in over 16s.
The committee emphasised the immediate risk posed by rapidly progressive symmetrical numbness, which might indicate a post-infective polyneuropathy (Guillain–Barré syndrome) or transverse myelitis and can be difficult to recognise in the early stages.
Although the committee agreed that recurrent, brief, fixed-pattern sensory disturbances are not the most common presentation of epilepsy, they thought referral would be important so as not to miss this important diagnosis.
The committee agreed that persistent, distally predominant altered sensation in the limbs in a person with brisk deep tendon reflexes might indicate a lesion in the brain or spinal cord. In a person with depressed reflexes, it is more likely to indicate a neuropathy.
The committee wanted to raise awareness of the possibility of migraine in people with some types of sensory symptoms, and noted that the NICE guideline on headaches in over 12s provides recommendations on recognition and referral for migraine.
The committee also wanted to encourage non-specialists to explore the possibility of peripheral neuropathy as a cause of sensory symptoms before referral. They thought this would help to ensure that people with these symptoms are referred to the correct service, which may be neurological or non-neurological.
The committee noted that transient sensory symptoms are common in people with a functional neurological disorder. They considered that these symptoms might not need neurological assessment.
The committee agreed that people with a functional neurological disorder might benefit from knowing that their symptoms are likely to fluctuate and evolve with time.
The committee noted that carpal tunnel syndrome is common and many regions have established management pathways that might not involve neurological services.
The committee agreed that this is a common condition that usually improves with time, and might benefit from weight loss.
In the committee's experience, cervical and lumbar radiculopathies usually settle spontaneously within a few weeks. However, the committee thought it important to highlight features that might suggest a more serious underlying condition and need further investigation.
The committee noted that this symptom is usually caused by compression related to sleeping posture and resolves rapidly without treatment.
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# Sleep disorders in adults
Recommendations 1.11.1 to 1.11.6
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on sleep disorders in adults.
The committee agreed that difficulty sleeping and brief involuntary movements in sleep are common and benign, and do not indicate a neurological problem.
The committee highlighted the substantial risk of sudden unexpected death in epilepsy (SUDEP) in people who have epileptic seizures during sleep. They therefore emphasised the need for prompt investigation for people with this symptom.
The committee thought it important that people with excessive sleepiness are offered assessment for sleep apnoea so that they can be referred in line with local policies and pathways for the management of this condition. They agreed that the Epworth score is a well-established measure of sleep apnoea suitable for use by non-specialists.
Although narcolepsy and cataplexy are rare conditions, the committee thought it important to highlight them to raise awareness among non-specialists.
The committee observed that sleep behaviour disorders vary in severity and on rare occasions can endanger life if they cause a person to undertake potentially harmful behaviours while asleep. They agreed that complex and severe sleep behaviour disorders need further assessment, and that the clinical judgement of the non-specialist is the best means of determining whether to offer further assessment to an individual.
Return to recommendations
# Smell or taste problems
Recommendations 1.12.1 to 1.12.5
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on smell or taste problems.
In the committee's experience, sudden-onset distortion of sense of smell or taste is usually idiopathic. The committee wanted to reassure non-specialists that this symptom is unlikely to indicate a neurological condition.
The committee agreed that brief, repetitive smell or taste hallucinations can be caused by temporal lobe epilepsy. They noted that this symptom is not likely to be associated with a brain tumour.
The committee noted that loss of sense of smell or taste is a fairly common reason for referral to neurological services, but rarely has a serious neurological cause. They therefore thought that neuroimaging is not usually needed.
The committee agreed that an exception to this is a loss of sense of smell or taste that can't be attributed to a rhinological cause, normal ageing or neurodegenerative disease, and lasts longer than 3 months.
The committee discussed loss of smell or taste after a head injury. They noted that this is common and does not indicate more extensive brain injury. Loss of sense of smell after a head trauma is not treatable and is often permanent.
Return to recommendations
# Speech, swallowing and language problems in adults
Recommendations 1.13.1 to 1.13.5
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on speech, swallowing and language problems in adults.
The committee agreed that sudden-onset speech or language disturbance could indicate a vascular event.
The committee noted that slurred or disrupted speech can indicate serious underlying neurological disease, such as motor neurone disease or myasthenia gravis. Although the prognosis in motor neurone disease is not greatly influenced by early diagnosis, it is important to consider other diagnoses such as myasthenia gravis, which is highly treatable.
The committee agreed that a quiet or wobbly voice (dysphonia) can be a symptom of laryngeal dystonia, which is potentially treatable.
The committee also wanted to raise awareness of dysphonia as a possible presenting symptom of Parkinson's disease.
The committee agreed that minor word-finding difficulties are a very common presentation in anxiety disorder and functional neurological disorders.
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# Tics and involuntary movements in adults
Recommendations 1.14.1 to 1.14.6
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on tics and involuntary movements in adults.
The committee agreed that tics are relatively common and, on their own, are benign. Treatment and management options are limited so there is little value in referring to secondary care. The committee noted that tic disorders are often accompanied by anxiety and distress that might be relieved by psychological therapy. If this is not effective and the tics are very severe or socially disabling, the committee thought that neurological referral to explore further treatment options might be beneficial.
The committee observed that involuntary movements (such as in chorea) are often mistaken for tics. Unlike tics, involuntary movements cannot be voluntarily suppressed and if they are severe or persistent, might benefit from treatment.
Small, involuntary muscle twitches are usually benign, and are especially common in the calf muscles. If accompanied by weakness, muscle wasting or muscular rigidity (stiffness), they could indicate neuromuscular disease. Otherwise, the committee considered that it is usually sufficient to reassure the person.
Return to recommendations
# Tremor in adults
Recommendations 1.15.1 to 1.15.4
## Why the committee made the recommendations
The committee used their knowledge and experience to develop the recommendations on tremor in adults. Although evidence was reviewed, none that could support recommendations was identified.
The committee observed that a unilateral or predominantly unilateral tremor, especially if more prominent at rest and accompanied by slowness, is particularly suggestive of Parkinson's disease.
The committee wanted to help non-specialists differentiate essential tremor from parkinsonian tremor. They noted that essential tremor is usually bilateral and does not affect muscle tone or speed of movement. They thought that essential tremor can usually be managed in primary care.
The committee agreed that troublesome head tremor can often be controlled using treatments available in a movement disorder clinic.
Return to recommendations
# Information and support
Recommendations 1.16.1 and 1.16.2
## Why the committee made the recommendations
The committee used their knowledge and experience to develop the recommendations on information and support. They agreed that this guideline covers a very broad population, and that it is unwise to give guidance on people's specific information and support needs before a diagnosis has been made. They therefore included information that might usefully be given to people presenting with neurological symptoms in the relevant recommendations, and highlighted the NICE guideline on patient experience in adult NHS services.
The committee agreed that healthcare professionals should advise people about the impact of neurological conditions on driving. They noted that people are free not to reveal health issues to their employer, school or college, but that employers and others who have this information are better able to make adjustments to help the person continue their work or studies.
Return to recommendations# Rationale: recommendations for children aged under 16
These sections briefly explain why the committee made the recommendations for children. They link to details of the evidence reviews and a full description of the committee's discussion.
# Attention, concentration and memory problems
Recommendations 1.17.1 to 1.17.4
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on attention, concentration and memory problems.
The committee noted that concentration and memory problems are common in children who have diagnosed or undiagnosed epilepsy. They agreed that, in a child not diagnosed with epilepsy, episodes of loss of awareness, attention or concentration might be unrecognised absence seizures that need further investigation.
In children already diagnosed with epilepsy, the committee discussed drowsiness caused by anti-epileptic medicines, especially in higher doses or if more than one medicine is being taken. Children and their parents or carers can be advised about this, and it might be possible to adjust doses to reduce the effect on concentration and memory.
The committee agreed that concentration and memory difficulties that interfere with a child's learning should have further assessment to avoid unscheduled healthcare visits for learning difficulties in the future.
The committee discussed the common perception of children with attention and concentration problems as having hyperactive, noisy and destructive behaviour. Such children readily come to the attention of primary care, school and paediatric neurodevelopmental services. The committee wanted to ensure that children who do not have hyperactivity but do have significant attention and concentration problems are also recognised. Because they do not behave in a disruptive manner, these children may not be identified promptly, and may later present with learning difficulties.
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# Blackouts and other paroxysmal events
Recommendations 1.18.1 to 1.18.5
## Why the committee made the recommendations
The committee used their knowledge and experience to develop the recommendations on blackouts and other paroxysmal events. Although evidence was reviewed, none that could support recommendations was identified.
Blackouts in children can be caused by neurological disorders, predominantly epilepsy, cardiac disorders or simple syncope. The committee observed that, even with a clear first-hand description of the event, it is not always possible to make a confident diagnosis without specialist assessment and investigations. The committee agreed that the recommendation for people with suspected epilepsy in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s is applicable to children aged under 16.
Vacant spells – often called absences – as a result of epilepsy in children can be difficult to distinguish from day-dreaming and loss of concentration, and need further assessment.
The committee agreed that all children under 12 with blackouts or transient loss of consciousness should be referred for urgent assessment because history and examination do not always allow a diagnosis to be made confidently and there are a number of potentially serious causes that need to be excluded.
Vasovagal syncope is common in young people, and is often inappropriately referred because of concern that it represents seizures. The committee considered that the recommendation on vasovagal syncope in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s is applicable to children aged 12 to 15 years.
Transient loss of consciousness after a head injury in children is usually immediate or within a few minutes. Much-delayed paroxysmal events after head injury in children – days or weeks later – are rare but warrant urgent referral for neurological assessment. The committee considered that the recommendations on pre-hospital assessment, advice and referral to hospital in the NICE guideline on head injury should be followed.
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# Confusion, acute
Recommendations 1.19.1 to 1.19.3
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on acute confusion.
Acute confusion in a child can be a symptom of a severe neurological illness such as meningitis, intracranial haemorrhage, raised intracranial pressure, or drug or alcohol poisoning. The committee agreed that all children presenting with acute confusion should be transferred to hospital immediately by the quickest means available. Hypoglycaemia can present with acute confusion and therefore blood glucose should be measured as soon as possible to avoid delays in diagnosis and treatment for the child once in hospital care. This will also save time for paramedic services.
Return to recommendations
# Dizziness and vertigo in children
Recommendations 1.20.1 to 1.20.5
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on dizziness and vertigo in children.
The committee wanted to reassure non-specialists that dizziness without any other symptoms is very unlikely to indicate a brain tumour. Brain tumours usually present with symptoms such as headache, nausea and vomiting, ataxia or drowsiness.
The committee also thought non-specialists should consider the possibility of migraine as a cause of dizziness. They agreed that clinical judgement should be used to determine the care pathway for children with dizziness and migraine.
The committee thought that non-specialists should bear in mind the possibility of postural hypotension, which is common in children aged over 8 years. They noted that postural hypotension might not be present at the time of examination and cannot always be excluded by measuring blood pressure.
The committee agreed that middle ear infection and middle ear effusion can be a cause of dizziness in children. They noted that the child may have fever, pain and diminished hearing, or a recent history of these, and that the eardrum might appear red and inflamed or bulging.
The committee identified recurrent dizziness in children as a red flag that warrants investigation once postural hypotension has been excluded. Cardiac dysrhythmias, although rare, can be a cause of dizziness, may be associated with exercise, and are potentially serious.
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# Headaches in children
Recommendations 1.21.1 to 1.21.7
## Why the committee made the recommendations
The committee used their knowledge and experience to develop the recommendations on headaches in children. Although evidence was reviewed, none that could support recommendations was identified.
The committee considered that children under 12 with headache and any of the 'red flag' symptoms detailed in this recommendation need immediate assessment, because these symptoms could indicate significant intracranial pathology, including a brain tumour.
The committee agreed that headache in a child aged under 4 years is an unusual symptom and, when present, has a high chance of being associated with a significant intracranial disease. Because the child is unable to articulate clearly what is wrong, parents may report excessive crying, a high-pitched cry or excessive irritability.
The committee agreed that examination of the retinal fundus to identify disc swelling is essential for children with recurrent headache. They acknowledged that not all non-specialists have the skills needed for retinal fundus examination so they recommended that this could be requested, for example, from an ophthalmologist or optician.
The committee discussed raised blood pressure as a rare cause of headaches in children. The headaches may be accompanied by dizziness, vomiting or blurred vision. Because normal blood pressure changes with age and body height, they recommended that measurements of blood pressure in children are compared with standardised blood pressure charts adjusted for age and height.
Headaches that are relieved by lying down might indicate spontaneous intracranial hypotension. Although this condition is rare, the committee agreed that children with this symptom would benefit from referral and treatment.
The committee accepted that migraine is common in children and does not usually need referral. They agreed that stress can trigger migraines or chronic headaches. They also noted that overuse of analgesics can cause recurrent headaches.
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# Head shape or size abnormalities
Recommendations 1.22.1 to 1.22.6
## Why the committee made the recommendations
The committee used their knowledge and experience to develop the recommendations on head shape or size abnormalities. Although evidence was reviewed, none that could support recommendations was identified.
The committee discussed a number of rare syndromes that involve premature closure of cranial sutures in association with other dysmorphic features, including disorders of facial growth and limb deformities. The investigation and management of these disorders is highly specialised and complex. The committee recommended urgent referral because early surgical intervention can be beneficial for these children.
The committee noted that abnormalities of head shape or size are most likely to indicate disorders of brain growth or raised intracranial pressure in children aged under 4 years, so measurement of head circumference is important in this age group if abnormalities are suspected. They agreed that GPs and health visitors should adopt standardised methods to measure head circumference and chart head growth, to ensure that accurate and consistent measurements are available to guide referral decisions.
Babies frequently have a preferred lying position with their head to one side. This can lead to positional plagiocephaly, a benign condition in which one side of the head is flattened. The committee discussed how measuring the distance between the tragus of the ear and the outer canthus of the eye is a useful adjunct to clinical inspection and can help to reassure parents or carers. However, the committee acknowledged that this is not an absolute discriminator. Clinical assessment is always subjective and there is no test, short of imaging (rarely justified in plagiocephaly), that is infallible. Therefore, if there is uncertainty, referral for specialist assessment is advisable.
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# Hypotonia ('floppiness')
Recommendations 1.23.1 and 1.23.2
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on hypotonia ('floppiness').
The committee thought it important to highlight potential causes of hypotonia so that babies with a possible serious disorder of cardiac, renal or liver function are referred immediately to paediatric services.
The committee noted that babies who exhibit unexplained floppiness together with weakness are much more likely to have an underlying progressive disorder of the nervous system and need urgent referral.
Return to recommendations
# Limb or facial weakness in children
Recommendations 1.24.1 to 1.24.4
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on limb or facial weakness in children.
In the committee's view, sudden or rapidly progressive limb or facial weakness in a child is usually a symptom of a pathology that needs immediate neurological investigation or management because the child's condition can deteriorate rapidly.
The committee noted that cerebral palsy is the most common chronic motor disorder that affects children, but other genetic and medical disorders can have a similar presentation. They agreed that the recommendations in the NICE guideline on cerebral palsy in under 25s should be followed.
See the rationale on early diagnosis of Duchenne muscular dystrophy.
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# Motor development delay and unsteadiness
Recommendations 1.25.1 to 1.25.5
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on motor development delay and unsteadiness. Although evidence on creatine kinase testing for Duchenne muscular dystrophy was reviewed, none that could support recommendations was identified.
The committee agreed that new-onset gait abnormality could indicate trauma, infection, appendicitis or a hip abnormality, so these children need to be referred immediately.
Although most children with motor development delay are simply at the slower end of the normal range of acquisition of motor skills, a small number will have a neurodevelopmental disorder such as muscular dystrophy or cerebral palsy. Assessment is relatively quick and the committee's view was that it is worth referring these children to a child development service to screen for problems and, in most cases, reassure parents. The committee agreed that the NICE guideline on cerebral palsy in under 25s provides further advice on referral for these children.
Early diagnosis of Duchenne muscular dystrophy is especially important so that the family can be offered genetic counselling. Creatinine kinase measurement is an inexpensive, routine test that can help identify this condition. If the test result is negative, Duchenne muscular dystrophy is unlikely.
The committee agreed that specialist investigation of motor development regression is best carried out by a paediatric neurodevelopmental service or paediatric neurology because of the complexity of the investigations needed.
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# Posture distortion in children
Recommendations 1.26.1 to 1.26.4
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on posture distortion in children.
Abnormal neck posture in a child who has had a recent head or neck trauma can indicate instability of cervical spine through bony or ligamentous injury, so the committee agreed that the child should be referred to an emergency department immediately, and immobilisation applied in line with the recommendations in the NICE guidelines on head injury and spinal injury.
The committee noted that an abnormal neck posture might be the result of painful enlarged lymph nodes that are a common presentation and can be managed in primary care.
The committee agreed that the most common cause of abnormal limb posture in children is pain or injury. If there is no history of an associated acute event or obvious musculoskeletal cause, the child needs to be referred to exclude progressive causes that need treatment.
The committee noted that abnormal head tilt can present before other typical symptoms of posterior fossa tumours, such as ataxia, vomiting and headaches. This finding is sometimes dismissed, leading to delay in diagnosis, and the committee therefore considered it useful to draw attention to the possibility.
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# Sensory symptoms such as tingling or numbness in children
Recommendations 1.27.1 to 1.27.5
## Why the committee made the recommendations
The committee used their knowledge and experience to develop the recommendations on sensory symptoms including tingling or numbness in children. Although evidence was reviewed, none that could support recommendations was identified.
Tingling together with other peripheral nervous system symptoms might indicate pathology affecting the spinal cord. It is not easy to recognise this pathology on clinical examination, so the committee agreed that children with these symptoms need to be referred urgently.
Tingling can also be the first symptom of Guillain−Barré syndrome which, although relatively rare, can affect respiratory function through motor impairment, so the committee agreed that children with tingling and features suggesting motor impairment need to be referred urgently.
The committee noted that transient, fixed-pattern sensory symptoms that are not associated with compression of a nerve can indicate epilepsy and that children with these symptoms should be referred. The NICE guideline on epilepsies provides advice on diagnosis and investigations for epilepsy.
The committee agreed that temporary tingling of this nature is commonly caused by carrying heavy objects or over-breathing, and these children do not need to be referred.
Return to recommendations
# Sleep disorders in children
Recommendations 1.28.1 to 1.28.9
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on sleep disorders in children.
The committee noted that in children with neuromuscular disorders such as Duchenne muscular dystrophy, headaches on awakening in the morning can be an early sign of respiratory failure caused by hypoventilation during sleep. These children are also more susceptible to sleep apnoea and other breathing disorders caused by decreased muscle tone in the muscles of the airway.
The committee agreed that nocturnal seizures are a risk factor for sudden unexpected death in epilepsy (SUDEP) and need prompt investigation. They acknowledged that it can be difficult to identify nocturnal epileptic seizures, but highlighted that red flags are a stereotyped pattern of behaviour during the episode, an episode that starts as a focal seizure and then becomes generalised, or difficulty rousing the child after the episode.
The committee agreed that narcolepsy is a condition that is easily missed in children. It can present as daytime drowsiness, falling asleep in unusual circumstances, or as poor school performance and poor concentration. Diagnosis, assessment and management are best achieved by a service with experience of this condition, so the committee recommended referral to neurological services.
The committee observed that sleep apnoea is not uncommon in babies and young children and might be caused by gastro-oesophageal reflux or intercurrent infection. In older children, it can be a result of enlarged tonsils and adenoids. Obesity can also cause sleep apnoea in children. They concluded that children with symptoms of sleep apnoea should be referred to determine the cause, and advice on weight loss should be offered for those who are obese.
The committee noted that new-onset night terrors are unusual in children aged over 5 years, and could indicate epilepsy. For this reason, they agreed that new-onset night terrors in children of this age, as well as children in whom night terrors continue after age 12, should be referred.
The committee recognised that clinicians are aware that sleep disturbance is common in childhood and often resolves as the child gets older. However, reassuring parents that sleep disturbances are a normal part of development might help to reduce the pressure for an unnecessary referral. Referring children aged under 5 years to a health visitor may be helpful.
The committee thought that that children with neurodevelopmental disorders or learning disabilities should be considered separately because referral to paediatric services may not be appropriate given the prevalence of sleep problems in these children. They agreed that clinical judgement should be used.
The committee thought it useful to point out that sleep disturbances might also be caused by gastro-oesophageal reflux or constipation, and agreed that the NICE guidelines on these conditions in children would be helpful.
Return to recommendations
# Speech problems in children
Recommendations 1.29.1 to 1.29.3
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on speech problems in children.
The committee agreed that new-onset slurred or disrupted speech not attributable to medicines, recreational drugs or alcohol can indicate an acute or progressive neurological disorder or epilepsy, and therefore children with this symptom need urgent neurological assessment.
The committee noted that problems with speech development are a very common presentation. They discussed the appropriate age for referral, noting that there is a wide range within which development can be considered normal. They therefore agreed that referrals should not be made before the age of 2 years. Until that age, development may be within normal limits, and speech difficulties may resolve unaided.
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# Squint
Recommendations 1.30.1 to 1.30.4
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on squint.
The committee agreed that referral should be immediate as new-onset squint with loss of red reflex in one or both eyes can indicate a retinoblastoma, or other progressive pathology of the eye. Additionally, following post publication feedback, NICE felt it was important to highlight that a new-onset squint with loss of red reflex in one or both eyes may also indicate a neurological condition associated with raised intracranial pressure or a brain tumour.
New-onset squint presenting with accompanying symptoms such as ataxia, vomiting or headache can indicate raised intracranial pressure. The committee agreed that children presenting with squint and any of these symptoms should be referred immediately.
Intracerebral tumour or inflammation can present with restriction of movement of one or both eyes, so the committee agreed that this symptom should trigger urgent referral.
In a non-paralytic squint, the child retains the ability to move both eyes fully in all directions. In the absence of any other signs or symptoms such as loss of red reflexes, ataxia, vomiting or headaches, the committee agreed that this symptom warrants a routine referral to ophthalmology.
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# Tics and involuntary movements in children
Recommendations 1.31.1 to 1.31.6
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on tics and involuntary movements in children.
The committee agreed that sudden onset of chorea, ataxia or dystonia in a child can be a symptom of a progressive neurological disease such as a space-occupying lesion, a metabolic disturbance, a degenerative condition, a para-infectious condition such as rheumatic fever, or drug-induced, so all children with this symptom should be referred immediately.
The committee agreed that most simple motor tics resolve on their own. Parents or carers often find them concerning and reassurance can be helpful. The committee added that referral might be helpful for children with tics that significantly impair quality of life, because drug treatment or habit reversal therapy can be helpful.
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# Tremor in children
Recommendations 1.32.1 to 1.32.4
## Why the committee made the recommendations
The committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on tremor in children.
The committee agreed that children with these symptoms or signs need to be referred for assessment because tremor can be the initial symptom of a space-occupying lesion in children if its onset is sudden or it is accompanied by other neurological signs or symptoms.
The committee discussed tremor as a side effect of sodium valproate or a beta-adrenergic agonist, or a result of hyperthyroidism, and agreed that these should be considered possible causes of isolated tremor in children taking these medicines.
Because tremor is rarely caused by a progressive neurological condition, the committee thought that effective management of the tremor should be the priority. They noted that occupational therapists have the skills to assess how the tremor affects the child's home and school life.
Return to recommendations# Context
Around 10% of visits to GPs and hospital emergency departments are made by people with symptoms or signs associated with neurological conditions. Many of these people will need referral to a specialist for diagnosis and treatment, but others can have their condition managed in primary care.
Currently there is a lack of support to help non-specialists identify when a referral for specialist investigation of neurological symptoms or signs should be made. This has led to delays in referral for people with treatable or potentially serious neurological conditions, and unnecessary referrals for others. Although many specialist professional and charitable bodies have produced guidance on specific neurological conditions, there is a need for overarching guidance that covers a wide range of neurological symptoms and signs.
This guideline provides recommendations on clinical assessment in non-specialist settings and indications for referral to specialist care (including referral for people with existing neurological conditions). The guideline focuses on the signs and symptoms that are most frequently under- or over-referred, or cause uncertainty among non-specialists. In some recommendations, additional educational information is provided to help guide non-specialists. If a sign or symptom is covered by other NICE guidance, a cross-referral to that guidance is included.
Because of a lack of published evidence in this area, the recommendations are largely based on the guideline committee's knowledge and experience. Some recommendations were also reviewed by external experts. Detailed information on how the recommendations were developed is in the methods section of the full guideline.
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{'Recommendations for adults aged over\xa016': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Blackouts in adults\n\nRefer urgently adults with new-onset blackouts (transient loss of consciousness), accompanied by features that are strongly suggestive of epileptic seizures, for neurological assessment in line with the recommendation for people with suspected epilepsy in the NICE guideline on transient loss of consciousness ('blackouts') in over\xa016s.\n\nDo not routinely refer adults with blackouts if there are clear features of vasovagal syncope, even if associated with brief jerking of the limbs. See the recommendation on diagnosing uncomplicated faint in the section on no further immediate management required in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on blackouts in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Dizziness and vertigo in adults\n\n## Sudden-onset dizziness with a focal neurological deficit\n\nFor adults with sudden-onset dizziness and a focal neurological deficit such as vertical or rotatory nystagmus, new-onset unsteadiness or new‑onset deafness:\n\nif the person has diabetes, check for and treat hypoglycaemia\n\nif the person does not have diabetes, or treating hypoglycaemia does not resolve the symptoms, and benign paroxysmal positional vertigo or postural hypotension do not account for the presentation, refer immediately to exclude posterior circulation stroke, in line with the NICE guideline on stroke and transient ischaemic attack in over\xa016s.\n\n## Sudden-onset acute vestibular syndrome\n\nFor adults with sudden-onset acute vestibular syndrome (vertigo, nausea or vomiting and gait unsteadiness), a HINTS (head-impulse–nystagmus–test-of-skew) test should be performed if a healthcare professional with training and experience in the use of this test is available.\n\nFor adults with sudden-onset acute vestibular syndrome who have had a HINTS test:\n\nbe aware that a negative HINTS test makes a diagnosis of stroke very unlikely\n\nrefer immediately for neuroimaging if the HINTS test shows indications of stroke (a normal head impulse test, direction-changing nystagmus or skew deviation).\n\nRefer immediately adults with sudden-onset acute vestibular syndrome in whom benign paroxysmal positional vertigo or postural hypotension do not account for the presentation, in line with local stroke pathways, if a healthcare professional with training and experience in the use of the HINTS test is not available.\n\n## Sudden-onset dizziness with no imbalance or focal neurological deficit\n\nBe aware that dizziness in adults with no imbalance or other focal neurological deficit is unlikely to indicate a serious neurological condition.\n\n## Vertigo on head movement\n\nFor adults with transient rotational vertigo on head movement:\n\nOffer the Hallpike manoeuvre to check for benign paroxysmal positional vertigo (BPPV) if a healthcare professional trained in its use is available. If there is no healthcare professional trained in the Hallpike manoeuvre available, refer in accordance with local pathways.\n\nIf BPPV is diagnosed, offer a canalith repositioning manoeuvre (such as the Epley manoeuvre) if a healthcare professional trained in its use is available and if the person does not have unstable cervical spine disease. If there is no healthcare professional trained in a canalith repositioning manoeuvre available, or the person has unstable cervical spine disease, refer in accordance with local pathways.\n\nBe aware that BPPV is common after a head injury or labyrinthitis.\n\n## Vestibular migraine\n\nBe alert to the possibility of vestibular migraine (migraine-associated vertigo) in adults who have episodes of dizziness that last between 5\xa0minutes and 72\xa0hours and a history of recurrent headache.\n\n## Recurrent dizziness as part of a functional neurological disorder\n\nBe aware that, for adults who have been diagnosed with a functional neurological disorder by a specialist, recurrent dizziness might be part of the disorder and the person might not need re‑referral if there are no new neurological signs. New symptoms or signs in adults who have been diagnosed with a functional neurological disorder by a specialist should be assessed as described in the relevant sections of this guideline.\n\nAdvise adults with recurrent dizziness and a diagnosed functional neurological disorder that their dizziness will fluctuate and might increase during times of stress.\n\n## Dizziness with altered consciousness\n\nRefer adults with recurrent fixed-pattern dizziness associated with alteration of consciousness to have an assessment for epilepsy in line with the NICE guideline on epilepsies.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on dizziness and vertigo in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Facial pain, atraumatic\n\n## Facial pain with persistent facial numbness or abnormal neurological signs\n\nRefer urgently adults with facial pain associated with persistent facial numbness or abnormal neurological signs for neuroimaging.\n\n## Unilateral facial pain triggered by touching the face (trigeminal neuralgia)\n\nRefer adults with unilateral facial pain that is triggered by touching the affected part of the face (trigeminal neuralgia) and is refractory to treatment, in line with the NICE guideline on neuropathic pain in adults.\n\n## Scalp tenderness or jaw claudication suggestive of temporal arteritis\n\nFor adults with scalp tenderness or jaw claudication suggestive of temporal arteritis, consider blood tests and follow local pathways for suspected giant cell (temporal) arteritis. Be aware that a normal ESR (erythrocyte sedimentation rate) does not exclude a diagnosis of giant cell arteritis.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on atraumatic facial pain\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Gait unsteadiness\n\n## Sudden-onset unsteady gait\n\nFor recommendations on assessing sudden-onset unsteady gait in adults, see the NICE guideline on stroke and transient ischaemic attack in over\xa016s.\n\n## Rapidly progressive unsteady gait (gait ataxia)\n\nRefer urgently adults with rapidly (within days to weeks) progressive unsteady gait (gait ataxia) for neurological assessment.\n\n## Gradually progressive unsteady gait (gait ataxia)\n\nRefer adults with gradually progressive unsteady gait (gait ataxia) for neurological assessment and:\n\ntake an alcohol history and follow the recommendations in the NICE guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence\n\ncheck thyroid function\n\ncheck for vitamin\xa0B12 and folate deficiency\n\nconsider serological testing for gluten sensitivity as recommended in the NICE guideline on coeliac disease.\n\n## Difficulty initiating and coordinating walking (gait apraxia)\n\nRefer adults who have difficulty initiating and coordinating walking (gait apraxia) to neurology or an elderly care clinic to exclude normal pressure hydrocephalus.\n\nFor adults with unsteadiness of gait who are at risk of falling, follow the recommendations on multifactorial falls risk assessment in the NICE guideline on falls in older people, and consider referring to a falls prevention team.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on gait unsteadiness\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Handwriting difficulties\n\nRefer adults who have sudden-onset difficulty with handwriting that has no obvious musculoskeletal cause for a neurological assessment according to local stroke pathways.\n\nAsk adults who have difficulty with handwriting that has no obvious musculoskeletal cause to demonstrate their handwriting and:\n\nif they have a problem with generating language rather than hand function, refer for neurological assessment\n\nif their handwriting is small and slow, consider referring for possible Parkinson's disease\n\nif their difficulty is specific to the task of handwriting and examination shows no other abnormalities, consider referring for possible focal dystonia.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on handwriting difficulties\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Headaches in adults\n\nFor advice on referral for headaches in adults, see the NICE guideline on headaches in over\xa012s.\n\n# Limb or facial weakness in adults\n\n## Sudden-onset limb weakness\n\nBe aware that sudden-onset weakness, even in restricted distribution (for example, sudden hand weakness), may be caused by a stroke or transient ischaemic attack. See the NICE guideline on stroke and transient ischaemic attack in over\xa016s for recommendations on assessing sudden-onset limb or facial weakness in adults.\n\n## Rapidly progressive symmetrical limb weakness\n\nRefer immediately adults with rapidly (within 4\xa0weeks) progressive symmetrical limb weakness for neurological assessment and assessment of bulbar and respiratory function.\n\n## Severe low back pain together with other symptoms\n\nRefer immediately, in line with local pathways, adults who have severe low back pain radiating into the leg and new-onset disturbance of bladder, bowel or sexual function, or new-onset perineal numbness, to have an assessment for cauda equina syndrome.\n\n## Rapidly progressive weakness of a single limb or hemiparesis\n\nRefer urgently adults with very rapidly (within hours to days) progressive weakness of a single limb or hemiparesis for investigation, including neuroimaging, in line with the recommendation on brain and central nervous system cancers in adults in the NICE guideline on suspected cancer.\n\n## Slowly progressive limb or neck weakness\n\nFor adults with slowly (within weeks to months) progressive limb or neck weakness:\n\nrefer for an assessment for neuromuscular disorders, in line with the recommendations on recognition and referral in the NICE guideline on motor neurone disease\n\nrefer urgently if there is any evidence of swallowing impairment\n\nrefer immediately if there is breathlessness at rest or when lying flat.\n\n## Lower limb claudication symptoms\n\nBe aware that lower limb claudication symptoms in adults with adequate peripheral circulation might be caused by lumbar canal stenosis and need specialist assessment and imaging.\n\n## Recurrent limb or facial weakness as part of a functional neurological disorder\n\nBe aware that, for adults who have been diagnosed with a functional neurological disorder by a specialist, recurrent limb weakness might be part of the disorder and the person might not need re‑referral if there are no new neurological signs. New symptoms or signs in adults who have been diagnosed with a functional neurological disorder by a specialist should be assessed as described in the relevant sections of this guideline.\n\nAdvise adults with limb or facial weakness ascribed to a functional neurological disorder that their limb or facial weakness might fluctuate and evolve over time and might increase during times of stress.\n\n## Compression neuropathy\n\nFor adults with clear features of compression neuropathy of the radial nerve, common peroneal nerve or ulnar nerve and no features of a nerve root lesion (radiculopathy):\n\nrefer to orthotic services for a splint\n\nreview the symptoms after 6\xa0weeks, and refer for neurological assessment if there is no evidence of improvement.For adults with features of radiculopathy, see the section on cervical or lumbar radiculopathy.\n\nAdvise adults with compression neuropathy to avoid any activity that might lead to further pressure on the affected nerve.\n\n## Bell's palsy\n\nDo not routinely refer adults with an uncomplicated episode of Bell's palsy (unilateral lower motor neurone pattern facial weakness affecting all parts of the face and including weakness of eye closure) and no evidence of another medical condition such as middle ear disease.\n\nAdvise adults with Bell's palsy about eye care, and explain that Bell's palsy improves at different rates and maximum recovery can take several months.\n\nConsider referring adults with Bell's palsy who have developed symptoms of aberrant reinnervation (including gustatory sweating or jaw-winking) 5\xa0months or more after the onset of Bell's palsy for neurological assessment and possible treatment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on limb or facial weakness in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Memory failure and cognitive deterioration\n\n## Memory problems in adults aged under\xa050\n\nFor adults aged under\xa050 with memory problems and no other neurological signs:\n\ndo not routinely refer if brief testing shows memory function to be normal and symptoms are consistent with concentration difficulties\n\nbe aware that memory problems or concentration difficulties can be caused by:\n\n\n\nrecreational, and some prescription, drugs\n\nalcohol\n\naffective disorders\n\nstress. For more information, see initial assessment in non-specialist settings in the NICE guideline on dementia.\n\n\n\n## Memory problems as part of an anxiety disorder or a functional neurological disorder\n\nBe aware that, for adults who have an anxiety disorder or have been diagnosed with a functional neurological disorder by a specialist, memory problems and concentration difficulties might be part of the disorder and the person might not need re‑referral if there are no new neurological signs. New symptoms or signs in adults who have been diagnosed with a functional neurological disorder by a specialist should be assessed as described in the relevant sections of this guideline.\n\n## Concentration difficulties associated with myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome or fibromyalgia\n\nDo not routinely refer adults for neurological assessment if they have concentration difficulties associated with myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome or fibromyalgia.\n\n## Progressive memory problems\n\nFor guidance on referring adults with progressive memory problems, see initial assessment in non-specialist settings in the NICE guideline on dementia.\n\n## Dense amnesia\n\nDo not routinely refer adults with a single episode of dense amnesia (inability to recall the recent past or form new memories) if:\n\nthe episode lasts less than 8\xa0hours and\n\nthere is complete recovery and\n\nthere are no features suggestive of an epileptic seizure (see seizure markers for suspected epilepsy in the NICE guideline on transient loss of consciousness ['blackouts'] in over\xa016s).Advise the person that they have probably had an episode of transient global amnesia and that the recurrence rate is low.\n\nRefer adults with recurrent episodes of dense amnesia to have an assessment for epileptic amnesia.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on memory failure and cognitive deterioration\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Posture distortion in adults\n\n## Dystonia\n\nSuspect cervical dystonia in adults who have persistent abnormalities of head or neck posture, with or without head tremor, especially if the symptom improves when the person touches their chin with their hand.\n\nDo not offer cervical imaging to evaluate suspected cervical dystonia in adults.\n\nBe aware that dystonia in adults can affect other parts of the body (for example, it can cause writer's cramp or in‑turned posture of the foot).\n\nRefer adults with suspected dystonia to have an assessment for diagnosis and possible botulinum toxin treatment.\n\n## Dystonia as a side effect of medications\n\nBe aware that antipsychotic and antiemetic medicines can trigger or exacerbate dystonia in adults.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on posture distortion in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Sensory symptoms including tingling or numbness in adults\n\n## Numbness and weakness\n\nAssess sudden-onset transient unilateral numbness in adults in line with the NICE guideline on stroke and transient ischaemic attack in over\xa016s.\n\nRefer immediately adults with rapidly progressive (within hours to days) symmetrical numbness and weakness or imbalance to have a neurological assessment.\n\n## Sensory disturbances\n\nRefer urgently adults with recurrent, brief (less than 2\xa0minutes), fixed-pattern disturbances of sensation to have an assessment for epilepsy.\n\nRefer adults with persistent, distally predominant altered sensation in the limbs, and brisk deep tendon reflexes, to have an assessment for possible brain or spine disease.\n\nSuspect migraine with aura in adults who have sensory symptoms that occur with or without headache and:\n\nare fully reversible and\n\ndevelop over at least 5\xa0minutes and\n\nlast between 5\xa0and 60\xa0minutes.For recommendations on diagnosing and managing migraine with aura, see the NICE guideline on headaches in over\xa012s.\n\nFor adults with persistent, distally predominant ('stocking' or 'glove and stocking') altered sensation in the limbs and depressed deep tendon reflexes:\n\nbe alert to the possibility of peripheral neuropathy and consider checking:\n\n\n\nvitamin B12 deficiency\n\nthyroid function\n\nfor evidence of coeliac disease in line with the NICE guideline on coeliac disease\n\nrenal function\n\nblood glucose\n\nESR (erythrocyte sedimentation rate)\n\nalcohol consumption, using a tool such as AUDIT (Alcohol Use Disorders Identification Test), in line with the NICE guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence\n\n\n\nif no causes of peripheral neuropathy are found, refer for neurological assessment.\n\n## Numbness and tingling as part of a functional neurological disorder\n\nBe aware that, for adults who have been diagnosed with a functional neurological disorder by a specialist, recurrent numbness and tingling might be part of the disorder and the person might not need re‑referral if there are no new neurological signs. New symptoms or signs in adults who have been diagnosed with a functional neurological disorder by a specialist should be assessed as described in the relevant sections of this guideline.\n\nAdvise adults with tingling and a diagnosis of functional neurological disorder that the tingling might fluctuate and evolve over time and could increase at times of stress.\n\n## Carpal tunnel syndrome\n\nRefer in line with local pathways if symptoms of carpal tunnel syndrome are severe or persistent after initial management.\n\n## Numbness, tingling or pain in the outer thigh\n\nReassure adults with unilateral or bilateral numbness, tingling or pain in the distribution of the lateral cutaneous nerve of the thigh (meralgia paraesthetica) that the condition is benign and might improve spontaneously. Consider referring for pain management only if the symptoms are severe.\n\n## Cervical or lumbar radiculopathy\n\nDo not routinely refer adults with symptoms of cervical radiculopathy that have remained stable for 6\xa0weeks or more unless:\n\npain is not controlled with analgesics or\n\nthe symptoms are disabling or\n\none of the following factors is present:\n\n\n\nage under\xa020\n\ngait disturbance\n\nclumsy or weak hands or legs\n\nbrisk deep tendon reflexes (triceps and lower limbs)\n\nextensor plantar responses\n\nnew-onset disturbance of bladder or bowel function.\n\n\n\nDo not routinely refer adults with symptoms of lumbar radiculopathy that have remained stable for 6\xa0weeks or more unless pain is not controlled with analgesics or symptoms are disabling, in line with the NICE guideline on low back pain and sciatica in over\xa016s.\n\n## Tingling or sensory disturbances on waking from sleep\n\nDo not routinely refer adults with recurrent episodes of tingling or sensory disturbance in the limbs that are present on waking from sleep and last less than 10\xa0minutes.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on sensory symptoms including tingling or numbness in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Sleep disorders in adults\n\n## Insomnia\n\nOffer advice on sleep hygiene to adults with insomnia.\n\nDo not routinely refer adults with insomnia, jerks on falling asleep or isolated brief episodes of sleep paralysis.\n\n## Symptoms that suggest new-onset epileptic seizures\n\nRefer urgently adults with symptoms suggestive of new-onset epileptic seizures in sleep for neurological assessment in line with the NICE guideline on epilepsies.\n\n## Excessive sleepiness and narcolepsy\n\nFor adults with excessive sleepiness:\n\nuse the Epworth score together with history of obstructive symptoms in sleep to assess the likelihood of sleep apnoea\n\nrefer in accordance with local policy\n\nif appropriate, offer advice on weight reduction, alcohol consumption and smoking cessation, in line with NICE guidance on obesity, alcohol-use disorders and smoking and tobacco.\n\nRefer adults with narcolepsy, with or without cataplexy, for neurological assessment.\n\n## Sleep behaviour disorders\n\nConsider referring adults with persistent symptoms suggestive of sleep behaviour disorders (such as agitated or violent movements that are more complex than a simple jerking motion) for neurological assessment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on sleep disorders in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Smell or taste problems\n\n## Distorted sense of smell or taste\n\nBe aware that sudden-onset distortion of sense of smell or taste in adults is rarely associated with structural neurological abnormality and usually resolves within a few months.\n\n## Smell or taste hallucinations\n\nRefer adults with transient, repetitive smell or taste hallucinations to have a neurological assessment for epilepsy.\n\n## Loss of sense of smell or taste\n\nConsider neuroimaging for adults with unexplained loss of sense of smell or taste that lasts more than 3\xa0months.\n\nDo not routinely refer adults with loss of sense of smell or taste and normal neuroimaging.\n\nDo not routinely refer adults who lose their sense of smell or taste immediately after a head injury.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on smell or taste problems\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Speech, swallowing and language problems in adults\n\n## Sudden-onset speech or language disturbance\n\nRefer immediately adults with sudden-onset speech or language disturbance to have an assessment for a vascular event, in line with local stroke pathways and following the recommendations in the NICE guideline on stroke and transient ischaemic attack in over\xa016s. [amended July 2019]\n\n## Progressive slurred or disrupted speech\n\nFor adults with progressive slurred or disrupted speech:\n\nrefer for an assessment for neuromuscular disorders, in line with the recommendations on recognition and referral in the NICE guideline on motor neurone disease\n\nrefer urgently if there is any evidence of swallowing impairment\n\nrefer immediately if there is breathlessness at rest or when lying flat.\n\n## Dysphonia\n\nConsider referring adults with isolated and unexplained persistent dysphonia (a quiet, hoarse or wobbly voice) to have an assessment for laryngeal dystonia (involuntary contractions of the vocal cords) if hoarseness caused by structural abnormality or malignancy has been excluded by ear, nose and throat examination.\n\nBe aware that persistent dysphonia in adults may be a presenting symptom of a neurological condition such as Parkinson's disease. For recommendations on the diagnosis and management of Parkinson's disease, see the NICE guideline on Parkinson's disease in adults.\n\n## Word-finding difficulties as part of an anxiety disorder or a functional neurological disorder\n\nBe aware that anxiety disorder and functional neurological disorders are the most common causes of minor word-finding difficulties in adults, and people with a diagnosis of anxiety disorder or functional neurological disorder made by a specialist might not need a referral.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on speech, swallowing and language problems in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Tics and involuntary movements in adults\n\n## Tics\n\nDo not routinely refer adults with tics (involuntary movements that can be temporarily suppressed at the expense of mounting inner tension) unless the tics are troublesome or accompanied by additional progressive neurological symptoms.\n\nConsider referring adults with a tic disorder for psychological therapy if the disorder distresses them.\n\nConsider referring adults who have completed psychological therapy for a tic disorder to have a neurological assessment if their symptoms are severe and the disorder continues to distress them, but tell the person that:\n\nthere are not many medicines available to treat a tic disorder\n\nthe medicines that are available don't always work well and can have serious side effects.\n\n## Involuntary movements\n\nDo not routinely refer adults with isolated involuntary movements of the eyelid unless the movements:\n\ncause involuntary tight eye closure of both eyes (blepharospasm) or\n\nhave persisted for more than 3\xa0months.\n\nIn adults with involuntary movements of the face, neck, limbs or trunk that cannot be temporarily suppressed by mental concentration:\n\nrefer for neurological assessment or\n\nrefer to neurology or an eye clinic, according to local provision, if the person has involuntary tight eye closure of both eyes (blepharospasm).\n\nDo not routinely refer adults with small involuntary muscular twitches (fasciculations) unless these are associated with muscle wasting and weakness or muscle rigidity.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on tics and involuntary movements in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Tremor in adults\n\n## Tremor suggesting Parkinson's disease\n\nRefer adults with suspected parkinsonian tremor, other asymmetric tremor, or tremor associated with stiffness, slowness, balance problems or gait disorders for neurological assessment before treatment, in line with the NICE guideline on Parkinson's disease in adults.\n\n## Essential tremor\n\nSuspect essential tremor in an adult with symmetrical postural tremor and no symptoms of parkinsonism.\n\nIn adults with suspected essential tremor:\n\nreview regular medication\n\ncheck thyroid function\n\nassess alcohol consumption using a tool such as AUDIT (Alcohol Use Disorders Identification Test), in line with the NICE guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence.Refer for neurological assessment only if the symptoms are disabling and first-line treatment as specified in the BNF is ineffective or not tolerated.\n\nConsider referring adults with troublesome tremor of the head to a movement disorder clinic.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on tremor in adults\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Information and support\n\nFollow the principles in the NICE guidelines on patient experience in adult NHS services and shared decision making in relation to communication (including different formats and languages), information, shared decision making and continuity of care.\n\nAdvise adults with suspected neurological conditions to:\n\ncheck the government's information on driving with medical conditions to find out whether they might have a condition that needs to be notified to the DVLA (Driver and Vehicle Licensing Agency)\n\nconsider telling their employer, school or college if their symptoms might affect their ability to work or study.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.", 'Recommendations for children aged under\xa016': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Attention, concentration and memory problems\n\n## Attention, concentration and memory problems related to epilepsy\n\nRefer urgently children who present with discrete episodes of loss of awareness (mid-activity vacant spells) or of attention and concentration difficulty, in line with the NICE guideline on epilepsies.\n\nBe aware that medicines commonly used to treat epilepsy in children can adversely affect concentration and memory.\n\n## Concentration or memory difficulties that interfere with learning or behaviour\n\nRefer children with concentration or memory difficulties that interfere with learning, school progress or behaviour to community paediatric or paediatric neurodevelopmental services for assessment.\n\nBe aware that some children with attention and concentration difficulties do not have hyperactivity.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on attention, concentration and memory problems\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Blackouts and other paroxysmal events\n\n## Blackouts and vacant spells\n\nRefer urgently children with new-onset blackouts (transient loss of consciousness) accompanied by seizure markers for neurological assessment, in line with the recommendation for people with suspected epilepsy in the NICE guideline on transient loss of consciousness ('blackouts') in over\xa016s.The committee agreed that the recommendation for people with suspected epilepsy in the NICE guideline on transient loss of consciousness ('blackouts') in over\xa016s is applicable to children aged under\xa016.\n\nRefer urgently children with mid-activity vacant spells or behavioural outbursts associated with altered consciousness or amnesia for the events to have a paediatric assessment.\n\n## Blackouts in children under 12\xa0years\n\nRefer urgently all children aged under 12\xa0years with blackouts for paediatric assessment.\n\n## Vasovagal syncope\n\nDo not routinely refer children aged over 12\xa0years with blackouts if there are clear features of vasovagal syncope, even if associated with brief jerking of the limbs, in line with the recommendation on diagnosing uncomplicated faint in the section on no further immediate management required in the NICE guideline on transient loss of consciousness ('blackouts') in over\xa016s.\n\n## Blackouts, seizures or amnesia after a head injury\n\nFor children who have blackouts, seizures or amnesia for events after a head injury, follow the recommendations on pre-hospital assessment, advice and referral to hospital in the NICE guideline on head injury.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on blackouts and other paroxysmal events\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Confusion, acute\n\nFor children with unexplained acute confusion:\n\narrange an emergency transfer to hospital and\n\nmeasure blood glucose.\n\nBe aware that acute confusion in children can be a symptom of meningitis, encephalitis or poisoning. If infection is suspected, follow the recommendations in the NICE guideline on sepsis for identifying people with suspected sepsis and face-to-face assessment of people with suspected sepsis.\n\nFor children with acute confusion who have a non-blanching rash or other signs or symptoms suggestive of meningococcal septicaemia, follow the recommendations on suspected meningococcal disease (meningitis with non-blanching rash or meningococcal septicaemia) in the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under\xa016s. For other signs and symptoms of meningococcal septicaemia, see bacterial meningitis and meningococcal septicaemia in children and young people – symptoms, signs and initial assessment in the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on acute confusion\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Dizziness and vertigo in children\n\n## Dizziness with no accompanying symptoms or signs\n\nBe aware that isolated dizziness in children is unlikely to be a symptom of a brain tumour if there are no accompanying symptoms or signs.\n\nBe aware that dizziness in children is often a symptom of migraine and may be the predominant feature.\n\n## Dizziness in older children\n\nBe aware that in older children (usually aged over 8\xa0years), dizziness related to change in posture is often caused by postural hypotension.\n\n## Dizziness caused by middle ear infection or effusion\n\nIn children with dizziness, examine the ears for any signs of infection, inflammation or eardrum perforation.\n\n## Recurrent dizziness\n\nFor children with recurrent episodes of dizziness:\n\nconsider referring for cardiological assessment if there are any factors that might suggest a cardiac cause, such as blackouts (transient loss of consciousness), a family history of cardiomyopathy or unexplained sudden death, or palpitations\n\nif there are episodes of dizziness with a fixed symptom pattern, be alert to the possibility of epilepsy as the cause and follow the recommendations in the NICE guideline on epilepsies.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on dizziness and vertigo in children\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Headaches in children\n\nFor recommendations on headaches or migraine in children aged over 12\xa0years, see the NICE guideline on headaches in over\xa012s.\n\n## Headaches in children under 12\xa0years\n\nRefer immediately children aged under 12\xa0years with headache for same-day assessment, according to local pathways, if they have any one of the following:\n\nheadache that wakes them at night\n\nheadache that is present on awakening in the morning\n\nheadache that progressively worsens\n\nheadache triggered or aggravated by coughing, sneezing or bending down\n\nheadache with fever and features of meningism\n\nheadache associated with vomiting\n\nheadache associated with ataxia\n\nheadache associated with change in conscious level or pervasive lethargy\n\nheadache occurring within 5\xa0days of a head injury\n\nheadache associated with squint or failure of upward gaze ('sunsetting').\n\n## Headaches in children under 4\xa0years\n\nRefer urgently all children aged under 4\xa0years with headache for neurological assessment.\n\n## Recurrent headaches and migraines\n\nPerform or request fundoscopy for all children with recurrent headache and refer urgently for neurological assessment if there are abnormalities.\n\nFor all children with recurrent headache:\n\nbe aware that hypertension might be the cause\n\nmeasure the child's blood pressure and check the measurement against blood pressure reference ranges adjusted for age and height\n\nrefer children if headaches are consistently worsened by upright posture and relieved by lying down.\n\nDo not routinely refer children with migraine unless it is affecting their school life, social life or family activities, or they have one of the features listed in recommendation\xa01.21.1.\n\nBe aware that emotional stress is a strong trigger of migraine and chronic, daily headache in children. Ask the child and their parent or carer about specific learning problems, bullying at school and stress in the family.\n\nAsk about analgesic use in children with recurrent headache to ensure that medicine use is not excessive and to assess the likelihood of medication overuse headache. See the NICE guideline on headaches in over\xa012s for more information on medication overuse headache.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on headaches in children\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Head shape or size abnormalities\n\n## Children with dysmorphic features and developmental delay\n\nRefer urgently to paediatric services children with dysmorphic features and developmental delay.\n\n## Children aged under 4\xa0years\n\nFor all children aged under 4\xa0years with suspected abnormal head shape or size:\n\ntake 3\xa0consecutive measurements of the child's head circumference at the same appointment, using a disposable paper tape measure\n\nplot the longest of the 3\xa0measurements on a standardised growth chart, corrected for gestational age\n\nif the child's head circumference is below the 2nd centile, refer for paediatric assessment.Offer follow-up measurements if needed, according to clinical judgement and taking the child's age into account.\n\nFor children with a head circumference measurement that differs by 2\xa0or more centile lines from a previous measurement on a standardised growth chart (for example, an increase from the 25th to the 75th centile, or a decrease from the 50th to the 9th centile):\n\nrefer to paediatric services for assessment and cranial imaging to exclude progressive hydrocephalus or microcephaly or\n\nrefer immediately to paediatric services if the child also has any of the following signs or symptoms of raised intracranial pressure:\n\n\n\ntense fontanelle\n\nsixth nerve palsy\n\nfailure of upward gaze ('sunsetting')\n\nvomiting\n\nunsteadiness (ataxia)\n\n\n\nheadache. [amended July 2019]\n\nFor children with a head circumference above the 98th centile that has not changed by more than 2\xa0centile lines from the previous measurement on a standardised growth chart, who are developing normally and who have no symptoms of raised intracranial pressure:\n\nnote the head size of the biological parents, if possible, to check for familial macrocephaly\n\nif familial macrocephaly is likely, do not routinely refer the child in the absence of any other problem.\n\n## Babies aged under 1\xa0year with plagiocephaly\n\nFor babies aged under 1\xa0year whose head is flattened on one side (plagiocephaly):\n\nbe aware that positional plagiocephaly (plagiocephaly caused by pressure outside the skull before or after birth) is the most common cause of asymmetric head shape\n\nmeasure the distance between the outer canthus of the baby's eye and the tragus of their ear on each side\n\nif the measurements differ, confirm positional plagiocephaly and do not routinely refer if the baby is developing normally\n\nif the measurements are the same, suspect unilateral premature closure of lambdoid suture and refer to paediatric services.\n\nAdvise parents or carers of babies with positional plagiocephaly that it is usually caused by the baby sleeping in one position and can be improved by changing the baby's position when they are lying, encouraging the baby to sit up when awake, and giving the baby time on their tummy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on head shape or size abnormalities\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Hypotonia ('floppiness')\n\nFor babies aged under 1\xa0year with acute-onset hypotonia (floppiness), examine the baby for signs of cardiac failure, enlargement of the liver or kidneys, pyrexia or an altered level of consciousness, and refer immediately to paediatric services.\n\nFor babies aged under 1\xa0year with hypotonia (floppiness) that has been present for weeks or months:\n\nif the baby is weak (for example, with feeding and breathing difficulties), refer urgently to paediatric services or\n\nif the baby is not weak and has no signs of intercurrent illness, consider referring in line with the recommendations on looking for signs of cerebral palsy in the NICE guideline on cerebral palsy under\xa025s.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on hypotonia ('floppiness')\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Limb or facial weakness in children\n\n## Sudden-onset or progressive limb or facial weakness\n\nRefer immediately children with sudden-onset or rapidly progressive (hours to days) limb or facial weakness for neurological assessment.\n\nRefer urgently children with progressive limb weakness for neurological assessment.\n\n## Limb weakness as part of a developmental disorder\n\nRefer children with limb weakness that is part of a developmental disorder to paediatric services, in line with the recommendations on looking for signs of cerebral palsy in the NICE guideline on cerebral palsy under\xa025s.\n\n## Boys with limb weakness\n\nFor boys with limb weakness, see the recommendations on boys with motor development delay and motor development regression.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on limb or facial weakness in children\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Motor development delay or regression, and unsteadiness\n\n## New-onset gait abnormality\n\nRefer immediately children with new-onset gait abnormality to acute paediatric services.\n\n## Motor development delay\n\nRefer children to a child development service, and consider referring for physiotherapy or occupational therapy, in line with the recommendations in the NICE guideline on cerebral palsy in under\xa025s, if they:\n\nare not sitting unsupported by 8\xa0months (corrected for gestational age) or\n\nare not walking independently by 15\xa0months (girls) or 18\xa0months (boys) (corrected for gestational age) or\n\nshow early asymmetry of hand function (hand preference) before 1\xa0year (corrected for gestational age).\n\nIf the child is a boy, consider measuring creatinine kinase level to exclude Duchenne muscular dystrophy before the boy has had a specialist review.\n\n## Motor development regression\n\nRefer children with motor development regression to a paediatric neurodevelopmental service or paediatric neurology depending on locally agreed pathways.\n\nIf the child is a boy, consider measuring creatinine kinase level to exclude Duchenne muscular dystrophy before the boy has had a specialist review.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on motor development delay and unsteadiness\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Posture distortion in children\n\n## Children with a recent head or neck trauma\n\nRefer immediately children with abnormal neck posture and a recent head or neck trauma to an emergency department for assessment, and follow the recommendations on cervical spine immobilisation in the section on initial assessment and care in the NICE guideline on head injury, and the recommendation on spinal immobilisation in the section on assessment for spinal injury in the NICE guideline on spinal injury.\n\n## Children with no recent trauma\n\nIn children with abnormal neck posture, check whether painful cervical lymphadenopathy is the cause.\n\nRefer children who develop abnormal limb posture that has no apparent musculoskeletal cause for neurological assessment.\n\nBe aware that abnormal head tilt in children can be a symptom of posterior fossa tumour.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on posture distortion in children\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Sensory symptoms such as tingling or numbness in children\n\n## Tingling together with other symptoms\n\nRefer urgently children who have tingling accompanied by other peripheral nervous system symptoms such as weakness, bladder dysfunction or bowel dysfunction for neurological assessment.\n\nBe aware that tingling in children may be the first symptom of an acute polyneuropathy (Guillain–Barré syndrome) or other neuro-inflammatory conditions. If the child has features suggesting motor impairment, refer urgently for neurological assessment.\n\n## Isolated tingling, altered sensation or paraesthesia\n\nRefer children with isolated tingling, altered sensation or paraesthesia for neurological assessment if the symptoms are episodic and are not associated with compression of a nerve. For more information, see the recommendations on diagnosis and investigations in the NICE guideline on epilepsies.\n\n## Temporary tingling caused by nerve compression or hyperventilation\n\nDo not routinely refer children for neurological assessment of temporary tingling or numbness if there is a clear history of the symptom being triggered by activities known to cause nerve compression, such as carrying a heavy backpack or sitting with crossed legs.\n\nBe aware that in children, hyperventilation is a common cause of transient tingling in the limbs.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on sensory symptoms such as tingling or numbness in children\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Sleep disorders in children\n\n## Symptoms suggesting possible respiratory failure\n\nRefer urgently children with neuromuscular disorders who have early-morning headaches or new-onset sleep disturbance for a respiratory assessment.\n\n## Sleep disorders suggesting nocturnal seizures\n\nRefer urgently children who have symptoms suggestive of new-onset epileptic seizures in sleep for neurological assessment.\n\n## Narcolepsy\n\nRefer children with symptoms suggestive of narcolepsy, with or without cataplexy, for neurological assessment or a sleep clinic assessment according to local pathways.\n\n## Sleep disorders suggesting sleep apnoea\n\nRefer children with symptoms of sleep apnoea to ear, nose and throat or paediatric respiratory services, as appropriate, and offer advice on weight loss if the child is obese.\n\n## Night terrors in children aged over 5\xa0years\n\nRefer children aged over 5\xa0years with new-onset night terrors and children with night terrors that persist after age\xa012.\n\n## Night terrors and other sleep disturbances in children aged under 5\xa0years\n\nReassure parents or carers of children aged under 5\xa0years who have night terrors, repetitive movements, sleep talking or sleep walking that these are common in healthy children and rarely indicate a neurological condition.\n\nOffer advice on sleep hygiene to parents or carers of children with insomnia, and consider referring to a health visitor if the child is aged under 5\xa0years.\n\n## Sleep disorders in children with neurodevelopmental disorders or learning disabilities\n\nConsider referring children with sleep disorders associated with neurodevelopmental disorders or learning disabilities to community paediatric services.\n\n## Sleep disorders as a result of gastro-oesophageal reflux or constipation\n\nBe aware that sleep disorders in children may be a symptom of gastro-oesophageal reflux or constipation. See the recommendations on diagnosing and investigating gastro-oesophageal reflux disease in the NICE guideline on gastro-oesophageal reflux disease in children and young people, and the NICE guideline on constipation in children and young people.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on sleep disorders in children\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Speech problems in children\n\n## New-onset slurred or disrupted speech\n\nRefer urgently children with new-onset slurred or disrupted speech that is not attributable to prescribed medicines, recreational drugs or alcohol for neurological assessment.\n\n## Problems with speech development in children aged over 2\xa0years\n\nConsider referring children aged over 2\xa0years with abnormal speech development to speech and language services.\n\nBe aware that delay or regression in speech and language in children can be a symptom of autism. Follow the recommendations in the NICE guideline on recognition, referral and diagnosis of autism spectrum disorder in under 19s for recognising children and young people with possible autism and referring children and young people to the autism team.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on speech problems in children\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Squint\n\n## New-onset squint with loss of red reflex\n\nRefer immediately children with new-onset squint that occurs together with loss of red reflex in one or both eyes to ophthalmology services. (Also see recommendations on childhood cancers in NICE's guideline on suspected cancer.)\n\n## New-onset squint with ataxia, vomiting or headache\n\nRefer immediately children with new-onset squint that occurs together with ataxia, vomiting or headache to acute paediatric services.\n\n## Paralytic squint\n\nRefer urgently children with paralytic squint for neurological assessment, even in the absence of other signs and symptoms of raised intracranial pressure.\n\n## Non-paralytic squint\n\nRefer children with non-paralytic squint to ophthalmology services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on squint\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Tics and involuntary movements in children\n\n## Sudden-onset involuntary movements\n\nRefer immediately children who have sudden-onset chorea, ataxia or dystonia for neurological assessment.\n\n## Tics\n\nDo not routinely refer children with simple motor tics that are not troublesome to the child.\n\nAdvise parents or carers of children with a tic disorder to discuss the disorder with the child's school, emphasising that the tic is an involuntary movement and the child should not be reprimanded for it.\n\nDo not offer medicine for motor tics in children without specialist referral and advice (see recommendation\xa01.31.6).\n\nBe aware that tics and stereotypies (repetitive or ritualistic movements such as body rocking) are more common in children with autism or a learning (intellectual) disability.\n\nFor children with a tic disorder that has a significant impact on their quality of life, consider referring according to local pathways, as follows:\n\nreferral to mental health services if the tic disorder is associated with symptoms of anxiety or obsessive compulsive behaviour\n\nreferral to the neurodevelopmental team if the tic disorder is associated with symptoms suggestive of autism or attention deficit hyperactivity disorder\n\nreferral for neurological assessment if the tic disorder is severe.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on tics and involuntary movements in children\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.\n\n# Tremor in children\n\n## Tremor of sudden onset or with accompanying neurological signs or symptoms\n\nRefer urgently children presenting with tremor for neurological assessment if:\n\nthey have additional neurological signs or symptoms such as unsteadiness or\n\nthe onset of the tremor was sudden.\n\n## Postural tremor\n\nBe aware that isolated postural tremor in children may be a side effect of sodium valproate or a beta-adrenergic agonist.\n\nConsider thyroid function tests for children with postural tremor and other symptoms or signs suggestive of thyroid overactivity.\n\nRefer children with postural tremor for occupational therapy only if the tremor is affecting activities of daily living such as writing, eating or dressing.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale section on tremor in children\xa0.\n\nFull details of the evidence and the committee's discussion are in the full guideline.\n\nLoading. Please wait.", 'Terms used in this guideline': '# Refer immediately\n\nTo be seen by the specialist service within a few hours, or even more quickly if necessary.\n\n# Refer urgently\n\nTo be seen by the specialist service within 2\xa0weeks.\n\n# Refer\n\nA routine referral.\n\n# Consider referring\n\nConsider a routine referral.\n\n# Dizziness\n\nA subjective sensation of spinning (vertigo) or a more vague sensation of unsteadiness, and sometimes a feeling of light-headedness or pre-syncope.\n\n# Functional neurological disorder\n\nA condition in which people experience neurological symptoms in the absence of any identifiable causative physical or structural abnormality.\n\n# Radiculopathy\n\nIrritation or damage to a nerve root as it exits the spinal canal. It is most commonly caused by mechanical compression from a prolapsed intervertebral disc or degenerative arthritis of the spine. Less frequently, an infection such as herpes zoster or Lyme disease is the cause. Symptoms include neck or low back pain radiating into a limb, tingling (paraesthesia), reduced or absent deep tendon reflex(es) and weakness in the distribution of the nerve root.', 'Rationale: recommendations for adults aged over\xa016': "These sections briefly explain why the committee made the recommendations for adults. They link to details of the evidence and a full description of the committee's discussion.\n\n# Blackouts in adults\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendations\n\nThe committee agreed that the NICE guideline on transient loss of consciousness ('blackouts') in over\xa016s provides comprehensive recommendations on recognition and referral.\n\nReturn to recommendations\n\n# Dizziness and vertigo in adults\n\nRecommendations 1.2.1 to 1.2.10\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with evidence, to develop the recommendations on dizziness and vertigo in adults.\n\nEvidence showed that sudden-onset dizziness is more likely to indicate a serious neurological condition if it is accompanied by imbalance and a focal abnormality. The committee confirmed that this is in line with their own clinical experience. They noted that these symptoms can also be caused by hypoglycaemia, and that prompt treatment of hypoglycaemia can reduce neurological damage.\n\nThe committee acknowledged the difficulty in differentiating between benign peripheral vertigo and the potentially more serious central vertigo that indicates a possible posterior circulation stroke. They agreed that a rapid bedside test would be a valuable addition to practice and could reduce unnecessary scans.\n\nThere is evidence showing that the accuracy of the bedside HINTS (head-impulse–nystagmus–test-of-skew) test is broadly similar to that of MRI in identifying people who have had a stroke and ruling out stroke in those who haven't. However, this accuracy is achieved only if the test is carried out by someone who has training and expertise in its use and interpretation. The committee noted that the HINTS test is non-invasive and would avoid the need for scans in people with a negative HINTS examination. To ensure that all people with stroke are identified promptly, the committee agreed that an immediate referral should be made if there is no healthcare professional with training in the HINTS test available.\n\nEvidence showed that dizziness on its own is less likely to indicate a serious neurological condition than dizziness accompanied by other symptoms or signs. The committee confirmed that this is in line with their own clinical experience. They agreed that dizziness is a common and often self-limiting symptom and that this recommendation will help to reduce unnecessary referrals.\n\nThe committee's clinical experience has shown that for many people, positional vertigo is rapidly relieved by a canalith repositioning manoeuvre such as the Epley manoeuvre. The committee agreed that this is a simple, low-risk and effective intervention that can be offered in primary care.\n\nThe committee agreed that the diagnostic criteria for vestibular migraine (vertigo associated with migraine) issued by the International Headache Society would be useful to aid recognition of this condition in primary care.\n\nIn the committee's experience, symptoms caused by a functional neurological disorder can mimic symptoms caused by a physical neurological disorder. Dizziness is a common example of such a symptom. The committee thought it important to make a recommendation highlighting this to enable non-specialists to recognise when recurrent dizziness can be managed as part of a functional neurological disorder, rather than a symptom needing referral for neurological investigation.\n\nThe committee noted that epilepsy can sometimes present as recurrent fixed-pattern dizziness associated with alteration of consciousness.\n\nReturn to recommendations\n\n# Facial pain, atraumatic\n\nRecommendations 1.3.1 to 1.3.3\n\n## Why the committee made the recommendations\n\nAlthough atraumatic facial pain is a common symptom, no evidence on associated features that might indicate a need for referral was identified. The committee used their knowledge and experience to highlight signs and symptoms that might indicate a need for referral.\n\nThe committee agreed that facial pain together with persistent numbness or abnormal neurological signs should be referred urgently for neuroimaging to exclude a possible infiltrative or intracranial mass lesion.\n\nThe committee agreed that trigeminal neuralgia can be managed in primary care, following the recommendations in the NICE guideline on neuropathic pain in adults. A lack of response indicates that specialist review of the diagnosis and treatment is needed.\n\nThe committee noted that temporal arteritis can be difficult to diagnose. Left untreated, it can lead to permanent neurological damage, so the committee thought it important that temporal arteritis is always considered as a possible cause of facial pain and headache in older people.\n\nReturn to recommendations\n\n# Gait unsteadiness\n\nRecommendations 1.4.1 to 1.4.5\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on gait unsteadiness.\n\nThe committee agreed that sudden onset of an unsteady gait could indicate a vascular event such as a stroke, and therefore people with this symptom should be referred urgently, in line with the NICE guideline on stroke and transient ischaemic attack in over\xa016s.\n\nThe committee noted that this is an unusual symptom that could indicate a number of underlying conditions, including a brain tumour, an infection or a paraneoplastic presentation of an ovarian, lung or breast cancer. Because of the seriousness of these conditions, the committee agreed that people with this symptom should be referred urgently for specialist investigation.\n\nThe committee agreed that referral is important to identify treatable causes of a gradually progressive unsteady gait. The committee also agreed that it would be useful to highlight simple measures that can be taken while waiting for an appointment in secondary care. Checking and addressing alcohol consumption, gluten sensitivity and thyroid function can aid management of associated conditions and help to inform diagnosis.\n\nThe committee agreed that raising awareness of normal pressure hydrocephalus as a possible cause of gait apraxia is important because it is easily overlooked and can sometimes be treated.\n\nReturn to recommendations\n\n# Handwriting difficulties\n\nRecommendations 1.5.1 and 1.5.2\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on handwriting difficulties.\n\nAlthough the committee thought that isolated handwriting difficulty is an unusual stroke presentation, they agreed that it is important to consider the possibility of stroke if handwriting difficulty occurs very suddenly.\n\nThe committee noted that difficulties with handwriting are not a common presentation in primary care and it can be difficult for non-specialists to recognise when they indicate an underlying neurological disorder.\n\nReturn to recommendations\n\n# Limb or facial weakness in adults\n\nRecommendations 1.7.1 to 1.7.13\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on limb or facial weakness in adults.\n\nIn the committee's experience, sudden-onset weakness that is restricted to a single limb is sometimes incorrectly attributed to a compression neuropathy or a musculoskeletal cause. They agreed that stroke or transient ischaemic attack should be suspected in all cases of sudden-onset limb or facial weakness.\n\nThe committee agreed that rapidly progressive symmetrical limb weakness can indicate a potentially life-threatening neuromuscular disorder or cervical myelopathy. These disorders can affect the respiratory muscles and cause respiratory failure. Their presenting features can be difficult to recognise in the early stages of the disorder.\n\nThe committee agreed that these symptoms can indicate cauda equina syndrome, which is a medical emergency.\n\nThe committee agreed that this symptom can indicate potentially serious neurological disease and needs to be assessed urgently.\n\nThe committee agreed that recognition and referral of slowly progressive limb or neck weakness is covered in the NICE guideline on motor neurone disease. If the weakness is accompanied by symptoms such as problems with swallowing or breathing, an urgent referral is needed.\n\nThe committee agreed that lower limb discomfort that comes on after walking and improves with rest (claudication), and that has no vascular cause, might indicate lumbar canal stenosis. If the pain is severe or disabling, a specialist assessment is indicated and this may be carried out by an extended scope practitioner, neurosurgeon or orthopaedic surgeon.\n\nThe committee noted that recurrent episodes of limb weakness are not uncommon in people with functional neurological disorders. They agreed that in these cases, referral after each episode of limb weakness is not necessary.\n\nThe committee agreed that reassuring adults about the nature of the underlying condition will help to allay their concerns and reduce requests for referrals.\n\nIn the committee's experience, compression neuropathies can be recognised on the basis of a history of prolonged pressure on the nerve and the pattern of weakness and numbness. They usually resolve spontaneously within 6\xa0weeks, although a splint might be needed for support during recovery. Reducing recurrent pressure or trauma on the affected nerve aids recovery.\n\nThe committee agreed that uncomplicated Bell's palsy can be diagnosed and managed in primary care. They thought it important that people with this condition know that recovery time can vary and that recovery might not be complete. Referral for specialist treatment can be beneficial for people who develop troublesome symptoms after recovering from Bell's palsy.\n\nReturn to recommendations\n\n# Memory failure and cognitive deterioration\n\nRecommendations 1.8.1 to 1.8.6\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on memory failure and cognitive deterioration. They reviewed evidence on specific tools for brief memory testing but no evidence to support a recommendation on specific tools was identified.\n\nThe committee agreed that, although difficulties with memory are common in people aged under\xa050, neurodegenerative disorders affecting memory are rare. Brief memory testing and knowledge of common causes of memory difficulties can reassure the clinician that referral is not needed. No evidence on the diagnostic accuracy of different tools for brief memory testing was identified so the committee agreed not to recommend any specific tests.\n\nThe committee noted that difficulty concentrating is a common symptom in people with an anxiety disorder or a functional neurological disorder. It often presents as a problem with memory.\n\nThe committee pointed out that difficulties with memory and concentration are common in myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome or fibromyalgia, and that these symptoms can be managed as part of the management of those conditions.\n\nThe committee agreed that the NICE guideline on dementia provides advice on referring adults with progressive memory problems.\n\nThe committee thought it important to raise awareness of transient global amnesia, which presents as a single episode of dense amnesia with complete recovery and no features of epilepsy, and has a very low recurrence rate. The committee wanted to help non-specialists differentiate this from transient epileptic amnesia, which is recurrent and needs further investigation.\n\nReturn to recommendations\n\n# Posture distortion in adults\n\nRecommendations 1.9.1 to 1.9.5\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on posture distortion in adults.\n\nThe committee wanted non-specialists to be aware that cervical dystonia is diagnosed on the basis of clinical features, and that imaging is unnecessary and can delay treatment. They also wanted to raise awareness of the wide range of ways in which dystonia can present, such as only during the performance of certain tasks or in certain parts of the body.\n\nThe committee discussed the possible misinterpretation of dystonia affecting neck and foot posture as an orthopaedic problem, leading to unnecessary orthopaedic referrals. They made a specific recommendation for neurological referral to ensure that dystonia caused by an underlying neurodegenerative condition, or by medication, is identified and managed. If the dystonia is idiopathic, treatment can be offered.\n\nThe committee wanted to point out that dystonia is a side effect of some widely used antipsychotic and antiemetic medicines. It typically occurs within a few days of starting the medicine. In these cases, the prescriber of the medicine should review it.\n\nReturn to recommendations\n\n# Sensory symptoms including tingling or numbness in adults\n\nRecommendations 1.10.1 to 1.10.13\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience to develop the recommendations on sensory symptoms including tingling or numbness in adults. Although evidence was reviewed, none that could support recommendations was identified.\n\nThe committee agreed that transient unilateral numbness of sudden onset should be managed in line with the NICE guideline on stroke and transient ischaemic attack in over\xa016s.\n\nThe committee emphasised the immediate risk posed by rapidly progressive symmetrical numbness, which might indicate a post-infective polyneuropathy (Guillain–Barré syndrome) or transverse myelitis and can be difficult to recognise in the early stages.\n\nAlthough the committee agreed that recurrent, brief, fixed-pattern sensory disturbances are not the most common presentation of epilepsy, they thought referral would be important so as not to miss this important diagnosis.\n\nThe committee agreed that persistent, distally predominant altered sensation in the limbs in a person with brisk deep tendon reflexes might indicate a lesion in the brain or spinal cord. In a person with depressed reflexes, it is more likely to indicate a neuropathy.\n\nThe committee wanted to raise awareness of the possibility of migraine in people with some types of sensory symptoms, and noted that the NICE guideline on headaches in over\xa012s provides recommendations on recognition and referral for migraine.\n\nThe committee also wanted to encourage non-specialists to explore the possibility of peripheral neuropathy as a cause of sensory symptoms before referral. They thought this would help to ensure that people with these symptoms are referred to the correct service, which may be neurological or non-neurological.\n\nThe committee noted that transient sensory symptoms are common in people with a functional neurological disorder. They considered that these symptoms might not need neurological assessment.\n\nThe committee agreed that people with a functional neurological disorder might benefit from knowing that their symptoms are likely to fluctuate and evolve with time.\n\nThe committee noted that carpal tunnel syndrome is common and many regions have established management pathways that might not involve neurological services.\n\nThe committee agreed that this is a common condition that usually improves with time, and might benefit from weight loss.\n\nIn the committee's experience, cervical and lumbar radiculopathies usually settle spontaneously within a few weeks. However, the committee thought it important to highlight features that might suggest a more serious underlying condition and need further investigation.\n\nThe committee noted that this symptom is usually caused by compression related to sleeping posture and resolves rapidly without treatment.\n\nReturn to recommendations\n\n# Sleep disorders in adults\n\nRecommendations 1.11.1 to 1.11.6\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on sleep disorders in adults.\n\nThe committee agreed that difficulty sleeping and brief involuntary movements in sleep are common and benign, and do not indicate a neurological problem.\n\nThe committee highlighted the substantial risk of sudden unexpected death in epilepsy (SUDEP) in people who have epileptic seizures during sleep. They therefore emphasised the need for prompt investigation for people with this symptom.\n\nThe committee thought it important that people with excessive sleepiness are offered assessment for sleep apnoea so that they can be referred in line with local policies and pathways for the management of this condition. They agreed that the Epworth score is a well-established measure of sleep apnoea suitable for use by non-specialists.\n\nAlthough narcolepsy and cataplexy are rare conditions, the committee thought it important to highlight them to raise awareness among non-specialists.\n\nThe committee observed that sleep behaviour disorders vary in severity and on rare occasions can endanger life if they cause a person to undertake potentially harmful behaviours while asleep. They agreed that complex and severe sleep behaviour disorders need further assessment, and that the clinical judgement of the non-specialist is the best means of determining whether to offer further assessment to an individual.\n\nReturn to recommendations\n\n# Smell or taste problems\n\nRecommendations 1.12.1 to 1.12.5\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on smell or taste problems.\n\nIn the committee's experience, sudden-onset distortion of sense of smell or taste is usually idiopathic. The committee wanted to reassure non-specialists that this symptom is unlikely to indicate a neurological condition.\n\nThe committee agreed that brief, repetitive smell or taste hallucinations can be caused by temporal lobe epilepsy. They noted that this symptom is not likely to be associated with a brain tumour.\n\nThe committee noted that loss of sense of smell or taste is a fairly common reason for referral to neurological services, but rarely has a serious neurological cause. They therefore thought that neuroimaging is not usually needed.\n\nThe committee agreed that an exception to this is a loss of sense of smell or taste that can't be attributed to a rhinological cause, normal ageing or neurodegenerative disease, and lasts longer than 3\xa0months.\n\nThe committee discussed loss of smell or taste after a head injury. They noted that this is common and does not indicate more extensive brain injury. Loss of sense of smell after a head trauma is not treatable and is often permanent.\n\nReturn to recommendations\n\n# Speech, swallowing and language problems in adults\n\nRecommendations 1.13.1 to 1.13.5\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on speech, swallowing and language problems in adults.\n\nThe committee agreed that sudden-onset speech or language disturbance could indicate a vascular event.\n\nThe committee noted that slurred or disrupted speech can indicate serious underlying neurological disease, such as motor neurone disease or myasthenia gravis. Although the prognosis in motor neurone disease is not greatly influenced by early diagnosis, it is important to consider other diagnoses such as myasthenia gravis, which is highly treatable.\n\nThe committee agreed that a quiet or wobbly voice (dysphonia) can be a symptom of laryngeal dystonia, which is potentially treatable.\n\nThe committee also wanted to raise awareness of dysphonia as a possible presenting symptom of Parkinson's disease.\n\nThe committee agreed that minor word-finding difficulties are a very common presentation in anxiety disorder and functional neurological disorders.\n\nReturn to recommendations\n\n# Tics and involuntary movements in adults\n\nRecommendations 1.14.1 to 1.14.6\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on tics and involuntary movements in adults.\n\nThe committee agreed that tics are relatively common and, on their own, are benign. Treatment and management options are limited so there is little value in referring to secondary care. The committee noted that tic disorders are often accompanied by anxiety and distress that might be relieved by psychological therapy. If this is not effective and the tics are very severe or socially disabling, the committee thought that neurological referral to explore further treatment options might be beneficial.\n\nThe committee observed that involuntary movements (such as in chorea) are often mistaken for tics. Unlike tics, involuntary movements cannot be voluntarily suppressed and if they are severe or persistent, might benefit from treatment.\n\nSmall, involuntary muscle twitches are usually benign, and are especially common in the calf muscles. If accompanied by weakness, muscle wasting or muscular rigidity (stiffness), they could indicate neuromuscular disease. Otherwise, the committee considered that it is usually sufficient to reassure the person.\n\nReturn to recommendations\n\n# Tremor in adults\n\nRecommendations 1.15.1 to 1.15.4\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience to develop the recommendations on tremor in adults. Although evidence was reviewed, none that could support recommendations was identified.\n\nThe committee observed that a unilateral or predominantly unilateral tremor, especially if more prominent at rest and accompanied by slowness, is particularly suggestive of Parkinson's disease.\n\nThe committee wanted to help non-specialists differentiate essential tremor from parkinsonian tremor. They noted that essential tremor is usually bilateral and does not affect muscle tone or speed of movement. They thought that essential tremor can usually be managed in primary care.\n\nThe committee agreed that troublesome head tremor can often be controlled using treatments available in a movement disorder clinic.\n\nReturn to recommendations\n\n# Information and support\n\nRecommendations 1.16.1 and 1.16.2\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience to develop the recommendations on information and support. They agreed that this guideline covers a very broad population, and that it is unwise to give guidance on people's specific information and support needs before a diagnosis has been made. They therefore included information that might usefully be given to people presenting with neurological symptoms in the relevant recommendations, and highlighted the NICE guideline on patient experience in adult NHS services.\n\nThe committee agreed that healthcare professionals should advise people about the impact of neurological conditions on driving. They noted that people are free not to reveal health issues to their employer, school or college, but that employers and others who have this information are better able to make adjustments to help the person continue their work or studies.\n\nReturn to recommendations", 'Rationale: recommendations for children aged under\xa016': "These sections briefly explain why the committee made the recommendations for children. They link to details of the evidence reviews and a full description of the committee's discussion.\n\n# Attention, concentration and memory problems\n\nRecommendations 1.17.1 to 1.17.4\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on attention, concentration and memory problems.\n\nThe committee noted that concentration and memory problems are common in children who have diagnosed or undiagnosed epilepsy. They agreed that, in a child not diagnosed with epilepsy, episodes of loss of awareness, attention or concentration might be unrecognised absence seizures that need further investigation.\n\nIn children already diagnosed with epilepsy, the committee discussed drowsiness caused by anti-epileptic medicines, especially in higher doses or if more than one medicine is being taken. Children and their parents or carers can be advised about this, and it might be possible to adjust doses to reduce the effect on concentration and memory.\n\nThe committee agreed that concentration and memory difficulties that interfere with a child's learning should have further assessment to avoid unscheduled healthcare visits for learning difficulties in the future.\n\nThe committee discussed the common perception of children with attention and concentration problems as having hyperactive, noisy and destructive behaviour. Such children readily come to the attention of primary care, school and paediatric neurodevelopmental services. The committee wanted to ensure that children who do not have hyperactivity but do have significant attention and concentration problems are also recognised. Because they do not behave in a disruptive manner, these children may not be identified promptly, and may later present with learning difficulties.\n\nReturn to recommendations\n\n# Blackouts and other paroxysmal events\n\nRecommendations 1.18.1 to 1.18.5\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience to develop the recommendations on blackouts and other paroxysmal events. Although evidence was reviewed, none that could support recommendations was identified.\n\nBlackouts in children can be caused by neurological disorders, predominantly epilepsy, cardiac disorders or simple syncope. The committee observed that, even with a clear first-hand description of the event, it is not always possible to make a confident diagnosis without specialist assessment and investigations. The committee agreed that the recommendation for people with suspected epilepsy in the NICE guideline on transient loss of consciousness ('blackouts') in over\xa016s is applicable to children aged under\xa016.\n\nVacant spells – often called absences – as a result of epilepsy in children can be difficult to distinguish from day-dreaming and loss of concentration, and need further assessment.\n\nThe committee agreed that all children under\xa012 with blackouts or transient loss of consciousness should be referred for urgent assessment because history and examination do not always allow a diagnosis to be made confidently and there are a number of potentially serious causes that need to be excluded.\n\nVasovagal syncope is common in young people, and is often inappropriately referred because of concern that it represents seizures. The committee considered that the recommendation on vasovagal syncope in the NICE guideline on transient loss of consciousness ('blackouts') in over\xa016s is applicable to children aged 12\xa0to 15\xa0years.\n\nTransient loss of consciousness after a head injury in children is usually immediate or within a few minutes. Much-delayed paroxysmal events after head injury in children – days or weeks later – are rare but warrant urgent referral for neurological assessment. The committee considered that the recommendations on pre-hospital assessment, advice and referral to hospital in the NICE guideline on head injury should be followed.\n\nReturn to recommendations\n\n# Confusion, acute\n\nRecommendations 1.19.1 to 1.19.3\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on acute confusion.\n\nAcute confusion in a child can be a symptom of a severe neurological illness such as meningitis, intracranial haemorrhage, raised intracranial pressure, or drug or alcohol poisoning. The committee agreed that all children presenting with acute confusion should be transferred to hospital immediately by the quickest means available. Hypoglycaemia can present with acute confusion and therefore blood glucose should be measured as soon as possible to avoid delays in diagnosis and treatment for the child once in hospital care. This will also save time for paramedic services.\n\nReturn to recommendations\n\n# Dizziness and vertigo in children\n\nRecommendations 1.20.1 to 1.20.5\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on dizziness and vertigo in children.\n\nThe committee wanted to reassure non-specialists that dizziness without any other symptoms is very unlikely to indicate a brain tumour. Brain tumours usually present with symptoms such as headache, nausea and vomiting, ataxia or drowsiness.\n\nThe committee also thought non-specialists should consider the possibility of migraine as a cause of dizziness. They agreed that clinical judgement should be used to determine the care pathway for children with dizziness and migraine.\n\nThe committee thought that non-specialists should bear in mind the possibility of postural hypotension, which is common in children aged over 8\xa0years. They noted that postural hypotension might not be present at the time of examination and cannot always be excluded by measuring blood pressure.\n\nThe committee agreed that middle ear infection and middle ear effusion can be a cause of dizziness in children. They noted that the child may have fever, pain and diminished hearing, or a recent history of these, and that the eardrum might appear red and inflamed or bulging.\n\nThe committee identified recurrent dizziness in children as a red flag that warrants investigation once postural hypotension has been excluded. Cardiac dysrhythmias, although rare, can be a cause of dizziness, may be associated with exercise, and are potentially serious.\n\nReturn to recommendations\n\n# Headaches in children\n\nRecommendations 1.21.1 to 1.21.7\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience to develop the recommendations on headaches in children. Although evidence was reviewed, none that could support recommendations was identified.\n\nThe committee considered that children under\xa012 with headache and any of the 'red flag' symptoms detailed in this recommendation need immediate assessment, because these symptoms could indicate significant intracranial pathology, including a brain tumour.\n\nThe committee agreed that headache in a child aged under 4\xa0years is an unusual symptom and, when present, has a high chance of being associated with a significant intracranial disease. Because the child is unable to articulate clearly what is wrong, parents may report excessive crying, a high-pitched cry or excessive irritability.\n\nThe committee agreed that examination of the retinal fundus to identify disc swelling is essential for children with recurrent headache. They acknowledged that not all non-specialists have the skills needed for retinal fundus examination so they recommended that this could be requested, for example, from an ophthalmologist or optician.\n\nThe committee discussed raised blood pressure as a rare cause of headaches in children. The headaches may be accompanied by dizziness, vomiting or blurred vision. Because normal blood pressure changes with age and body height, they recommended that measurements of blood pressure in children are compared with standardised blood pressure charts adjusted for age and height.\n\nHeadaches that are relieved by lying down might indicate spontaneous intracranial hypotension. Although this condition is rare, the committee agreed that children with this symptom would benefit from referral and treatment.\n\nThe committee accepted that migraine is common in children and does not usually need referral. They agreed that stress can trigger migraines or chronic headaches. They also noted that overuse of analgesics can cause recurrent headaches.\n\nReturn to recommendations\n\n# Head shape or size abnormalities\n\nRecommendations 1.22.1 to 1.22.6\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience to develop the recommendations on head shape or size abnormalities. Although evidence was reviewed, none that could support recommendations was identified.\n\nThe committee discussed a number of rare syndromes that involve premature closure of cranial sutures in association with other dysmorphic features, including disorders of facial growth and limb deformities. The investigation and management of these disorders is highly specialised and complex. The committee recommended urgent referral because early surgical intervention can be beneficial for these children.\n\nThe committee noted that abnormalities of head shape or size are most likely to indicate disorders of brain growth or raised intracranial pressure in children aged under 4\xa0years, so measurement of head circumference is important in this age group if abnormalities are suspected. They agreed that GPs and health visitors should adopt standardised methods to measure head circumference and chart head growth, to ensure that accurate and consistent measurements are available to guide referral decisions.\n\nBabies frequently have a preferred lying position with their head to one side. This can lead to positional plagiocephaly, a benign condition in which one side of the head is flattened. The committee discussed how measuring the distance between the tragus of the ear and the outer canthus of the eye is a useful adjunct to clinical inspection and can help to reassure parents or carers. However, the committee acknowledged that this is not an absolute discriminator. Clinical assessment is always subjective and there is no test, short of imaging (rarely justified in plagiocephaly), that is infallible. Therefore, if there is uncertainty, referral for specialist assessment is advisable.\n\nReturn to recommendations\n\n# Hypotonia ('floppiness')\n\nRecommendations 1.23.1 and 1.23.2\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on hypotonia ('floppiness').\n\nThe committee thought it important to highlight potential causes of hypotonia so that babies with a possible serious disorder of cardiac, renal or liver function are referred immediately to paediatric services.\n\nThe committee noted that babies who exhibit unexplained floppiness together with weakness are much more likely to have an underlying progressive disorder of the nervous system and need urgent referral.\n\nReturn to recommendations\n\n# Limb or facial weakness in children\n\nRecommendations 1.24.1 to 1.24.4\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on limb or facial weakness in children.\n\nIn the committee's view, sudden or rapidly progressive limb or facial weakness in a child is usually a symptom of a pathology that needs immediate neurological investigation or management because the child's condition can deteriorate rapidly.\n\nThe committee noted that cerebral palsy is the most common chronic motor disorder that affects children, but other genetic and medical disorders can have a similar presentation. They agreed that the recommendations in the NICE guideline on cerebral palsy in under\xa025s should be followed.\n\nSee the rationale on early diagnosis of Duchenne muscular dystrophy.\n\nReturn to recommendations\n\n# Motor development delay and unsteadiness\n\nRecommendations 1.25.1 to 1.25.5\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on motor development delay and unsteadiness. Although evidence on creatine kinase testing for Duchenne muscular dystrophy was reviewed, none that could support recommendations was identified.\n\nThe committee agreed that new-onset gait abnormality could indicate trauma, infection, appendicitis or a hip abnormality, so these children need to be referred immediately.\n\nAlthough most children with motor development delay are simply at the slower end of the normal range of acquisition of motor skills, a small number will have a neurodevelopmental disorder such as muscular dystrophy or cerebral palsy. Assessment is relatively quick and the committee's view was that it is worth referring these children to a child development service to screen for problems and, in most cases, reassure parents. The committee agreed that the NICE guideline on cerebral palsy in under\xa025s provides further advice on referral for these children.\n\nEarly diagnosis of Duchenne muscular dystrophy is especially important so that the family can be offered genetic counselling. Creatinine kinase measurement is an inexpensive, routine test that can help identify this condition. If the test result is negative, Duchenne muscular dystrophy is unlikely.\n\nThe committee agreed that specialist investigation of motor development regression is best carried out by a paediatric neurodevelopmental service or paediatric neurology because of the complexity of the investigations needed.\n\nReturn to recommendations\n\n# Posture distortion in children\n\nRecommendations 1.26.1 to 1.26.4\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on posture distortion in children.\n\nAbnormal neck posture in a child who has had a recent head or neck trauma can indicate instability of cervical spine through bony or ligamentous injury, so the committee agreed that the child should be referred to an emergency department immediately, and immobilisation applied in line with the recommendations in the NICE guidelines on head injury and spinal injury.\n\nThe committee noted that an abnormal neck posture might be the result of painful enlarged lymph nodes that are a common presentation and can be managed in primary care.\n\nThe committee agreed that the most common cause of abnormal limb posture in children is pain or injury. If there is no history of an associated acute event or obvious musculoskeletal cause, the child needs to be referred to exclude progressive causes that need treatment.\n\nThe committee noted that abnormal head tilt can present before other typical symptoms of posterior fossa tumours, such as ataxia, vomiting and headaches. This finding is sometimes dismissed, leading to delay in diagnosis, and the committee therefore considered it useful to draw attention to the possibility.\n\nReturn to recommendations\n\n# Sensory symptoms such as tingling or numbness in children\n\nRecommendations 1.27.1 to 1.27.5\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience to develop the recommendations on sensory symptoms including tingling or numbness in children. Although evidence was reviewed, none that could support recommendations was identified.\n\nTingling together with other peripheral nervous system symptoms might indicate pathology affecting the spinal cord. It is not easy to recognise this pathology on clinical examination, so the committee agreed that children with these symptoms need to be referred urgently.\n\nTingling can also be the first symptom of Guillain−Barré syndrome which, although relatively rare, can affect respiratory function through motor impairment, so the committee agreed that children with tingling and features suggesting motor impairment need to be referred urgently.\n\nThe committee noted that transient, fixed-pattern sensory symptoms that are not associated with compression of a nerve can indicate epilepsy and that children with these symptoms should be referred. The NICE guideline on epilepsies provides advice on diagnosis and investigations for epilepsy.\n\nThe committee agreed that temporary tingling of this nature is commonly caused by carrying heavy objects or over-breathing, and these children do not need to be referred.\n\nReturn to recommendations\n\n# Sleep disorders in children\n\nRecommendations 1.28.1 to 1.28.9\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on sleep disorders in children.\n\nThe committee noted that in children with neuromuscular disorders such as Duchenne muscular dystrophy, headaches on awakening in the morning can be an early sign of respiratory failure caused by hypoventilation during sleep. These children are also more susceptible to sleep apnoea and other breathing disorders caused by decreased muscle tone in the muscles of the airway.\n\nThe committee agreed that nocturnal seizures are a risk factor for sudden unexpected death in epilepsy (SUDEP) and need prompt investigation. They acknowledged that it can be difficult to identify nocturnal epileptic seizures, but highlighted that red flags are a stereotyped pattern of behaviour during the episode, an episode that starts as a focal seizure and then becomes generalised, or difficulty rousing the child after the episode.\n\nThe committee agreed that narcolepsy is a condition that is easily missed in children. It can present as daytime drowsiness, falling asleep in unusual circumstances, or as poor school performance and poor concentration. Diagnosis, assessment and management are best achieved by a service with experience of this condition, so the committee recommended referral to neurological services.\n\nThe committee observed that sleep apnoea is not uncommon in babies and young children and might be caused by gastro-oesophageal reflux or intercurrent infection. In older children, it can be a result of enlarged tonsils and adenoids. Obesity can also cause sleep apnoea in children. They concluded that children with symptoms of sleep apnoea should be referred to determine the cause, and advice on weight loss should be offered for those who are obese.\n\nThe committee noted that new-onset night terrors are unusual in children aged over 5\xa0years, and could indicate epilepsy. For this reason, they agreed that new-onset night terrors in children of this age, as well as children in whom night terrors continue after age\xa012, should be referred.\n\nThe committee recognised that clinicians are aware that sleep disturbance is common in childhood and often resolves as the child gets older. However, reassuring parents that sleep disturbances are a normal part of development might help to reduce the pressure for an unnecessary referral. Referring children aged under 5\xa0years to a health visitor may be helpful.\n\nThe committee thought that that children with neurodevelopmental disorders or learning disabilities should be considered separately because referral to paediatric services may not be appropriate given the prevalence of sleep problems in these children. They agreed that clinical judgement should be used.\n\nThe committee thought it useful to point out that sleep disturbances might also be caused by gastro-oesophageal reflux or constipation, and agreed that the NICE guidelines on these conditions in children would be helpful.\n\nReturn to recommendations\n\n# Speech problems in children\n\nRecommendations 1.29.1 to 1.29.3\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on speech problems in children.\n\nThe committee agreed that new-onset slurred or disrupted speech not attributable to medicines, recreational drugs or alcohol can indicate an acute or progressive neurological disorder or epilepsy, and therefore children with this symptom need urgent neurological assessment.\n\nThe committee noted that problems with speech development are a very common presentation. They discussed the appropriate age for referral, noting that there is a wide range within which development can be considered normal. They therefore agreed that referrals should not be made before the age of 2\xa0years. Until that age, development may be within normal limits, and speech difficulties may resolve unaided.\n\nReturn to recommendations\n\n# Squint\n\nRecommendations 1.30.1 to 1.30.4\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on squint.\n\nThe committee agreed that referral should be immediate as new-onset squint with loss of red reflex in one or both eyes can indicate a retinoblastoma, or other progressive pathology of the eye. Additionally, following post publication feedback, NICE felt it was important to highlight that a new-onset squint with loss of red reflex in one or both eyes may also indicate a neurological condition associated with raised intracranial pressure or a brain tumour.\n\nNew-onset squint presenting with accompanying symptoms such as ataxia, vomiting or headache can indicate raised intracranial pressure. The committee agreed that children presenting with squint and any of these symptoms should be referred immediately.\n\nIntracerebral tumour or inflammation can present with restriction of movement of one or both eyes, so the committee agreed that this symptom should trigger urgent referral.\n\nIn a non-paralytic squint, the child retains the ability to move both eyes fully in all directions. In the absence of any other signs or symptoms such as loss of red reflexes, ataxia, vomiting or headaches, the committee agreed that this symptom warrants a routine referral to ophthalmology.\n\nReturn to recommendations\n\n# Tics and involuntary movements in children\n\nRecommendations 1.31.1 to 1.31.6\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on tics and involuntary movements in children.\n\nThe committee agreed that sudden onset of chorea, ataxia or dystonia in a child can be a symptom of a progressive neurological disease such as a space-occupying lesion, a metabolic disturbance, a degenerative condition, a para-infectious condition such as rheumatic fever, or drug-induced, so all children with this symptom should be referred immediately.\n\nThe committee agreed that most simple motor tics resolve on their own. Parents or carers often find them concerning and reassurance can be helpful. The committee added that referral might be helpful for children with tics that significantly impair quality of life, because drug treatment or habit reversal therapy can be helpful.\n\nReturn to recommendations\n\n# Tremor in children\n\nRecommendations 1.32.1 to 1.32.4\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience, together with validation by external experts, to develop the recommendations on tremor in children.\n\nThe committee agreed that children with these symptoms or signs need to be referred for assessment because tremor can be the initial symptom of a space-occupying lesion in children if its onset is sudden or it is accompanied by other neurological signs or symptoms.\n\nThe committee discussed tremor as a side effect of sodium valproate or a beta-adrenergic agonist, or a result of hyperthyroidism, and agreed that these should be considered possible causes of isolated tremor in children taking these medicines.\n\nBecause tremor is rarely caused by a progressive neurological condition, the committee thought that effective management of the tremor should be the priority. They noted that occupational therapists have the skills to assess how the tremor affects the child's home and school life.\n\nReturn to recommendations", 'Context': "Around 10% of visits to GPs and hospital emergency departments are made by people with symptoms or signs associated with neurological conditions. Many of these people will need referral to a specialist for diagnosis and treatment, but others can have their condition managed in primary care.\n\nCurrently there is a lack of support to help non-specialists identify when a referral for specialist investigation of neurological symptoms or signs should be made. This has led to delays in referral for people with treatable or potentially serious neurological conditions, and unnecessary referrals for others. Although many specialist professional and charitable bodies have produced guidance on specific neurological conditions, there is a need for overarching guidance that covers a wide range of neurological symptoms and signs.\n\nThis guideline provides recommendations on clinical assessment in non-specialist settings and indications for referral to specialist care (including referral for people with existing neurological conditions). The guideline focuses on the signs and symptoms that are most frequently under- or over-referred, or cause uncertainty among non-specialists. In some recommendations, additional educational information is provided to help guide non-specialists. If a sign or symptom is covered by other NICE guidance, a cross-referral to that guidance is included.\n\nBecause of a lack of published evidence in this area, the recommendations are largely based on the guideline committee's knowledge and experience. Some recommendations were also reviewed by external experts. Detailed information on how the recommendations were developed is in the methods section of the full guideline."}
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https://www.nice.org.uk/guidance/ng127
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This guideline covers the initial assessment of symptoms and signs that might indicate a neurological condition. It helps non-specialist healthcare professionals to identify people who should be offered referral for specialist investigation.
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d9c2c0f8e849ff7f406b34eb8a316f88ee4e1454
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Long-acting reversible contraception
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Long-acting reversible contraception
This guideline covers long-acting reversible contraception. It aims to increase the use of long-action reversible contraception by improving the information given to women about their contraceptive choices.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
This guideline offers the best-practice advice on the provision of information and care for women who are considering or using LARC. Treatment and care should take into account women's individual needs and preferences.
# Contraception and principles of care
## Contraceptive provision
Women requiring contraception should be given information about and offered a choice of all methods, including long-acting reversible contraception (LARC) methods.
Women should be provided with the method of contraception that is most acceptable to them, provided it is not contraindicated.
## Provision of information and informed choice
Women considering LARC methods should receive detailed information – both verbal and written – that will enable them to choose a method and use it effectively. This information should take into consideration their individual needs and should include:
contraceptive efficacy
duration of use
risks and possible side effects
non-contraceptive benefits
the procedure for initiation and removal/discontinuation
when to seek help while using the method. See the implementation resource for this guideline, which provides links to up to date, relevant and valid information about LARC methods.
Counselling about contraception should be sensitive to cultural differences and religious beliefs.
Healthcare professionals should have access to trained interpreters for women who are not English speaking, and to advocates for women with sensory impairments or learning disabilities.
## Contraceptive prescribing
A medical history – including relevant family, menstrual, contraceptive and sexual history – should be taken as part of the routine assessment of medical eligibility for individual contraceptive methods.
Healthcare professionals helping women to make contraceptive choices should be familiar with nationally agreed guidance on medical eligibility and recommendations for contraceptive use.
When considering choice of LARC methods for specific groups of women and women with medical conditions, healthcare professionals should be aware of and discuss with each woman any issues that might affect her choice (see the implementation resource for this guideline, which provides links to up to date, relevant and valid information about LARC methods).
Healthcare professionals should exclude pregnancy by taking menstrual and sexual history before initiating any contraceptive methods.
Healthcare professionals should supply an interim method of contraception at first appointment if required.
Healthcare professionals should ensure that informed consent is obtained from the woman whenever any method of LARC is being used outside the terms of the UK Marketing Authorisation. This should be discussed and documented in the notes.
Women who have a current venous thromboembolism (VTE) and need hormonal contraception while having treatment for the VTE should be referred to a specialist in contraceptive care.
## Contraception and sexually transmitted infection
Healthcare professionals providing contraceptive advice should promote safer sex.
Healthcare professionals providing contraceptive advice should be able to assess risk for sexually transmitted infections (STIs) and advise testing when appropriate.
Healthcare professionals should be able to provide information about local services for STI screening, investigation and treatment.
## Contraception for special groups
Healthcare professionals should be aware of the law relating to the provision of advice and contraception for young people and for people with learning disabilities. Child protection issues and the Fraser guidelines should be considered when providing contraception for women younger than 16 years. (See the Department of Health's best practice guidance for doctors and other healthcare professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health).
Women with learning and/or physical disabilities should be supported in making their own decisions about contraception.
Contraception should be seen in terms of the needs of the individual rather than in terms of relieving the anxieties of carers or relatives.
When a woman with a learning disability is unable to understand and take responsibility for decisions about contraception, carers and other involved parties should meet to address issues around the woman's contraceptive need and to establish a care plan.
## Training of healthcare professionals in contraceptive care
Healthcare professionals advising women about contraceptive choices should be competent to:
help women to consider and compare the risks and benefits of all methods relevant to their individual needs
manage common side effects and problems.
Contraceptive service providers who do not provide LARC in their practice or service should have an agreed mechanism in place for referring women for LARC.
Healthcare professionals providing intrauterine or subdermal contraceptives should receive training to develop and maintain the relevant skills to provide these methods.
IUDs and the IUS should only be fitted by trained personnel with continuing experience of inserting at least one IUD or one IUS a month.
Contraceptive implants should be inserted and removed only by healthcare professionals trained in the procedure.# Recommendations for research
The scarcity of robust evidence to answer important clinical questions on the use of LARC methods by women in the UK posed great challenges to the developers of the original guideline (October, 2005). In the majority of cases, the guideline recommendations were based on extrapolated evidence that is indirect or of poor methodological quality. In 2005, the Guideline Development Group made the following recommendations for research on the basis of its review of the evidence.
In making these recommendations for research, the guideline developers consider it important and relevant that the research should be specific to the UK population because there are cultural differences in the response to side effects and non‑contraceptive effects of hormonal contraceptives. In addition, freedom to choose any contraceptive method and the provision of a free contraceptive health service in the UK can influence important outcomes such as continuation rates and patterns of method switching.
# Typical use of contraception
Few women use contraception perfectly (that is, exactly in accordance with the product instructions) and consistently. Pregnancy rates during typical use reflect effectiveness of a method among women who use the method incorrectly or inconsistently. Few data are available on typical use of any contraceptive method among women in the UK. Much of the data on contraceptive effectiveness used in the guideline come from clinical trials or surveys undertaken in other countries such as the USA. Large prospective cohort studies are needed to compare the contraceptive effectiveness of LARC methods with non‑LARC methods during typical use in the UK.
# Patterns of LARC use
Most women will need to use contraception for more than 30 years. Patterns of contraceptive use vary with age, ethnicity, marital status, fertility intention, education and lifestyle. Large prospective cohort studies are needed to identify:
patterns of use (initiation, continuation and switching between methods) of LARC methods compared with non‑LARC methods
factors that influence the patterns of use of LARC.
# Uptake and acceptance of LARC
In addition to individual circumstances and needs, a woman's choice and acceptance of LARC may be influenced by potential health disbenefits (side effects and risks) as well as non‑contraceptive benefits of LARC (such as alleviation of menorrhagia). Large population studies of appropriate design are needed to determine the effect of these factors on the uptake of LARC methods and the implications for NHS resources.
# Bone mineral density in women using DMPA
The effect of injectable contraceptives on bone mineral density in women who have used DMPA for longer than 2 years is uncertain. Adequately powered surveys or cross‑sectional studies are needed to examine the recovery of bone mineral density after discontinuation of DMPA after long‑term and very long‑term use. Studies are also needed to examine the risk of bone fractures in older women.# Context
It is estimated that about 30% of pregnancies are unplanned. The effectiveness of the barrier method and oral contraceptive pills depends on their correct and consistent use. By contrast, the effectiveness of long-acting reversible contraceptive (LARC) methods does not depend on daily concordance. The uptake of LARC is low in Great Britain, at around 12% of women aged 16 to 49 in 2008 to 2009, compared with 25% for the oral contraceptive pill and 25% for male condoms.
Expert clinical opinion is that LARC methods may have a wider role in contraception and their increased uptake could help to reduce unintended pregnancy. The current limited use of LARC suggests that healthcare professionals need better guidance and training so that they can help women make an informed choice. Health providers and commissioners also need a clear understanding of the relative cost effectiveness of LARC compared with other methods of fertility control. Enabling women to make an informed choice about LARC and addressing women's preferences is an important objective of this guideline.
LARC is defined in this guideline as contraceptive methods that require administration less than once per cycle or month. Included in the category of LARC are:
copper intrauterine devices
progestogen-only intrauterine systems
progestogen-only injectable contraceptives
progestogen-only subdermal implants
The guideline offers the best-practice advice for all women of reproductive age who may wish to regulate their fertility by using LARC methods. It covers specific issues for the use of these methods during the menarche and before the menopause, and by particular groups, including women who have HIV, learning disabilities or physical disabilities, or are younger than 16 years.
Drug recommendations
The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline offers the best-practice advice on the provision of information and care for women who are considering or using LARC. Treatment and care should take into account women's individual needs and preferences.\n\n# Contraception and principles of care\n\n## Contraceptive provision\n\nWomen requiring contraception should be given information about and offered a choice of all methods, including long-acting reversible contraception (LARC) methods.\n\nWomen should be provided with the method of contraception that is most acceptable to them, provided it is not contraindicated.\n\n## Provision of information and informed choice\n\nWomen considering LARC methods should receive detailed information – both verbal and written – that will enable them to choose a method and use it effectively. This information should take into consideration their individual needs and should include:\n\ncontraceptive efficacy\n\nduration of use\n\nrisks and possible side effects\n\nnon-contraceptive benefits\n\nthe procedure for initiation and removal/discontinuation\n\nwhen to seek help while using the method. See the implementation resource for this guideline, which provides links to up to date, relevant and valid information about LARC methods.\n\nCounselling about contraception should be sensitive to cultural differences and religious beliefs.\n\nHealthcare professionals should have access to trained interpreters for women who are not English speaking, and to advocates for women with sensory impairments or learning disabilities.\n\n## Contraceptive prescribing\n\nA medical history – including relevant family, menstrual, contraceptive and sexual history – should be taken as part of the routine assessment of medical eligibility for individual contraceptive methods.\n\nHealthcare professionals helping women to make contraceptive choices should be familiar with nationally agreed guidance on medical eligibility and recommendations for contraceptive use.\n\nWhen considering choice of LARC methods for specific groups of women and women with medical conditions, healthcare professionals should be aware of and discuss with each woman any issues that might affect her choice (see the implementation resource for this guideline, which provides links to up to date, relevant and valid information about LARC methods).\n\nHealthcare professionals should exclude pregnancy by taking menstrual and sexual history before initiating any contraceptive methods.\n\nHealthcare professionals should supply an interim method of contraception at first appointment if required.\n\nHealthcare professionals should ensure that informed consent is obtained from the woman whenever any method of LARC is being used outside the terms of the UK Marketing Authorisation. This should be discussed and documented in the notes.\n\nWomen who have a current venous thromboembolism (VTE) and need hormonal contraception while having treatment for the VTE should be referred to a specialist in contraceptive care.\n\n## Contraception and sexually transmitted infection\n\nHealthcare professionals providing contraceptive advice should promote safer sex.\n\nHealthcare professionals providing contraceptive advice should be able to assess risk for sexually transmitted infections (STIs) and advise testing when appropriate.\n\nHealthcare professionals should be able to provide information about local services for STI screening, investigation and treatment.\n\n## Contraception for special groups\n\nHealthcare professionals should be aware of the law relating to the provision of advice and contraception for young people and for people with learning disabilities. Child protection issues and the Fraser guidelines should be considered when providing contraception for women younger than 16\xa0years. (See the Department of Health's best practice guidance for doctors and other healthcare professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health).\n\nWomen with learning and/or physical disabilities should be supported in making their own decisions about contraception.\n\nContraception should be seen in terms of the needs of the individual rather than in terms of relieving the anxieties of carers or relatives.\n\nWhen a woman with a learning disability is unable to understand and take responsibility for decisions about contraception, carers and other involved parties should meet to address issues around the woman's contraceptive need and to establish a care plan.\n\n## Training of healthcare professionals in contraceptive care\n\nHealthcare professionals advising women about contraceptive choices should be competent to:\n\nhelp women to consider and compare the risks and benefits of all methods relevant to their individual needs\n\nmanage common side effects and problems.\n\nContraceptive service providers who do not provide LARC in their practice or service should have an agreed mechanism in place for referring women for LARC.\n\nHealthcare professionals providing intrauterine or subdermal contraceptives should receive training to develop and maintain the relevant skills to provide these methods.\n\nIUDs and the IUS should only be fitted by trained personnel with continuing experience of inserting at least one IUD or one IUS a month.\n\nContraceptive implants should be inserted and removed only by healthcare professionals trained in the procedure.", 'Recommendations for research': "The scarcity of robust evidence to answer important clinical questions on the use of LARC methods by women in the UK posed great challenges to the developers of the original guideline (October, 2005). In the majority of cases, the guideline recommendations were based on extrapolated evidence that is indirect or of poor methodological quality. In 2005, the Guideline Development Group made the following recommendations for research on the basis of its review of the evidence.\n\nIn making these recommendations for research, the guideline developers consider it important and relevant that the research should be specific to the UK population because there are cultural differences in the response to side effects and non‑contraceptive effects of hormonal contraceptives. In addition, freedom to choose any contraceptive method and the provision of a free contraceptive health service in the UK can influence important outcomes such as continuation rates and patterns of method switching.\n\n# Typical use of contraception\n\nFew women use contraception perfectly (that is, exactly in accordance with the product instructions) and consistently. Pregnancy rates during typical use reflect effectiveness of a method among women who use the method incorrectly or inconsistently. Few data are available on typical use of any contraceptive method among women in the UK. Much of the data on contraceptive effectiveness used in the guideline come from clinical trials or surveys undertaken in other countries such as the USA. Large prospective cohort studies are needed to compare the contraceptive effectiveness of LARC methods with non‑LARC methods during typical use in the UK.\n\n# Patterns of LARC use\n\nMost women will need to use contraception for more than 30\xa0years. Patterns of contraceptive use vary with age, ethnicity, marital status, fertility intention, education and lifestyle. Large prospective cohort studies are needed to identify:\n\npatterns of use (initiation, continuation and switching between methods) of LARC methods compared with non‑LARC methods\n\nfactors that influence the patterns of use of LARC.\n\n# Uptake and acceptance of LARC\n\nIn addition to individual circumstances and needs, a woman's choice and acceptance of LARC may be influenced by potential health disbenefits (side effects and risks) as well as non‑contraceptive benefits of LARC (such as alleviation of menorrhagia). Large population studies of appropriate design are needed to determine the effect of these factors on the uptake of LARC methods and the implications for NHS resources.\n\n# Bone mineral density in women using DMPA\n\nThe effect of injectable contraceptives on bone mineral density in women who have used DMPA for longer than 2\xa0years is uncertain. Adequately powered surveys or cross‑sectional studies are needed to examine the recovery of bone mineral density after discontinuation of DMPA after long‑term and very long‑term use. Studies are also needed to examine the risk of bone fractures in older women.", 'Context': "It is estimated that about 30% of pregnancies are unplanned. The effectiveness of the barrier method and oral contraceptive pills depends on their correct and consistent use. By contrast, the effectiveness of long-acting reversible contraceptive (LARC) methods does not depend on daily concordance. The uptake of LARC is low in Great Britain, at around 12% of women aged 16 to 49\xa0in 2008 to 2009, compared with 25% for the oral contraceptive pill and 25% for male condoms.\n\nExpert clinical opinion is that LARC methods may have a wider role in contraception and their increased uptake could help to reduce unintended pregnancy. The current limited use of LARC suggests that healthcare professionals need better guidance and training so that they can help women make an informed choice. Health providers and commissioners also need a clear understanding of the relative cost effectiveness of LARC compared with other methods of fertility control. Enabling women to make an informed choice about LARC and addressing women's preferences is an important objective of this guideline.\n\nLARC is defined in this guideline as contraceptive methods that require administration less than once per cycle or month. Included in the category of LARC are:\n\ncopper intrauterine devices\n\nprogestogen-only intrauterine systems\n\nprogestogen-only injectable contraceptives\n\nprogestogen-only subdermal implants\n\nThe guideline offers the best-practice advice for all women of reproductive age who may wish to regulate their fertility by using LARC methods. It covers specific issues for the use of these methods during the menarche and before the menopause, and by particular groups, including women who have HIV, learning disabilities or physical disabilities, or are younger than 16\xa0years.\n\nDrug recommendations\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients."}
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https://www.nice.org.uk/guidance/cg30
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This guideline covers long-acting reversible contraception. It aims to increase the use of long-action reversible contraception by improving the information given to women about their contraceptive choices.
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1331468ac19ac6f745c335f768efbc153628cb82
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nice
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Lenalidomide for treating myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality
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Lenalidomide for treating myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality
Evidence-based recommendations on lenalidomide (Revlimid) for treating myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality in adults.
# Guidance
Lenalidomide is recommended as an option, within its marketing authorisation, that is for treating transfusion‑dependent anaemia caused by low or intermediate‑1 risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It is recommended only if the company provides it according to the commercial arrangement.# The technology
Lenalidomide (Revlimid, Celgene) is a structural analogue of thalidomide. It has anti‑neoplastic, anti‑angiogenic, pro‑erythropoeitic and immunomodulatory properties. Lenalidomide inhibits the proliferation of certain haematopoietic tumour cells, enhances T cell- and natural killer cell‑mediated immunity, increases fetal haemoglobin production by CD34+ haematopoietic stem cells and inhibits production of pro‑inflammatory cytokines. Lenalidomide has a marketing authorisation 'for the treatment of patients with transfusion‑dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate'.
The summary of product characteristics lists the following adverse reactions for lenalidomide: fatigue, neutropenia, constipation, diarrhoea, muscle cramp, anaemia, thrombocytopenia and rash. The summary of product characteristics recommends a starting dose of 10 mg orally, once daily, on days 1 to 21 of repeated 28 day cycles, with dose reductions (5.0 mg, 2.5 mg or 2.5 mg every other day) to manage adverse events. Dosage is continued or modified based on clinical and laboratory findings. Lenalidomide is structurally similar to thalidomide, which causes severe birth defects, so a risk minimisation plan has been developed and agreed with the Medicines and Healthcare products Regulatory Agency to avoid fetal exposure to lenalidomide. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Lenalidomide is available in 21‑day packs of 10 mg and 5 mg capsules at net prices of £3780 and £3570 respectively (excluding VAT; 'British national formulary' edition 67). The cost of a 28‑day cycle of treatment with 10 mg of lenalidomide (excluding VAT) is £3780. The pricing arrangement considered during guidance development was that the company (Celgene) had agreed a complex patient access scheme with the Department of Health, in which the NHS paid for lenalidomide treatment for up to 26 monthly cycles. The company subsequently provided free of charge lenalidomide for those people who had more than 26 monthly cycles. A commercial arrangement has now been agreed. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# The company's submission
The Appraisal Committee (section 7) considered evidence submitted by Celgene and a review of this evidence by the Evidence Review Group (ERG; section 8).
# Clinical effectiveness
The company performed a systematic review of the evidence on the clinical effectiveness of lenalidomide for low- or intermediate‑1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality that is red blood cell transfusion dependent. The review identified a single phase III, randomised, double‑blind study (MDS‑004), which compared lenalidomide 10 mg (n=69) and lenalidomide 5 mg (n=69) with placebo (n=67). Treatment was given every day of a 28‑day cycle, except in the lenalidomide 10 mg arm, in which 10 mg lenalidomide was given on days 1–21 only. MDS‑004 was a multinational study that enrolled people from 37 study sites including the UK, France, Germany, Italy, Spain, Belgium, Netherlands, Sweden and Israel. The study population comprised adults with MDS whose condition was transfusion dependent and who had International Prognostic Scoring System (IPSS) of low‑risk (49%) or intermediate‑1 risk (51%) MDS with a deletion 5q cytogenetic abnormality. MDS‑004 was stratified according to IPSS karyotype score (0 versus >0; that is, isolated deletion 5q cytogenetic abnormality versus isolated deletion 5q cytogenetic abnormality plus 1 or more additional cytogenetic abnormalities ). In the MDS‑004 study, 51.8% of the total patient population had had previous erythropoietin therapy (58.5% in the 10 mg lenalidomide treatment arm).
People in MDS‑004 who had at least a minor erythroid response (that is, a 50% decrease in transfusion requirements) by week 16 could continue treatment (double‑blind) for up to 52 weeks, or until erythroid relapse, disease progression or unacceptable toxicity. People receiving placebo or lenalidomide 5 mg who didn't have a minor erythroid response by week 16 could cross over to the lenalidomide 5 mg or 10 mg treatment arms, respectively. Open‑label treatment was then continued for up to 156 weeks. People with disease progression at any time and those randomly assigned to lenalidomide 10 mg without minor erythroid response by week 16 were withdrawn from the study. The company stated that the lenalidomide dose was reduced if dose‑limiting toxicities occurred, and complete blood counts were obtained weekly after the development of dose‑limiting Grade 3 or 4 neutropenia or thrombocytopenia.
Three study populations were defined in MDS‑004: the intention‑to‑treat (ITT) population, the safety population and the modified‑ITT (mITT) population. The ITT population included all randomised people (n=205). The safety population included all randomised people who received at least 1 dose of study drug (n=205). The mITT population included people with low- or intermediate‑1 risk MDS with deletion 5q and documented red blood cell transfusion dependence, who received at least 1 dose of study drug (n=139). Confirmation of deletion 5q status (karyotype analysis) and bone marrow morphology was performed by haematological review after randomisation. Therefore some people not fulfilling the inclusion criteria (that is, people without confirmed deletion 5q status) were included in the ITT population. For the mITT population, 76.3% had an isolated deletion 5q cytogenetic abnormality and 23.7% had deletion 5q plus one or more additional cytogenetic abnormalities. The baseline characteristics of the people in the treatment arms for the mITT population were similar.
The primary end point of the MDS‑004 trial was transfusion independence lasting for at least 26 consecutive weeks. Secondary end points included erythroid response at 16 weeks, duration of red blood cell transfusion independence, cytogenetic response at weeks 12, 24 and every 24 weeks thereafter, overall survival, progression to acute myeloid leukaemia (AML) and adverse events. Health‑related quality of life was assessed using the Functional Assessment of Cancer Therapy‑Anaemia (FACT‑An) questionnaire at weeks 12, 24, 36 and 48.
For the double‑blind phase of MDS‑004, statistically significantly more people in the mITT population were transfusion independent for at least 26 weeks with lenalidomide 10 mg (56.1%) and 5 mg (42.6%) than with placebo (5.9%; p<0.001 compared with both lenalidomide groups). Using the International Working Group 2000 and 2006 criteria for erythroid response, transfusion independence rates for at least 8 weeks in the mITT population were also statistically significantly higher for the lenalidomide 5 mg and 10 mg treatment groups compared with placebo. Similar results were obtained for the ITT population. Median duration of transfusion independence of at least 8 weeks was not reached in the lenalidomide 5 mg or 10 mg treatment groups.
In the safety population, median time to progression to AML (from date of randomisation to progression to AML, death, or last known contact for people without AML, whichever was earliest) was 30.9 months (range 2.1–56.5 months) in the placebo group, 36.1 months (range 0.4–57.7 months) in the lenalidomide 10 mg group and 31.8 months (range 0.8–59.4 months) in the lenalidomide 5 mg group. Before crossover at 16 weeks, 2 people (3.0%) in the placebo group, 0 in the lenalidomide 10 mg group and 2 (2.9%) in the lenalidomide 5 mg group had progressed to AML. Overall, 52 people (25.4%) progressed to AML during the double‑blind and open‑label phases. The cumulative risk of AML for the lenalidomide 5 mg and 10 mg groups combined was 16.8% (95% CI 9.8–23.7) at 2 years and 25.1% (95% CI 17.1–33.1) at 3 years. Of those who were randomly assigned to placebo and never received lenalidomide (n=11), including 3 people who completed 52 weeks of the study protocol, 4 (36.4%) progressed to AML. Of the people who initially received placebo and then crossed over to lenalidomide 5 mg, 30.4% (17 out of 56) progressed to AML, as did 23.2% (16 out of 69) people in the lenalidomide 5 mg group and 21.7% (15 out of 69) people in the lenalidomide 10 mg group.
The median duration of overall survival follow‑up in the safety population was 35.9 months (range 2.1–56.5 months) in the placebo group, 36.9 months (range 0.4–57.7 months) in the lenalidomide 10 mg group and 35.5 months (range 1.9–59.4 months) in the lenalidomide 5 mg group. Based on Kaplan–Meier curves, the median length of overall survival was 42.4 months in the lenalidomide 10 mg group (95% CI 31.9 to not reached), 35.5 months in the 5 mg group (95% CI 24.6 to not reached), and 44.5 months (95% CI 35.5 to not reached) in the placebo group. The company stated that overall survival was similar between people included in and excluded from the mITT population (p=0.9218).The company did not adjust the overall survival results using formal statistical methods for any treatment crossover that occurred.
In MDS‑004, cytogenetic response was assessed using International Working Group 2000 criteria. Cytogenetic responses help to establish the degree to which the natural history of myelodysplastic syndromes may be affected by therapy. Cytogenetic response (complete plus partial) rates in the mITT population were 50% in the lenalidomide 10 mg group and 25% in the 5 mg group, respectively. No cytogenetic responses occurred in the placebo group (p<0.001 compared with both lenalidomide groups). Cytogenetic progression (development of new independent clones as well as additional aberrations together with deletion 5q) was observed in 23.5% of people treated with lenalidomide 10 mg (p=0.50 compared with placebo), 31.3% of people treated with lenalidomide 5 mg (p=0.17 compared with placebo), and 14.3% of people receiving placebo. Similar results were observed in the ITT population. Median time to cytogenetic progression was 93 days (range 85–170 days) in the lenalidomide 10 mg group, 85 days (range 83–339 days) in the lenalidomide 5 mg group, and 99 days (range 83–172 days) in the placebo group.
Health‑related quality of life data were collected for 167 people in MDS‑004 using the FACT‑An questionnaire. Baseline and week 12 (that is, before crossover) FACT‑An scores were available for 71% of randomly assigned people (lenalidomide 10 mg, n=48; 5 mg, n=45; placebo, n=52). Mean change in FACT‑An score from baseline to week 12 was statistically significantly higher in the lenalidomide 10 mg (5.8; p<0.05) and 5 mg (5.9; p<0.05) groups than in the placebo group (−2.5).
The company reported adverse event rates for the double‑blind safety population in MDS‑004. A higher proportion of people in the lenalidomide 10 mg (95.7%) and 5 mg groups (98.6%) had at least 1 drug‑related adverse event compared with the placebo group (49.3%). The most frequently reported drug‑related adverse events were neutropenia (14.9% in the placebo group, and 75.4% in each of the lenalidomide groups) and thrombocytopenia (3.0% in the placebo group, 39.1% in the lenalidomide 5 mg group and 47.8% in the lenalidomide 10 mg group). For serious infections, only rates of grade 3 or 4 pneumonia were reported by the company (1.5% in the placebo group, 1.4% in the lenalidomide 5 mg group and 4.3% in the lenalidomide 10 mg group).
# Cost effectiveness
The company developed a de novo Markov model that simulated cohorts of people with low- to intermediate‑1 risk MDS with deletion 5q receiving lenalidomide 10 mg or best supportive care. The model cycle length was 4 weeks to reflect the dosing interval for lenalidomide treatment. A half‑cycle correction was not applied. The time horizon of the model was 20 years based on an average age of 67 years in the MDS‑004 study. An NHS and personal social services perspective was taken and costs and benefits were discounted at 3.5%. The company provided 4 models in total, the first being the original base‑case (model 1). Model 2 was provided in response to the first appraisal consultation document incorporating revisions to address concerns raised by Committee. Models 3 and 4 were submitted to incorporate the patient access scheme and further revisions to address further concerns raised by the Committee. Sections 3.12 to 3.26 below discuss model 1. Models 2, 3 and 4 are discussed in sections 3.41 to 3.48.
The model included 13 health states and a death state. The structure was developed to reflect 3 key features of MDS deletion 5q treatment:
transfusion dependence or independence
need for iron chelation after a certain number of red blood cell transfusions
AML progression. After starting treatment, people move to 3 possible health states relating to transfusion status: transfusion independent and transfusion dependent with or without chelation. Additional states were defined to reflect response to iron chelation, potential hepatic and diabetic complications, and increased risk of cardiac disease caused by red blood cell transfusion. In addition, people who were transfusion dependent or independent with or without complications could develop AML.
Clinical‑effectiveness data from the ITT population in the MDS‑004 study were used in the model. The company stated that this population more closely matched the NICE scope than the mITT population. It also stated that using the mITT population substantially reduced the amount of available data and that, in this population, no statistically significant differences were observed in key end points between trial arms in MDS‑004. The company assumed that people in the lenalidomide group remained on treatment (10 mg per day for 21 days of a 28‑day cycle) until their condition stopped responding to treatment, that is, they became transfusion dependent. Best supportive care was based on the placebo arm of the MDS‑004 study, which included blood transfusions for those who were transfusion‑dependent. The company stated that, in UK clinical practice, best supportive care may also include an erythropoiesis stimulating agent (ESA). Therefore, the company assumed that 28% of people in the best supportive care group received an ESA for 3 cycles based on the proportion of people in the UK in MDS‑004 who received an ESA before the trial started. In addition, it was assumed that granulocyte colony‑stimulating factor (G‑CSF) for 3 cycles would be used as part of best supportive care when the condition did not respond to an ESA.
In the model, treatment response was defined as becoming transfusion independent. The proportion of people who became transfusion independent for 56 consecutive days (based on International Working Group 2000 criteria) was 60.9% for the lenalidomide group and 7.5% for the best supportive care group. The response rates for people who received an ESA and a G‑CSF in the best supportive care group (21.7%) were taken from a separate study that reported response rates after combination therapy (Jadersten et al. 2005). However, the company stated that this was unlikely to be representative of ESA and G‑CSF use in the UK because combination therapy is started after the failure of ESA monotherapy. On the basis of a separate study by Balleari et al. (2006), the company assumed that response rates to monotherapy with either ESA or a G‑CSF would be half of those to combination therapy (10.8%).
The duration of response to treatment with lenalidomide and best supportive care in the model was based on patient‑level data taken from the MDS‑004 ITT population. Because of patient crossover in MDS‑004, the company used log‑rank tests to determine whether there was a significant difference in response duration according to whether a treatment was provided as first- or second‑line treatment in the study. The results showed that the order in which people received treatment in MDS‑004 did not have a significant impact on duration of response. Parametric response duration curves were fitted to data from the lenalidomide 10 mg treatment arm in MDS‑004 to estimate response duration in the lenalidomide group. The company stated that response duration curves could not be estimated for people in the placebo arm because of insufficient numbers of people whose condition responded to treatment (n=5). Therefore, the company used data from the lenalidomide 5 mg treatment arm in MDS‑004 to approximate duration of response to best supportive care. Based on goodness‑of‑fit tests using the Integrated Brier Score and Akaike Information Criterion, the log‑normal distribution was fitted to both response duration curves.
The company assumed that people in the transfusion‑dependent states in the model received red blood cell and platelet transfusions. On the basis of data from MDS‑004, it was assumed that people needed an average of 1.89 red blood cell transfusions to provide 4.57 red blood cell units and an average of 0.02 platelet transfusions to provide 0.06 platelet units per 28‑day cycle. The company also assumed that people who were transfusion dependent had an increased risk of cardiac disease, based on the findings of a study by Malcovati et al. (2011). A Gompertz curve was fitted to data from this study to estimate the probability of being transfusion dependent and progressing to cardiac disease.
The company assumed that people who were transfusion dependent started iron chelation therapy to avoid complications associated with iron overload. It was assumed that people started iron chelation therapy when they reached a threshold of 25 red blood cell units. The company also assumed that people had already received 9.15 red blood cell units per 8 weeks based on the average number of units that people had received before entering the MDS‑004 study. A response rate for iron chelation of 66% was taken from a study by Kontoghiorges et al. (2000) and was assumed to occur in the first cycle of treatment. People who needed iron chelation moved to either the chelation or chelation failure state. The company assumed that people whose disease responded to treatment continued to receive iron chelation until progression to AML or death. People in the model whose disease did not respond to iron chelation therapy were assumed to be at risk of iron overload complications, including diabetes mellitus and hepatic complications. The probabilities of developing diabetes mellitus (0.21%) and hepatic complications (0.66%) per 28–day cycle on iron chelation were taken from a study by Jaeger et al. (2008).
The company stated that survival with MDS is strongly related to transfusion dependence. Data from the MDS‑004 study were used to estimate separate mortality curves for people who were transfusion dependent or independent at 8 weeks. Based on goodness‑of‑fit, the Weibull distribution was fitted to data from MDS‑004. The company stated that crossover of people in the MDS‑004 study at week 16 precluded any long‑term assessment of the impact of lenalidomide on survival and, as a result, using only MDS‑004 study data was likely to result in an underestimate of overall survival. Therefore, the median survival for best supportive care in the model was adjusted to match the combined median survival data reported from a phase II trial, MDS‑003, and the phase III MDS‑004 study, resulting in a figure of 3.8 years.
The time to progression to AML in the model was taken from an individual patient‑level analysis from the MDS‑004 study and was estimated separately for transfusion dependence and independence. On the basis of goodness‑of‑fit, the Weibull distribution was chosen to estimate time to AML progression curves. AML‑related mortality could not be estimated from the MDS‑004 study because the number of people who died from AML was too low. Therefore, the company used data from a study by Wahlin et al. (2001) of older people with AML, including 113 people with MDS caused by deletion 5q. Although the log‑normal function provided the best fit to the data from this study, it also resulted in a 'long tail' whereby some people remained alive for an unrealistically long time. A Weibull distribution was therefore chosen to estimate the survival time for people who developed AML in the model because it did not result in such a 'long tail'.
The company included grade 3 or 4 neutropenia and thrombocytopenia episodes in the model, because of differences in these adverse events between the placebo and lenalidomide treatment arms in MDS‑004. The company stated that it was unlikely that all neutropenia and thrombocytopenia events could be attributed to lenalidomide treatment because MDS is characterised by these peripheral cytopenias. Therefore, the number of people who had neutropenia and thrombocytopenia in the lenalidomide group was adjusted by subtracting those who had these events in the placebo group. The company assumed that any adverse events in the lenalidomide group occurred only in the first 4 cycles of the model. Based on data from MDS‑004, the company assumed that only a proportion of people who had neutropenia (27.7%) and thrombocytopenia (6%) needed additional treatment. The company did not include other adverse events such as deep vein thrombosis or pulmonary embolism in the model because of the low incidence of these events in MDS‑004.
The model accounted for 2 periods of treatment interruption during which people in the lenalidomide group did not receive treatment. Based on data from the MDS‑004 ITT population, it was assumed that 68.7% of people in the lenalidomide group had a first dose interruption and 73.8% had a second dose interruption. The mean time to first treatment interruption was 54.2 days and the length of treatment interruption was 17.5 days. After the first dose interruption, people in the lenalidomide group resumed treatment at a lower dose of 5 mg for 28 days per cycle. The mean time to second treatment interruption (from the start of the first interruption) was 72.1 days and the length of interruption was 13.9 days. After the second dose interruption, people in the lenalidomide group resumed treatment at a lower dose of 5 mg for 14 days per cycle. The cost of lenalidomide treatment was adjusted to take these treatment interruptions into consideration but the company stated that there was no need for clinical outcomes to be adjusted in a similar way, because the efficacy data for the ITT population used in the model already accounted for these interruptions. The company presented further analyses on treatment interruptions, which is discussed in sections 3.46 and 3.49.
The MDS‑004 trial assessed health‑related quality of life using the EQ‑5D at baseline, and the FACT‑An questionnaire at baseline and at weeks 12, 24, 36 and 48. The company conducted preliminary analyses to explore any relationship between EQ‑5D utility values and the FACT‑An. However, regression models to map FACT‑An scores from MDS‑004 to EQ‑5D utility values resulted in an unacceptable level of error. Therefore, the company performed a systematic literature search to identify relevant health‑related quality of life data for people with MDS. Four potentially relevant studies were identified (Buckstein et al. 2009 and 2011, Goss et al. 2006 and Szende et al. 2009). The company chose to use Szende et al. (2009). In this study, utility data were collected from 47 people with MDS, of mean age 67 years (including 21 from the UK), using visual analogue scale and time trade‑off methods. People were interviewed to elicit utility values for transfusion independence and transfusion dependence. The resulting mean utility values for the UK sample using the time trade‑off method were 0.85 for transfusion independence and 0.65 for transfusion dependence. The study did not estimate utility values for the AML state, so the company assumed that people in the AML state had the same utility value as for transfusion dependence (0.65). Utility values in the model were adjusted by an age‑dependent factor taken from Kind et al. (1999). The studies by Buckstein et al. reported EQ‑5D utility values for 69 Canadian people (mean age 73 years) with MDS, resulting in utility values of 0.80 for transfusion independence and 0.63 for transfusion dependence. The study by Goss et al. (2006) reported utility values estimated using the time trade‑off technique in 8 people with low- and intermediate‑1 risk MDS from the USA, resulting in utility values of 0.91 for transfusion independence and 0.50 for transfusion dependence. The utility values from both of these studies were used in additional scenario analyses conducted by the company.
Utility decrements associated with iron chelation therapy (21% for intravenous iron chelation and 0% for oral chelation) were obtained from a study by McLeod (2009). Utility decrements for adverse events, including cardiac disease (17.9%), diabetes (12.3%) and hepatic complications (8.0%) were obtained from studies by Fryback (1993) and Wong (1995). The model did not incorporate utility decrements for people who had neutropenia and thrombocytopenia episodes. The company's justification was that these adverse events were likely to only have a short‑term effect on quality of life.
The company's model (model 1) included drug acquisition, monitoring costs and costs of adverse events. The acquisition costs of lenalidomide were based on the dosing observed in the MDS‑004 trial, which included dose interruption because of adverse events. The costs of ESA (£885 per cycle) and G‑CSF (£633 per cycle) were also included for 28% of people in the best supportive care group. Drug acquisition prices were obtained from the BNF edition 64. In addition, monitoring costs (including GP visits and blood tests) and transfusion costs (including administration and acquisition of red blood cell and platelet units) were included. The costs of treating AML (£1919.40 per cycle) were taken from Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia (NICE technology appraisal guidance 218). The costs of thrombocytopenia and neutropenia episodes of £1636.38 were taken from NHS reference costs 2011/12. The model also included the annual costs of iron chelation and transfusion‑dependent complications, which were taken from the literature. To estimate the costs of iron chelation therapy, the company assumed that people had either intravenous desferrioxamine (29%) or oral deferasirox (71%) based on prescription cost analysis data for England (2010), resulting in a total cost of £1383.39 per cycle. The frequency of monitoring associated with lenalidomide treatment was taken directly from the summary of product characteristics: GP visits (and blood counts) occurred weekly for the first 8 weeks, bi‑weekly for the next 4 weeks and then 4‑weekly thereafter. For best supportive care, monitoring was assumed to occur once every 4 weeks throughout treatment.
The company's model (model 1) estimated 5.69 and 4.53 total undiscounted life years gained with lenalidomide and best supportive care, respectively. The company's base‑case deterministic cost‑effectiveness analysis resulted in an incremental cost‑effectiveness ratio (ICER) of £56,965 per quality‑adjusted life year (QALY) gained for lenalidomide compared with best supportive care (incremental costs £50,582 and incremental QALYs 0.89). The probabilistic cost‑effectiveness analysis estimated an ICER of £58,178 per QALY gained. Results of the probabilistic sensitivity analysis showed that at £30,000 per QALY gained, lenalidomide had a 0% probability of being cost effective.
The company undertook a series of deterministic sensitivity analyses. The cost‑effectiveness estimate of lenalidomide compared with best supportive care was most sensitive to the utility value for the transfusion‑independent state. The ICER was also sensitive to the utility value for the transfusion‑dependent state. The company also conducted further scenario analyses, which included altering the population used to estimate the model parameters, altering the proportion in the best supportive care group who received an ESA, altering the number of red blood cell units people received before iron chelation therapy was started, using alternative utility values from the studies by Goss and Buckstein and using alternative methods of extrapolating response duration, AML progression and overall survival. The ICERs were robust to nearly all of the scenarios explored. However, when the company applied alternative utility values for the transfusion‑independent (0.91), transfusion‑dependent (0.5) and AML (0.5) states taken from the study by Goss et al. (2006), the ICER reduced to £47,621 per QALY gained.
# Evidence Review Group comments
The ERG considered that the company had identified all the available evidence on the clinical effectiveness of lenalidomide for treating myelodysplastic syndromes associated with the deletion 5q cytogenetic abnormality. The ERG noted that a significant proportion of the lenalidomide 5 mg and 10 mg groups had an adverse event resulting in dose interruption or reduction. It also noted that dose reductions made it difficult to distinguish between the 5 mg and 10 mg lenalidomide treatment groups. It noted that because of crossover, only 1 person in the placebo group completed the 52‑week double-blind phase. The ERG suggested that one of the main concerns for people receiving lenalidomide is the incidence of increased clonal evolution and progression to AML. The ERG was concerned that because people could switch from placebo to active drug treatment in MDS‑004, the chances of detecting prolonged survival or acceleration of leukaemia progression were limited. Overall, the ERG considered that assessment of the long‑term effectiveness of lenalidomide was compromised because people in the MDS‑004 study were allowed to switch treatment after 16 weeks.
The ERG noted that data were reported separately for 2 populations in the MDS‑004 study: the ITT and mITT population, although not all results were reported for both populations. The ERG also noted that confirmation of deletion 5q status (by karyotype analysis) and bone marrow morphology were performed by central haematological review after randomisation, resulting in people whose disease did not meet the study inclusion criteria being included in the ITT population. The ERG noted that it was not clear how differences between these 2 populations could influence the results.
The ERG stated that the company's economic model (model 1) was generally well presented and reported. However, the ERG noted that the model described in the company's submission did not fully correspond with the model structure in the electronic model provided. It also noted that the company did not consider progression to intermediate‑2 or high‑risk MDS in the model because these data were not collected in MDS‑004. The ERG considered that it would have been more reasonable for a lifetime model to incorporate all future costs and effects, including the possibility of disease progression and reduced transfusion burden. The ERG disagreed with the company's decision not to apply a half‑cycle correction in the model because of the short cycle length of 28 days. The ERG considered that short cycles would involve small changes between 2 consecutive cycles, because cycle length depends on the changes observed in patient distribution from 1 cycle to another. The ERG noted that the cycles at the start of the model showed a significant redistribution between the various health states, suggesting that a cycle of 28 days was rather long during this phase of the model.
The ERG noted that in the company's economic model, best supportive care was defined as blood transfusions for transfusion dependence. No changes to best supportive care (in terms of transfusion frequency or iron chelation therapy) were assumed when cardiac conditions, diabetes, or hepatic conditions occurred. The ERG considered that it was unclear whether best supportive care as represented in the model was similar enough to clinical practice in England.
The ERG considered the response rates used in the company's model, which were based on the MDS‑004 ITT population. The ERG noted that the company's description of the model stated that response to treatment was assumed to occur within the first cycle, so that all patients spent the first cycle in the transfusion‑dependent state. However, the ERG noted that the model started with the results of the treatment initiation and that people moved immediately from the first cycle onwards to the transfusion‑independent state. The ERG considered that this assumption may have been optimistic because the overall response rate also included people whose condition did not respond immediately to treatment. In response to clarification, the company provided data on the proportion of people responding to treatment according to 28‑day cycles in the MDS‑004 study, which showed that the lenalidomide 10 mg arm had a response rate of 60.9% after 112 days and the placebo arm had a response rate of 7.5% after 182 days. The ERG considered that it would have been more appropriate to use these data rather than assuming that all of those whose condition responded to treatment were transfusion independent from cycle 1 onwards.
The ERG noted that neither the proportion of people receiving ESA as part of best supportive care nor the response rate to ESA could be obtained from the MDS‑004 trial, which introduced additional uncertainty in the model. It noted that, according to expert opinion given to the ERG, there was some uncertainty about the effect of providing ESA to people with MDS with deletion 5q. The ERG also noted that the initial response rates to best supportive care in the model were weighted twice by the proportion of people (28%) who received ESA and G‑CSF therapy. In response to clarification, the company confirmed that these were programming errors. The ERG considered that, in the absence of other available data, it was appropriate for the company to assume that response duration for the best supportive care group could be estimated from the lenalidomide 5 mg treatment arm in MDS‑004. However, it also considered that the company's rationale for using response duration estimates from the lenalidomide 5 mg arm rather than the 10 mg arm seemed arbitrary.
The ERG noted that the cost effectiveness of lenalidomide was sensitive to the proportion of people in the lenalidomide treatment group who had a second dose interruption in the model. The ERG noted that these values were directly obtained from the MDS‑004 trial, but that only cost estimates were assumed to be affected by treatment interruptions in the model, and the clinical effectiveness of lenalidomide was unaffected. The ERG suggested that, in clinical practice, treatment interruptions would affect the response rates to lenalidomide treatment. The ERG also noted that the programming of dose interruptions in the electronic model contained errors.
The ERG noted that all people in the model would be monitored by a GP. In response to clarification, the company stated that the cost of haematology visits were included in the costs of transfusion dependence and associated adverse events and that, as a result, haematology visits were not included as part of monitoring in the model. However, the ERG considered that because most people in the model were not treated for adverse events, it would be more reasonable for them to be monitored by a haematologist rather than a GP. The ERG therefore conducted an exploratory scenario analysis assuming that all monitoring would take place at a haematologist visit.
The ERG noted that the utility values (that is, the measure of health) were taken from a study by Szende et al. (2009). This provided evidence that transfusion independence is associated with significantly better quality of life scores (p < 0.001) compared to fewer transfusions and transfusion dependence. The ERG highlighted some concerns with the values applied in the model.
The Szende study did not conform to the NICE reference case because it was obtained from a sample of people in the UK with MDS rather than a sample of the general UK population without the condition.
The ERG noted that the model included transfusion dependent and transfusion independent health states. It commented that in clinical practice, people may lie between these states, that is, they are neither completely dependent on transfusion nor completely independent, they need some transfusions. The ERG noted than the transfusion dependent health state included all those that were not transfusion independent, that is, it included those who were completely dependent on transfusion and those who weren't completely dependent, but were not independent either. The ERG commented that the value of 0.65 was elicited for people who were completely transfusion dependent (requiring a lot of transfusions) and therefore may under estimate the utility value of the transfusion dependent health state, as it also included people who only need a few transfusions.
The ERG highlighted that the health state description for transfusion dependence in the Szende et al. (2009) study was very broad, in that it covered a range of health problems and the level of transfusion dependence was not the only difference between the health states being compared for the elicitation. This meant that the transfusion‑dependent state may have already incorporated some of the adverse events associated with transfusion and chelation therapy, or complications such as cardiac disease, diabetes or hepatic complications. The ERG considered it likely that some double counting was included in the model by also using utility decrements, such as for chelation therapy and complications (see section 3.23).
The ERG considered that the utility value of 0.65 from the Szende et al. (2009) study for people in the transfusion‑dependent state may underestimate utility for the reasons described above. The ERG commented that this would favour lenalidomide because people in the best supportive care group spent a much longer time in this health state compared with the lenalidomide group, thus increasing the QALY difference between lenalidomide and best supportive care in the model.
The ERG questioned whether it was appropriate to use the same utility values for the AML state as the transfusion‑dependent state because this implied that being partly or completely transfusion dependent had the same impact on quality of life as having AML. However, the ERG noted that because there was no difference between the 2 treatment groups in the time spent in the AML state in the model, the impact of the utility value for the AML state was negligible.
The ERG noted that the company did not apply utility decrements for neutropenia and thrombocytopenia events associated with lenalidomide treatment. The ERG accepted that the impact of these events on health‑related quality of life was likely to be small.
The ERG identified several issues in relation to the resource use and cost estimates used in the company's model. The ERG noted that people receiving iron chelation therapy in the model either had intravenous desferrioxamine or oral deferasirox treatment based on prescription cost analysis data in England from 2010. The ERG considered that deferiprone, which is a third possible iron chelation therapy listed in the prescription cost analysis, should also have been included. When the ERG included deferiprone and adjusted the proportion of people who were treated with the 3 iron chelation therapies based on 2011 prescription cost analysis data, this reduced the total cost of iron chelation therapy from £1383 to £1332 per 28‑day cycle. The ERG noted that the company's estimated cost of AML treatment of £1919.40 was based on a 5‑week cycle rather than a 4‑week cycle used in the model. The ERG also identified alternative cost estimates for episodes of neutropenia (£1045) and thrombocytopenia (£1768) from the NHS reference costs (2011/12). The ERG considered that the company's assumption of standard errors of 10% of the mean cost estimates for complications and adverse events used in the probabilistic sensitivity analysis were too small and that standard errors of 20% of the mean estimate would be more reasonable. Similarly, the ERG noted that the company's probabilistic sensitivity analysis did not account for uncertainty around the number of monitoring visits in both treatment groups.
The ERG ran the company's model incorporating the following adjustments:
Programming errors confirmed by the company were removed.
Programming errors for dose interruptions and days on active treatment in the model were removed.
A half‑cycle correction was included.
Costs of iron chelation therapy were updated to £1332 per cycle to include deferiprone.
Treatment costs of AML were amended to £1451 per 28 day cycle.
Response was distributed over time according to the trial instead of all patients from cycle 1 onwards.
Costs of neutropenia and thrombocytopenia were amended to £1045 and £1768 respectively.
Updated the costs of monitoring, complications and adverse events.
When the ERG included all of these changes in the company's model (model 1) the deterministic ICER without the patient access scheme increased from £56,965 to £62,674 per QALY gained for lenalidomide compared with best supportive care (incremental costs £50,898 and incremental QALYs 0.81). The probabilistic ICER was £65,052 per QALY gained.
The ERG reproduced the company's sensitivity and scenario analyses in the amended model (model 1). The sensitivity analyses found that the cost effectiveness of lenalidomide compared with best supportive care was most sensitive to the utility values for the transfusion‑independent state and the response rate for the lenalidomide treatment group. When the ERG re‑ran the company's scenario analyses, the only scenario that had a substantive impact in the ICER was using utility values from Goss et al. (2006), which reduced the ICER to £51,956 per QALY gained (see section 3.26).
The ERG undertook additional scenario analyses. The scenarios that had the most substantial effect on the ICER were the utility value for transition dependence and the proportion of people who received intravenous iron chelation therapy. When the utility value for transfusion dependence was increased from 0.65 to 0.77 (the value for reduced transfusion burden taken from Szende et al. ), the ICER for lenalidomide compared with best supportive care increased to £68,357 per QALY gained compared with the company's base‑case ICER of £56,965 per QALY gained. When the proportion who received intravenous iron chelation therapy was increased from 5.7% to 100%, the ICER reduced to £56,750 per QALY gained. Assuming that people in the transfusion‑dependent state would start iron chelation therapy after 4 cycles increased the ICER to £67,428 per QALY gained. Assuming that all monitoring would take place at a haematologist visit increased the ICER to £64,079 per QALY gained.
# Company's response to the appraisal consultation document
The company submitted the results of a systematic literature review to show transfusion dependence was a prognostic factor for overall survival and rate of progression to AML. Of the 17 studies (mainly retrospective case series or register populations) meeting the inclusion criteria, 16 studies reported statistically significant associations between transfusion status and overall survival. This association was explained by:
transfusion dependence and anaemia leading to increased death from causes other than leukaemia (particularly cardiac death)
transfusion dependence and anaemia leading to increased risk of AML and death caused by leukaemia
transfusion independence after dependency at baseline improving overall survival because of reduced complications from chronic anaemia. The company also cited literature that examined the relationship between AML and both transfusion status and erythroid response, arguing that lenalidomide triggers programmed cell death in the deletion (5q) clone, and that the MDS‑004 trial showed significant reductions in progression to AML for people whose condition responded to lenalidomide.
In response to the appraisal consultation document, the company revised the economic model according to the adjustments described in section 3.37, which increased the base‑case ICER from £56,965 to £62,674 per QALY gained (model 2). It also accepted that monitoring would be undertaken by a haematologist rather than a GP, increasing the ICER (model 2) to £65,153 per QALY gained. A model scenario was explored in which the progression to AML was the same for the lenalidomide and best supportive care arms which increased the ICER (model 2) to £68,125 per QALY gained. The company also provided further information to explain a labelling error in its model about iron chelation. It outlined that the underlying model was accurate for the assumption of when iron chelation started, despite this labelling error, and that no adjustments in the base‑case ICER were needed. Finally, the company submitted its methods for attempting to map FACT‑An scores to EQ-5D and the way it accounted for crossover in the trial arms.
The ERG considered the additional information submitted by the company, and the updated model (model 2). It agreed that this information, combined with the results of the MDS‑004 trial, suggested that it was reasonable to assume a 2‑step relationship: first between lenalidomide response and transfusion independence, and then between transfusion independence and overall survival. However, there was uncertainty in the strength of the relationship between transfusion independence and overall survival beyond 5 years. For AML progression, the ERG outlined differing evidence from the MDS‑004 trial. While Kaplan–Meier survival curves showed significant differences in progression to AML in favour of those whose disease responded to lenalidomide, a univariate Cox‑regression of time to AML showed that response status was not a significant variable in the association between lenalidomide and reduced rate of progression to AML.
# Company's patient access scheme and further revisions to the company's model
The company has agreed a patient access scheme for lenalidomide with the Department of Health. The company requested permission to submit the patient access scheme as part of the technology appraisal, which was agreed by NICE as an exceptional circumstance. It is a standard scheme, with the NHS paying for up to 26 cycles of treatment with lenalidomide. The company will then provide free‑of‑charge lenalidomide for people needing treatment beyond 26 cycles, which could take the form of a rebate, vouchers or free stock of the drug. The company provided updated analyses (model 3) that:
incorporated the patient access scheme – the company assumed that 31.9% would have 26 cycles of treatment and would therefore be eligible for the rebate of free subsequent treatment to the NHS as outlined in the patient access scheme, based on the MDS‑004 trial
included the adjustments stated in section 3.37, including a half‑cycle correction
amended the rate of progression to AML in the lenalidomide arm to be the same as in the best supportive care arm
assumed routine monitoring by a haematologist rather than a GP.
The company presented revised analyses (model 3) with and without the patient access scheme. The resulting deterministic ICERs for lenalidomide compared with best supportive care were £68,125 per QALY gained (without the patient access scheme;) and £24,544 per QALY gained (with the patient access scheme). The mean probabilistic ICER including the patient access scheme was £25,468 per QALY gained. Sensitivity analyses showed that the ICER was most sensitive to median survival from the MDS‑003 and MDS‑004 trials, with a maximum deterministic ICER of £33,309 per QALY gained. The company presented scenario analyses, including varying utilities, where the ICERs ranged from £19,135 to £25,861 per QALY gained when alternative utility sources were used (Goss and Buckstein, respectively), and varying the selection of survival curves where ICERs ranged from £24,776 to £30,022 per QALY gained.
# Committee request for additional cost‑effectiveness analysis
The Committee were unable to make a decision based on the evidence submitted with the patient access scheme because of uncertainty in the proportion who would receive lenalidomide after 26 cycles, how long they would receive it for, and the impact of dose interruptions. The Committee therefore requested further cost‑effectiveness analysis with the patient access scheme to address these uncertainties and better understand how it would apply to clinical practice. The Committee noted that dose interruptions had not appropriately been taken into account when the patient access scheme was incorporated into the model, and that interruptions would delay when the patient access scheme would take effect for people who have dose‑interruptions. Cycles may be missed to manage toxicity, which would delay when a patient reached 26 cycles, the point at which the patient access scheme allowed free lenalidomide. The company therefore updated the base case to account for 16 days of treatment interruptions and explored the impact of longer dose interruptions (model 4). The updated base‑case ICER was £25,310 per QALY gained for lenalidomide compared with best supportive care. Probabilistic sensitivity analyses estimated a mean ICER of £25,708 per QALY gained. The probability of being cost effective was 25.4% and 64.5% at £20,000 and £30,000 per QALY gained respectively. Increasing the length of interruptions reduced the ICER; accounting for 42 days of treatment interruptions reduced the ICER to £22,209 per QALY gained for lenalidomide compared with best supportive care.
At the request of the Committee, the company presented evidence to support the proportion of people who would be expected to be eligible for the patient access scheme (31.9%):
Published data (Fenaux et al. 2011) from an interim analysis showed that, of those in the 10 mg lenalidomide arm of MDS‑004, 38% were still on treatment after 26 cycles. The company applied a correction factor to this value to reduce survival on both arms to the levels seen in real‑life practice, subsequently estimating that 31.9% would remain on treatment after 26 cycles in clinical practice.
Real‑world UK data from Celgene's in‑house database suggested that 28% of people reached 26 cycles of treatment with lenalidomide.
Published registry data indicated that response duration ranged from 27.6 to 36 months.The company presented a threshold analysis that showed if the proportion eligible for the patient access scheme was less than 27%, the ICER (model 4) would be greater than £30,000 per QALY gained.
The patient access scheme presented by the company would not take effect until after a minimum of 2 years, or longer with dose interruptions. At the request of the Committee, the company presented further cost‑effectiveness analyses, including scenarios for various time horizons to understand how the cost effectiveness would change over time as the patient access scheme was implemented. Applying time horizons of 2, 3, 5 and 10 years in model 4 gave ICERs of £119,876, £63,780, £30,923 and £23,420 per QALY gained respectively for lenalidomide compared with best supportive care.
The ERG validated the changes to the company's model, confirming that the patient access scheme was incorporated appropriately. It agreed with the company that the real‑world evidence suggested that about 30% of people reach 26 cycles of treatment, and the ERG stated that this was a reasonable assumption. It commented that the company's estimate of 16 days of treatment interruptions may be an underestimate and it could be closer to 19 days. The ERG showed that this had a negligible impact on the ICER with the company's base case increasing from £25,310 per QALY gained to £25,455 per QALY gained. It stated that the first 5 years of the model were more certain than the later years because they were based on available data. The ERG noted that most of the QALY gains in the model were in these first 5 years (64%), and that 90% of the QALY gains occur within 10 years.
Full details of all the evidence are available.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of lenalidomide, having considered evidence on the nature of low‑ or intermediate‑1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate, and the value placed on the benefits of lenalidomide by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the treatment pathway in the UK for people with MDS associated with an isolated deletion 5q cytogenetic abnormality, taking into account the marketing authorisation for lenalidomide (for treating transfusion‑dependent anaemia caused by low‑ or intermediate‑1 risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate). It heard from the clinical specialist that the main treatment option currently available for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality is best supportive care, which involves regular red blood cell transfusions, and that low‑dose standard chemotherapy or immunosuppressive therapies are used for some people. The clinical specialist also stated that some people would also receive an erythropoiesis stimulating agent (ESA) as part of best supportive care and that iron chelation therapy is used to avoid longer‑term complications associated with transfusion. Therefore, the Committee agreed that as defined in the scope, best supportive care was the appropriate comparator
The Committee heard from the clinical specialist that lenalidomide is an effective targeted therapy which reduces the need for blood transfusions. The patient experts agreed that this was a major benefit, with reduced fatigue significantly improving quality of life. They highlighted that having regular blood transfusions and blood tests at hospital is both inconvenient, because it needs regular time off work and usual activities, and demoralising because the person is constantly reminded of their condition. The patient experts suggested that lenalidomide, by contrast, is a convenient, effective oral drug that reduces the need for blood transfusions. The Committee recognised the need for treatments that would reduce blood transfusion dependence for people with MDS associated with an isolated deletion 5q cytogenetic abnormality.
# Clinical effectiveness
The Committee discussed the clinical effectiveness of lenalidomide in people with low‑ or intermediate‑1 risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It noted that the evidence presented by the company was taken primarily from the MDS‑004 study. This included a broader range of people than that specified in the marketing authorisation and NICE scope for lenalidomide, because the marketing authorisation stated 'when other therapeutic options are insufficient or inadequate', which was not an inclusion criteria for the study, and therefore those on the trial may have a better prognosis than the population specified by the marketing authorisation. In addition, the study included people with low‑ or intermediate‑1 risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, whilst the marketing authorisation specified an isolated deletion 5q cytogenetic abnormality. The Committee heard from the company during consultation that the additional cytogenetic abnormalities included in the trial population may mean the trial population had a poorer prognosis than that of the population covered by the marketing authorisation. The Committee agreed that, on balance, the study was generalisable to the marketing authorisation population, and how lenalidomide would be used in clinical practice. It concluded that it would be able to consider all of the evidence in the MDS‑004 study when making recommendations on lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality.
The Committee considered the results of the MDS‑004 study. It noted that the rates of transfusion independence (at 26 weeks, lenalidomide 10 mg: 56.1%, placebo: 5.9%; p<0.001, see section 3.5) and improvements in the Functional Assessment of Cancer Therapy‑Anaemia (FACT‑An) questionnaire (mean change, lenalidomide 10 mg: 5.8, placebo: -2.5; p<0.05. See section 3.9) were significantly better in people treated with lenalidomide compared with placebo. The Committee concluded that lenalidomide is a clinically effective treatment for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
The Committee discussed overall survival from MDS‑004, noting that overall survival with placebo and lenalidomide was greater than 35 months and that there was no statistically significant difference between lenalidomide and placebo (lenalidomide 10 mg: 36.9 months, placebo: 35.9 months). It was aware that people in the placebo arm could cross over to lenalidomide treatment after 16 weeks (see section 3.2), and therefore the overall survival benefit of lenalidomide compared with placebo may be under estimated. The Committee noted that the company had presented separate mortality curves for people who were transfusion dependent or independent at 8 weeks in MDS‑004 which suggested that survival was strongly related to transfusion status in people with low or intermediate‑1 risk MDS associated with a deletion 5q cytogenetic abnormality. The Committee noted that the company's comments in response to consultation included an updated analysis of these data at 7 years, which continued to support a link between transfusion independence and overall survival. The Committee also considered the following:
ERG comments that it was reasonable to assume a two‑step relationship between lenalidomide response and transfusion independence, and then between transfusion independence and overall survival (see section 3.43).
A consultation comment from a professional group that data suggested people with low risk MDS and anaemia, whose condition responds to therapies that increase haemoglobin concentration, have improved survival compared with those who did not receive treatment.
The ERG clinical expert had advised that there were uncertainties in the strength of the relationship between transfusion dependence and overall survival.
A clinical specialist stated that it was unclear if an increase in transfusion independence would improve overall survival in clinical practice, in the population specified by the marketing authorisation. Overall the Committee concluded that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence.
The Committee discussed progression to acute myeloid leukaemia (AML). It understood from the company's systematic review that published data showed higher transfusion independence rates were associated with reduced risk of progression to AML (see section 3.41). The Committee noted that the company had stated transfusion status was a statistically significant predictor for AML progression in MDS‑004, but that the ERG had presented contradictory evidence (see section 3.43). The Committee was aware of the lenalidomide safety briefing sent from the company to healthcare professionals that outlined a 13.8% 2‑year risk of AML progression with lenalidomide treatment for MDS associated with a deletion 5q cytogenetic abnormality, and that lenalidomide's summary of product characteristics stated lenalidomide was associated with an increase in AML progression and second primary malignancies in people with multiple myeloma. However, it heard from the clinical specialist that longer-term data suggest that lenalidomide treatment does not increase the rate of AML progression in people who have low or intermediate‑1 risk MDS with deletion 5q cytogenetic abnormality. The Committee concluded that there was considerable uncertainty over whether lenalidomide was associated with changes in the rates of AML progression for people with low or intermediate‑1 risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
The Committee considered adverse reactions associated with lenalidomide treatment from the MDS‑004 study. It noted that the most frequently reported adverse reactions associated with lenalidomide treatment were neutropenia and thrombocytopenia. The Committee was also aware that lenalidomide may be associated with higher rates of venous thromboembolism than placebo. However, it heard from the clinical specialist that the risk of thromboembolic events was manageable for people with low- and intermediate‑1 risk MDS. It heard from the clinical specialist and patient experts that adverse reactions associated with lenalidomide treatment are managed with dose interruptions and are generally well tolerated. The Committee concluded that, although lenalidomide is associated with some adverse reactions, these can be managed by dose interruptions.
# Cost effectiveness
The Committee considered the company's original economic model, the company's revised economic model, the company's revised economic model with the patient access scheme, and the ERG's critique and exploratory analyses. It acknowledged that the company had amended the model in response to earlier concerns that were raised by the ERG and the Committee (sections 3.37 and 3.44). These amendments included the:
costs associated with iron chelation, AML and thrombocytopenia
incorporation of the patient access scheme
rate of AML progression which was assumed to be the same for lenalidomide and best supportive care
monitoring being conducted by a haematologist (rather than GP).The Committee concluded that the updated models were appropriate for decision‑making.
The Committee discussed further the overall survival estimates as presented in the company's models, and considered the following:
The company did not extrapolate survival estimates for the lenalidomide and best supportive care arms from the MDS‑004 study because people could cross over after 16 weeks.
The company had estimated survival based on transfusion dependency at 8 weeks in MDS‑004, stating that transfusion status was a predictor of overall survival in people with MDS (see section 4.5).The Committee agreed that increased transfusion independence could be associated with improved survival but recognised that its strength over the 20‑year time frame of the model was unclear (see section 4.6). The Committee concluded that, although the strength of the relationship was uncertain, it was reasonable for the model to include some benefit in overall survival for people whose condition responds to lenalidomide compared with best supportive care.
The Committee considered the utility values associated with transfusion status. The Committee noted that EQ‑5D utility values were collected at the start of the MDS‑004 study but not at subsequent follow‑up, and that the company stated it was not possible to reliably estimate utility values by mapping from the FACT‑An scores to the EQ‑5D because of differences between the EQ‑5D utility values collected in the MDS‑004 study and those predicted by mapping. The Committee noted that the company used values that were taken from a published study (Szende et al. 2009) that derived utility values according to transfusion dependence and independence directly from people with MDS. It considered the ERG's comments that using a utility value of 0.65 for people in the transfusion‑dependent state may favour lenalidomide because people in the best supportive care group spent a much longer time in this health state. This would increase the QALY difference between the treatment arms. It was aware that the utility values from Szende et al. were not in line with the NICE reference case for measuring and valuing health effects, which states that the value of changes in health‑related quality of life should be based on public preferences rather than people who have the condition. However, the Committee heard from the patient experts that the utility values used in the company's base‑case analyses were a reasonable reflection of the negative impact that transfusion dependence has on health‑related quality of life. It noted that sensitivity analyses which varied the utility values in model 4, including the patient access scheme, gave a range of ICERs between £19,700 and £26,700 per QALY gained (base case: £25,300 per QALY gained) for lenalidomide compared with best supportive care. The Committee concluded that the utility values were a reasonable reflection of the impact of transfusion status on health‑related quality of life in people with low or intermediate‑1 risk MDS associated with deletion 5q cytogenetic abnormality, and could therefore be used for decision‑making in this appraisal.
The Committee discussed the patient access scheme, noting that it was not a simple discount. The NHS pays for lenalidomide treatment for the first 26 cycles, after which it is provided free of charge, and therefore the whole population would not benefit from the reduction in price because only some people, those receiving it after 26 cycles, would be eligible. The Committee noted that the reduction in costs achieved through the patient access scheme would be based on the number of people remaining on treatment after 26 cycles, and how long they survived and continued treatment. The Committee was aware that the data supporting survival after 26 cycles were from small numbers in the MDS‑004 trial (less than 38 people), and were therefore very uncertain. The Committee discussed whether the assumption in the model that 31.9% of people would remain on treatment for more than 26 cycles was realistic, and whether the cost savings associated with the patient access scheme were likely to be realised in clinical practice. The Committee considered the company's evidence that supported the assumption of 31.9% of people reaching 26 cycles in practice (see section 3.47), and noted that this was supported by a clinical specialist. It was concerned, however, about discrepancies between this estimate and those implied by the published paper, but heard from the company that this was because the published paper included data from an earlier time point. The Committee agreed that, because the proportion of people surviving beyond 26 cycles in clinical practice was uncertain (see above and section 4.5), so were the potential cost savings from the patient access scheme, and therefore further validation of the proportion of people on treatment beyond 26 cycles was still required. The Committee recognised that the probabilistic sensitivity analysis presented by the company was unlikely to have captured the uncertainty of the patient access scheme in terms of the proportion who would survive beyond 26 cycles. It noted that the base case of model 4 (see sections 3.46 to 3.49) was associated with a 25% chance of lenalidomide being cost effective at £20,000 per quality‑adjusted life year (QALY) gained (and 65% at £30,000 per QALY gained). It also noted that, if the proportion of people who reached 26 cycles was less than 27%, the ICER would be greater than £30,000 per QALY gained. The Committee agreed that the ICER was uncertain but accepted that a commitment from the company to publish data on the proportion of people on treatment beyond 26 cycles would provide reassurance that the patient access scheme will provide value to the NHS.
The Committee noted that as the patient access scheme was based on the number of treatment cycles, any treatment interruptions would delay when the patient access scheme would take effect and therefore delay the time to the NHS receiving the rebate or discount. The Committee acknowledged that accounting for treatment interruptions reduced the ICER minimally (from £25,300 with 16 days of interruptions to £22,200 with 42 days; see section 3.46). The Committee was aware that accounting for treatment interruptions in the model reduced lenalidomide costs but did not affect treatment benefit. The Committee was aware that the nature of the patient access scheme meant that accounting for treatment interruptions introduces uncertainty about when people would reach 26 cycles of treatment, and therefore when the savings from the patient access scheme could be claimed by the NHS. It heard from the company that they actively monitor the number of cycles that people receive and that this should provide reassurance that the scheme would be realised in practice. The Committee concluded that although treatment interruptions introduce uncertainty on the timing of when the patient access scheme could be claimed, this did not have a substantial impact on the ICER.
The Committee considered the ICERs resulting from the company's economic analyses, as well as the results of the ERG's exploratory analyses. The Committee noted that the revised company's base‑case ICER, which included the patient access scheme and accounted for treatment interruptions (model 4; see sections 3.46 to 3.49), for lenalidomide compared with best supportive care was approximately £25,300 per QALY gained. The Committee agreed that the patient access scheme increased all of the uncertainties, and there was a risk that savings from the patient access scheme would not be realised in clinical practice. The Committee acknowledged that the data collection committed to by the company will ensure that the uncertainties of the assumptions used to model the patient access scheme can be addressed when the guidance is reviewed. However, it would not be able to address the loss in health benefits for other patients in the NHS that may result in the interim from lenalidomide not being a cost effective use of NHS resources. It understood that the company is keen to work with the Department of Health should such a situation arise, to ensure that the NHS realises the full financial benefits of the patient access scheme. The Committee concluded that lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality was a cost‑effective use of NHS resources, when taking these assurances into account.
The Committee discussed how innovative lenalidomide is in its potential to make a significant and substantial impact on health‑related benefits. It heard about the notable benefits of lenalidomide from patient and professional groups during consultation. It agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions meant that lenalidomide offered a substantial step change in treatment.
The Committee examined whether there were any potential issues affecting groups protected by equality legislation. The Committee noted the comments from consultees about the Jehovah's Witness group, who are unable to receive blood transfusion for religious reasons. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of people, or about the effectiveness of lenalidomide in this population. Therefore the Committee agreed that it did not need to amend any of its recommendations for the group of people unable to receive blood transfusions.
# Summary of Appraisal Committee's key conclusions
TA322
Appraisal title: Lenalidomide for treating myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality
Section
Key conclusion
Lenalidomide is recommended as an option within its marketing authorisation, that is, for treating transfusion‑dependent anaemia caused by low or intermediate‑1‑risk myelodysplastic syndromes (MDS) associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
The Committee concluded that lenalidomide is a clinically effective treatment for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate, because it was associated with a statistically significant improvement in transfusion independence and health related quality of life compared with placebo. The Committee agreed that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence.
The Committee noted that the revised company's base‑case incremental cost‑effectiveness ratio (ICER) for lenalidomide compared with best supportive care with the patient access scheme was £25,300 per QALY gained. The Committee noted that the patient access scheme was not a simple discount and that would only benefit those on treatment after 26 cycles. The Committee agreed that because the proportion of people on treatment beyond 26 cycles was uncertain so were the potential cost savings from the patient access scheme, and noted that if the proportion of people who reached 26 cycles was less than 27%, the ICER would be greater than £30,000 per QALY gained.
The Committee agreed that the ICER was uncertain, because of the patient access scheme, but accepted that a commitment from the company to publish data on the proportion of people on treatment beyond 26 cycles would provide reassurance that lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality was recommended as a cost‑effective use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments
The main treatment option currently available for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate is best supportive care, which involves regular red blood cell transfusions.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?
The Committee heard that lenalidomide is an effective targeted therapy which reduces the need for blood transfusions, subsequently reducing fatigue significantly and improving quality of life. The patient experts suggested that lenalidomide is a convenient, effective oral drug. The Committee agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions meant that lenalidomide offered a substantial step change in treatment
What is the position of the treatment in the pathway of care for the condition?
Lenalidomide has a marketing authorisation 'for the treatment of transfusion‑dependent anaemia due to low- or intermediate‑1‑risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate'.
Adverse reactions
The Committee concluded that, although lenalidomide is associated with some adverse reactions, these can be managed by dose interruptions.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The company presented data from a randomised controlled trial, MDS‑004, which didn't include many people but was still robust enough, and on balance was generalisable to the decision problem.
Relevance to general clinical practice in the NHS
The Committee noted that the MDS‑004 study included a broader range of people than that specified in the marketing authorisation and the NICE scope because the marketing authorisation specified 'when other therapeutic options are insufficient or inadequate', which was not an inclusion criteria of the study. In addition, the study included people with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. The company explained that the additional cytogenetic abnormalities included in the trial population may mean the trial population had a poorer prognosis than that of the marketing authorisation. Despite these differences the Committee agreed that on balance the study was generalisable to the marketing authorisation population, and how lenalidomide would be used in clinical practice.
Uncertainties generated by the evidence
The main uncertainty in the clinical evidence was the relationship between lenalidomide response, transfusion independence and overall survival. Overall survival could not be estimated from the clinical trial as people on the placebo arm could receive lenalidomide after 16 weeks. Instead overall survival was estimated based upon transfusion independence. During consultation the company presented longer term data (from 7 years follow up rather than 5) that continued to support a relationship between transfusion independence and overall survival. The Committee agreed that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence, but that this was uncertain.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
None were identified.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that, on the basis of the evidence on transfusion independence and health‑related quality of life, lenalidomide is a clinically effective treatment for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
Evidence for cost effectiveness
Availability and nature of evidence
The company developed a de novo Markov model that compared lenalidomide 10 mg with best supportive care for low‑ to intermediate‑1 risk MDS with deletion 5q.
The Committee considered revised models from the company in response to a NICE request for additional analyses relating to the modelling of the patient access scheme. It acknowledged that the company had amended the model in response to concerns that were raised. The Committee considered the revised models appropriate for its decision‑making.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The realisation of the patient access scheme in clinical practice was uncertain. The patient access scheme was not a simple discount, instead, after 26 cycles, lenalidomide would be provided free of charge to the NHS. The survival estimates in the model were uncertain and therefore so was the proportion of people who would remain on treatment after 26 cycles to become eligible for the patient access scheme, and therefore the cost savings to the NHS under this scheme were uncertain. The Committee agreed that the ICER was uncertain but accepted that a commitment from the company to publish data on the proportion of people on treatment beyond 26 cycles would provide reassurance that the patient access scheme will provide value to the NHS.
Incorporation of health‑related quality‑of‑life benefits and utility values
Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee concluded that the utility values were a reasonable reflection of the impact of transfusion status on health‑related quality of life in people with low or intermediate‑1 risk MDS associated with deletion 5q cytogenetic abnormality, and could therefore use these values for decision‑making in this appraisal.
The Committee agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions meant that lenalidomide offered a substantial step change in treatment.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable.
What are the key drivers of cost effectiveness?
The Committee noted that overall survival and the patient access scheme were key drivers of the ICER estimates in the company's model.
Most likely cost‑effectiveness estimate (given as an ICER)
The Committee noted that the revised company's base‑case ICER, which included the patient access scheme and accounted for treatment interruptions (model 4), for lenalidomide compared with best supportive care was approximately £25,300 per QALY gained.
The Committee agreed that the patient access scheme increased all of the uncertainties, and there was a risk that savings from the patient access scheme would not be realised in clinical practice, because of the uncertainty about survival estimates.
The Committee acknowledged that the data collection committed to by the company will ensure that the uncertainties of the assumptions used to model the patient access scheme can be addressed when the guidance is reviewed. However, it would not be able to address the loss in health benefits for other patients in the NHS that may result in the interim from lenalidomide not being a cost effective use of NHS resources. It understood that the company is keen to work with the Department of Health should such a situation arise, to ensure that the NHS realises the full financial benefits of the patient access scheme. The Committee concluded that lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality was a cost‑effective use of NHS resources, when taking these assurances into account
Additional factors taken into account
Patient access schemes (PPRS)
The Committee discussed the patient access scheme, noting that it was not a simple discount, The NHS pays for lenalidomide treatment for up to 26 cycles. The patient access scheme presented would not benefit the whole patient population because only some people would become eligible, those who continued to receive lenalidomide after 26 cycles. It noted that the reduction in costs achieved through the patient access scheme would be based on the number of people surviving after 26 cycles, and how long they survived and continued treatment, and that this was uncertain. The Committee highlighted that if the patient access scheme could be underwritten, for example, by the company offering a rebate in the event that the number of people remaining on treatment after 26 cycles was less than 31.9%, this could provide some reassurance and reduce some of the uncertainty associated with the scheme.
End‑of‑life considerations
Not applicable.
Equalities considerations and social value judgements
The Committee noted the comments from consultees about the Jehovah's Witness group who are unable to receive blood transfusion for religious reasons. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of people, or about the effectiveness of lenalidomide in this patient population. Therefore the Committee agreed that it did not need to amend any of its recommendations for the group of people unable to receive blood transfusions.
# Recommendations for further research
The Committee noted that the cost effectiveness of lenalidomide compared with standard care for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate, was sensitive to whether the patient access scheme would be realised in clinical practice. The Committee agreed that it would be critical to generate evidence to support the following:
The proportion of people who become eligible for the patient access scheme, that is, that they remain on treatment beyond 26 cycles.
The benefit of lenalidomide after 26 cycles, that is the associated overall survival and health related quality of life for those who remain on treatment beyond 26 cycles.
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{'Guidance': 'Lenalidomide is recommended as an option, within its marketing authorisation, that is for treating transfusion‑dependent anaemia caused by low or intermediate‑1 risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It is recommended only if the company provides it according to the commercial arrangement.', 'The technology ': "Lenalidomide (Revlimid, Celgene) is a structural analogue of thalidomide. It has anti‑neoplastic, anti‑angiogenic, pro‑erythropoeitic and immunomodulatory properties. Lenalidomide inhibits the proliferation of certain haematopoietic tumour cells, enhances T cell- and natural killer cell‑mediated immunity, increases fetal haemoglobin production by CD34+ haematopoietic stem cells and inhibits production of pro‑inflammatory cytokines. Lenalidomide has a marketing authorisation 'for the treatment of patients with transfusion‑dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate'.\n\nThe summary of product characteristics lists the following adverse reactions for lenalidomide: fatigue, neutropenia, constipation, diarrhoea, muscle cramp, anaemia, thrombocytopenia and rash. The summary of product characteristics recommends a starting dose of 10\xa0mg orally, once daily, on days 1\xa0to 21 of repeated 28\xa0day cycles, with dose reductions (5.0\xa0mg, 2.5\xa0mg or 2.5\xa0mg every other day) to manage adverse events. Dosage is continued or modified based on clinical and laboratory findings. Lenalidomide is structurally similar to thalidomide, which causes severe birth defects, so a risk minimisation plan has been developed and agreed with the Medicines and Healthcare products Regulatory Agency to avoid fetal exposure to lenalidomide. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nLenalidomide is available in 21‑day packs of 10\xa0mg and 5\xa0mg capsules at net prices of £3780\xa0and £3570\xa0respectively (excluding VAT; 'British national formulary' [BNF] edition\xa067). The cost of a 28‑day cycle of treatment with 10\xa0mg of lenalidomide (excluding VAT) is £3780. The pricing arrangement considered during guidance development was that the company (Celgene) had agreed a complex patient access scheme with the Department of Health, in which the NHS paid for lenalidomide treatment for up to 26\xa0monthly cycles. The company subsequently provided free of charge lenalidomide for those people who had more than 26\xa0monthly cycles. A commercial arrangement has now been agreed. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", "The company's submission": "The Appraisal Committee (section\xa07) considered evidence submitted by Celgene and a review of this evidence by the Evidence Review Group (ERG; section\xa08).\n\n# Clinical effectiveness\n\nThe company performed a systematic review of the evidence on the clinical effectiveness of lenalidomide for low- or intermediate‑1\xa0risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality that is red blood cell transfusion dependent. The review identified a single phase\xa0III, randomised, double‑blind study (MDS‑004), which compared lenalidomide 10\xa0mg (n=69) and lenalidomide 5\xa0mg (n=69) with placebo (n=67). Treatment was given every day of a 28‑day cycle, except in the lenalidomide 10\xa0mg arm, in which 10\xa0mg lenalidomide was given on days 1–21 only. MDS‑004\xa0was a multinational study that enrolled people from 37\xa0study sites including the UK, France, Germany, Italy, Spain, Belgium, Netherlands, Sweden and Israel. The study population comprised adults with MDS whose condition was transfusion dependent and who had International Prognostic Scoring System (IPSS) of low‑risk (49%) or intermediate‑1\xa0risk (51%) MDS with a deletion 5q cytogenetic abnormality. MDS‑004 was stratified according to IPSS karyotype score (0\xa0versus >0; that is, isolated deletion 5q cytogenetic abnormality versus isolated deletion 5q cytogenetic abnormality [76.3%] plus 1\xa0or more additional cytogenetic abnormalities [23.7%]). In the MDS‑004 study, 51.8% of the total patient population had had previous erythropoietin therapy (58.5% in the 10\xa0mg lenalidomide treatment arm).\n\nPeople in MDS‑004\xa0who had at least a minor erythroid response (that is, a 50% decrease in transfusion requirements) by week\xa016 could continue treatment (double‑blind) for up to 52\xa0weeks, or until erythroid relapse, disease progression or unacceptable toxicity. People receiving placebo or lenalidomide 5\xa0mg who didn't have a minor erythroid response by week\xa016 could cross over to the lenalidomide 5\xa0mg or 10\xa0mg treatment arms, respectively. Open‑label treatment was then continued for up to 156\xa0weeks. People with disease progression at any time and those randomly assigned to lenalidomide 10\xa0mg without minor erythroid response by week\xa016 were withdrawn from the study. The company stated that the lenalidomide dose was reduced if dose‑limiting toxicities occurred, and complete blood counts were obtained weekly after the development of dose‑limiting Grade 3 or 4 neutropenia or thrombocytopenia.\n\nThree study populations were defined in MDS‑004: the intention‑to‑treat (ITT) population, the safety population and the modified‑ITT (mITT) population. The ITT population included all randomised people (n=205). The safety population included all randomised people who received at least 1\xa0dose of study drug (n=205). The mITT population included people with low- or intermediate‑1 risk MDS with deletion 5q and documented red blood cell transfusion dependence, who received at least 1\xa0dose of study drug (n=139). Confirmation of deletion 5q status (karyotype analysis) and bone marrow morphology was performed by haematological review after randomisation. Therefore some people not fulfilling the inclusion criteria (that is, people without confirmed deletion 5q status) were included in the ITT population. For the mITT population, 76.3% had an isolated deletion 5q cytogenetic abnormality and 23.7% had deletion 5q plus one or more additional cytogenetic abnormalities. The baseline characteristics of the people in the treatment arms for the mITT population were similar.\n\nThe primary end point of the MDS‑004\xa0trial was transfusion independence lasting for at least 26\xa0consecutive weeks. Secondary end points included erythroid response at 16\xa0weeks, duration of red blood cell transfusion independence, cytogenetic response at weeks\xa012, 24 and every 24\xa0weeks thereafter, overall survival, progression to acute myeloid leukaemia (AML) and adverse events. Health‑related quality of life was assessed using the Functional Assessment of Cancer Therapy‑Anaemia (FACT‑An) questionnaire at weeks\xa012, 24, 36\xa0and 48.\n\nFor the double‑blind phase of MDS‑004, statistically significantly more people in the mITT population were transfusion independent for at least 26\xa0weeks with lenalidomide 10\xa0mg (56.1%) and 5\xa0mg (42.6%) than with placebo (5.9%; p<0.001\xa0compared with both lenalidomide groups). Using the International Working Group 2000\xa0and 2006\xa0criteria for erythroid response, transfusion independence rates for at least 8\xa0weeks in the mITT population were also statistically significantly higher for the lenalidomide 5\xa0mg and 10\xa0mg treatment groups compared with placebo. Similar results were obtained for the ITT population. Median duration of transfusion independence of at least 8\xa0weeks was not reached in the lenalidomide 5\xa0mg or 10\xa0mg treatment groups.\n\nIn the safety population, median time to progression to AML (from date of randomisation to progression to AML, death, or last known contact for people without AML, whichever was earliest) was 30.9\xa0months (range 2.1–56.5\xa0months) in the placebo group, 36.1\xa0months (range 0.4–57.7\xa0months) in the lenalidomide 10\xa0mg group and 31.8\xa0months (range 0.8–59.4\xa0months) in the lenalidomide 5\xa0mg group. Before crossover at 16\xa0weeks, 2\xa0people (3.0%) in the placebo group, 0\xa0in the lenalidomide 10\xa0mg group and 2\xa0(2.9%) in the lenalidomide 5\xa0mg group had progressed to AML. Overall, 52\xa0people (25.4%) progressed to AML during the double‑blind and open‑label phases. The cumulative risk of AML for the lenalidomide 5\xa0mg and 10\xa0mg groups combined was 16.8% (95% CI 9.8–23.7) at 2\xa0years and 25.1% (95% CI 17.1–33.1) at 3\xa0years. Of those who were randomly assigned to placebo and never received lenalidomide (n=11), including 3 people who completed 52\xa0weeks of the study protocol, 4 (36.4%) progressed to AML. Of the people who initially received placebo and then crossed over to lenalidomide 5\xa0mg, 30.4% (17 out of 56) progressed to AML, as did 23.2% (16 out of 69) people in the lenalidomide 5\xa0mg group and 21.7% (15 out of 69) people in the lenalidomide 10\xa0mg group.\n\nThe median duration of overall survival follow‑up in the safety population was 35.9\xa0months (range 2.1–56.5\xa0months) in the placebo group, 36.9\xa0months (range 0.4–57.7\xa0months) in the lenalidomide 10\xa0mg group and 35.5\xa0months (range 1.9–59.4\xa0months) in the lenalidomide 5\xa0mg group. Based on Kaplan–Meier curves, the median length of overall survival was 42.4\xa0months in the lenalidomide 10\xa0mg group (95% CI 31.9\xa0to not reached), 35.5\xa0months in the 5\xa0mg group (95% CI 24.6\xa0to not reached), and 44.5\xa0months (95% CI 35.5\xa0to not reached) in the placebo group. The company stated that overall survival was similar between people included in and excluded from the mITT population (p=0.9218).The company did not adjust the overall survival results using formal statistical methods for any treatment crossover that occurred.\n\nIn MDS‑004, cytogenetic response was assessed using International Working Group 2000\xa0criteria. Cytogenetic responses help to establish the degree to which the natural history of myelodysplastic syndromes may be affected by therapy. Cytogenetic response (complete plus partial) rates in the mITT population were 50% in the lenalidomide 10\xa0mg group and 25% in the 5\xa0mg group, respectively. No cytogenetic responses occurred in the placebo group (p<0.001\xa0compared with both lenalidomide groups). Cytogenetic progression (development of new independent clones as well as additional aberrations together with deletion 5q) was observed in 23.5% of people treated with lenalidomide 10\xa0mg (p=0.50\xa0compared with placebo), 31.3% of people treated with lenalidomide 5\xa0mg (p=0.17\xa0compared with placebo), and 14.3% of people receiving placebo. Similar results were observed in the ITT population. Median time to cytogenetic progression was 93\xa0days (range 85–170\xa0days) in the lenalidomide 10\xa0mg group, 85\xa0days (range 83–339\xa0days) in the lenalidomide 5\xa0mg group, and 99\xa0days (range 83–172\xa0days) in the placebo group.\n\nHealth‑related quality of life data were collected for 167\xa0people in MDS‑004\xa0using the FACT‑An questionnaire. Baseline and week\xa012 (that is, before crossover) FACT‑An scores were available for 71% of randomly assigned people (lenalidomide 10\xa0mg, n=48; 5\xa0mg, n=45; placebo, n=52). Mean change in FACT‑An score from baseline to week\xa012 was statistically significantly higher in the lenalidomide 10\xa0mg (5.8; p<0.05) and 5\xa0mg (5.9; p<0.05) groups than in the placebo group (−2.5).\n\nThe company reported adverse event rates for the double‑blind safety population in MDS‑004. A higher proportion of people in the lenalidomide 10\xa0mg (95.7%) and 5\xa0mg groups (98.6%) had at least 1\xa0drug‑related adverse event compared with the placebo group (49.3%). The most frequently reported drug‑related adverse events were neutropenia (14.9% in the placebo group, and 75.4% in each of the lenalidomide groups) and thrombocytopenia (3.0% in the placebo group, 39.1% in the lenalidomide 5\xa0mg group and 47.8% in the lenalidomide 10\xa0mg group). For serious infections, only rates of grade 3\xa0or 4\xa0pneumonia were reported by the company (1.5% in the placebo group, 1.4% in the lenalidomide 5\xa0mg group and 4.3% in the lenalidomide 10\xa0mg group).\n\n# Cost effectiveness\n\nThe company developed a de novo Markov model that simulated cohorts of people with low- to intermediate‑1\xa0risk MDS with deletion 5q receiving lenalidomide 10\xa0mg or best supportive care. The model cycle length was 4\xa0weeks to reflect the dosing interval for lenalidomide treatment. A half‑cycle correction was not applied. The time horizon of the model was 20\xa0years based on an average age of 67\xa0years in the MDS‑004\xa0study. An NHS and personal social services perspective was taken and costs and benefits were discounted at 3.5%. The company provided 4 models in total, the first being the original base‑case (model 1). Model 2 was provided in response to the first appraisal consultation document incorporating revisions to address concerns raised by Committee. Models 3 and 4 were submitted to incorporate the patient access scheme and further revisions to address further concerns raised by the Committee. Sections\xa03.12 to 3.26 below discuss model\xa01. Models 2, 3 and 4 are discussed in sections\xa03.41 to 3.48.\n\nThe model included 13 health states and a death state. The structure was developed to reflect 3\xa0key features of MDS deletion 5q treatment:\n\ntransfusion dependence or independence\n\nneed for iron chelation after a certain number of red blood cell transfusions\n\nAML progression. After starting treatment, people move to 3\xa0possible health states relating to transfusion status: transfusion independent and transfusion dependent with or without chelation. Additional states were defined to reflect response to iron chelation, potential hepatic and diabetic complications, and increased risk of cardiac disease caused by red blood cell transfusion. In addition, people who were transfusion dependent or independent with or without complications could develop AML.\n\nClinical‑effectiveness data from the ITT population in the MDS‑004\xa0study were used in the model. The company stated that this population more closely matched the NICE scope than the mITT population. It also stated that using the mITT population substantially reduced the amount of available data and that, in this population, no statistically significant differences were observed in key end points between trial arms in MDS‑004. The company assumed that people in the lenalidomide group remained on treatment (10\xa0mg per day for 21\xa0days of a 28‑day cycle) until their condition stopped responding to treatment, that is, they became transfusion dependent. Best supportive care was based on the placebo arm of the MDS‑004\xa0study, which included blood transfusions for those who were transfusion‑dependent. The company stated that, in UK clinical practice, best supportive care may also include an erythropoiesis stimulating agent (ESA). Therefore, the company assumed that 28% of people in the best supportive care group received an ESA for 3\xa0cycles based on the proportion of people in the UK in MDS‑004\xa0who received an ESA before the trial started. In addition, it was assumed that granulocyte colony‑stimulating factor (G‑CSF) for 3\xa0cycles would be used as part of best supportive care when the condition did not respond to an ESA.\n\nIn the model, treatment response was defined as becoming transfusion independent. The proportion of people who became transfusion independent for 56\xa0consecutive days (based on International Working Group 2000\xa0criteria) was 60.9% for the lenalidomide group and 7.5% for the best supportive care group. The response rates for people who received an ESA and a G‑CSF in the best supportive care group (21.7%) were taken from a separate study that reported response rates after combination therapy (Jadersten et al. 2005). However, the company stated that this was unlikely to be representative of ESA and G‑CSF use in the UK because combination therapy is started after the failure of ESA monotherapy. On the basis of a separate study by Balleari et al. (2006), the company assumed that response rates to monotherapy with either ESA or a G‑CSF would be half of those to combination therapy (10.8%).\n\nThe duration of response to treatment with lenalidomide and best supportive care in the model was based on patient‑level data taken from the MDS‑004\xa0ITT population. Because of patient crossover in MDS‑004, the company used log‑rank tests to determine whether there was a significant difference in response duration according to whether a treatment was provided as first- or second‑line treatment in the study. The results showed that the order in which people received treatment in MDS‑004 did not have a significant impact on duration of response. Parametric response duration curves were fitted to data from the lenalidomide 10\xa0mg treatment arm in MDS‑004 to estimate response duration in the lenalidomide group. The company stated that response duration curves could not be estimated for people in the placebo arm because of insufficient numbers of people whose condition responded to treatment (n=5). Therefore, the company used data from the lenalidomide 5\xa0mg treatment arm in MDS‑004 to approximate duration of response to best supportive care. Based on goodness‑of‑fit tests using the Integrated Brier Score and Akaike Information Criterion, the log‑normal distribution was fitted to both response duration curves.\n\nThe company assumed that people in the transfusion‑dependent states in the model received red blood cell and platelet transfusions. On the basis of data from MDS‑004, it was assumed that people needed an average of 1.89\xa0red blood cell transfusions to provide 4.57\xa0red blood cell units and an average of 0.02\xa0platelet transfusions to provide 0.06\xa0platelet units per 28‑day cycle. The company also assumed that people who were transfusion dependent had an increased risk of cardiac disease, based on the findings of a study by Malcovati et al. (2011). A Gompertz curve was fitted to data from this study to estimate the probability of being transfusion dependent and progressing to cardiac disease.\n\nThe company assumed that people who were transfusion dependent started iron chelation therapy to avoid complications associated with iron overload. It was assumed that people started iron chelation therapy when they reached a threshold of 25\xa0red blood cell units. The company also assumed that people had already received 9.15\xa0red blood cell units per 8\xa0weeks based on the average number of units that people had received before entering the MDS‑004\xa0study. A response rate for iron chelation of 66% was taken from a study by Kontoghiorges et al. (2000) and was assumed to occur in the first cycle of treatment. People who needed iron chelation moved to either the chelation or chelation failure state. The company assumed that people whose disease responded to treatment continued to receive iron chelation until progression to AML or death. People in the model whose disease did not respond to iron chelation therapy were assumed to be at risk of iron overload complications, including diabetes mellitus and hepatic complications. The probabilities of developing diabetes mellitus (0.21%) and hepatic complications (0.66%) per 28–day cycle on iron chelation were taken from a study by Jaeger et al. (2008).\n\nThe company stated that survival with MDS is strongly related to transfusion dependence. Data from the MDS‑004\xa0study were used to estimate separate mortality curves for people who were transfusion dependent or independent at 8\xa0weeks. Based on goodness‑of‑fit, the Weibull distribution was fitted to data from MDS‑004. The company stated that crossover of people in the MDS‑004\xa0study at week\xa016 precluded any long‑term assessment of the impact of lenalidomide on survival and, as a result, using only MDS‑004\xa0study data was likely to result in an underestimate of overall survival. Therefore, the median survival for best supportive care in the model was adjusted to match the combined median survival data reported from a phase II trial, MDS‑003, and the phase III MDS‑004\xa0study, resulting in a figure of 3.8\xa0years.\n\nThe time to progression to AML in the model was taken from an individual patient‑level analysis from the MDS‑004\xa0study and was estimated separately for transfusion dependence and independence. On the basis of goodness‑of‑fit, the Weibull distribution was chosen to estimate time to AML progression curves. AML‑related mortality could not be estimated from the MDS‑004\xa0study because the number of people who died from AML was too low. Therefore, the company used data from a study by Wahlin et al. (2001) of older people with AML, including 113\xa0people with MDS caused by deletion 5q. Although the log‑normal function provided the best fit to the data from this study, it also resulted in a 'long tail' whereby some people remained alive for an unrealistically long time. A Weibull distribution was therefore chosen to estimate the survival time for people who developed AML in the model because it did not result in such a 'long tail'.\n\nThe company included grade 3\xa0or 4\xa0neutropenia and thrombocytopenia episodes in the model, because of differences in these adverse events between the placebo and lenalidomide treatment arms in MDS‑004. The company stated that it was unlikely that all neutropenia and thrombocytopenia events could be attributed to lenalidomide treatment because MDS is characterised by these peripheral cytopenias. Therefore, the number of people who had neutropenia and thrombocytopenia in the lenalidomide group was adjusted by subtracting those who had these events in the placebo group. The company assumed that any adverse events in the lenalidomide group occurred only in the first 4\xa0cycles of the model. Based on data from MDS‑004, the company assumed that only a proportion of people who had neutropenia (27.7%) and thrombocytopenia (6%) needed additional treatment. The company did not include other adverse events such as deep vein thrombosis or pulmonary embolism in the model because of the low incidence of these events in MDS‑004.\n\nThe model accounted for 2\xa0periods of treatment interruption during which people in the lenalidomide group did not receive treatment. Based on data from the MDS‑004\xa0ITT population, it was assumed that 68.7% of people in the lenalidomide group had a first dose interruption and 73.8% had a second dose interruption. The mean time to first treatment interruption was 54.2\xa0days and the length of treatment interruption was 17.5\xa0days. After the first dose interruption, people in the lenalidomide group resumed treatment at a lower dose of 5\xa0mg for 28\xa0days per cycle. The mean time to second treatment interruption (from the start of the first interruption) was 72.1\xa0days and the length of interruption was 13.9\xa0days. After the second dose interruption, people in the lenalidomide group resumed treatment at a lower dose of 5\xa0mg for 14\xa0days per cycle. The cost of lenalidomide treatment was adjusted to take these treatment interruptions into consideration but the company stated that there was no need for clinical outcomes to be adjusted in a similar way, because the efficacy data for the ITT population used in the model already accounted for these interruptions. The company presented further analyses on treatment interruptions, which is discussed in sections\xa03.46 and 3.49.\n\nThe MDS‑004\xa0trial assessed health‑related quality of life using the EQ‑5D at baseline, and the FACT‑An questionnaire at baseline and at weeks 12, 24, 36\xa0and 48. The company conducted preliminary analyses to explore any relationship between EQ‑5D utility values and the FACT‑An. However, regression models to map FACT‑An scores from MDS‑004\xa0to EQ‑5D utility values resulted in an unacceptable level of error. Therefore, the company performed a systematic literature search to identify relevant health‑related quality of life data for people with MDS. Four potentially relevant studies were identified (Buckstein et al. 2009\xa0and 2011, Goss et al. 2006\xa0and Szende et al. 2009). The company chose to use Szende et al. (2009). In this study, utility data were collected from 47\xa0people with MDS, of mean age 67\xa0years (including 21\xa0from the UK), using visual analogue scale and time trade‑off methods. People were interviewed to elicit utility values for transfusion independence and transfusion dependence. The resulting mean utility values for the UK sample using the time trade‑off method were 0.85 for transfusion independence and 0.65 for transfusion dependence. The study did not estimate utility values for the AML state, so the company assumed that people in the AML state had the same utility value as for transfusion dependence (0.65). Utility values in the model were adjusted by an age‑dependent factor taken from Kind et al. (1999). The studies by Buckstein et al. reported EQ‑5D utility values for 69\xa0Canadian people (mean age 73\xa0years) with MDS, resulting in utility values of 0.80\xa0for transfusion independence and 0.63\xa0for transfusion dependence. The study by Goss et al. (2006) reported utility values estimated using the time trade‑off technique in 8\xa0 people with low- and intermediate‑1 risk MDS from the USA, resulting in utility values of 0.91\xa0for transfusion independence and 0.50\xa0for transfusion dependence. The utility values from both of these studies were used in additional scenario analyses conducted by the company.\n\nUtility decrements associated with iron chelation therapy (21% for intravenous iron chelation and 0% for oral chelation) were obtained from a study by McLeod (2009). Utility decrements for adverse events, including cardiac disease (17.9%), diabetes (12.3%) and hepatic complications (8.0%) were obtained from studies by Fryback (1993) and Wong (1995). The model did not incorporate utility decrements for people who had neutropenia and thrombocytopenia episodes. The company's justification was that these adverse events were likely to only have a short‑term effect on quality of life.\n\nThe company's model (model\xa01) included drug acquisition, monitoring costs and costs of adverse events. The acquisition costs of lenalidomide were based on the dosing observed in the MDS‑004\xa0trial, which included dose interruption because of adverse events. The costs of ESA (£885\xa0per cycle) and G‑CSF (£633\xa0per cycle) were also included for 28% of people in the best supportive care group. Drug acquisition prices were obtained from the BNF edition\xa064. In addition, monitoring costs (including GP visits and blood tests) and transfusion costs (including administration and acquisition of red blood cell and platelet units) were included. The costs of treating AML (£1919.40\xa0per cycle) were taken from Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia (NICE technology appraisal guidance 218). The costs of thrombocytopenia and neutropenia episodes of £1636.38\xa0were taken from NHS reference costs 2011/12. The model also included the annual costs of iron chelation and transfusion‑dependent complications, which were taken from the literature. To estimate the costs of iron chelation therapy, the company assumed that people had either intravenous desferrioxamine (29%) or oral deferasirox (71%) based on prescription cost analysis data for England (2010), resulting in a total cost of £1383.39\xa0per cycle. The frequency of monitoring associated with lenalidomide treatment was taken directly from the summary of product characteristics: GP visits (and blood counts) occurred weekly for the first 8\xa0weeks, bi‑weekly for the next 4\xa0weeks and then 4‑weekly thereafter. For best supportive care, monitoring was assumed to occur once every 4\xa0weeks throughout treatment.\n\nThe company's model (model 1) estimated 5.69 and 4.53 total undiscounted life years gained with lenalidomide and best supportive care, respectively. The company's base‑case deterministic cost‑effectiveness analysis resulted in an incremental cost‑effectiveness ratio (ICER) of £56,965\xa0per quality‑adjusted life year (QALY) gained for lenalidomide compared with best supportive care (incremental costs £50,582\xa0and incremental QALYs 0.89). The probabilistic cost‑effectiveness analysis estimated an ICER of £58,178\xa0per QALY gained. Results of the probabilistic sensitivity analysis showed that at £30,000\xa0per QALY gained, lenalidomide had a 0% probability of being cost effective.\n\nThe company undertook a series of deterministic sensitivity analyses. The cost‑effectiveness estimate of lenalidomide compared with best supportive care was most sensitive to the utility value for the transfusion‑independent state. The ICER was also sensitive to the utility value for the transfusion‑dependent state. The company also conducted further scenario analyses, which included altering the population used to estimate the model parameters, altering the proportion in the best supportive care group who received an ESA, altering the number of red blood cell units people received before iron chelation therapy was started, using alternative utility values from the studies by Goss and Buckstein and using alternative methods of extrapolating response duration, AML progression and overall survival. The ICERs were robust to nearly all of the scenarios explored. However, when the company applied alternative utility values for the transfusion‑independent (0.91), transfusion‑dependent (0.5) and AML (0.5) states taken from the study by Goss et al. (2006), the ICER reduced to £47,621\xa0per QALY gained.\n\n# Evidence Review Group comments\n\nThe ERG considered that the company had identified all the available evidence on the clinical effectiveness of lenalidomide for treating myelodysplastic syndromes associated with the deletion 5q cytogenetic abnormality. The ERG noted that a significant proportion of the lenalidomide 5\xa0mg and 10\xa0mg groups had an adverse event resulting in dose interruption or reduction. It also noted that dose reductions made it difficult to distinguish between the 5\xa0mg and 10\xa0mg lenalidomide treatment groups. It noted that because of crossover, only 1\xa0person in the placebo group completed the 52‑week double-blind phase. The ERG suggested that one of the main concerns for people receiving lenalidomide is the incidence of increased clonal evolution and progression to AML. The ERG was concerned that because people could switch from placebo to active drug treatment in MDS‑004, the chances of detecting prolonged survival or acceleration of leukaemia progression were limited. Overall, the ERG considered that assessment of the long‑term effectiveness of lenalidomide was compromised because people in the MDS‑004\xa0study were allowed to switch treatment after 16\xa0weeks.\n\nThe ERG noted that data were reported separately for 2\xa0populations in the MDS‑004\xa0study: the ITT and mITT population, although not all results were reported for both populations. The ERG also noted that confirmation of deletion 5q status (by karyotype analysis) and bone marrow morphology were performed by central haematological review after randomisation, resulting in people whose disease did not meet the study inclusion criteria being included in the ITT population. The ERG noted that it was not clear how differences between these 2\xa0populations could influence the results.\n\nThe ERG stated that the company's economic model (model 1) was generally well presented and reported. However, the ERG noted that the model described in the company's submission did not fully correspond with the model structure in the electronic model provided. It also noted that the company did not consider progression to intermediate‑2\xa0or high‑risk MDS in the model because these data were not collected in MDS‑004. The ERG considered that it would have been more reasonable for a lifetime model to incorporate all future costs and effects, including the possibility of disease progression and reduced transfusion burden. The ERG disagreed with the company's decision not to apply a half‑cycle correction in the model because of the short cycle length of 28\xa0days. The ERG considered that short cycles would involve small changes between 2\xa0consecutive cycles, because cycle length depends on the changes observed in patient distribution from 1 cycle to another. The ERG noted that the cycles at the start of the model showed a significant redistribution between the various health states, suggesting that a cycle of 28\xa0days was rather long during this phase of the model.\n\nThe ERG noted that in the company's economic model, best supportive care was defined as blood transfusions for transfusion dependence. No changes to best supportive care (in terms of transfusion frequency or iron chelation therapy) were assumed when cardiac conditions, diabetes, or hepatic conditions occurred. The ERG considered that it was unclear whether best supportive care as represented in the model was similar enough to clinical practice in England.\n\nThe ERG considered the response rates used in the company's model, which were based on the MDS‑004\xa0ITT population. The ERG noted that the company's description of the model stated that response to treatment was assumed to occur within the first cycle, so that all patients spent the first cycle in the transfusion‑dependent state. However, the ERG noted that the model started with the results of the treatment initiation and that people moved immediately from the first cycle onwards to the transfusion‑independent state. The ERG considered that this assumption may have been optimistic because the overall response rate also included people whose condition did not respond immediately to treatment. In response to clarification, the company provided data on the proportion of people responding to treatment according to 28‑day cycles in the MDS‑004\xa0study, which showed that the lenalidomide 10\xa0mg arm had a response rate of 60.9% after 112\xa0days and the placebo arm had a response rate of 7.5% after 182\xa0days. The ERG considered that it would have been more appropriate to use these data rather than assuming that all of those whose condition responded to treatment were transfusion independent from cycle 1\xa0onwards.\n\nThe ERG noted that neither the proportion of people receiving ESA as part of best supportive care nor the response rate to ESA could be obtained from the MDS‑004\xa0trial, which introduced additional uncertainty in the model. It noted that, according to expert opinion given to the ERG, there was some uncertainty about the effect of providing ESA to people with MDS with deletion 5q. The ERG also noted that the initial response rates to best supportive care in the model were weighted twice by the proportion of people (28%) who received ESA and G‑CSF therapy. In response to clarification, the company confirmed that these were programming errors. The ERG considered that, in the absence of other available data, it was appropriate for the company to assume that response duration for the best supportive care group could be estimated from the lenalidomide 5\xa0mg treatment arm in MDS‑004. However, it also considered that the company's rationale for using response duration estimates from the lenalidomide 5\xa0mg arm rather than the 10\xa0mg arm seemed arbitrary.\n\nThe ERG noted that the cost effectiveness of lenalidomide was sensitive to the proportion of people in the lenalidomide treatment group who had a second dose interruption in the model. The ERG noted that these values were directly obtained from the MDS‑004\xa0trial, but that only cost estimates were assumed to be affected by treatment interruptions in the model, and the clinical effectiveness of lenalidomide was unaffected. The ERG suggested that, in clinical practice, treatment interruptions would affect the response rates to lenalidomide treatment. The ERG also noted that the programming of dose interruptions in the electronic model contained errors.\n\nThe ERG noted that all people in the model would be monitored by a GP. In response to clarification, the company stated that the cost of haematology visits were included in the costs of transfusion dependence and associated adverse events and that, as a result, haematology visits were not included as part of monitoring in the model. However, the ERG considered that because most people in the model were not treated for adverse events, it would be more reasonable for them to be monitored by a haematologist rather than a GP. The ERG therefore conducted an exploratory scenario analysis assuming that all monitoring would take place at a haematologist visit.\n\nThe ERG noted that the utility values (that is, the measure of health) were taken from a study by Szende et al. (2009). This provided evidence that transfusion independence is associated with significantly better quality of life scores (p < 0.001) compared to fewer transfusions and transfusion dependence. The ERG highlighted some concerns with the values applied in the model.\n\nThe Szende study did not conform to the NICE reference case because it was obtained from a sample of people in the UK with MDS rather than a sample of the general UK population without the condition.\n\nThe ERG noted that the model included transfusion dependent and transfusion independent health states. It commented that in clinical practice, people may lie between these states, that is, they are neither completely dependent on transfusion nor completely independent, they need some transfusions. The ERG noted than the transfusion dependent health state included all those that were not transfusion independent, that is, it included those who were completely dependent on transfusion and those who weren't completely dependent, but were not independent either. The ERG commented that the value of 0.65 was elicited for people who were completely transfusion dependent (requiring a lot of transfusions) and therefore may under estimate the utility value of the transfusion dependent health state, as it also included people who only need a few transfusions.\n\nThe ERG highlighted that the health state description for transfusion dependence in the Szende et\xa0al. (2009) study was very broad, in that it covered a range of health problems and the level of transfusion dependence was not the only difference between the health states being compared for the elicitation. This meant that the transfusion‑dependent state may have already incorporated some of the adverse events associated with transfusion and chelation therapy, or complications such as cardiac disease, diabetes or hepatic complications. The ERG considered it likely that some double counting was included in the model by also using utility decrements, such as for chelation therapy and complications (see section 3.23).\n\nThe ERG considered that the utility value of 0.65 from the Szende et al. (2009) study\xa0for people in the transfusion‑dependent state may underestimate utility for the reasons described above. The ERG commented that this would favour lenalidomide because people in the best supportive care group spent a much longer time in this health state compared with the lenalidomide group, thus increasing the QALY difference between lenalidomide and best supportive care in the model.\n\nThe ERG questioned whether it was appropriate to use the same utility values for the AML state as the transfusion‑dependent state because this implied that being partly or completely transfusion dependent had the same impact on quality of life as having AML. However, the ERG noted that because there was no difference between the 2\xa0treatment groups in the time spent in the AML state in the model, the impact of the utility value for the AML state was negligible.\n\nThe ERG noted that the company did not apply utility decrements for neutropenia and thrombocytopenia events associated with lenalidomide treatment. The ERG accepted that the impact of these events on health‑related quality of life was likely to be small.\n\nThe ERG identified several issues in relation to the resource use and cost estimates used in the company's model. The ERG noted that people receiving iron chelation therapy in the model either had intravenous desferrioxamine or oral deferasirox treatment based on prescription cost analysis data in England from 2010. The ERG considered that deferiprone, which is a third possible iron chelation therapy listed in the prescription cost analysis, should also have been included. When the ERG included deferiprone and adjusted the proportion of people who were treated with the 3\xa0iron chelation therapies based on 2011\xa0prescription cost analysis data, this reduced the total cost of iron chelation therapy from £1383\xa0to £1332\xa0per 28‑day cycle. The ERG noted that the company's estimated cost of AML treatment of £1919.40\xa0was based on a 5‑week cycle rather than a 4‑week cycle used in the model. The ERG also identified alternative cost estimates for episodes of neutropenia (£1045) and thrombocytopenia (£1768) from the NHS reference costs (2011/12). The ERG considered that the company's assumption of standard errors of 10% of the mean cost estimates for complications and adverse events used in the probabilistic sensitivity analysis were too small and that standard errors of 20% of the mean estimate would be more reasonable. Similarly, the ERG noted that the company's probabilistic sensitivity analysis did not account for uncertainty around the number of monitoring visits in both treatment groups.\n\nThe ERG ran the company's model incorporating the following adjustments:\n\nProgramming errors confirmed by the company were removed.\n\nProgramming errors for dose interruptions and days on active treatment in the model were removed.\n\nA half‑cycle correction was included.\n\nCosts of iron chelation therapy were updated to £1332\xa0per cycle to include deferiprone.\n\nTreatment costs of AML were amended to £1451\xa0per 28\xa0day cycle.\n\nResponse was distributed over time according to the trial instead of all patients from cycle 1\xa0onwards.\n\nCosts of neutropenia and thrombocytopenia were amended to £1045\xa0and £1768\xa0respectively.\n\nUpdated the costs of monitoring, complications and adverse events.\n\nWhen the ERG included all of these changes in the company's model (model\xa01) the deterministic ICER without the patient access scheme increased from £56,965 to £62,674\xa0per QALY gained for lenalidomide compared with best supportive care (incremental costs £50,898\xa0and incremental QALYs 0.81). The probabilistic ICER was £65,052\xa0per QALY gained.\n\nThe ERG reproduced the company's sensitivity and scenario analyses in the amended model (model\xa01). The sensitivity analyses found that the cost effectiveness of lenalidomide compared with best supportive care was most sensitive to the utility values for the transfusion‑independent state and the response rate for the lenalidomide treatment group. When the ERG re‑ran the company's scenario analyses, the only scenario that had a substantive impact in the ICER was using utility values from Goss et al. (2006), which reduced the ICER to £51,956\xa0per QALY gained (see section\xa03.26).\n\nThe ERG undertook additional scenario analyses. The scenarios that had the most substantial effect on the ICER were the utility value for transition dependence and the proportion of people who received intravenous iron chelation therapy. When the utility value for transfusion dependence was increased from 0.65\xa0to 0.77\xa0(the value for reduced transfusion burden taken from Szende et al. ), the ICER for lenalidomide compared with best supportive care increased to £68,357\xa0per QALY gained compared with the company's base‑case ICER of £56,965 per QALY gained. When the proportion who received intravenous iron chelation therapy was increased from 5.7% to 100%, the ICER reduced to £56,750\xa0per QALY gained. Assuming that people in the transfusion‑dependent state would start iron chelation therapy after 4\xa0cycles increased the ICER to £67,428\xa0per QALY gained. Assuming that all monitoring would take place at a haematologist visit increased the ICER to £64,079\xa0per QALY gained.\n\n# Company's response to the appraisal consultation document\n\nThe company submitted the results of a systematic literature review to show transfusion dependence was a prognostic factor for overall survival and rate of progression to AML. Of the 17 studies (mainly retrospective case series or register populations) meeting the inclusion criteria, 16 studies reported statistically significant associations between transfusion status and overall survival. This association was explained by:\n\ntransfusion dependence and anaemia leading to increased death from causes other than leukaemia (particularly cardiac death)\n\ntransfusion dependence and anaemia leading to increased risk of AML and death caused by leukaemia\n\ntransfusion independence after dependency at baseline improving overall survival because of reduced complications from chronic anaemia. The company also cited literature that examined the relationship between AML and both transfusion status and erythroid response, arguing that lenalidomide triggers programmed cell death in the deletion (5q) clone, and that the MDS‑004\xa0trial showed significant reductions in progression to AML for people whose condition responded to lenalidomide.\n\nIn response to the appraisal consultation document, the company revised the economic model according to the adjustments described in section\xa03.37, which increased the base‑case ICER from £56,965 to £62,674 per QALY gained (model 2). It also accepted that monitoring would be undertaken by a haematologist rather than a GP, increasing the ICER (model 2) to £65,153 per QALY gained. A model scenario was explored in which the progression to AML was the same for the lenalidomide and best supportive care arms which increased the ICER (model 2) to £68,125 per QALY gained. The company also provided further information to explain a labelling error in its model about iron chelation. It outlined that the underlying model was accurate for the assumption of when iron chelation started, despite this labelling error, and that no adjustments in the base‑case ICER were needed. Finally, the company submitted its methods for attempting to map FACT‑An scores to EQ-5D and the way it accounted for crossover in the trial arms.\n\nThe ERG considered the additional information submitted by the company, and the updated model (model 2). It agreed that this information, combined with the results of the MDS‑004\xa0trial, suggested that it was reasonable to assume a 2‑step relationship: first between lenalidomide response and transfusion independence, and then between transfusion independence and overall survival. However, there was uncertainty in the strength of the relationship between transfusion independence and overall survival beyond 5\xa0years. For AML progression, the ERG outlined differing evidence from the MDS‑004\xa0trial. While Kaplan–Meier survival curves showed significant differences in progression to AML in favour of those whose disease responded to lenalidomide, a univariate Cox‑regression of time to AML showed that response status was not a significant variable in the association between lenalidomide and reduced rate of progression to AML.\n\n# Company's patient access scheme and further revisions to the company's model\n\nThe company has agreed a patient access scheme for lenalidomide with the Department of Health. The company requested permission to submit the patient access scheme as part of the technology appraisal, which was agreed by NICE as an exceptional circumstance. It is a standard scheme, with the NHS paying for up to 26\xa0cycles of treatment with lenalidomide. The company will then provide free‑of‑charge lenalidomide for people needing treatment beyond 26\xa0cycles, which could take the form of a rebate, vouchers or free stock of the drug. The company provided updated analyses (model 3) that:\n\nincorporated the patient access scheme – the company assumed that 31.9% would have 26\xa0cycles of treatment and would therefore be eligible for the rebate of free subsequent treatment to the NHS as outlined in the patient access scheme, based on the MDS‑004 trial\n\nincluded the adjustments stated in section\xa03.37, including a half‑cycle correction\n\namended the rate of progression to AML in the lenalidomide arm to be the same as in the best supportive care arm\n\nassumed routine monitoring by a haematologist rather than a GP.\n\nThe company presented revised analyses (model 3) with and without the patient access scheme. The resulting deterministic ICERs for lenalidomide compared with best supportive care were £68,125 per QALY gained (without the patient access scheme;) and £24,544 per QALY gained (with the patient access scheme). The mean probabilistic ICER including the patient access scheme was £25,468 per QALY gained. Sensitivity analyses showed that the ICER was most sensitive to median survival from the MDS‑003 and MDS‑004 trials, with a maximum deterministic ICER of £33,309 per QALY gained. The company presented scenario analyses, including varying utilities, where the ICERs ranged from £19,135 to £25,861 per QALY gained when alternative utility sources were used (Goss and Buckstein, respectively), and varying the selection of survival curves where ICERs ranged from £24,776 to £30,022 per QALY gained.\n\n# Committee request for additional cost‑effectiveness analysis\n\nThe Committee were unable to make a decision based on the evidence submitted with the patient access scheme because of uncertainty in the proportion who would receive lenalidomide after 26 cycles, how long they would receive it for, and the impact of dose interruptions. The Committee therefore requested further cost‑effectiveness analysis with the patient access scheme to address these uncertainties and better understand how it would apply to clinical practice. The Committee noted that dose interruptions had not appropriately been taken into account when the patient access scheme was incorporated into the model, and that interruptions would delay when the patient access scheme would take effect for people who have dose‑interruptions. Cycles may be missed to manage toxicity, which would delay when a patient reached 26\xa0cycles, the point at which the patient access scheme allowed free lenalidomide. The company therefore updated the base case to account for 16\xa0days of treatment interruptions and explored the impact of longer dose interruptions (model 4). The updated base‑case ICER was £25,310 per QALY gained for lenalidomide compared with best supportive care. Probabilistic sensitivity analyses estimated a mean ICER of £25,708 per QALY gained. The probability of being cost effective was 25.4% and 64.5% at £20,000 and £30,000 per QALY gained respectively. Increasing the length of interruptions reduced the ICER; accounting for 42\xa0days of treatment interruptions reduced the ICER to £22,209 per QALY gained for lenalidomide compared with best supportive care.\n\nAt the request of the Committee, the company presented evidence to support the proportion of people who would be expected to be eligible for the patient access scheme (31.9%):\n\nPublished data (Fenaux et al. 2011) from an interim analysis showed that, of those in the 10\xa0mg lenalidomide arm of MDS‑004, 38% were still on treatment after 26\xa0cycles. The company applied a correction factor to this value to reduce survival on both arms to the levels seen in real‑life practice, subsequently estimating that 31.9% would remain on treatment after 26\xa0cycles in clinical practice.\n\nReal‑world UK data from Celgene's in‑house database suggested that 28% of people reached 26\xa0cycles of treatment with lenalidomide.\n\nPublished registry data indicated that response duration ranged from 27.6 to 36\xa0months.The company presented a threshold analysis that showed if the proportion eligible for the patient access scheme was less than 27%, the ICER (model 4) would be greater than £30,000 per QALY gained.\n\nThe patient access scheme presented by the company would not take effect until after a minimum of 2\xa0years, or longer with dose interruptions. At the request of the Committee, the company presented further cost‑effectiveness analyses, including scenarios for various time horizons to understand how the cost effectiveness would change over time as the patient access scheme was implemented. Applying time horizons of 2, 3, 5 and 10\xa0years in model 4 gave ICERs of £119,876, £63,780, £30,923 and £23,420 per QALY gained respectively for lenalidomide compared with best supportive care.\n\nThe ERG validated the changes to the company's model, confirming that the patient access scheme was incorporated appropriately. It agreed with the company that the real‑world evidence suggested that about 30% of people reach 26\xa0cycles of treatment, and the ERG stated that this was a reasonable assumption. It commented that the company's estimate of 16\xa0days of treatment interruptions may be an underestimate and it could be closer to 19\xa0days. The ERG showed that this had a negligible impact on the ICER with the company's base case increasing from £25,310 per QALY gained to £25,455 per QALY gained. It stated that the first 5\xa0years of the model were more certain than the later years because they were based on available data. The ERG noted that most of the QALY gains in the model were in these first 5\xa0years (64%), and that 90% of the QALY gains occur within 10\xa0years.\n\nFull details of all the evidence are available.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of lenalidomide, having considered evidence on the nature of low‑ or intermediate‑1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate, and the value placed on the benefits of lenalidomide by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the treatment pathway in the UK for people with MDS associated with an isolated deletion 5q cytogenetic abnormality, taking into account the marketing authorisation for lenalidomide (for treating transfusion‑dependent anaemia caused by low‑ or intermediate‑1 risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate). It heard from the clinical specialist that the main treatment option currently available for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality is best supportive care, which involves regular red blood cell transfusions, and that low‑dose standard chemotherapy or immunosuppressive therapies are used for some people. The clinical specialist also stated that some people would also receive an erythropoiesis stimulating agent (ESA) as part of best supportive care and that iron chelation therapy is used to avoid longer‑term complications associated with transfusion. Therefore, the Committee agreed that as defined in the scope, best supportive care was the appropriate comparator\n\nThe Committee heard from the clinical specialist that lenalidomide is an effective targeted therapy which reduces the need for blood transfusions. The patient experts agreed that this was a major benefit, with reduced fatigue significantly improving quality of life. They highlighted that having regular blood transfusions and blood tests at hospital is both inconvenient, because it needs regular time off work and usual activities, and demoralising because the person is constantly reminded of their condition. The patient experts suggested that lenalidomide, by contrast, is a convenient, effective oral drug that reduces the need for blood transfusions. The Committee recognised the need for treatments that would reduce blood transfusion dependence for people with MDS associated with an isolated deletion 5q cytogenetic abnormality.\n\n# Clinical effectiveness\n\nThe Committee discussed the clinical effectiveness of lenalidomide in people with low‑ or intermediate‑1\xa0risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It noted that the evidence presented by the company was taken primarily from the MDS‑004\xa0study. This included a broader range of people than that specified in the marketing authorisation and NICE scope for lenalidomide, because the marketing authorisation stated 'when other therapeutic options are insufficient or inadequate', which was not an inclusion criteria for the study, and therefore those on the trial may have a better prognosis than the population specified by the marketing authorisation. In addition, the study included people with low‑ or intermediate‑1\xa0risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, whilst the marketing authorisation specified an isolated deletion 5q cytogenetic abnormality. The Committee heard from the company during consultation that the additional cytogenetic abnormalities included in the trial population may mean the trial population had a poorer prognosis than that of the population covered by the marketing authorisation. The Committee agreed that, on balance, the study was generalisable to the marketing authorisation population, and how lenalidomide would be used in clinical practice. It concluded that it would be able to consider all of the evidence in the MDS‑004 study when making recommendations on lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality.\n\nThe Committee considered the results of the MDS‑004\xa0study. It noted that the rates of transfusion independence (at 26\xa0weeks, lenalidomide 10\xa0mg: 56.1%, placebo: 5.9%; p<0.001, see section 3.5) and improvements in the Functional Assessment of Cancer Therapy‑Anaemia (FACT‑An) questionnaire (mean change, lenalidomide 10\xa0mg: 5.8, placebo: -2.5; p<0.05. See section\xa03.9) were significantly better in people treated with lenalidomide compared with placebo. The Committee concluded that lenalidomide is a clinically effective treatment for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.\n\nThe Committee discussed overall survival from MDS‑004, noting that overall survival with placebo and lenalidomide was greater than 35\xa0months and that there was no statistically significant difference between lenalidomide and placebo (lenalidomide 10\xa0mg: 36.9\xa0months, placebo: 35.9\xa0months). It was aware that people in the placebo arm could cross over to lenalidomide treatment after 16\xa0weeks (see section\xa03.2), and therefore the overall survival benefit of lenalidomide compared with placebo may be under estimated. The Committee noted that the company had presented separate mortality curves for people who were transfusion dependent or independent at 8\xa0weeks in MDS‑004 which suggested that survival was strongly related to transfusion status in people with low or intermediate‑1 risk MDS associated with a deletion 5q cytogenetic abnormality. The Committee noted that the company's comments in response to consultation included an updated analysis of these data at 7\xa0years, which continued to support a link between transfusion independence and overall survival. The Committee also considered the following:\n\nERG comments that it was reasonable to assume a two‑step relationship between lenalidomide response and transfusion independence, and then between transfusion independence and overall survival (see section\xa03.43).\n\nA consultation comment from a professional group that data suggested people with low risk MDS and anaemia, whose condition responds to therapies that increase haemoglobin concentration, have improved survival compared with those who did not receive treatment.\n\nThe ERG clinical expert had advised that there were uncertainties in the strength of the relationship between transfusion dependence and overall survival.\n\nA clinical specialist stated that it was unclear if an increase in transfusion independence would improve overall survival in clinical practice, in the population specified by the marketing authorisation. Overall the Committee concluded that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence.\n\nThe Committee discussed progression to acute myeloid leukaemia (AML). It understood from the company's systematic review that published data showed higher transfusion independence rates were associated with reduced risk of progression to AML (see section\xa03.41). The Committee noted that the company had stated transfusion status was a statistically significant predictor for AML progression in MDS‑004, but that the ERG had presented contradictory evidence (see section\xa03.43). The Committee was aware of the lenalidomide safety briefing sent from the company to healthcare professionals that outlined a 13.8% 2‑year risk of AML progression with lenalidomide treatment for MDS associated with a deletion 5q cytogenetic abnormality, and that lenalidomide's summary of product characteristics stated lenalidomide was associated with an increase in AML progression and second primary malignancies in people with multiple myeloma. However, it heard from the clinical specialist that longer-term data suggest that lenalidomide treatment does not increase the rate of AML progression in people who have low or intermediate‑1 risk MDS with deletion 5q cytogenetic abnormality. The Committee concluded that there was considerable uncertainty over whether lenalidomide was associated with changes in the rates of AML progression for people with low or intermediate‑1 risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.\n\nThe Committee considered adverse reactions associated with lenalidomide treatment from the MDS‑004\xa0study. It noted that the most frequently reported adverse reactions associated with lenalidomide treatment were neutropenia and thrombocytopenia. The Committee was also aware that lenalidomide may be associated with higher rates of venous thromboembolism than placebo. However, it heard from the clinical specialist that the risk of thromboembolic events was manageable for people with low- and intermediate‑1 risk MDS. It heard from the clinical specialist and patient experts that adverse reactions associated with lenalidomide treatment are managed with dose interruptions and are generally well tolerated. The Committee concluded that, although lenalidomide is associated with some adverse reactions, these can be managed by dose interruptions.\n\n# Cost effectiveness\n\nThe Committee considered the company's original economic model, the company's revised economic model, the company's revised economic model with the patient access scheme, and the ERG's critique and exploratory analyses. It acknowledged that the company had amended the model in response to earlier concerns that were raised by the ERG and the Committee (sections 3.37 and 3.44). These amendments included the:\n\ncosts associated with iron chelation, AML and thrombocytopenia\n\nincorporation of the patient access scheme\n\nrate of AML progression which was assumed to be the same for lenalidomide and best supportive care\n\nmonitoring being conducted by a haematologist (rather than GP).The Committee concluded that the updated models were appropriate for decision‑making.\n\nThe Committee discussed further the overall survival estimates as presented in the company's models, and considered the following:\n\nThe company did not extrapolate survival estimates for the lenalidomide and best supportive care arms from the MDS‑004\xa0study because people could cross over after 16\xa0weeks.\n\nThe company had estimated survival based on transfusion dependency at 8\xa0weeks in MDS‑004, stating that transfusion status was a predictor of overall survival in people with MDS (see section\xa04.5).The Committee agreed that increased transfusion independence could be associated with improved survival but recognised that its strength over the 20‑year time frame of the model was unclear (see section\xa04.6). The Committee concluded that, although the strength of the relationship was uncertain, it was reasonable for the model to include some benefit in overall survival for people whose condition responds to lenalidomide compared with best supportive care.\n\nThe Committee considered the utility values associated with transfusion status. The Committee noted that EQ‑5D utility values were collected at the start of the MDS‑004\xa0study but not at subsequent follow‑up, and that the company stated it was not possible to reliably estimate utility values by mapping from the FACT‑An scores to the EQ‑5D because of differences between the EQ‑5D utility values collected in the MDS‑004 study and those predicted by mapping. The Committee noted that the company used values that were taken from a published study (Szende et al. 2009) that derived utility values according to transfusion dependence and independence directly from people with MDS. It considered the ERG's comments that using a utility value of 0.65\xa0for people in the transfusion‑dependent state may favour lenalidomide because people in the best supportive care group spent a much longer time in this health state. This would increase the QALY difference between the treatment arms. It was aware that the utility values from Szende et al. were not in line with the NICE reference case for measuring and valuing health effects, which states that the value of changes in health‑related quality of life should be based on public preferences rather than people who have the condition. However, the Committee heard from the patient experts that the utility values used in the company's base‑case analyses were a reasonable reflection of the negative impact that transfusion dependence has on health‑related quality of life. It noted that sensitivity analyses which varied the utility values in model\xa04, including the patient access scheme, gave a range of ICERs between £19,700 and £26,700 per QALY gained (base case: £25,300 per QALY gained) for lenalidomide compared with best supportive care. The Committee concluded that the utility values were a reasonable reflection of the impact of transfusion status on health‑related quality of life in people with low or intermediate‑1 risk MDS associated with deletion 5q cytogenetic abnormality, and could therefore be used for decision‑making in this appraisal.\n\nThe Committee discussed the patient access scheme, noting that it was not a simple discount. The NHS pays for lenalidomide treatment for the first 26\xa0cycles, after which it is provided free of charge, and therefore the whole population would not benefit from the reduction in price because only some people, those receiving it after 26 cycles, would be eligible. The Committee noted that the reduction in costs achieved through the patient access scheme would be based on the number of people remaining on treatment after 26\xa0cycles, and how long they survived and continued treatment. The Committee was aware that the data supporting survival after 26\xa0cycles were from small numbers in the MDS‑004 trial (less than 38\xa0people), and were therefore very uncertain. The Committee discussed whether the assumption in the model that 31.9% of people would remain on treatment for more than 26\xa0cycles was realistic, and whether the cost savings associated with the patient access scheme were likely to be realised in clinical practice. The Committee considered the company's evidence that supported the assumption of 31.9% of people reaching 26\xa0cycles in practice (see section\xa03.47), and noted that this was supported by a clinical specialist. It was concerned, however, about discrepancies between this estimate and those implied by the published paper, but heard from the company that this was because the published paper included data from an earlier time point. The Committee agreed that, because the proportion of people surviving beyond 26\xa0cycles in clinical practice was uncertain (see above and section\xa04.5), so were the potential cost savings from the patient access scheme, and therefore further validation of the proportion of people on treatment beyond 26\xa0cycles was still required. The Committee recognised that the probabilistic sensitivity analysis presented by the company was unlikely to have captured the uncertainty of the patient access scheme in terms of the proportion who would survive beyond 26\xa0cycles. It noted that the base case of model\xa04 (see sections\xa03.46 to 3.49) was associated with a 25% chance of lenalidomide being cost effective at £20,000 per quality‑adjusted life year (QALY) gained (and 65% at £30,000 per QALY gained). It also noted that, if the proportion of people who reached 26\xa0cycles was less than 27%, the ICER would be greater than £30,000 per QALY gained. The Committee agreed that the ICER was uncertain but accepted that a commitment from the company to publish data on the proportion of people on treatment beyond 26\xa0cycles would provide reassurance that the patient access scheme will provide value to the NHS.\n\nThe Committee noted that as the patient access scheme was based on the number of treatment cycles, any treatment interruptions would delay when the patient access scheme would take effect and therefore delay the time to the NHS receiving the rebate or discount. The Committee acknowledged that accounting for treatment interruptions reduced the ICER minimally (from £25,300 with 16\xa0days of interruptions to £22,200 with 42\xa0days; see section\xa03.46). The Committee was aware that accounting for treatment interruptions in the model reduced lenalidomide costs but did not affect treatment benefit. The Committee was aware that the nature of the patient access scheme meant that accounting for treatment interruptions introduces uncertainty about when people would reach 26\xa0cycles of treatment, and therefore when the savings from the patient access scheme could be claimed by the NHS. It heard from the company that they actively monitor the number of cycles that people receive and that this should provide reassurance that the scheme would be realised in practice. The Committee concluded that although treatment interruptions introduce uncertainty on the timing of when the patient access scheme could be claimed, this did not have a substantial impact on the ICER.\n\nThe Committee considered the ICERs resulting from the company's economic analyses, as well as the results of the ERG's exploratory analyses. The Committee noted that the revised company's base‑case ICER, which included the patient access scheme and accounted for treatment interruptions (model\xa04; see sections\xa03.46 to 3.49), for lenalidomide compared with best supportive care was approximately £25,300 per QALY gained. The Committee agreed that the patient access scheme increased all of the uncertainties, and there was a risk that savings from the patient access scheme would not be realised in clinical practice. The Committee acknowledged that the data collection committed to by the company will ensure that the uncertainties of the assumptions used to model the patient access scheme can be addressed when the guidance is reviewed. However, it would not be able to address the loss in health benefits for other patients in the NHS that may result in the interim from lenalidomide not being a cost effective use of NHS resources. It understood that the company is keen to work with the Department of Health should such a situation arise, to ensure that the NHS realises the full financial benefits of the patient access scheme. The Committee concluded that lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality was a cost‑effective use of NHS resources, when taking these assurances into account.\n\nThe Committee discussed how innovative lenalidomide is in its potential to make a significant and substantial impact on health‑related benefits. It heard about the notable benefits of lenalidomide from patient and professional groups during consultation. It agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions meant that lenalidomide offered a substantial step change in treatment.\n\nThe Committee examined whether there were any potential issues affecting groups protected by equality legislation. The Committee noted the comments from consultees about the Jehovah's Witness group, who are unable to receive blood transfusion for religious reasons. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of people, or about the effectiveness of lenalidomide in this population. Therefore the Committee agreed that it did not need to amend any of its recommendations for the group of people unable to receive blood transfusions.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA322\n\nAppraisal title: Lenalidomide for treating myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality\n\nSection\n\nKey conclusion\n\nLenalidomide is recommended as an option within its marketing authorisation, that is, for treating transfusion‑dependent anaemia caused by low or intermediate‑1‑risk myelodysplastic syndromes (MDS) associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.\n\nThe Committee concluded that lenalidomide is a clinically effective treatment for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate, because it was associated with a statistically significant improvement in transfusion independence and health related quality of life compared with placebo. The Committee agreed that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence.\n\nThe Committee noted that the revised company's base‑case incremental cost‑effectiveness ratio (ICER) for lenalidomide compared with best supportive care with the patient access scheme was £25,300 per QALY gained. The Committee noted that the patient access scheme was not a simple discount and that would only benefit those on treatment after 26\xa0cycles. The Committee agreed that because the proportion of people on treatment beyond 26\xa0cycles was uncertain so were the potential cost savings from the patient access scheme, and noted that if the proportion of people who reached 26\xa0cycles was less than 27%, the ICER would be greater than £30,000 per QALY gained.\n\nThe Committee agreed that the ICER was uncertain, because of the patient access scheme, but accepted that a commitment from the company to publish data on the proportion of people on treatment beyond 26 cycles would provide reassurance that lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality was recommended as a cost‑effective use of NHS resources.\n\n, 4.4, 4.5, 4.11, 4.13\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe main treatment option currently available for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate is best supportive care, which involves regular red blood cell transfusions.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee heard that lenalidomide is an effective targeted therapy which reduces the need for blood transfusions, subsequently reducing fatigue significantly and improving quality of life. The patient experts suggested that lenalidomide is a convenient, effective oral drug. The Committee agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions meant that lenalidomide offered a substantial step change in treatment\n\n, 4.14\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nLenalidomide has a marketing authorisation 'for the treatment of transfusion‑dependent anaemia due to low- or intermediate‑1‑risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate'.\n\n\n\nAdverse reactions\n\nThe Committee concluded that, although lenalidomide is associated with some adverse reactions, these can be managed by dose interruptions.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe company presented data from a randomised controlled trial, MDS‑004, which didn't include many people but was still robust enough, and on balance was generalisable to the decision problem.\n\n, 4.4, 4.5\n\nRelevance to general clinical practice in the NHS\n\nThe Committee noted that the MDS‑004\xa0study included a broader range of people than that specified in the marketing authorisation and the NICE scope because the marketing authorisation specified 'when other therapeutic options are insufficient or inadequate', which was not an inclusion criteria of the study. In addition, the study included people with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. The company explained that the additional cytogenetic abnormalities included in the trial population may mean the trial population had a poorer prognosis than that of the marketing authorisation. Despite these differences the Committee agreed that on balance the study was generalisable to the marketing authorisation population, and how lenalidomide would be used in clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe main uncertainty in the clinical evidence was the relationship between lenalidomide response, transfusion independence and overall survival. Overall survival could not be estimated from the clinical trial as people on the placebo arm could receive lenalidomide after 16 weeks. Instead overall survival was estimated based upon transfusion independence. During consultation the company presented longer term data (from 7 years follow up rather than 5) that continued to support a relationship between transfusion independence and overall survival. The Committee agreed that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence, but that this was uncertain.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone were identified.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that, on the basis of the evidence on transfusion independence and health‑related quality of life, lenalidomide is a clinically effective treatment for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company developed a de novo Markov model that compared lenalidomide 10\xa0mg with best supportive care for low‑ to intermediate‑1\xa0risk MDS with deletion 5q.\n\nThe Committee considered revised models from the company in response to a NICE request for additional analyses relating to the modelling of the patient access scheme. It acknowledged that the company had amended the model in response to concerns that were raised. The Committee considered the revised models appropriate for its decision‑making.\n\n\n\n\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe realisation of the patient access scheme in clinical practice was uncertain. The patient access scheme was not a simple discount, instead, after 26 cycles, lenalidomide would be provided free of charge to the NHS. The survival estimates in the model were uncertain and therefore so was the proportion of people who would remain on treatment after 26 cycles to become eligible for the patient access scheme, and therefore the cost savings to the NHS under this scheme were uncertain. The Committee agreed that the ICER was uncertain but accepted that a commitment from the company to publish data on the proportion of people on treatment beyond 26 cycles would provide reassurance that the patient access scheme will provide value to the NHS.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee concluded that the utility values were a reasonable reflection of the impact of transfusion status on health‑related quality of life in people with low or intermediate‑1 risk MDS associated with deletion 5q cytogenetic abnormality, and could therefore use these values for decision‑making in this appraisal.\n\nThe Committee agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions meant that lenalidomide offered a substantial step change in treatment.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted that overall survival and the patient access scheme were key drivers of the ICER estimates in the company's model.\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe Committee noted that the revised company's base‑case ICER, which included the patient access scheme and accounted for treatment interruptions (model 4), for lenalidomide compared with best supportive care was approximately £25,300 per QALY gained.\n\nThe Committee agreed that the patient access scheme increased all of the uncertainties, and there was a risk that savings from the patient access scheme would not be realised in clinical practice, because of the uncertainty about survival estimates.\n\nThe Committee acknowledged that the data collection committed to by the company will ensure that the uncertainties of the assumptions used to model the patient access scheme can be addressed when the guidance is reviewed. However, it would not be able to address the loss in health benefits for other patients in the NHS that may result in the interim from lenalidomide not being a cost effective use of NHS resources. It understood that the company is keen to work with the Department of Health should such a situation arise, to ensure that the NHS realises the full financial benefits of the patient access scheme. The Committee concluded that lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality was a cost‑effective use of NHS resources, when taking these assurances into account\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe Committee discussed the patient access scheme, noting that it was not a simple discount, The NHS pays for lenalidomide treatment for up to 26 cycles. The patient access scheme presented would not benefit the whole patient population because only some people would become eligible, those who continued to receive lenalidomide after 26 cycles. It noted that the reduction in costs achieved through the patient access scheme would be based on the number of people surviving after 26\xa0cycles, and how long they survived and continued treatment, and that this was uncertain. The Committee highlighted that if the patient access scheme could be underwritten, for example, by the company offering a rebate in the event that the number of people remaining on treatment after 26 cycles was less than 31.9%, this could provide some reassurance and reduce some of the uncertainty associated with the scheme.\n\n\n\nEnd‑of‑life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee noted the comments from consultees about the Jehovah's Witness group who are unable to receive blood transfusion for religious reasons. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of people, or about the effectiveness of lenalidomide in this patient population. Therefore the Committee agreed that it did not need to amend any of its recommendations for the group of people unable to receive blood transfusions.\n\n", 'Recommendations for further research ': 'The Committee noted that the cost effectiveness of lenalidomide compared with standard care for people with low‑ or intermediate‑1‑risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate, was sensitive to whether the patient access scheme would be realised in clinical practice. The Committee agreed that it would be critical to generate evidence to support the following:\n\nThe proportion of people who become eligible for the patient access scheme, that is, that they remain on treatment beyond 26\xa0cycles.\n\nThe benefit of lenalidomide after 26\xa0cycles, that is the associated overall survival and health related quality of life for those who remain on treatment beyond 26\xa0cycles.'}
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https://www.nice.org.uk/guidance/ta322
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Evidence-based recommendations on lenalidomide (Revlimid) for treating myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality in adults.
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60bfe35257fc6b27d424af3cec6ea350281fa1a3
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nice
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Lenalidomide for the treatment of multiple myeloma in people who have received at least 2 prior therapies
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Lenalidomide for the treatment of multiple myeloma in people who have received at least 2 prior therapies
Evidence-based recommendations on lenalidomide (Revlimid) for treating multiple myeloma in adults who have had at least 2 prior therapies.
# Guidance
Lenalidomide in combination with dexamethasone is recommended, within its licensed indication, as an option for the treatment of multiple myeloma only in people who have received 2 or more prior therapies. It is recommended only if the company provides lenalidomide according to the commercial arrangement.
People currently receiving lenalidomide for the treatment of multiple myeloma, but who have not received 2 or more prior therapies, should have the option to continue therapy until they and their clinicians consider it appropriate to stop.# The technology
Lenalidomide (Revlimid, Celgene) is an immunomodulating agent. It belongs to a class of agents often referred to as immunomodulatory derivatives, which are all structural derivatives of thalidomide. The exact mechanism of action of lenalidomide is not understood but it has anti-neoplastic, anti-angiogenic and pro-erythropoietic properties. Lenalidomide in combination with dexamethasone is licensed for the treatment of multiple myeloma in patients who have received at least one prior therapy. The recommended starting dose of lenalidomide for adults over 18 years is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles. Treatment with lenalidomide is continued until disease progression or unacceptable adverse effects occur. For full details, see the summary of product characteristics.
The most serious adverse effects of lenalidomide treatment are grade 4 neutropenia and venous thromboembolism. The most frequently observed adverse effects, which occurred significantly more frequently in the lenalidomide/dexamethasone group compared with the placebo/dexamethasone group in clinical trials (see section 3), were neutropenia, fatigue, asthenia, constipation, muscle cramp, thrombocytopenia, anaemia, diarrhoea and rash. Lenalidomide is structurally related to thalidomide and there is a risk of teratogenesis. Pregnancy must be ruled out before starting treatment in women of child-bearing age, and these women must use effective contraception while on lenalidomide. For full details of adverse effects and contraindications, see the summary of product characteristics.
Lenalidomide 25 mg capsules cost £4368 per 21 capsules (excluding VAT; 'British national formulary' edition 55). Dosage is continued or modified based upon clinical and laboratory findings. For example, if lenalidomide is continued for ten 28-day cycles without dose reduction, the cost would be £43,680. The pricing arrangement considered during guidance development was that the manufacturer (Celgene) had agreed a complex patient access scheme with the Department of Health, in which the cost of lenalidomide for people who remain on treatment for more than 26 cycles would be met by the manufacturer. A commercial arrangement has now been agreed. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the manufacturer's responsibility to let relevant NHS organisations know details of the discount.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of lenalidomide and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer produced an analysis of the clinical and cost effectiveness of lenalidomide for the treatment of multiple myeloma in people who had received at least one prior therapy. This included people at first and subsequent relapse and people who had progressive disease after two or more cycles of anti-myeloma treatment. The trial population was divided into five subgroups for the economic analysis. For people who had received only one prior therapy the main comparator was bortezomib monotherapy, which is currently recommended as a treatment option in 'Bortezomib monotherapy for relapsed multiple myeloma' (NICE technology appraisal guidance 129). For people in whom bortezomib was contraindicated, people who had received two or more prior therapies and people who had received prior thalidomide (only one prior therapy or two or more prior therapies), the comparator was dexamethasone.
Two randomised controlled trials (RCTs), of identical design but differing in their locations (MM-009 and MM-010), compared treatment with lenalidomide plus dexamethasone (len/dex) with dexamethasone alone for patients with multiple myeloma who had received at least one prior therapy. In both arms, the regimen of dexamethasone was pulsed high-dose dexamethasone in 28-day cycles. The trials enrolled 353 and 351 patients, respectively (n = 704). Patients were stratified according to their serum concentration of β2-microglobulin, previous stem-cell transplantation and number of previous anti-myeloma therapies. Treatment was continued until the disease progressed or unacceptable adverse effects occurred. The primary outcome was time to progression (TTP). Secondary outcomes were overall survival, response rates, adverse effects and time to decrease in performance status. Response was assessed using the European Group for Blood and Marrow Transplantation criteria, and six response categories were defined: complete response, near-complete response, partial response, stable disease, disease progression and 'response not evaluable'. A number of post-hoc subgroups from the pooled populations were investigated, including patients with pre-existing peripheral neuropathy and patients who had received prior thalidomide or bortezomib therapy. At disease progression or unblinding, patients in the dexamethasone monotherapy group were allowed to receive lenalidomide.
The median TTP at unblinding from the pooled trials was 48.3 weeks (95% confidence interval 41.1 to 60.1 weeks) for the len/dex arms and 20.1 weeks (95% CI 19.9 to 20.7 weeks) for the dexamethasone arms. The pooled hazard ratio for TTP was 0.35 (95% CI 0.29 to 0.43; log-rank p < 0.001). The median overall survival in one trial, analysed 3 years and 3 months after study initiation, was 29.6 months in the len/dex arm and 20.2 months in the dexamethasone arm (hazard ratio 0.44; 95% CI 0.30 to 0.65; p < 0.001). In the second trial, the median overall survival was analysed 2 years and 8 months after study initiation; it could not be estimated in the len/dex arm (because of the number of patients still alive), and was 20.6 months in the dexamethasone arm (hazard ratio 0.66; 95% CI 0.45 to 0.96; p = 0.03). For the pooled trials, the subgroup of patients who had received one prior therapy had a median survival of 169.1 weeks in the len/dex arm compared with 145.4 weeks in the dexamethasone arm. For the subgroup of patients who had received two or more prior therapies, the median survival was 144.0 weeks in the len/dex arm compared with 118.0 weeks in the dexamethasone arm. A complete, near-complete or partial response was obtained in 60.6% of patients in the len/dex arms and 21.9% of patients in the dexamethasone arms. The remaining 39.4% of patients in the len/dex arms and 78.1% of patients in the dexamethasone arms had stable or progressive disease, or were not evaluable. The odds ratio for this dichotomised response (complete, near-complete or partial response versus stable disease, progressive disease or response not evaluable) was 5.48 (95% CI 3.94 to 7.63; p < 0.001). Over the course of the first 23 cycles in the trial, about 70% of the treatment days for all patients in the trial were at the full dose of lenalidomide. The dose of lenalidomide was reduced on about 25% of the treatment days, and treatment was interrupted on about 5% of the days.
The results for overall survival were affected by crossover of patients at unblinding: 170 of 351 patients in the dexamethasone arm opted to receive lenalidomide at disease progression or unblinding. However, these patients were analysed as remaining in the dexamethasone arm. The TTP was also affected by the crossover, but to a lesser degree because most patients (over 75%) had shown disease progression at unblinding.
In both trials, the differences in TTP and response rates (in favour of len/dex) were observed in all of the prespecified subgroups. The post-hoc subgroups in the trial showed that the efficacy of len/dex relative to dexamethasone alone remained statistically significant in subgroups that had received prior treatment with thalidomide or bortezomib and in subgroups specified by the number of previous therapies for multiple myeloma.
A meta-analysis was also performed to combine the results of the trials and to confirm the results obtained by the pooling of trials. This resulted in a median difference in TTP of 28.24 weeks (95% CI 18.39 to 38.08 weeks) and an odds ratio for overall survival of 1.44 (95% CI 1.34 to 1.56). The hazard ratio was not calculated. There was no evidence of heterogeneity between the trials.
An indirect comparison was undertaken to compare len/dex with bortezomib monotherapy because there were no head-to-head trials. The results of the trials for len/dex were compared with the results of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) RCT. The APEX study compared bortezomib with high-dose dexamethasone. For median TTP, len/dex had a 34-week advantage over bortezomib for people who had received one prior therapy only, and there were no statistically significant differences for the secondary outcomes of complete response, partial response and progressive disease. However, this analysis is limited by the small number of data points. In addition, the common comparator (high-dose dexamethasone) was an active treatment and was not used in the same dose across the trials, and the definition of response differed between the trials.
The economic evaluation in the manufacturer's submission used a discrete-event simulation model. This model used two separate prediction equations to calculate TTP and post-progression survival values, which were then added together to give overall survival. A cohort was created by randomly sampling (with replacement) patients from the pooled trial populations. For subgroups within the model, the cohort was created from the relevant population. The model attempted to capture the variability between individuals in the trial and to allow correlation between observed parameters to be retained.
The model divided patients from both arms of both trials into four groups according to their level of response. In building a cohort for the study population or any of the subgroups, the model ensured that the proportion of patients achieving a particular response in the trial was replicated in the cohort. To calculate TTP, the model assumed a Weibull distribution. For bortezomib, the response rates were taken from the APEX trial and the equation for TTP was calibrated such that the median TTP was the same as that within the trial.
The equation for post-progression survival was assumed to take an exponential form. However, the trial results were affected by the crossover of patients at unblinding from the dexamethasone arm to receive lenalidomide. Therefore the equation included an adjustment factor that calibrated the modelled median overall survival in the dexamethasone group after progression to be equal to that observed in the UK Medical Research Council (MRC) multiple myeloma trials. This assumed that survival of people with multiple myeloma in this cohort was the same when treated with dexamethasone as with all other regimens used in the MRC trials. The patient profiles from the RCTs in the manufacturer's submission were applied to the predictors in the survival equations derived from the MRC trial data to predict survival in the dexamethasone arm if crossover had not occurred.
The model considered subgroups of patients who had received one prior therapy (with this group divided further into those who did and did not have peripheral neuropathy), patients who had received two or more prior therapies, and patients who had received thalidomide (divided further into those who had received only one prior therapy and those who had received two or more prior therapies). For patients who had received only one prior therapy, len/dex was compared with bortezomib monotherapy. For patients with peripheral neuropathy and for those who had received two or more prior therapies, the comparator was dexamethasone alone.
The utility values were based on a study that evaluated intensive chemotherapy followed by myeloablation and autologous stem-cell transplantation in people with multiple myeloma. For the complete response, partial response and stable disease states, a utility value of 0.81 was used. This value was based on the utility of the general public at an age (median 54 years) corresponding to that of the patients in the study. A utility value of 0.64 was applied to the progressive disease state. After 2 years, a utility value of 0.77 was applied to those patients whose disease had not progressed.
Only grade 3 and 4 adverse effects were included in the model. Utility decrements for adverse effects were not included. Resource-use data associated with, for example, adverse effects, routine follow-up and laboratory tests were collected to build up a profile of resource use, depending on disease state and treatment. Resource-use profiles were developed for people during relapse and/or on treatment, and for people in remission on maintenance therapy or off therapy. Resource use was estimated by interviewing 15 specialists across England and Wales who specialised in the management of multiple myeloma.
The economic analysis did not produce cost-effectiveness estimates for the whole trial population. In the base case, for the subgroup with one prior therapy, the model resulted in an incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained for lenalidomide that the manufacturer stated was not cost effective compared with bortezomib. For the one prior therapy subgroup, the ICER was £46,865 per QALY gained for lenalidomide compared with dexamethasone. For patients who had received two or more prior therapies the ICER was £24,584 per QALY gained. In the subgroup of patients who had received prior thalidomide, the ICERs were £38,861 per QALY gained for patients with only one prior therapy and £22,589 per QALY gained for patients who had received two or more prior therapies.
The ERG explored the precision with which the fitted curve for len/dex matched the actual trial data used in the model. It observed that the fitted curve overestimated overall survival. The ERG noted that the overall survival curve for the dexamethasone arm in the cost-effectiveness model had been adjusted to predict the median overall survival predicted from the MRC trials. However, the ERG stated that it was more methodologically correct to adjust the dexamethasone overall survival calculation in the model to predict the mean overall survival predicted from the MRC trials, because the ICERs calculated from the model were a ratio of means and not medians.
The ERG conducted an exploratory analysis with an improved fit of the len/dex overall survival curve and also with the dexamethasone curve adjusted to the mean overall survival in the MRC trials. For the subgroup of patients who had received only one prior therapy where len/dex was compared with bortezomib, the ICER increased more than 30-fold from the manufacturer's base case. For the subgroup who had received one prior therapy where the comparator was dexamethasone, the ICER increased from £46,865 to £69,500 per QALY gained. For the subgroup of patients who had received two or more prior therapies, the ICER increased from £24,584 to £47,100 per QALY gained. For patients who had received prior thalidomide, the ICER increased from £38,861 to £56,500 per QALY gained if they had received only one prior therapy and from £22,589 to £43,600 per QALY gained if they had received two or more prior therapies.
In addition, the ERG noted that the costs associated with routine medical management (non-drug costs) assumed in the model were lower than the figures that were accepted in the appraisal of bortezomib and may therefore have been underestimated. It also noted that the model had no disutility attached to the occurrence of adverse effects. Finally, it noted that the cost of anti-thrombotic prophylaxis that was routinely used with lenalidomide was not included in the model. The ERG stated that the inclusion of the above considerations in the model would further increase the ICERs for all subgroups above the values obtained in the exploratory reanalyses quoted above.
For the subgroup of patients who had received only one prior therapy, the ERG repeated the indirect comparison of len/dex with bortezomib using methods that it considered to be more appropriate. This resulted in a hazard ratio of 0.557 (95% CI 0.337 to 0.912). The ERG pointed out that this comparison was with bortezomib as monotherapy and that bortezomib was commonly used in combination with dexamethasone in routine clinical practice. The economic analysis for the comparison of len/dex with bortezomib also assumed a maximum of eight cycles of bortezomib instead of the 11 allowed in the trial, and did not model the response-based rebate scheme recommended in NICE technology appraisal guidance 129. The ERG also suggested that the administration costs associated with bortezomib may have been overestimated in the manufacturer's model. In addition, the dose intensity for bortezomib was assumed to be 100%; that is, the analysis did not allow for dose reductions and treatment interruptions, which had been included for lenalidomide. All of the above issues would have had the effect of increasing the ICERs for the comparison of len/dex with bortezomib in the subgroup of patients who had received only one prior therapy.
After the first Appraisal Committee meeting, the manufacturer presented an updated cost-effectiveness analysis. The manufacturer stated that this updated analysis would only consider all patients who had received two or more prior therapies and the subgroup of patients who had received thalidomide as one of these prior therapies. The manufacturer accepted the ERG's approach to modelling the len/dex overall survival curve. However, the manufacturer did not agree with the calibration of the overall survival curve for dexamethasone alone in the cost-effectiveness model to the mean overall survival predicted from the MRC trials. The manufacturer stated that a curve calibrated to the mean rather than the median overall survival was less representative of the published curves, and that using the mean placed more emphasis on the tail of the distribution, where there were fewer patients and greater uncertainty. The manufacturer maintained that it was appropriate to calibrate the curve to the predicted median survival in the updated analysis. In addition, the updated analysis incorporated costs for outpatient visits into routine management costs, and inflated the routine management costs to 2008 values. The effects of adding costs for the prophylaxis of deep vein thrombosis and disutility for long-term adverse effects were also explored in the updated model through sensitivity analyses. The manufacturer also proposed a patient access scheme in which the cost of lenalidomide to the NHS for a person with multiple myeloma will be capped at 26 cycles of treatment (each of 28 days, so normally administered over 2 years). A cycle will still be considered as having been completed within the scheme even if there are dose reductions and treatment interruptions during the cycle. The drug cost of lenalidomide (excluding any related costs) for people who remain on treatment for more than 26 cycles will be met by the manufacturer. The Department of Health in England and the Department of Health and Social Services in Wales accepted the consideration of this scheme by NICE.
Taking all these factors into account in the model, for patients who had received two or more prior therapies the incremental life-year gain was 2.77, the incremental QALY gain was 1.86 and the ICER was £30,350 per QALY gained. For patients who had received thalidomide as one of the prior therapies the incremental life-year gain was 2.51, the incremental QALY gain was 1.7 and the ICER was £28,941 per QALY gained. These ICERs were relatively insensitive to the addition of costs for prophylaxis of deep vein thrombosis or disutility for long-term adverse effects.
The ERG considered the updated analyses from the manufacturer and agreed with the implementation of the stated changes. It noted that the model predicted that, for the group of patients who had received two or more prior therapies, the patient access scheme applied to 17% of the people in the model. The estimated average cost of treatment with lenalidomide to the NHS per person over a modelled lifetime (median overall survival approximately 2.7 years) decreased from £59,800 to £51,800 with the patient access scheme. For the subgroup of patients who had received thalidomide as one of their prior therapies the patient access scheme applied to 11% of people in the model, and the modelled lifetime cost of treatment with lenalidomide to the NHS per person decreased from £49,800 to £46,300 with the patient access scheme.
The ERG repeated the exploratory analysis on the updated model using their preferred approach with the dexamethasone overall survival curve calibrated to the mean survival predicted from the MRC trials and the patient access scheme implemented in the model. For the subgroup of patients who had received two or more prior therapies, the incremental life-year gain was 1.81 and the incremental QALY gain was 1.24 at an incremental cost of £54,291, giving an ICER of £43,800 per QALY gained. For patients who had received thalidomide as one of the prior therapies, the incremental life-year gain was 1.71 and the incremental QALY gain was 1.15 at an incremental cost of £47,531, giving an ICER of £41,300 per QALY gained.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of lenalidomide, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of lenalidomide by people with the condition, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
The Committee understood that multiple myeloma is an incurable disease. It was aware that the disease and its course are heterogeneous and that for relapsed multiple myeloma the choice of therapy for a particular person is influenced by the initial treatment and their response to it, the inherent characteristics of the disease and the person's performance status and preferences. The Committee heard from clinical specialists and patient experts that lenalidomide is an important advance in the treatment of multiple myeloma and could be considered as an alternative to bortezomib (currently recommended as a treatment option in NICE technology appraisal guidance 129) at first relapse. The Committee noted the importance that patients, their carers and physicians placed on having effective options to treat multiple myeloma at presentation and at subsequent relapses. However, it understood that the optimal sequence of agents to use is as yet unclear and depends on several factors, including a person's treatment history, comorbidities and disease characteristics.
The Committee understood that, in accordance with current NICE guidance (NICE technology appraisal guidance 129), bortezomib is routinely used in clinical practice for the treatment of progressive multiple myeloma in people who are at first relapse having received only one prior therapy. Therefore it considered bortezomib to be the most appropriate comparator for lenalidomide in people who have had only one prior therapy. The Committee noted that bortezomib is usually used in combination with dexamethasone, but that there is variation in clinical practice and limited formal evidence for the superior efficacy of this combination compared with bortezomib monotherapy.
The Committee considered the options available for the treatment of multiple myeloma at second and subsequent relapse. Current NICE guidance restricts the use of bortezomib to first relapse because the use of bortezomib at subsequent relapses was found not to be cost effective (NICE technology appraisal guidance 129), with ICERs of £77,000 or more per life year gained. Thalidomide is not licensed for this indication, and an application for a licence for the treatment of relapsed or refractory multiple myeloma was withdrawn. However, thalidomide is used as a treatment option for multiple myeloma within the NHS, although the extent of this use is not known. The Committee also noted a statement from the manufacturer that there is a lack of evidence for the efficacy of thalidomide for this indication, particularly after failure of two or more therapies. The Committee understood that a variety of other regimens could be used at second and subsequent relapse, but that no studies had been identified that have demonstrated the superiority of these compared with dexamethasone alone. Therefore it accepted that in people who have received two or more prior therapies, high-dose dexamethasone was a reasonable comparator for lenalidomide.
The Committee discussed the RCTs comparing len/dex with dexamethasone alone for the management of relapsed multiple myeloma. It noted that TTP (the primary outcome) was statistically significantly increased in the len/dex arm for the whole trial population as well as in subgroups of people who had received prior therapy with bortezomib or thalidomide. It considered that the RCTs provided evidence that overall survival and response rates were also higher with len/dex compared with dexamethasone alone. The Committee concluded that the len/dex combination improved outcomes in people with relapsed multiple myeloma when compared with dexamethasone. This included people who had received either one or two or more prior therapies, and when prior therapies included the use of thalidomide.
The Committee next discussed the relative effectiveness of len/dex compared with bortezomib. It noted that the evidence for the effectiveness of len/dex compared with bortezomib monotherapy was derived from an indirect comparison via the common comparator of high-dose dexamethasone. It considered that there was uncertainty in the results of the indirect comparison because of heterogeneity between the studies, such as differences in the regimen of dexamethasone and the definition of response. The Committee noted that there was additional uncertainty in interpreting the context of current practice, as it understood that bortezomib is usually used in combination with dexamethasone in clinical practice.
The Committee discussed the adverse effects associated with lenalidomide. It noted that from the patients' viewpoint lenalidomide is associated with a more favourable adverse effect profile than most other regimens and agents used in the management of relapsed multiple myeloma. It heard from clinical specialists and patient experts that lenalidomide might be particularly useful for people with pre-existing peripheral neuropathy, in whom the use of bortezomib at first relapse is restricted. However, the Committee noted that lenalidomide is associated with a statistically significant increased risk of venous thrombosis and embolism. It heard from clinical specialists that this risk is usually managed with prophylaxis in the form of low-dose aspirin in people with multiple myeloma. However, in people with a history of venous thromboembolism or other relevant risk factors, the use of warfarin or low-molecular-weight heparin would be considered. The Committee heard that with such prophylaxis the risk would return to baseline levels. The additional cost incurred for the management of people with multiple myeloma would be minimal if low-dose aspirin was used, but could have an impact if either low-molecular-weight heparin or warfarin was needed.
The Committee considered the manufacturer's economic evaluation of the use of lenalidomide and the critique from the ERG. It accepted that the general structure of the manufacturer's model was reasonable. It considered that the subgroups in the model were those relevant to decision-making in routine clinical practice. It discussed the sensitivity and scenario analyses presented by the manufacturer, as well as those explored by the ERG using the manufacturer's model. In particular, the Committee discussed the methods used for adjustment for the crossover effect in the RCTs, the extrapolation of survival data, the costs of medical management and administration of bortezomib therapy, and the utility values reflecting health-related quality of life for the pre-progression and post-progression states and from adverse effects.
The Committee noted that the trial results included a crossover effect and considered whether it was appropriate to use data from historical MRC trials to predict survival for people treated with dexamethasone in this population in the absence of an unbiased estimate from the trials of lenalidomide. The Committee was aware that the MRC data were derived from trials of agents in first-line therapy for multiple myeloma. Despite this, it accepted that these data represented the best available survival data for people with multiple myeloma to be used in extrapolation of overall survival in the current analysis. The Committee also noted that use of these data assumed that dexamethasone monotherapy was a suitable proxy (in the absence of more specific evidence) for all anti-myeloma therapies used in relapse. The Committee also considered that there was no evidence to indicate that the effectiveness of dexamethasone in relation to survival had changed over time since the MRC trials. It accepted the statements from the clinical specialists indicating that where improvements were noticed these were likely to be attributable to the use of the newer agents and stem-cell transplantation.
The Committee considered the ERG's exploratory reanalysis with an improved fit of the len/dex overall survival curve to the trial data and calibration of the dexamethasone overall survival curve to predict mean (and not median) overall survival based on a risk equation for survival derived from the MRC trials. The Committee considered that the ERG's approach to modelling overall survival in both the len/dex and dexamethasone arms was valid and resulted in more plausible estimates of cost effectiveness than those presented by the manufacturer. The Committee noted that these adjustments to the modelling of survival may have different effects in different subgroups and that the ERG's adjustments had been made separately to subgroups defined according to number of prior therapies.
The Committee considered the base-case ICERs resulting from the manufacturer's economic analysis, as well as the results of the ERG's exploratory analysis using the alternative approach to the modelling of overall survival. It noted that, in the manufacturer's base case, none of the ICERs for lenalidomide for the subgroups with only one prior therapy were within the range that would normally be considered a cost-effective use of NHS resources. The Committee noted that the comparison of len/dex with bortezomib in the subgroup of people who had received only one prior therapy resulted in a high ICER. The Committee also considered that the ICER for the comparison with bortezomib would increase further if the model took into account: the bortezomib response-based rebate scheme (as described in NICE technology appraisal guidance 129); the lower costs of bortezomib administration suggested by the ERG; the higher maximum number of cycles of bortezomib; and the likely dosage reduction for bortezomib. When the ERG's approach to modelling overall survival was used, the ICER was more than £69,000 per QALY gained for the comparison of lenalidomide with dexamethasone in people who had received one prior therapy only. For the comparison with dexamethasone in people who had received one prior therapy and that therapy was thalidomide, the ICER was more than £56,000 per QALY gained.
The Committee considered other issues with the base-case analysis. The model did not fully include costs and utility decrements owing to adverse effects, and the Committee considered that if appropriate costs and disutilities for adverse effects and anti-thrombosis prophylaxis were used in the model, the ICERs for lenalidomide would increase. It also noted that the utility in the model for the pre-progression state was that of the normal population at age 54 years, and that this is considerably younger than the average age of people who usually develop multiple myeloma. The Committee noted the results of the exploratory analysis by the ERG, which showed that using lower administration costs for bortezomib, using higher costs for routine medical management and modelling the bortezomib response-based rebate scheme all had the effect of increasing the ICERs for lenalidomide for the subgroup of patients who had received one prior therapy. The Committee concluded that, in the light of these additional issues, the most plausible ICERs in all subgroups would be higher than those stated in 4.11.
The Committee discussed the updated analysis presented by the manufacturer. It noted that the manufacturer had chosen not to present any new analysis for people who had received only one prior therapy. The Committee discussed whether there were any further factors that would have a bearing on its considerations about the cost effectiveness of lenalidomide in this patient group. These included the degree of certainty in the ICERs, the severity of the illness experienced by people with multiple myeloma who have received one prior therapy and the innovative nature of lenalidomide. It did not identify any factors that would alter its conclusions based on the evidence currently available. Overall, the Committee concluded that the use of lenalidomide for the treatment of multiple myeloma in people who had received only one prior therapy would not be a cost-effective use of NHS resources.
The Committee considered the subgroups of people who had received two or more prior therapies, including the subgroup who had received thalidomide as one of these therapies. When the ERG's approach to modelling overall survival was used, the ICERs for lenalidomide for these subgroups increased to at least £47,100 per QALY gained for those who had received two or more prior therapies, and to at least £43,600 per QALY gained for those who had received two or more prior therapies of which one was thalidomide.
The Committee discussed the updated analysis from the manufacturer and the exploratory reanalysis by the ERG for people who had received two or more prior therapies. The Committee concluded that the changes to the len/dex curve, utilities and costs had been implemented appropriately. The Committee noted that the variable that had the greatest impact on cost effectiveness was the method of calibrating the dexamethasone overall survival curve in the economic model (that is, to the predicted median or mean survival for the trial population) from the risk equation for survival derived from the MRC trials. The Committee noted that the data from the MRC trials were complete, with most participants having reached the outcome of interest (that is, there was very little censoring of the data), and that in such a situation the mean was a better estimate of average survival. It considered that, since the mean overall survival was used in the calculations of cost effectiveness, calibrating the overall survival predicted by the MRC data calibration model to the mean was more representative of the costs and benefits for this population. In addition, the Committee noted that when median survival was used to calibrate the survival curve, the improvement in overall survival predicted by the model was out of proportion to the observed improvement in progression-free survival from the lenalidomide trials. This relationship between the progression-free survival and overall survival from the lenalidomide trials was, however, maintained when calibrating the overall survival curve in the dexamethasone arm to the mean survival predicted from the MRC trials. The Committee understood that the choice between the use of mean or median survival was a scientific judgement, but concluded that for the purposes of decision-making in this situation, the ICER estimates from using the mean were most appropriate.
The Committee accepted that the patient access scheme for lenalidomide was correctly implemented by the manufacturer in the economic evaluation. It noted that, in the economic model, the patient access scheme was included by capping the maximum cost of lenalidomide for an individual patient at 26 cycles of 28 days each, equivalent to 2 years. The Committee noted that the manufacturer stated that treatment interruptions within cycles were generally short, and that no patients missed entire cycles in the clinical trial. The cost of lenalidomide per cycle in the model was adjusted, as in the base case, to take into account the treatment reductions and interruptions noted in the first 23 cycles in the trials. The Committee concluded that the relevant and appropriate ICERs upon which to make a decision were £43,800 per QALY gained for the subgroup of patients who had received two or more prior therapies and £41,300 per QALY gained for the subgroup who had received two or more prior therapies including thalidomide. These ICERs represented the cost effectiveness of lenalidomide with the patient access scheme triggered after 26 cycles, regardless of any dose reductions or treatment interruptions that may occur during a cycle, and were the basis for the Committee's decisions.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
No alternative treatment with comparable benefits is available through the NHS.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.
The Committee next discussed whether the subgroup of people with multiple myeloma who had received two or more prior therapies, and the benefit provided by lenalidomide, fulfilled the criteria for consideration as an appraisal of a life-extending, end-of-life treatment. The Committee noted from the clinical trials and the MRC data that normal life expectancy without lenalidomide was unlikely to be greater than 24 months and was potentially as low as 9 months. The Committee considered that evidence from the lenalidomide trials suggested that lenalidomide increased survival by more than 3 months compared with dexamethasone, and that crossover in the dexamethasone arm means that this benefit is likely to have been underestimated. The Committee considered that the potential alternatives, thalidomide and bortezomib, were unlikely to be routinely available on the NHS, as discussed in section 4.4. The Committee noted from the manufacturer's submission that the estimated eligible population was approximately 2100. In summary, the Committee was satisfied that the population and the technology of interest meet the criteria for accepting that this is an appraisal of a life-extending, end-of-life treatment and that the evidence presented for this consideration was supported by robust data.
The Committee subsequently considered the ERG's cost-effectiveness estimates using the manufacturer's model in the context of a life-extending, end-of-life treatment. It noted that the QALY increment associated with the most plausible cost-effectiveness estimates was approximately 1.24 QALYs. The Committee considered that the magnitude of the additional weight that would need to be assigned to the original QALY benefit for the cost effectiveness of lenalidomide to fall within the currently applied ICER threshold range was acceptable. Additionally, the Committee noted from the model that the extension to life with lenalidomide was approximately 1.81 years. The Committee considered that the impact of giving greater weight to QALYs achieved in the later stages of terminal diseases, using the assumption that the extended survival period is experienced at the full quality of life anticipated for a healthy person of the same age, was acceptable.
In summary, the Committee accepted that, for people with multiple myeloma who had received two or more prior therapies, the most plausible ICERs were those suggested by the ERG on the basis of exploration of the manufacturer's model and with the implementation of the patient access scheme (where the manufacturer would bear the costs of lenalidomide beyond 26 cycles for people whose disease had not progressed at this time). For the purpose of the recommendations, the patient access scheme would be triggered by the completion of 26 cycles (which normally takes 2 years), regardless of treatment interruptions and dose reductions within those cycles. The Committee accepted that the benefits provided by lenalidomide fitted the criteria for consideration for appraising a life-extending, end-of-life treatment. The Committee concluded that the additional weights that need to be attached to the QALYs to achieve ICERs within the normal threshold range are acceptable in these circumstances. Consequently the Committee recommended lenalidomide, within its licensed indication, as an option for the treatment of multiple myeloma in people who have received two or more prior therapies. The Committee noted that some people who have not received two or more prior therapies may be currently receiving lenalidomide for the treatment of multiple myeloma, and recommended that these people should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# Recommendations for further research
The Committee considered that rigorous data collection is needed on the life-extending benefits of lenalidomide when used in people with multiple myeloma who have received two or more prior therapies.
|
{'Guidance': 'Lenalidomide in combination with dexamethasone is recommended, within its licensed indication, as an option for the treatment of multiple myeloma only in people who have received 2\xa0or more prior therapies. It is recommended only if the company provides lenalidomide according to the commercial arrangement.\n\nPeople currently receiving lenalidomide for the treatment of multiple myeloma, but who have not received 2\xa0or more prior therapies, should have the option to continue therapy until they and their clinicians consider it appropriate to stop.', 'The technology ': "Lenalidomide (Revlimid, Celgene) is an immunomodulating agent. It belongs to a class of agents often referred to as immunomodulatory derivatives, which are all structural derivatives of thalidomide. The exact mechanism of action of lenalidomide is not understood but it has anti-neoplastic, anti-angiogenic and pro-erythropoietic properties. Lenalidomide in combination with dexamethasone is licensed for the treatment of multiple myeloma in patients who have received at least one prior therapy. The recommended starting dose of lenalidomide for adults over 18\xa0years is 25\xa0mg orally once daily on days 1 to 21 of repeated 28-day cycles. Treatment with lenalidomide is continued until disease progression or unacceptable adverse effects occur. For full details, see the summary of product characteristics.\n\nThe most serious adverse effects of lenalidomide treatment are grade 4 neutropenia and venous thromboembolism. The most frequently observed adverse effects, which occurred significantly more frequently in the lenalidomide/dexamethasone group compared with the placebo/dexamethasone group in clinical trials (see section 3), were neutropenia, fatigue, asthenia, constipation, muscle cramp, thrombocytopenia, anaemia, diarrhoea and rash. Lenalidomide is structurally related to thalidomide and there is a risk of teratogenesis. Pregnancy must be ruled out before starting treatment in women of child-bearing age, and these women must use effective contraception while on lenalidomide. For full details of adverse effects and contraindications, see the summary of product characteristics.\n\nLenalidomide 25\xa0mg capsules cost £4368 per 21 capsules (excluding VAT; 'British national formulary' [BNF] edition 55). Dosage is continued or modified based upon clinical and laboratory findings. For example, if lenalidomide is continued for ten 28-day cycles without dose reduction, the cost would be £43,680. The pricing arrangement considered during guidance development was that the manufacturer (Celgene) had agreed a complex patient access scheme with the Department of Health, in which the cost of lenalidomide for people who remain on treatment for more than 26\xa0cycles would be met by the manufacturer. A commercial arrangement has now been agreed. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the manufacturer's responsibility to let relevant NHS organisations know details of the discount.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of lenalidomide and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer produced an analysis of the clinical and cost effectiveness of lenalidomide for the treatment of multiple myeloma in people who had received at least one prior therapy. This included people at first and subsequent relapse and people who had progressive disease after two or more cycles of anti-myeloma treatment. The trial population was divided into five subgroups for the economic analysis. For people who had received only one prior therapy the main comparator was bortezomib monotherapy, which is currently recommended as a treatment option in 'Bortezomib monotherapy for relapsed multiple myeloma' (NICE technology appraisal guidance 129). For people in whom bortezomib was contraindicated, people who had received two or more prior therapies and people who had received prior thalidomide (only one prior therapy or two or more prior therapies), the comparator was dexamethasone.\n\nTwo randomised controlled trials (RCTs), of identical design but differing in their locations (MM-009 and MM-010), compared treatment with lenalidomide plus dexamethasone (len/dex) with dexamethasone alone for patients with multiple myeloma who had received at least one prior therapy. In both arms, the regimen of dexamethasone was pulsed high-dose dexamethasone in 28-day cycles. The trials enrolled 353 and 351 patients, respectively (n\xa0=\xa0704). Patients were stratified according to their serum concentration of β2-microglobulin, previous stem-cell transplantation and number of previous anti-myeloma therapies. Treatment was continued until the disease progressed or unacceptable adverse effects occurred. The primary outcome was time to progression (TTP). Secondary outcomes were overall survival, response rates, adverse effects and time to decrease in performance status. Response was assessed using the European Group for Blood and Marrow Transplantation criteria, and six response categories were defined: complete response, near-complete response, partial response, stable disease, disease progression and 'response not evaluable'. A number of post-hoc subgroups from the pooled populations were investigated, including patients with pre-existing peripheral neuropathy and patients who had received prior thalidomide or bortezomib therapy. At disease progression or unblinding, patients in the dexamethasone monotherapy group were allowed to receive lenalidomide.\n\nThe median TTP at unblinding from the pooled trials was 48.3\xa0weeks (95% confidence interval [CI] 41.1 to 60.1\xa0weeks) for the len/dex arms and 20.1 weeks (95% CI 19.9 to 20.7\xa0weeks) for the dexamethasone arms. The pooled hazard ratio for TTP was 0.35 (95% CI 0.29 to 0.43; log-rank p\xa0<\xa00.001). The median overall survival in one trial, analysed 3\xa0years and 3\xa0months after study initiation, was 29.6\xa0months in the len/dex arm and 20.2\xa0months in the dexamethasone arm (hazard ratio 0.44; 95% CI 0.30 to 0.65; p\xa0<\xa00.001). In the second trial, the median overall survival was analysed 2\xa0years and 8\xa0months after study initiation; it could not be estimated in the len/dex arm (because of the number of patients still alive), and was 20.6\xa0months in the dexamethasone arm (hazard ratio 0.66; 95% CI 0.45 to 0.96; p\xa0=\xa00.03). For the pooled trials, the subgroup of patients who had received one prior therapy had a median survival of 169.1 weeks in the len/dex arm compared with 145.4 weeks in the dexamethasone arm. For the subgroup of patients who had received two or more prior therapies, the median survival was 144.0 weeks in the len/dex arm compared with 118.0\xa0weeks in the dexamethasone arm. A complete, near-complete or partial response was obtained in 60.6% of patients in the len/dex arms and 21.9% of patients in the dexamethasone arms. The remaining 39.4% of patients in the len/dex arms and 78.1% of patients in the dexamethasone arms had stable or progressive disease, or were not evaluable. The odds ratio for this dichotomised response (complete, near-complete or partial response versus stable disease, progressive disease or response not evaluable) was 5.48 (95% CI 3.94 to 7.63; p\xa0<\xa00.001). Over the course of the first 23\xa0cycles in the trial, about 70% of the treatment days for all patients in the trial were at the full dose of lenalidomide. The dose of lenalidomide was reduced on about 25% of the treatment days, and treatment was interrupted on about 5% of the days.\n\nThe results for overall survival were affected by crossover of patients at unblinding: 170 of 351 patients in the dexamethasone arm opted to receive lenalidomide at disease progression or unblinding. However, these patients were analysed as remaining in the dexamethasone arm. The TTP was also affected by the crossover, but to a lesser degree because most patients (over 75%) had shown disease progression at unblinding.\n\nIn both trials, the differences in TTP and response rates (in favour of len/dex) were observed in all of the prespecified subgroups. The post-hoc subgroups in the trial showed that the efficacy of len/dex relative to dexamethasone alone remained statistically significant in subgroups that had received prior treatment with thalidomide or bortezomib and in subgroups specified by the number of previous therapies for multiple myeloma.\n\nA meta-analysis was also performed to combine the results of the trials and to confirm the results obtained by the pooling of trials. This resulted in a median difference in TTP of 28.24 weeks (95%\xa0CI 18.39 to 38.08\xa0weeks) and an odds ratio for overall survival of 1.44 (95% CI 1.34 to 1.56). The hazard ratio was not calculated. There was no evidence of heterogeneity between the trials.\n\nAn indirect comparison was undertaken to compare len/dex with bortezomib monotherapy because there were no head-to-head trials. The results of the trials for len/dex were compared with the results of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) RCT. The APEX study compared bortezomib with high-dose dexamethasone. For median TTP, len/dex had a 34-week advantage over bortezomib for people who had received one prior therapy only, and there were no statistically significant differences for the secondary outcomes of complete response, partial response and progressive disease. However, this analysis is limited by the small number of data points. In addition, the common comparator (high-dose dexamethasone) was an active treatment and was not used in the same dose across the trials, and the definition of response differed between the trials.\n\nThe economic evaluation in the manufacturer's submission used a discrete-event simulation model. This model used two separate prediction equations to calculate TTP and post-progression survival values, which were then added together to give overall survival. A cohort was created by randomly sampling (with replacement) patients from the pooled trial populations. For subgroups within the model, the cohort was created from the relevant population. The model attempted to capture the variability between individuals in the trial and to allow correlation between observed parameters to be retained.\n\nThe model divided patients from both arms of both trials into four groups according to their level of response. In building a cohort for the study population or any of the subgroups, the model ensured that the proportion of patients achieving a particular response in the trial was replicated in the cohort. To calculate TTP, the model assumed a Weibull distribution. For bortezomib, the response rates were taken from the APEX trial and the equation for TTP was calibrated such that the median TTP was the same as that within the trial.\n\nThe equation for post-progression survival was assumed to take an exponential form. However, the trial results were affected by the crossover of patients at unblinding from the dexamethasone arm to receive lenalidomide. Therefore the equation included an adjustment factor that calibrated the modelled median overall survival in the dexamethasone group after progression to be equal to that observed in the UK Medical Research Council (MRC) multiple myeloma trials. This assumed that survival of people with multiple myeloma in this cohort was the same when treated with dexamethasone as with all other regimens used in the MRC trials. The patient profiles from the RCTs in the manufacturer's submission were applied to the predictors in the survival equations derived from the MRC trial data to predict survival in the dexamethasone arm if crossover had not occurred.\n\nThe model considered subgroups of patients who had received one prior therapy (with this group divided further into those who did and did not have peripheral neuropathy), patients who had received two or more prior therapies, and patients who had received thalidomide (divided further into those who had received only one prior therapy and those who had received two or more prior therapies). For patients who had received only one prior therapy, len/dex was compared with bortezomib monotherapy. For patients with peripheral neuropathy and for those who had received two or more prior therapies, the comparator was dexamethasone alone.\n\nThe utility values were based on a study that evaluated intensive chemotherapy followed by myeloablation and autologous stem-cell transplantation in people with multiple myeloma. For the complete response, partial response and stable disease states, a utility value of 0.81 was used. This value was based on the utility of the general public at an age (median 54\xa0years) corresponding to that of the patients in the study. A utility value of 0.64 was applied to the progressive disease state. After 2\xa0years, a utility value of 0.77 was applied to those patients whose disease had not progressed.\n\nOnly grade 3 and 4 adverse effects were included in the model. Utility decrements for adverse effects were not included. Resource-use data associated with, for example, adverse effects, routine follow-up and laboratory tests were collected to build up a profile of resource use, depending on disease state and treatment. Resource-use profiles were developed for people during relapse and/or on treatment, and for people in remission on maintenance therapy or off therapy. Resource use was estimated by interviewing 15 specialists across England and Wales who specialised in the management of multiple myeloma.\n\nThe economic analysis did not produce cost-effectiveness estimates for the whole trial population. In the base case, for the subgroup with one prior therapy, the model resulted in an incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained for lenalidomide that the manufacturer stated was not cost effective compared with bortezomib. For the one prior therapy subgroup, the ICER was £46,865 per QALY gained for lenalidomide compared with dexamethasone. For patients who had received two or more prior therapies the ICER was £24,584 per QALY gained. In the subgroup of patients who had received prior thalidomide, the ICERs were £38,861 per QALY gained for patients with only one prior therapy and £22,589 per QALY gained for patients who had received two or more prior therapies.\n\nThe ERG explored the precision with which the fitted curve for len/dex matched the actual trial data used in the model. It observed that the fitted curve overestimated overall survival. The ERG noted that the overall survival curve for the dexamethasone arm in the cost-effectiveness model had been adjusted to predict the median overall survival predicted from the MRC trials. However, the ERG stated that it was more methodologically correct to adjust the dexamethasone overall survival calculation in the model to predict the mean overall survival predicted from the MRC trials, because the ICERs calculated from the model were a ratio of means and not medians.\n\nThe ERG conducted an exploratory analysis with an improved fit of the len/dex overall survival curve and also with the dexamethasone curve adjusted to the mean overall survival in the MRC trials. For the subgroup of patients who had received only one prior therapy where len/dex was compared with bortezomib, the ICER increased more than 30-fold from the manufacturer's base case. For the subgroup who had received one prior therapy where the comparator was dexamethasone, the ICER increased from £46,865 to £69,500 per QALY gained. For the subgroup of patients who had received two or more prior therapies, the ICER increased from £24,584 to £47,100 per QALY gained. For patients who had received prior thalidomide, the ICER increased from £38,861 to £56,500 per QALY gained if they had received only one prior therapy and from £22,589 to £43,600 per QALY gained if they had received two or more prior therapies.\n\nIn addition, the ERG noted that the costs associated with routine medical management (non-drug costs) assumed in the model were lower than the figures that were accepted in the appraisal of bortezomib and may therefore have been underestimated. It also noted that the model had no disutility attached to the occurrence of adverse effects. Finally, it noted that the cost of anti-thrombotic prophylaxis that was routinely used with lenalidomide was not included in the model. The ERG stated that the inclusion of the above considerations in the model would further increase the ICERs for all subgroups above the values obtained in the exploratory reanalyses quoted above.\n\nFor the subgroup of patients who had received only one prior therapy, the ERG repeated the indirect comparison of len/dex with bortezomib using methods that it considered to be more appropriate. This resulted in a hazard ratio of 0.557 (95% CI 0.337 to 0.912). The ERG pointed out that this comparison was with bortezomib as monotherapy and that bortezomib was commonly used in combination with dexamethasone in routine clinical practice. The economic analysis for the comparison of len/dex with bortezomib also assumed a maximum of eight cycles of bortezomib instead of the 11 allowed in the trial, and did not model the response-based rebate scheme recommended in NICE technology appraisal guidance 129. The ERG also suggested that the administration costs associated with bortezomib may have been overestimated in the manufacturer's model. In addition, the dose intensity for bortezomib was assumed to be 100%; that is, the analysis did not allow for dose reductions and treatment interruptions, which had been included for lenalidomide. All of the above issues would have had the effect of increasing the ICERs for the comparison of len/dex with bortezomib in the subgroup of patients who had received only one prior therapy.\n\nAfter the first Appraisal Committee meeting, the manufacturer presented an updated cost-effectiveness analysis. The manufacturer stated that this updated analysis would only consider all patients who had received two or more prior therapies and the subgroup of patients who had received thalidomide as one of these prior therapies. The manufacturer accepted the ERG's approach to modelling the len/dex overall survival curve. However, the manufacturer did not agree with the calibration of the overall survival curve for dexamethasone alone in the cost-effectiveness model to the mean overall survival predicted from the MRC trials. The manufacturer stated that a curve calibrated to the mean rather than the median overall survival was less representative of the published curves, and that using the mean placed more emphasis on the tail of the distribution, where there were fewer patients and greater uncertainty. The manufacturer maintained that it was appropriate to calibrate the curve to the predicted median survival in the updated analysis. In addition, the updated analysis incorporated costs for outpatient visits into routine management costs, and inflated the routine management costs to 2008 values. The effects of adding costs for the prophylaxis of deep vein thrombosis and disutility for long-term adverse effects were also explored in the updated model through sensitivity analyses. The manufacturer also proposed a patient access scheme in which the cost of lenalidomide to the NHS for a person with multiple myeloma will be capped at 26\xa0cycles of treatment (each of 28 days, so normally administered over 2\xa0years). A cycle will still be considered as having been completed within the scheme even if there are dose reductions and treatment interruptions during the cycle. The drug cost of lenalidomide (excluding any related costs) for people who remain on treatment for more than 26\xa0cycles will be met by the manufacturer. The Department of Health in England and the Department of Health and Social Services in Wales accepted the consideration of this scheme by NICE.\n\nTaking all these factors into account in the model, for patients who had received two or more prior therapies the incremental life-year gain was 2.77, the incremental QALY gain was 1.86 and the ICER was £30,350 per QALY gained. For patients who had received thalidomide as one of the prior therapies the incremental life-year gain was 2.51, the incremental QALY gain was 1.7 and the ICER was £28,941 per QALY gained. These ICERs were relatively insensitive to the addition of costs for prophylaxis of deep vein thrombosis or disutility for long-term adverse effects.\n\nThe ERG considered the updated analyses from the manufacturer and agreed with the implementation of the stated changes. It noted that the model predicted that, for the group of patients who had received two or more prior therapies, the patient access scheme applied to 17% of the people in the model. The estimated average cost of treatment with lenalidomide to the NHS per person over a modelled lifetime (median overall survival approximately 2.7\xa0years) decreased from £59,800 to £51,800 with the patient access scheme. For the subgroup of patients who had received thalidomide as one of their prior therapies the patient access scheme applied to 11% of people in the model, and the modelled lifetime cost of treatment with lenalidomide to the NHS per person decreased from £49,800 to £46,300 with the patient access scheme.\n\nThe ERG repeated the exploratory analysis on the updated model using their preferred approach with the dexamethasone overall survival curve calibrated to the mean survival predicted from the MRC trials and the patient access scheme implemented in the model. For the subgroup of patients who had received two or more prior therapies, the incremental life-year gain was 1.81 and the incremental QALY gain was 1.24 at an incremental cost of £54,291, giving an ICER of £43,800 per QALY gained. For patients who had received thalidomide as one of the prior therapies, the incremental life-year gain was 1.71 and the incremental QALY gain was 1.15 at an incremental cost of £47,531, giving an ICER of £41,300 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of lenalidomide, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of lenalidomide by people with the condition, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee understood that multiple myeloma is an incurable disease. It was aware that the disease and its course are heterogeneous and that for relapsed multiple myeloma the choice of therapy for a particular person is influenced by the initial treatment and their response to it, the inherent characteristics of the disease and the person's performance status and preferences. The Committee heard from clinical specialists and patient experts that lenalidomide is an important advance in the treatment of multiple myeloma and could be considered as an alternative to bortezomib (currently recommended as a treatment option in NICE technology appraisal guidance 129) at first relapse. The Committee noted the importance that patients, their carers and physicians placed on having effective options to treat multiple myeloma at presentation and at subsequent relapses. However, it understood that the optimal sequence of agents to use is as yet unclear and depends on several factors, including a person's treatment history, comorbidities and disease characteristics.\n\nThe Committee understood that, in accordance with current NICE guidance (NICE technology appraisal guidance 129), bortezomib is routinely used in clinical practice for the treatment of progressive multiple myeloma in people who are at first relapse having received only one prior therapy. Therefore it considered bortezomib to be the most appropriate comparator for lenalidomide in people who have had only one prior therapy. The Committee noted that bortezomib is usually used in combination with dexamethasone, but that there is variation in clinical practice and limited formal evidence for the superior efficacy of this combination compared with bortezomib monotherapy.\n\nThe Committee considered the options available for the treatment of multiple myeloma at second and subsequent relapse. Current NICE guidance restricts the use of bortezomib to first relapse because the use of bortezomib at subsequent relapses was found not to be cost effective (NICE technology appraisal guidance 129), with ICERs of £77,000 or more per life year gained. Thalidomide is not licensed for this indication, and an application for a licence for the treatment of relapsed or refractory multiple myeloma was withdrawn. However, thalidomide is used as a treatment option for multiple myeloma within the NHS, although the extent of this use is not known. The Committee also noted a statement from the manufacturer that there is a lack of evidence for the efficacy of thalidomide for this indication, particularly after failure of two or more therapies. The Committee understood that a variety of other regimens could be used at second and subsequent relapse, but that no studies had been identified that have demonstrated the superiority of these compared with dexamethasone alone. Therefore it accepted that in people who have received two or more prior therapies, high-dose dexamethasone was a reasonable comparator for lenalidomide.\n\nThe Committee discussed the RCTs comparing len/dex with dexamethasone alone for the management of relapsed multiple myeloma. It noted that TTP (the primary outcome) was statistically significantly increased in the len/dex arm for the whole trial population as well as in subgroups of people who had received prior therapy with bortezomib or thalidomide. It considered that the RCTs provided evidence that overall survival and response rates were also higher with len/dex compared with dexamethasone alone. The Committee concluded that the len/dex combination improved outcomes in people with relapsed multiple myeloma when compared with dexamethasone. This included people who had received either one or two or more prior therapies, and when prior therapies included the use of thalidomide.\n\nThe Committee next discussed the relative effectiveness of len/dex compared with bortezomib. It noted that the evidence for the effectiveness of len/dex compared with bortezomib monotherapy was derived from an indirect comparison via the common comparator of high-dose dexamethasone. It considered that there was uncertainty in the results of the indirect comparison because of heterogeneity between the studies, such as differences in the regimen of dexamethasone and the definition of response. The Committee noted that there was additional uncertainty in interpreting the context of current practice, as it understood that bortezomib is usually used in combination with dexamethasone in clinical practice.\n\nThe Committee discussed the adverse effects associated with lenalidomide. It noted that from the patients' viewpoint lenalidomide is associated with a more favourable adverse effect profile than most other regimens and agents used in the management of relapsed multiple myeloma. It heard from clinical specialists and patient experts that lenalidomide might be particularly useful for people with pre-existing peripheral neuropathy, in whom the use of bortezomib at first relapse is restricted. However, the Committee noted that lenalidomide is associated with a statistically significant increased risk of venous thrombosis and embolism. It heard from clinical specialists that this risk is usually managed with prophylaxis in the form of low-dose aspirin in people with multiple myeloma. However, in people with a history of venous thromboembolism or other relevant risk factors, the use of warfarin or low-molecular-weight heparin would be considered. The Committee heard that with such prophylaxis the risk would return to baseline levels. The additional cost incurred for the management of people with multiple myeloma would be minimal if low-dose aspirin was used, but could have an impact if either low-molecular-weight heparin or warfarin was needed.\n\nThe Committee considered the manufacturer's economic evaluation of the use of lenalidomide and the critique from the ERG. It accepted that the general structure of the manufacturer's model was reasonable. It considered that the subgroups in the model were those relevant to decision-making in routine clinical practice. It discussed the sensitivity and scenario analyses presented by the manufacturer, as well as those explored by the ERG using the manufacturer's model. In particular, the Committee discussed the methods used for adjustment for the crossover effect in the RCTs, the extrapolation of survival data, the costs of medical management and administration of bortezomib therapy, and the utility values reflecting health-related quality of life for the pre-progression and post-progression states and from adverse effects.\n\nThe Committee noted that the trial results included a crossover effect and considered whether it was appropriate to use data from historical MRC trials to predict survival for people treated with dexamethasone in this population in the absence of an unbiased estimate from the trials of lenalidomide. The Committee was aware that the MRC data were derived from trials of agents in first-line therapy for multiple myeloma. Despite this, it accepted that these data represented the best available survival data for people with multiple myeloma to be used in extrapolation of overall survival in the current analysis. The Committee also noted that use of these data assumed that dexamethasone monotherapy was a suitable proxy (in the absence of more specific evidence) for all anti-myeloma therapies used in relapse. The Committee also considered that there was no evidence to indicate that the effectiveness of dexamethasone in relation to survival had changed over time since the MRC trials. It accepted the statements from the clinical specialists indicating that where improvements were noticed these were likely to be attributable to the use of the newer agents and stem-cell transplantation.\n\nThe Committee considered the ERG's exploratory reanalysis with an improved fit of the len/dex overall survival curve to the trial data and calibration of the dexamethasone overall survival curve to predict mean (and not median) overall survival based on a risk equation for survival derived from the MRC trials. The Committee considered that the ERG's approach to modelling overall survival in both the len/dex and dexamethasone arms was valid and resulted in more plausible estimates of cost effectiveness than those presented by the manufacturer. The Committee noted that these adjustments to the modelling of survival may have different effects in different subgroups and that the ERG's adjustments had been made separately to subgroups defined according to number of prior therapies.\n\nThe Committee considered the base-case ICERs resulting from the manufacturer's economic analysis, as well as the results of the ERG's exploratory analysis using the alternative approach to the modelling of overall survival. It noted that, in the manufacturer's base case, none of the ICERs for lenalidomide for the subgroups with only one prior therapy were within the range that would normally be considered a cost-effective use of NHS resources. The Committee noted that the comparison of len/dex with bortezomib in the subgroup of people who had received only one prior therapy resulted in a high ICER. The Committee also considered that the ICER for the comparison with bortezomib would increase further if the model took into account: the bortezomib response-based rebate scheme (as described in NICE technology appraisal guidance 129); the lower costs of bortezomib administration suggested by the ERG; the higher maximum number of cycles of bortezomib; and the likely dosage reduction for bortezomib. When the ERG's approach to modelling overall survival was used, the ICER was more than £69,000 per QALY gained for the comparison of lenalidomide with dexamethasone in people who had received one prior therapy only. For the comparison with dexamethasone in people who had received one prior therapy and that therapy was thalidomide, the ICER was more than £56,000 per QALY gained.\n\nThe Committee considered other issues with the base-case analysis. The model did not fully include costs and utility decrements owing to adverse effects, and the Committee considered that if appropriate costs and disutilities for adverse effects and anti-thrombosis prophylaxis were used in the model, the ICERs for lenalidomide would increase. It also noted that the utility in the model for the pre-progression state was that of the normal population at age 54\xa0years, and that this is considerably younger than the average age of people who usually develop multiple myeloma. The Committee noted the results of the exploratory analysis by the ERG, which showed that using lower administration costs for bortezomib, using higher costs for routine medical management and modelling the bortezomib response-based rebate scheme all had the effect of increasing the ICERs for lenalidomide for the subgroup of patients who had received one prior therapy. The Committee concluded that, in the light of these additional issues, the most plausible ICERs in all subgroups would be higher than those stated in 4.11.\n\nThe Committee discussed the updated analysis presented by the manufacturer. It noted that the manufacturer had chosen not to present any new analysis for people who had received only one prior therapy. The Committee discussed whether there were any further factors that would have a bearing on its considerations about the cost effectiveness of lenalidomide in this patient group. These included the degree of certainty in the ICERs, the severity of the illness experienced by people with multiple myeloma who have received one prior therapy and the innovative nature of lenalidomide. It did not identify any factors that would alter its conclusions based on the evidence currently available. Overall, the Committee concluded that the use of lenalidomide for the treatment of multiple myeloma in people who had received only one prior therapy would not be a cost-effective use of NHS resources.\n\nThe Committee considered the subgroups of people who had received two or more prior therapies, including the subgroup who had received thalidomide as one of these therapies. When the ERG's approach to modelling overall survival was used, the ICERs for lenalidomide for these subgroups increased to at least £47,100 per QALY gained for those who had received two or more prior therapies, and to at least £43,600 per QALY gained for those who had received two or more prior therapies of which one was thalidomide.\n\nThe Committee discussed the updated analysis from the manufacturer and the exploratory reanalysis by the ERG for people who had received two or more prior therapies. The Committee concluded that the changes to the len/dex curve, utilities and costs had been implemented appropriately. The Committee noted that the variable that had the greatest impact on cost effectiveness was the method of calibrating the dexamethasone overall survival curve in the economic model (that is, to the predicted median or mean survival for the trial population) from the risk equation for survival derived from the MRC trials. The Committee noted that the data from the MRC trials were complete, with most participants having reached the outcome of interest (that is, there was very little censoring of the data), and that in such a situation the mean was a better estimate of average survival. It considered that, since the mean overall survival was used in the calculations of cost effectiveness, calibrating the overall survival predicted by the MRC data calibration model to the mean was more representative of the costs and benefits for this population. In addition, the Committee noted that when median survival was used to calibrate the survival curve, the improvement in overall survival predicted by the model was out of proportion to the observed improvement in progression-free survival from the lenalidomide trials. This relationship between the progression-free survival and overall survival from the lenalidomide trials was, however, maintained when calibrating the overall survival curve in the dexamethasone arm to the mean survival predicted from the MRC trials. The Committee understood that the choice between the use of mean or median survival was a scientific judgement, but concluded that for the purposes of decision-making in this situation, the ICER estimates from using the mean were most appropriate.\n\nThe Committee accepted that the patient access scheme for lenalidomide was correctly implemented by the manufacturer in the economic evaluation. It noted that, in the economic model, the patient access scheme was included by capping the maximum cost of lenalidomide for an individual patient at 26\xa0cycles of 28\xa0days each, equivalent to 2\xa0years. The Committee noted that the manufacturer stated that treatment interruptions within cycles were generally short, and that no patients missed entire cycles in the clinical trial. The cost of lenalidomide per cycle in the model was adjusted, as in the base case, to take into account the treatment reductions and interruptions noted in the first 23 cycles in the trials. The Committee concluded that the relevant and appropriate ICERs upon which to make a decision were £43,800 per QALY gained for the subgroup of patients who had received two or more prior therapies and £41,300 per QALY gained for the subgroup who had received two or more prior therapies including thalidomide. These ICERs represented the cost effectiveness of lenalidomide with the patient access scheme triggered after 26\xa0cycles, regardless of any dose reductions or treatment interruptions that may occur during a cycle, and were the basis for the Committee's decisions.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nNo alternative treatment with comparable benefits is available through the NHS.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe Committee next discussed whether the subgroup of people with multiple myeloma who had received two or more prior therapies, and the benefit provided by lenalidomide, fulfilled the criteria for consideration as an appraisal of a life-extending, end-of-life treatment. The Committee noted from the clinical trials and the MRC data that normal life expectancy without lenalidomide was unlikely to be greater than 24\xa0months and was potentially as low as 9\xa0months. The Committee considered that evidence from the lenalidomide trials suggested that lenalidomide increased survival by more than 3\xa0months compared with dexamethasone, and that crossover in the dexamethasone arm means that this benefit is likely to have been underestimated. The Committee considered that the potential alternatives, thalidomide and bortezomib, were unlikely to be routinely available on the NHS, as discussed in section 4.4. The Committee noted from the manufacturer's submission that the estimated eligible population was approximately 2100. In summary, the Committee was satisfied that the population and the technology of interest meet the criteria for accepting that this is an appraisal of a life-extending, end-of-life treatment and that the evidence presented for this consideration was supported by robust data.\n\nThe Committee subsequently considered the ERG's cost-effectiveness estimates using the manufacturer's model in the context of a life-extending, end-of-life treatment. It noted that the QALY increment associated with the most plausible cost-effectiveness estimates was approximately 1.24 QALYs. The Committee considered that the magnitude of the additional weight that would need to be assigned to the original QALY benefit for the cost effectiveness of lenalidomide to fall within the currently applied ICER threshold range was acceptable. Additionally, the Committee noted from the model that the extension to life with lenalidomide was approximately 1.81\xa0years. The Committee considered that the impact of giving greater weight to QALYs achieved in the later stages of terminal diseases, using the assumption that the extended survival period is experienced at the full quality of life anticipated for a healthy person of the same age, was acceptable.\n\nIn summary, the Committee accepted that, for people with multiple myeloma who had received two or more prior therapies, the most plausible ICERs were those suggested by the ERG on the basis of exploration of the manufacturer's model and with the implementation of the patient access scheme (where the manufacturer would bear the costs of lenalidomide beyond 26\xa0cycles\xa0[normally 2\xa0years] for people whose disease had not progressed at this time). For the purpose of the recommendations, the patient access scheme would be triggered by the completion of 26\xa0cycles (which normally takes 2\xa0years), regardless of treatment interruptions and dose reductions within those cycles. The Committee accepted that the benefits provided by lenalidomide fitted the criteria for consideration for appraising a life-extending, end-of-life treatment. The Committee concluded that the additional weights that need to be attached to the QALYs to achieve ICERs within the normal threshold range are acceptable in these circumstances. Consequently the Committee recommended lenalidomide, within its licensed indication, as an option for the treatment of multiple myeloma in people who have received two or more prior therapies. The Committee noted that some people who have not received two or more prior therapies may be currently receiving lenalidomide for the treatment of multiple myeloma, and recommended that these people should have the option to continue treatment until they and their clinicians consider it appropriate to stop.", 'Recommendations for further research ': 'The Committee considered that rigorous data collection is needed on the life-extending benefits of lenalidomide when used in people with multiple myeloma who have received two or more prior therapies.'}
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https://www.nice.org.uk/guidance/ta171
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Evidence-based recommendations on lenalidomide (Revlimid) for treating multiple myeloma in adults who have had at least 2 prior therapies.
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d5425d8eb27d70660de989407dea06e5140b435f
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nice
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Valve-in-valve TAVI for aortic bioprosthetic valve dysfunction
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Valve-in-valve TAVI for aortic bioprosthetic valve dysfunction
Evidence-based recommendations on valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) for aortic bioprosthetic valve dysfunction in adults. This involves placing a new bioprosthetic valve inside a failing bioprosthetic valve.
# Recommendations
Current evidence on the safety and efficacy of valve-in-valve transcatheter aortic valve implantation (ViV‑TAVI) for aortic bioprosthetic dysfunction is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Details of all patients should be entered into the UK TAVI registry.
Device-related adverse events should be reported to the Medicines and Healthcare products Regulatory Agency.
Patient selection should be done by a multidisciplinary team, which must include interventional cardiologists experienced in the procedure, cardiac surgeons, an expert in cardiac imaging and, when appropriate, a cardiac anaesthetist and a specialist in elderly medicine. The multidisciplinary team should determine the risk level for each patient and the device most suitable for them.
During the consent process, patients should be told about all treatment options, and their advantages and disadvantages.
ViV‑TAVI is a technically challenging procedure that should only be done in specialised centres, and only by clinicians and teams with special training and experience in complex endovascular interventions. Units doing this procedure should have both cardiac and vascular surgical support for the emergency treatment of complications and subsequent patient care.# The condition, current treatments and procedure
# The condition
The 2 main indications for aortic valve replacement are aortic stenosis and aortic regurgitation. Symptoms of both conditions typically include shortness of breath and chest pain on exertion. The increased cardiac workload can lead to heart failure.
# Current treatments
Aortic valve replacement with an artificial prosthesis (biological or mechanical) is the conventional treatment for patients with severe aortic valve dysfunction. Valves may be placed by either open heart surgery or using transcatheter aortic valve implantation (TAVI; see NICE's interventional procedures guidance on TAVI). Although bioprosthetic valves have some advantages over mechanical valves, they may degenerate and fail over time. The standard treatment for a failed bioprosthetic valve is open heart surgery, with a further valve replacement. Reoperative surgery is associated with significant morbidity and a higher risk of mortality than primary surgery.
Valve-in-valve (ViV) TAVI has been developed as a less invasive alternative treatment that avoids the need for cardiopulmonary bypass. It can be used for treating failed bioprosthetic aortic valves originally placed by either open heart surgery or TAVI.
# The procedure
The procedure is done with the patient under general or local anaesthesia with sedation, using fluoroscopy. Prophylactic antibiotics and anticoagulant medication are used.
A new prosthetic valve is mounted within a stent, which is either self-expanding or expanded using balloon inflation. It is delivered by a catheter across the failed bioprosthetic aortic valve. Access to the aortic valve can be achieved transluminally, with entry to the circulation through the femoral or other large artery (sometimes known as a percutaneous or endovascular approach), or through apical puncture of the left ventricle (a transapical or transventricular approach). In the transluminal approach, surgical exposure and closure of the artery may be needed. How access to the aortic valve is achieved depends on whether there are factors that make the passage of a catheter through the circulation difficult, such as peripheral arterial disease.
The procedure is technically similar to TAVI for aortic stenosis into a native aortic valve, but some modifications to the technique have been reported. The new prosthetic valve is placed tightly into the orifice of the failed bioprosthetic valve, pushing the old valve leaflets aside. Gradual valve deployment (without rapid inflation of the balloon) is done and angiography is used to ensure accurate positioning of the valve. The old prosthesis is also used as a guide for positioning the new valve. The external diameter of the new valve should usually match or exceed the internal diameter of the old valve. Anticoagulation or antiplatelet therapy may be continued after the procedure.
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{'Recommendations': 'Current evidence on the safety and efficacy of valve-in-valve transcatheter aortic valve implantation (ViV‑TAVI) for aortic bioprosthetic dysfunction is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nDetails of all patients should be entered into the UK TAVI registry.\n\nDevice-related adverse events should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nPatient selection should be done by a multidisciplinary team, which must include interventional cardiologists experienced in the procedure, cardiac surgeons, an expert in cardiac imaging and, when appropriate, a cardiac anaesthetist and a specialist in elderly medicine. The multidisciplinary team should determine the risk level for each patient and the device most suitable for them.\n\nDuring the consent process, patients should be told about all treatment options, and their advantages and disadvantages.\n\nViV‑TAVI is a technically challenging procedure that should only be done in specialised centres, and only by clinicians and teams with special training and experience in complex endovascular interventions. Units doing this procedure should have both cardiac and vascular surgical support for the emergency treatment of complications and subsequent patient care.', 'The condition, current treatments and procedure': "# The condition\n\nThe 2\xa0main indications for aortic valve replacement are aortic stenosis and aortic regurgitation. Symptoms of both conditions typically include shortness of breath and chest pain on exertion. The increased cardiac workload can lead to heart failure.\n\n# Current treatments\n\nAortic valve replacement with an artificial prosthesis (biological or mechanical) is the conventional treatment for patients with severe aortic valve dysfunction. Valves may be placed by either open heart surgery or using transcatheter aortic valve implantation (TAVI; see NICE's interventional procedures guidance on TAVI). Although bioprosthetic valves have some advantages over mechanical valves, they may degenerate and fail over time. The standard treatment for a failed bioprosthetic valve is open heart surgery, with a further valve replacement. Reoperative surgery is associated with significant morbidity and a higher risk of mortality than primary surgery.\n\nValve-in-valve (ViV) TAVI has been developed as a less invasive alternative treatment that avoids the need for cardiopulmonary bypass. It can be used for treating failed bioprosthetic aortic valves originally placed by either open heart surgery or TAVI.\n\n# The procedure\n\nThe procedure is done with the patient under general or local anaesthesia with sedation, using fluoroscopy. Prophylactic antibiotics and anticoagulant medication are used.\n\nA new prosthetic valve is mounted within a stent, which is either self-expanding or expanded using balloon inflation. It is delivered by a catheter across the failed bioprosthetic aortic valve. Access to the aortic valve can be achieved transluminally, with entry to the circulation through the femoral or other large artery (sometimes known as a percutaneous or endovascular approach), or through apical puncture of the left ventricle (a transapical or transventricular approach). In the transluminal approach, surgical exposure and closure of the artery may be needed. How access to the aortic valve is achieved depends on whether there are factors that make the passage of a catheter through the circulation difficult, such as peripheral arterial disease.\n\nThe procedure is technically similar to TAVI for aortic stenosis into a native aortic valve, but some modifications to the technique have been reported. The new prosthetic valve is placed tightly into the orifice of the failed bioprosthetic valve, pushing the old valve leaflets aside. Gradual valve deployment (without rapid inflation of the balloon) is done and angiography is used to ensure accurate positioning of the valve. The old prosthesis is also used as a guide for positioning the new valve. The external diameter of the new valve should usually match or exceed the internal diameter of the old valve. Anticoagulation or antiplatelet therapy may be continued after the procedure."}
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https://www.nice.org.uk/guidance/ipg653
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Evidence-based recommendations on valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) for aortic bioprosthetic valve dysfunction in adults. This involves placing a new bioprosthetic valve inside a failing bioprosthetic valve.
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925f2009895257fe325abaf76abca7630e7c9658
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nice
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Reinforcement of a permanent stoma with a synthetic or biological mesh to prevent a parastomal hernia
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Reinforcement of a permanent stoma with a synthetic or biological mesh to prevent a parastomal hernia
Evidence-based recommendations on reinforcement of a permanent stoma with a synthetic or biological mesh to prevent a parastomal hernia. This involves inserting a piece of mesh to strengthen the abdominal wall.
# Recommendations
The evidence on the safety of reinforcement of a permanent stoma with a synthetic or biological mesh to prevent a parastomal hernia shows there are serious but well-recognised complications. The evidence on efficacy is limited in quantity and quality. Therefore, this procedure should not be used unless special arrangements are in place for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do reinforcement of a permanent stoma with a synthetic or biological mesh to prevent a parastomal hernia should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
All adverse events involving the medical devices (including the synthetic or biological mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.
Further research could be in the form of randomised controlled trials, observational studies and analysis of registry data. It should report details of patient selection, the type of synthetic or biological mesh used, mesh-associated complications and long-term outcomes (at least 3 years). In participating centres, clinicians should encourage patients to take part in the National Institute for Health Research CIPHER study.# The condition, current treatments and procedure
# The condition
Stomas are created surgically to divert the contents of the urinary or digestive tract through an opening in the abdominal wall. A parastomal hernia allows protrusion of abdominal contents through the abdominal-wall defect created by the stoma. They are relatively common, usually developing gradually and increasing in size over time. A parastomal hernia may remain asymptomatic, but can cause problems such as unacceptable physical appearance, poorly fitting stoma device, bowel obstruction, and bowel ischaemia and strangulation.
# Current treatments
A parastomal hernia can be repaired surgically, using an open or laparoscopic approach. Surgical repair is associated with its own morbidity and there is a high risk of recurrence.
# The procedure
This procedure is done using general anaesthesia, at the same time as the creation of the stoma. A space is formed between the rectus abdominus muscle and the rectus sheath of the abdominal wall, and a piece of synthetic or biological mesh is inserted into the space. The bowel or ureter is passed through the mesh and then through the abdominal wall. The mesh and the bowel or ureter are stitched to the abdominal wall. The aim is to strengthen the abdominal wall and prevent parastomal herniation.
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{'Recommendations': "The evidence on the safety of reinforcement of a permanent stoma with a synthetic or biological mesh to prevent a parastomal hernia shows there are serious but well-recognised complications. The evidence on efficacy is limited in quantity and quality. Therefore, this procedure should not be used unless special arrangements are in place for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do reinforcement of a permanent stoma with a synthetic or biological mesh to prevent a parastomal hernia should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nAll adverse events involving the medical devices (including the synthetic or biological mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nFurther research could be in the form of randomised controlled trials, observational studies and analysis of registry data. It should report details of patient selection, the type of synthetic or biological mesh used, mesh-associated complications and long-term outcomes (at least 3\xa0years). In participating centres, clinicians should encourage patients to take part in the National Institute for Health Research CIPHER study.", 'The condition, current treatments and procedure': '# The condition\n\nStomas are created surgically to divert the contents of the urinary or digestive tract through an opening in the abdominal wall. A parastomal hernia allows protrusion of abdominal contents through the abdominal-wall defect created by the stoma. They are relatively common, usually developing gradually and increasing in size over time. A parastomal hernia may remain asymptomatic, but can cause problems such as unacceptable physical appearance, poorly fitting stoma device, bowel obstruction, and bowel ischaemia and strangulation.\n\n# Current treatments\n\nA parastomal hernia can be repaired surgically, using an open or laparoscopic approach. Surgical repair is associated with its own morbidity and there is a high risk of recurrence.\n\n# The procedure\n\nThis procedure is done using general anaesthesia, at the same time as the creation of the stoma. A space is formed between the rectus abdominus muscle and the rectus sheath of the abdominal wall, and a piece of synthetic or biological mesh is inserted into the space. The bowel or ureter is passed through the mesh and then through the abdominal wall. The mesh and the bowel or ureter are stitched to the abdominal wall. The aim is to strengthen the abdominal wall and prevent parastomal herniation.'}
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https://www.nice.org.uk/guidance/ipg654
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Evidence-based recommendations on reinforcement of a permanent stoma with a synthetic or biological mesh to prevent a parastomal hernia. This involves inserting a piece of mesh to strengthen the abdominal wall.
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7069cf9f4a1c4b8d944f87d4fc1ac370332055af
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nice
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Cardiac contractility modulation device implantation for heart failure
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Cardiac contractility modulation device implantation for heart failure
Evidence-based recommendations on cardiac contractility modulation device implantation for heart failure in adults. This involves placing a device under the skin of the chest, which delivers electrical pulses to make the heart contract more strongly.
# Recommendations
The evidence on cardiac contractility modulation device implantation for heart failure raises no major safety concerns. However, the evidence on efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should ideally be in the form of randomised controlled trials. These should report details of patient selection, duration and timing of stimulation, and duration of effect of stimulation. Outcomes should include ejection fraction, oxygen consumption, New York Heart Association classification and patient-reported outcomes, including quality of life.# The condition, current treatments and procedure
# The condition
Heart failure is a complex clinical syndrome of symptoms and signs that happen when the heart is not working well enough, leading to reduced blood flow to body tissues. It can lead to oedema in the lungs (causing breathlessness) and swelling of the legs. Other symptoms include reduced ability to exercise, fatigue and malaise. Heart failure can be caused by structural or functional abnormalities of the heart.
# Current treatments
NICE's guideline describes the diagnosis and management of chronic heart failure in adults. Treatments for heart failure include drugs to improve heart function, cardiac rehabilitation, cardiac resynchronisation therapy and cardiac transplantation. Cardiac contractility modulation device implantation may be an option for people with advanced heart failure that hasn't responded to conventional therapy.
# The procedure
Cardiac contractility modulation device implantation for heart failure is usually done under local anaesthesia. A device similar to a pacemaker is implanted in the right or left pectoral region and is connected to 2 standard pacemaker leads that are threaded through veins into the right ventricle. The electrodes in the right ventricle are placed on the ventricular septum at least 2 cm apart. These sense ventricular activity and deliver cardiac contractility modulation signals. An optional additional lead may be used to sense atrial activity (usually placed in the right atrial appendage). In contrast to a pacemaker or a defibrillator, the system is designed to modulate the strength of contraction of the heart muscle rather than the rhythm. Pulses are delivered at regular intervals throughout the day.
The device is recharged using a home-based charger system, typically on a weekly basis. Charging sessions last about 40 to 60 minutes.
The aim is to improve the heart's contractility, therefore improving a person's ability to exercise and quality of life.
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{'Recommendations': 'The evidence on cardiac contractility modulation device implantation for heart failure raises no major safety concerns. However, the evidence on efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should ideally be in the form of randomised controlled trials. These should report details of patient selection, duration and timing of stimulation, and duration of effect of stimulation. Outcomes should include ejection fraction, oxygen consumption, New York Heart Association classification and patient-reported outcomes, including quality of life.', 'The condition, current treatments and procedure': "# The condition\n\nHeart failure is a complex clinical syndrome of symptoms and signs that happen when the heart is not working well enough, leading to reduced blood flow to body tissues. It can lead to oedema in the lungs (causing breathlessness) and swelling of the legs. Other symptoms include reduced ability to exercise, fatigue and malaise. Heart failure can be caused by structural or functional abnormalities of the heart.\n\n# Current treatments\n\nNICE's guideline describes the diagnosis and management of chronic heart failure in adults. Treatments for heart failure include drugs to improve heart function, cardiac rehabilitation, cardiac resynchronisation therapy and cardiac transplantation. Cardiac contractility modulation device implantation may be an option for people with advanced heart failure that hasn't responded to conventional therapy.\n\n# The procedure\n\nCardiac contractility modulation device implantation for heart failure is usually done under local anaesthesia. A device similar to a pacemaker is implanted in the right or left pectoral region and is connected to 2\xa0standard pacemaker leads that are threaded through veins into the right ventricle. The electrodes in the right ventricle are placed on the ventricular septum at least 2\xa0cm apart. These sense ventricular activity and deliver cardiac contractility modulation signals. An optional additional lead may be used to sense atrial activity (usually placed in the right atrial appendage). In contrast to a pacemaker or a defibrillator, the system is designed to modulate the strength of contraction of the heart muscle rather than the rhythm. Pulses are delivered at regular intervals throughout the day.\n\nThe device is recharged using a home-based charger system, typically on a weekly basis. Charging sessions last about 40\xa0to 60\xa0minutes.\n\nThe aim is to improve the heart's contractility, therefore improving a person's ability to exercise and quality of life."}
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https://www.nice.org.uk/guidance/ipg655
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Evidence-based recommendations on cardiac contractility modulation device implantation for heart failure in adults. This involves placing a device under the skin of the chest, which delivers electrical pulses to make the heart contract more strongly.
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5406f93a2d4293d5ce6f1a415f141ce4c9709948
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nice
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Lenalidomide plus dexamethasone for multiple myeloma after 1 treatment with bortezomib
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Lenalidomide plus dexamethasone for multiple myeloma after 1 treatment with bortezomib
Evidence-based recommendations on lenalidomide (Revlimid) plus dexamethasone for multiple myeloma after 1 treatment with bortezomib in adults.
# Recommendations
Lenalidomide plus dexamethasone is recommended as an option for treating multiple myeloma in adults only if:
they have had only 1 previous therapy, which included bortezomib, and
the company provides it according to the commercial arrangement.
This recommendation is not intended to affect treatment with lenalidomide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Currently, multiple myeloma is first treated with thalidomide-based therapy but, if a person can't have thalidomide, bortezomib-based therapy can be given. For people who have had bortezomib as a first treatment, the second treatment would be with cytotoxic chemotherapy. However, clinical evidence shows that lenalidomide plus dexamethasone is more effective than cytotoxic chemotherapy.
The most plausible cost-effectiveness estimate for lenalidomide plus dexamethasone may be above the range that NICE normally considers to be a cost-effective use of NHS resources. However, lenalidomide has been recommended for use as a first treatment (for which it is cost effective). Therefore, the need for lenalidomide as a second treatment will likely decrease because people are more likely to have it as a first treatment in the future. However, some people who are currently taking bortezomib as a first treatment will value access to lenalidomide as an effective next treatment option. Given that NICE already recommends lenalidomide as both a first and third treatment for multiple myeloma, it is appropriate to recommend lenalidomide for this small patient group as a second treatment.# Information about lenalidomide
Marketing authorisation
Lenalidomide (Revlimid; Celgene) in combination with dexamethasone has a marketing authorisation for treating 'multiple myeloma in adult patients who have received at least one prior therapy'. It also has a marketing authorisation for 'previously untreated multiple myeloma in people who are not eligible for transplant'.
Dosage in the marketing authorisation
The recommended starting dosage is 25 mg orally once daily on days 1 to 21 of repeated 28‑day cycles.
Price
Lenalidomide is available as a 21‑capsule pack. The cost per pack (excluding VAT; British National Formulary online, accessed April 2019) varies according to capsule size: £3,426.00 (2.5 mg), £3,570.00 (5 mg), £3,675.00 (7.5 mg), £3,780.00 (10 mg), £3,969.00 (15 mg), £4,168.50 (20 mg) and £4,368.00 (25 mg).
The company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
This is a partial review of NICE's technology appraisal guidance on lenalidomide for the treatment of multiple myeloma in people who have received at least 2 prior therapies. The appraisal committee (section 5) considered evidence from a number of sources, including a review by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Pathway, population and comparators
## The relevant population is people who cannot have a stem cell transplant or first-line thalidomide, and who have already had bortezomib
The committee acknowledged that the treatment pathway differs depending on whether the person can have a stem cell transplant. The committee understood that the population relevant to this appraisal includes people for whom neither a stem cell transplant nor thalidomide is suitable. The committee discussed who would have lenalidomide plus dexamethasone after first relapse. It recognised that although lenalidomide and thalidomide are structurally similar, some people who cannot have thalidomide can have lenalidomide. The committee noted that people who could not have thalidomide first line would have a bortezomib-based therapy (for example, bortezomib plus melphalan and prednisolone), as recommended in NICE's technology appraisal guidance on bortezomib. It agreed that the relevant population includes people who cannot have a stem cell transplant or first-line thalidomide, and who instead will have had at least 1 previous treatment with a bortezomib-based therapy.
## The only relevant comparator is cytotoxic chemotherapy
In the final scope issued by NICE, potential comparators were bortezomib-based therapies, cytotoxic chemotherapy (such as melphalan) and bendamustine. The committee discussed each of these in turn.
The committee had previously heard from a clinical expert that, at second line, some patients are offered bortezomib plus an alkylating agent and corticosteroids. However, the committee understood that, since 2015, retreatment with bortezomib has no longer been available through the Cancer Drugs Fund. The committee also heard that NHS England had advised NICE that it would no longer commission retreating multiple myeloma with a bortezomib-based therapy. The committee concluded that a bortezomib-based therapy was not an appropriate comparator in this appraisal.
The clinical experts explained that cytotoxic chemotherapy with an alkylating agent is a treatment option after bortezomib-based first-line therapies, with an alternative alkylating agent taken after disease progression on bortezomib-based therapy. The committee concluded that cytotoxic therapy was a relevant comparator because it is used in clinical practice in the absence of lenalidomide plus dexamethasone.
The clinical experts stated that bendamustine is usually offered later in the treatment pathway, as a fourth- or fifth-line treatment. The committee concluded that bendamustine was not an appropriate comparator.The committee considered whether dexamethasone alone (the comparator in the lenalidomide trials, see section 3.4) was an appropriate comparator. The company explained that patients often have corticosteroids as part of their first treatment, and that clinicians do not usually offer dexamethasone alone as a second-line treatment. Because dexamethasone alone is not used in the NHS, the committee concluded that it was not a relevant comparator.
# Clinical and patient perspective
## There is an unmet need for an effective second-line treatment for multiple myeloma after bortezomib
Comments received during consultation suggested an unmet need for an effective treatment after first-line bortezomib-based therapy. The committee noted that, if lenalidomide plus dexamethasone were not available for use after only 1 previous treatment, people would need to have cytotoxic chemotherapy before being eligible for treatments such as lenalidomide and panobinostat and, later in the treatment pathway, pomalidomide and daratumumab. The committee was aware that NICE is currently appraising lenalidomide plus dexamethasone as a first-line treatment. It also noted other comments received during consultation that cytotoxic chemotherapy may have limited effectiveness at this point in the treatment pathway. It also heard from a patient expert that using lenalidomide plus dexamethasone earlier in the treatment pathway may provide more benefit than using it later. The committee recognised that patients value oral treatments such as lenalidomide plus dexamethasone because some people find it difficult to travel to hospital for repeated treatment with intravenous or subcutaneous therapies. It acknowledged that many patients preferred treatment with lenalidomide plus dexamethasone. The committee concluded that there is an unmet need for a more effective second-line treatment for multiple myeloma after bortezomib, and that patients and clinicians would value lenalidomide plus dexamethasone as an option early in the treatment pathway for multiple myeloma.
# Clinical effectiveness
## There is no clinical trial evidence directly comparing lenalidomide plus dexamethasone with cytotoxic chemotherapy
The company did not identify any randomised controlled trials that compared lenalidomide plus dexamethasone with cytotoxic chemotherapy (the only relevant comparator). For lenalidomide plus dexamethasone, the company presented a pooled analysis of 2 randomised controlled trials: MM‑009 and MM‑010 (see table 2). For cytotoxic chemotherapy (melphalan plus prednisolone), the company presented data from a small single-arm trial (Petrucci et al. 1989).
Study characteristics
Pooled MM‑009 and MM‑010 trials
Petrucci et al. (1989)
Study design
Multinational randomised controlled trial
Single-arm trial
Patients in the trial
About 35% of patients had 1 prior therapy and about 65% had had at least 2 prior therapies
Patients had disease that had relapsed or was refractory to chemotherapy. The number of prior therapies was not reported.
Sample size (intervention)
(lenalidomide plus dexamethasone), 351 (placebo plus dexamethasone)
(melphalan plus prednisolone)
Median progression-free survival in months
(lenalidomide plus dexamethasone), 4.6 (placebo plus dexamethasone)
Not reported
Median overall survival in months
(lenalidomide plus dexamethasone), 31.6 (placebo plus dexamethasone)
## Lenalidomide plus dexamethasone is more effective than dexamethasone alone in the relevant population
The committee agreed that MM‑009 and MM‑010 had shown that lenalidomide plus dexamethasone was more effective than placebo plus dexamethasone for extending progression-free and overall survival (see table 2). However, it recognised that dexamethasone alone was not a relevant comparator in this appraisal (see section 3.2). The committee also recognised that the population in the trials did not match the population for this appraisal because:
-nly 2 out of 353 patients in the pooled lenalidomide group had had 1 previous bortezomib-based therapy
the trials' inclusion criteria did not specify that thalidomide treatment was inappropriate, contraindicated or could not be tolerated
the trials' patients were younger than the multiple myeloma population addressed in this appraisal
the trials included a high proportion of patients who had had 2 or more previous therapies.The clinical experts explained that, based on their experience, the results from MM‑009 and MM‑010 were generalisable to the population of interest despite the differences. The committee concluded that, for treating multiple myeloma in the population relevant to this appraisal, lenalidomide plus dexamethasone was more effective than dexamethasone alone.
## Lenalidomide plus dexamethasone is more effective than chemotherapy
The committee was aware that the company estimated the effectiveness of cytotoxic chemotherapy using data from a small single-arm trial without a control group. It noted that a crude comparison suggested that median survival times were substantially longer for patients having lenalidomide than for patients having cytotoxic chemotherapy (see section 3.4, table 2). The committee had concerns about confounding, and it was aware that this non-randomised comparison was at high risk of bias. It was also concerned that it was unclear how patients were chosen for the Petrucci et al. (1989) trial. The clinical experts explained that, despite the lack of robust comparative evidence, in their experience lenalidomide plus dexamethasone was more effective than cytotoxic chemotherapy. The committee agreed that the evidence was very uncertain, but noted the size of effect in favour of lenalidomide plus dexamethasone compared with melphalan shown by the difference in survival times, and the opinion of several clinical experts. The committee therefore concluded that lenalidomide plus dexamethasone was likely to be more effective than cytotoxic chemotherapy for treating multiple myeloma in the population relevant to this appraisal.
# The company's modelling: overview
## The committee considered the company's multistate modelling from February and June 2016
This section describes the committee's consideration of the company's multistate modelling submitted in February and June 2016, rather than the modelling submitted before this. The company used 'multistate' modelling in the 2016 modelling because it meant that the survival curves for progression-free and overall survival did not cross (this had been a problem in previous versions of the model). The committee's discussion of previous model versions (that is, before February 2016) is described in the second appraisal consultation document.
The February 2016 modelling compared lenalidomide plus dexamethasone with cytotoxic chemotherapy (melphalan) using a crude indirect comparison, based on the Petrucci et al. (1989) trial of melphalan (see section 3.9 to section 3.13).
The June 2016 modelling used direct trial data from MM‑009 and MM‑010 and assumed that melphalan had the same clinical effectiveness as dexamethasone (see section 3.14 to section 3.16).The committee used the June 2016 model for decision making.
## The company's approach to modelling survival with lenalidomide plus dexamethasone is appropriate
In both 2016 models, the company chose a multistate-modelling approach to calculate the probability of moving between model states. The committee noted that the lenalidomide trials had a maximum follow up of 3.6 years and heard that the company no longer collected data from MM‑009 and MM‑010. It agreed that there was uncertainty about outcomes after the trial follow up in the extrapolated portion of the survival curves, which covered a further 20 years. The clinical experts explained that the company's predicted survival times with lenalidomide plus dexamethasone seemed reasonable. The committee concluded that, although there was some uncertainty about long-term outcomes with lenalidomide plus dexamethasone, the company's approach to modelling survival in both 2016 models was appropriate.
# The company's modelling: February 2016
## The crude indirect comparison is not suitable for decision making
The company's model from February 2016 used observational data from Petrucci et al. (1989) to estimate the effectiveness of melphalan. The committee agreed that there were 4 fundamental problems with the crude indirect comparison:
it was at high risk of bias and the statistical techniques may not have been technically correct (see section 3.10, section 3.11 and section 3.13)
the melphalan data came from only 34 patients (see section 3.4)
the model predictions lacked external validity (see section 3.12).The committee concluded that, taking all these issues into account, the crude indirect comparison was not suitable for decision making.
## There is a high risk of bias and the statistical methods are incorrect
In its base-case assumptions, the company calculated a crude hazard ratio for survival with lenalidomide relative to melphalan by taking the ratio of median survival times with melphalan (estimated from Petrucci et al. 1989) compared with lenalidomide (estimated from MM‑009 and MM‑010). It then applied this hazard ratio to the modelled survival for patients having lenalidomide to predict progression-free and overall survival with melphalan. The committee had 2 major concerns about this approach to modelling:
The model was based on a crude indirect comparison using non-randomised data, meaning that there was a high risk of bias (see section 3.6).
Calculating hazard ratios using medians is only valid when using an exponential distribution to extrapolate outcomes. The model did not use a single exponential distribution; instead, it used a multistate model that was similar to several exponential distributions fitted to different time periods. In its response to the committee's request for additional evidence, the company accepted that this method had limitations, and explained that a single exponential curve did not fit the data well for lenalidomide.The committee concluded that the company's model based on a crude indirect comparison was at high risk of bias and relied on statistical techniques that are not technically correct.
## The company's adjustment for subsequent treatments gives illogical results
The committee considered the company's approach to modelling subsequent treatments (that is, third- and fourth-line therapies) after relapsing on second-line treatment. The committee agreed that it was important to consider subsequent treatments and to include both their costs and effectiveness in the model. It noted that the company's model assumed that all patients having melphalan would go on to have third-line lenalidomide; for this reason, the company extended the survival times for melphalan patients to reflect the benefit of third-line treatment. The committee expressed concerns that including third-line lenalidomide in the comparator arm had produced implausible results. The company agreed that the model produced illogical results, but only when using bortezomib as a comparator, and said that this was not the case for the comparison with melphalan. In contrast, the ERG advised that the results for retreatment with bortezomib (even though the committee no longer consider it a comparator) suggested that the company's method for adjusting for subsequent treatments was unsuitable and should not be used. The committee concluded that the company's model based on a crude indirect comparison was further limited because the adjustment for subsequent treatments gave illogical results.
## The February 2016 model lacks external validity
The committee had further concerns about the external validity of the model. This was because the model predicted a mean survival benefit of 34.2 months (2.7 years) for lenalidomide plus dexamethasone compared with melphalan, whereas MM‑009 and MM‑010 showed a median survival benefit of only 6.4 months for lenalidomide plus dexamethasone compared with dexamethasone alone. The committee was concerned that these results were not plausible because, based on clinical advice, it would be expected that the difference in survival compared with melphalan would be less than the survival benefit of lenalidomide plus dexamethasone compared with dexamethasone alone (see section 3.6). To explore this issue further, the committee asked the company to use its model to predict survival times with dexamethasone alone. Although dexamethasone was not a comparator, the committee used this analysis to assess the external validity of the model. The company's model predicted that the mean survival time for patients having dexamethasone (informed by MM‑009 and MM‑010) was 4.9 years, compared with only 3.2 years with melphalan (informed by Petrucci et al. 1989). In this analysis, the company assumed that only 48% of patients on dexamethasone had third-line lenalidomide (informed by MM‑009 and MM‑010), but that all patients on melphalan had third-line lenalidomide, which was expected to increase survival times. The committee agreed that these results were not plausible; based on clinical advice, it expected survival times with melphalan to be similar to or better than with dexamethasone, whereas these results showed the opposite effect. The committee concluded that the company's model based on a crude indirect comparison lacked external validity.
## The February 2016 model implies that treatment benefit with lenalidomide continues after stopping treatment
The committee discussed the long-term survival benefit of lenalidomide plus dexamethasone compared with melphalan in the company's model based on a crude indirect comparison. It noted that the company applied the hazard ratios throughout the model, which implied that the relative survival benefit of lenalidomide continued after patients stopped treatment. The committee was concerned that there was no evidence of an ongoing survival benefit after patients stopped treatment. The committee was aware of scenarios from the company and the ERG that explored different assumptions about long-term survival. The committee agreed this was an additional uncertainty associated with this modelling approach.
# The company's modelling: June 2016
## The June 2016 model has limitations but assuming equivalence between melphalan and dexamethasone is preferable to the February 2016 model
In June 2016, the company submitted an alternative approach. This used the same model structure but assumed that melphalan had the same clinical effectiveness as dexamethasone. In the analyses assuming equivalence of melphalan to dexamethasone, the company used data from the dexamethasone group of MM‑009 and MM‑010 to predict clinical outcomes with melphalan. The company, ERG and committee agreed that this approach to modelling offered several advantages over the previous approach using a crude indirect comparison. Specifically, the analyses assuming equivalence:
used a large, randomised data set; this meant the comparison was at low risk of bias
captured the effect of third-line lenalidomide in the melphalan arm because 48% of patients in the dexamethasone group had subsequent lenalidomide in MM‑009 and MM‑010; this meant it was not necessary to adjust the comparator arm to reflect the benefit of third-line lenalidomide
did not need hazard ratios to be calculated using median survival times because patient-level data for both arms of the model were available from MM‑009 and MM‑010.The ERG noted that it did not have access to the Kaplan–Meier data for patients having second-line dexamethasone in MM‑009 and MM‑010. So, it was unable to assess whether the model predictions were a good fit to the mortality data from the MM‑009 and MM‑010 trials. The committee agreed that this added uncertainty to the analysis. While acknowledging this shortcoming, the committee concluded that the analysis assuming equivalence was preferable to the previous approach based on a crude indirect comparison.
## The June 2016 model may underestimate the ICER for lenalidomide plus dexamethasone compared with melphalan
The company stated that the assumption of equivalence was supported by a randomised controlled trial comparing 4 treatments, including melphalan plus prednisolone and including dexamethasone in patients who had not had previous treatment (Facon et al. 2006). The trial showed no difference in overall survival (the primary endpoint) between dexamethasone and melphalan. The committee was not convinced that melphalan had the same clinical effectiveness as dexamethasone because Facon et al. showed that progression-free survival was longer with melphalan. It was also aware that Facon et al. did not recruit enough patients, based on the sample size calculations, to detect a difference in survival. It also noted that clinical opinion suggested that melphalan might be more effective, in which case the analysis assuming equivalence would be biased in favour of lenalidomide plus dexamethasone. The committee concluded that the analysis assuming equivalence may have underestimated the incremental cost-effectiveness ratio (ICER) for lenalidomide plus dexamethasone compared with melphalan.
## There is uncertainty about the modelling of progression-free survival, but it has a modest effect on the ICER
The ERG observed that, in the modelling of progression-free survival with dexamethasone (used as a proxy for melphalan), the company's extrapolation had a 'long tail'. This meant that some patients survived for several years without their disease progressing. The ERG advised that this extrapolation was implausible. Its analyses used the company's progression-free survival curve for the first 1.5 years but, after that time, the ERG chose an exponential distribution. The committee found it difficult to identify a preferred extrapolation curve because it did not have access to the Kaplan–Meier curves from the trial that showed the number of patients at risk. Without this information, its best estimate was that the true curve was likely to be somewhere between the company's and ERG's approaches. The committee concluded that the ERG's approach was reasonable, but also noted that the cost-effectiveness results were not very sensitive to the choice of curve for progression-free survival.
# Utility values
## The utility values in both models are uncertain because they are based on limited evidence
The committee discussed the company's choice of utility values. It noted that the company took EQ‑5D utility values from a model by van Agthoven et al. (2004). The original source of these utility values was a 2002 PhD thesis which, to the committee's knowledge, had not been published in a peer-reviewed journal when discussed at the committee's first meeting. The committee also noted that the utility values were derived from a population younger than the population in this appraisal, and the values were higher than the average population of the same age. In addition, the company took the utility decrements for adverse events from several different sources that used different methods, were from other countries and included people with different types of cancer. The committee concluded that there was a limited evidence base to support the utility values and this added to the uncertainty in the model.
# The most plausible ICER
## The ICER for lenalidomide plus dexamethasone compared with melphalan may be higher than £30,000 per QALY gained
The committee preferred an analysis that included:
using data from the dexamethasone arm of the MM‑009 and MM‑010 trials as a proxy for the clinical effectiveness of melphalan (see section 3.14)
a correction of an error in the model identified by the ERG and agreed by the company.The company's ICER was between £20,000 and £30,000 per quality-adjusted life year (QALY) gained. The committee was aware that this ICER included the new, simple-discount patient access scheme (PAS) in the intervention arm and the existing complex PAS (cost capped after 26 cycles) in the comparator arm to reflect the assumption that the new PAS would take effect only if NICE produces positive guidance. However, the committee was aware that, because NHS England had concerns about the operation of the complex PAS, it had renegotiated this scheme with the company. Therefore, the committee considered that there was merit in considering ICERs with the simple-discount PAS applied in both the intervention and comparator arms. The company's ICER corresponding with this scenario exceeded £30,000 per QALY gained. The committee took into account the ERG's different estimate of progression-free survival with dexamethasone (see section 3.16), noting that this resulted in a broadly similar ICER to the company's. The committee was aware that both the company's and ERG's analyses still assumed that melphalan had the same clinical effectiveness as dexamethasone, and the committee agreed that melphalan was likely to be more effective than dexamethasone. This meant that the ICERs were underestimated (see section 3.15). Therefore, the committee considered that the most plausible ICER for lenalidomide plus dexamethasone compared with melphalan was higher than the company's and ERG's ICERs, although how much higher was uncertain. It concluded that the most plausible ICER may be higher than £30,000 per QALY gained.
# Innovation
## Lenalidomide is not a step change in treatment and most benefits are included in the QALY calculations
The committee discussed whether lenalidomide could be defined as a step change in treatment, and whether it offered health-related benefits not captured in the modelling. The committee did not consider lenalidomide a step change in treatment because it is already offered to patients with myeloma at a later stage of the disease. However, it agreed that lenalidomide would be convenient as an oral treatment, and could save time and resources for people with multiple myeloma. It concluded that this benefit may not have been captured in the QALY calculations, but it was unlikely to alter the committee's conclusions on the cost effectiveness of lenalidomide given the high ICER.
# End-of-life considerations
## Lenalidomide does not meet the end-of-life criteria
The committee considered whether lenalidomide meets the end-of-life criteria for people with multiple myeloma who have had 1 previous treatment including bortezomib, and for whom thalidomide and a stem cell transplant are not suitable. It was aware that the company had not presented data to support considering lenalidomide as an end-of-life therapy, and that the company did not consider that lenalidomide met the end-of-life criteria for this population. The committee noted that the model predicted that patients in the comparator arms lived longer than 24 months, and therefore concluded that lenalidomide in this indication did not meet the criterion for life expectancy. Because it did not meet this criterion, the committee agreed that it did not need to discuss the end-of-life criteria further.
# Conclusion
## The changing treatment pathway for multiple myeloma should be taken into account in decision making
The committee was aware that there was an ongoing separate NICE appraisal for lenalidomide as a first-line treatment for multiple myeloma. It understood that the most plausible ICER for lenalidomide in this indication was within the range normally considered a cost-effective use of NHS resources for a subgroup of people who cannot have thalidomide. Recommending lenalidomide first line for people who cannot have thalidomide would change the treatment pathway, and the committee agreed that it was appropriate to take this into account when making its recommendations for lenalidomide as a second-line treatment option. The clinical experts stated that they would prefer to use lenalidomide earlier rather than later in the treatment pathway, and that retreatment with lenalidomide is unlikely. It agreed that because lenalidomide would be used as a first-line treatment option, the population likely to have lenalidomide second line (and therefore the unmet need) would decrease over time. The committee also noted that there remained an unmet need for a more effective next treatment than cytotoxic therapy for people who are currently taking bortezomib as their first treatment for multiple myeloma. It concluded that the changing multiple myeloma treatment pathway, and the potential availability of lenalidomide earlier in the treatment pathway should be taken into account in its decision making. The committee further concluded that these changes to the treatment pathway would reduce but not eliminate the unmet need for a more effective second-line treatment than cytotoxic chemotherapy for some people.
## Lenalidomide plus dexamethasone is recommended in this indication despite the high ICERs
The committee noted that the most plausible ICER may be above the range usually considered a cost-effective use of NHS resources. However, when making its decision, the committee took into account:
the unmet need for an alternative treatment option to cytotoxic chemotherapy for people who had 1 previous treatment, which included bortezomib
that lenalidomide is a cost-effective first-line treatment for people who cannot have thalidomide in a separate parallel appraisal
that the treatment pathway for multiple myeloma is likely to change and, if lenalidomide were to be available as a first-line treatment for people who cannot have thalidomide, fewer people would have lenalidomide as a second-line treatment after bortezomib
that, if it did not recommend lenalidomide for use after 1 previous treatment including bortezomib, people currently having bortezomib first line would continue to have less effective cytotoxic chemotherapy before moving on to more effective treatments, which it agreed was inappropriate.Taking all these factors into account, the committee concluded that it was appropriate to recommend lenalidomide plus dexamethasone for treating multiple myeloma in adults who have had only 1 previous therapy, which included bortezomib.
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{'Recommendations': "Lenalidomide plus dexamethasone is recommended as an option for treating multiple myeloma in adults only if:\n\nthey have had only 1\xa0previous therapy, which included bortezomib, and\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with lenalidomide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrently, multiple myeloma is first treated with thalidomide-based therapy but, if a person can't have thalidomide, bortezomib-based therapy can be given. For people who have had bortezomib as a first treatment, the second treatment would be with cytotoxic chemotherapy. However, clinical evidence shows that lenalidomide plus dexamethasone is more effective than cytotoxic chemotherapy.\n\nThe most plausible cost-effectiveness estimate for lenalidomide plus dexamethasone may be above the range that NICE normally considers to be a cost-effective use of NHS resources. However, lenalidomide has been recommended for use as a first treatment (for which it is cost effective). Therefore, the need for lenalidomide as a second treatment will likely decrease because people are more likely to have it as a first treatment in the future. However, some people who are currently taking bortezomib as a first treatment will value access to lenalidomide as an effective next treatment option. Given that NICE already recommends lenalidomide as both a first and third treatment for multiple myeloma, it is appropriate to recommend lenalidomide for this small patient group as a second treatment.", 'Information about lenalidomide': "Marketing authorisation\n\nLenalidomide (Revlimid; Celgene) in combination with dexamethasone has a marketing authorisation for treating 'multiple myeloma in adult patients who have received at least one prior therapy'. It also has a marketing authorisation for 'previously untreated multiple myeloma in people who are not eligible for transplant'.\n\nDosage in the marketing authorisation\n\nThe recommended starting dosage is 25\xa0mg orally once daily on days\xa01 to\xa021 of repeated 28‑day cycles.\n\nPrice\n\nLenalidomide is available as a 21‑capsule pack. The cost per pack (excluding VAT; British National Formulary online, accessed April 2019) varies according to capsule size: £3,426.00 (2.5\xa0mg), £3,570.00 (5\xa0mg), £3,675.00 (7.5\xa0mg), £3,780.00 (10\xa0mg), £3,969.00 (15\xa0mg), £4,168.50 (20\xa0mg) and £4,368.00 (25\xa0mg).\n\nThe company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "This is a partial review of NICE's technology appraisal guidance on lenalidomide for the treatment of multiple myeloma in people who have received at least 2 prior therapies. The appraisal committee (section\xa05) considered evidence from a number of sources, including a review by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Pathway, population and comparators\n\n## The relevant population is people who cannot have a stem cell transplant or first-line thalidomide, and who have already had bortezomib\n\nThe committee acknowledged that the treatment pathway differs depending on whether the person can have a stem cell transplant. The committee understood that the population relevant to this appraisal includes people for whom neither a stem cell transplant nor thalidomide is suitable. The committee discussed who would have lenalidomide plus dexamethasone after first relapse. It recognised that although lenalidomide and thalidomide are structurally similar, some people who cannot have thalidomide can have lenalidomide. The committee noted that people who could not have thalidomide first line would have a bortezomib-based therapy (for example, bortezomib plus melphalan and prednisolone), as recommended in NICE's technology appraisal guidance on bortezomib. It agreed that the relevant population includes people who cannot have a stem cell transplant or first-line thalidomide, and who instead will have had at least 1\xa0previous treatment with a bortezomib-based therapy.\n\n## The only relevant comparator is cytotoxic chemotherapy\n\nIn the final scope issued by NICE, potential comparators were bortezomib-based therapies, cytotoxic chemotherapy (such as melphalan) and bendamustine. The committee discussed each of these in turn.\n\nThe committee had previously heard from a clinical expert that, at second line, some patients are offered bortezomib plus an alkylating agent and corticosteroids. However, the committee understood that, since 2015, retreatment with bortezomib has no longer been available through the Cancer Drugs Fund. The committee also heard that NHS England had advised NICE that it would no longer commission retreating multiple myeloma with a bortezomib-based therapy. The committee concluded that a bortezomib-based therapy was not an appropriate comparator in this appraisal.\n\nThe clinical experts explained that cytotoxic chemotherapy with an alkylating agent is a treatment option after bortezomib-based first-line therapies, with an alternative alkylating agent taken after disease progression on bortezomib-based therapy. The committee concluded that cytotoxic therapy was a relevant comparator because it is used in clinical practice in the absence of lenalidomide plus dexamethasone.\n\nThe clinical experts stated that bendamustine is usually offered later in the treatment pathway, as a fourth- or fifth-line treatment. The committee concluded that bendamustine was not an appropriate comparator.The committee considered whether dexamethasone alone (the comparator in the lenalidomide trials, see section\xa03.4) was an appropriate comparator. The company explained that patients often have corticosteroids as part of their first treatment, and that clinicians do not usually offer dexamethasone alone as a second-line treatment. Because dexamethasone alone is not used in the NHS, the committee concluded that it was not a relevant comparator.\n\n# Clinical and patient perspective\n\n## There is an unmet need for an effective second-line treatment for multiple myeloma after bortezomib\n\nComments received during consultation suggested an unmet need for an effective treatment after first-line bortezomib-based therapy. The committee noted that, if lenalidomide plus dexamethasone were not available for use after only 1\xa0previous treatment, people would need to have cytotoxic chemotherapy before being eligible for treatments such as lenalidomide and panobinostat and, later in the treatment pathway, pomalidomide and daratumumab. The committee was aware that NICE is currently appraising lenalidomide plus dexamethasone as a first-line treatment. It also noted other comments received during consultation that cytotoxic chemotherapy may have limited effectiveness at this point in the treatment pathway. It also heard from a patient expert that using lenalidomide plus dexamethasone earlier in the treatment pathway may provide more benefit than using it later. The committee recognised that patients value oral treatments such as lenalidomide plus dexamethasone because some people find it difficult to travel to hospital for repeated treatment with intravenous or subcutaneous therapies. It acknowledged that many patients preferred treatment with lenalidomide plus dexamethasone. The committee concluded that there is an unmet need for a more effective second-line treatment for multiple myeloma after bortezomib, and that patients and clinicians would value lenalidomide plus dexamethasone as an option early in the treatment pathway for multiple myeloma.\n\n# Clinical effectiveness\n\n## There is no clinical trial evidence directly comparing lenalidomide plus dexamethasone with cytotoxic chemotherapy\n\nThe company did not identify any randomised controlled trials that compared lenalidomide plus dexamethasone with cytotoxic chemotherapy (the only relevant comparator). For lenalidomide plus dexamethasone, the company presented a pooled analysis of 2\xa0randomised controlled trials: MM‑009 and MM‑010 (see table\xa02). For cytotoxic chemotherapy (melphalan plus prednisolone), the company presented data from a small single-arm trial (Petrucci et al. 1989).\n\nStudy characteristics\n\nPooled MM‑009 and MM‑010 trials\n\nPetrucci et al. (1989)\n\nStudy design\n\nMultinational randomised controlled trial\n\nSingle-arm trial\n\nPatients in the trial\n\nAbout 35% of patients had 1\xa0prior therapy and about 65% had had at least 2\xa0prior therapies\n\nPatients had disease that had relapsed or was refractory to chemotherapy. The number of prior therapies was not reported.\n\nSample size (intervention)\n\n(lenalidomide plus dexamethasone), 351 (placebo plus dexamethasone)\n\n(melphalan plus prednisolone)\n\nMedian progression-free survival in months\n\n(lenalidomide plus dexamethasone), 4.6 (placebo plus dexamethasone)\n\nNot reported\n\nMedian overall survival in months\n\n(lenalidomide plus dexamethasone), 31.6 (placebo plus dexamethasone)\n\n\n\n## Lenalidomide plus dexamethasone is more effective than dexamethasone alone in the relevant population\n\nThe committee agreed that MM‑009 and MM‑010 had shown that lenalidomide plus dexamethasone was more effective than placebo plus dexamethasone for extending progression-free and overall survival (see table\xa02). However, it recognised that dexamethasone alone was not a relevant comparator in this appraisal (see section\xa03.2). The committee also recognised that the population in the trials did not match the population for this appraisal because:\n\nonly 2\xa0out of\xa0353 patients in the pooled lenalidomide group had had 1\xa0previous bortezomib-based therapy\n\nthe trials' inclusion criteria did not specify that thalidomide treatment was inappropriate, contraindicated or could not be tolerated\n\nthe trials' patients were younger than the multiple myeloma population addressed in this appraisal\n\nthe trials included a high proportion of patients who had had 2\xa0or more previous therapies.The clinical experts explained that, based on their experience, the results from MM‑009 and MM‑010 were generalisable to the population of interest despite the differences. The committee concluded that, for treating multiple myeloma in the population relevant to this appraisal, lenalidomide plus dexamethasone was more effective than dexamethasone alone.\n\n## Lenalidomide plus dexamethasone is more effective than chemotherapy\n\nThe committee was aware that the company estimated the effectiveness of cytotoxic chemotherapy using data from a small single-arm trial without a control group. It noted that a crude comparison suggested that median survival times were substantially longer for patients having lenalidomide than for patients having cytotoxic chemotherapy (see section 3.4, table\xa02). The committee had concerns about confounding, and it was aware that this non-randomised comparison was at high risk of bias. It was also concerned that it was unclear how patients were chosen for the Petrucci et al. (1989) trial. The clinical experts explained that, despite the lack of robust comparative evidence, in their experience lenalidomide plus dexamethasone was more effective than cytotoxic chemotherapy. The committee agreed that the evidence was very uncertain, but noted the size of effect in favour of lenalidomide plus dexamethasone compared with melphalan shown by the difference in survival times, and the opinion of several clinical experts. The committee therefore concluded that lenalidomide plus dexamethasone was likely to be more effective than cytotoxic chemotherapy for treating multiple myeloma in the population relevant to this appraisal.\n\n# The company's modelling: overview\n\n## The committee considered the company's multistate modelling from February and June 2016\n\nThis section describes the committee's consideration of the company's multistate modelling submitted in February and June 2016, rather than the modelling submitted before this. The company used 'multistate' modelling in the 2016 modelling because it meant that the survival curves for progression-free and overall survival did not cross (this had been a problem in previous versions of the model). The committee's discussion of previous model versions (that is, before February 2016) is described in the second appraisal consultation document.\n\nThe February 2016 modelling compared lenalidomide plus dexamethasone with cytotoxic chemotherapy (melphalan) using a crude indirect comparison, based on the Petrucci et al. (1989) trial of melphalan (see section\xa03.9 to\xa0section 3.13).\n\nThe June 2016 modelling used direct trial data from MM‑009 and MM‑010 and assumed that melphalan had the same clinical effectiveness as dexamethasone (see section\xa03.14 to\xa0section 3.16).The committee used the June 2016 model for decision making.\n\n## The company's approach to modelling survival with lenalidomide plus dexamethasone is appropriate\n\nIn both 2016 models, the company chose a multistate-modelling approach to calculate the probability of moving between model states. The committee noted that the lenalidomide trials had a maximum follow up of 3.6\xa0years and heard that the company no longer collected data from MM‑009 and MM‑010. It agreed that there was uncertainty about outcomes after the trial follow up in the extrapolated portion of the survival curves, which covered a further 20\xa0years. The clinical experts explained that the company's predicted survival times with lenalidomide plus dexamethasone seemed reasonable. The committee concluded that, although there was some uncertainty about long-term outcomes with lenalidomide plus dexamethasone, the company's approach to modelling survival in both 2016 models was appropriate.\n\n# The company's modelling: February 2016\n\n## The crude indirect comparison is not suitable for decision making\n\nThe company's model from February 2016 used observational data from Petrucci et al. (1989) to estimate the effectiveness of melphalan. The committee agreed that there were 4\xa0fundamental problems with the crude indirect comparison:\n\nit was at high risk of bias and the statistical techniques may not have been technically correct (see section\xa03.10, section\xa03.11 and section\xa03.13)\n\nthe melphalan data came from only 34\xa0patients (see section\xa03.4)\n\nthe model predictions lacked external validity (see section\xa03.12).The committee concluded that, taking all these issues into account, the crude indirect comparison was not suitable for decision making.\n\n## There is a high risk of bias and the statistical methods are incorrect\n\nIn its base-case assumptions, the company calculated a crude hazard ratio for survival with lenalidomide relative to melphalan by taking the ratio of median survival times with melphalan (estimated from Petrucci et al. 1989) compared with lenalidomide (estimated from MM‑009 and MM‑010). It then applied this hazard ratio to the modelled survival for patients having lenalidomide to predict progression-free and overall survival with melphalan. The committee had 2\xa0major concerns about this approach to modelling:\n\nThe model was based on a crude indirect comparison using non-randomised data, meaning that there was a high risk of bias (see section\xa03.6).\n\nCalculating hazard ratios using medians is only valid when using an exponential distribution to extrapolate outcomes. The model did not use a single exponential distribution; instead, it used a multistate model that was similar to several exponential distributions fitted to different time periods. In its response to the committee's request for additional evidence, the company accepted that this method had limitations, and explained that a single exponential curve did not fit the data well for lenalidomide.The committee concluded that the company's model based on a crude indirect comparison was at high risk of bias and relied on statistical techniques that are not technically correct.\n\n## The company's adjustment for subsequent treatments gives illogical results\n\nThe committee considered the company's approach to modelling subsequent treatments (that is, third- and fourth-line therapies) after relapsing on second-line treatment. The committee agreed that it was important to consider subsequent treatments and to include both their costs and effectiveness in the model. It noted that the company's model assumed that all patients having melphalan would go on to have third-line lenalidomide; for this reason, the company extended the survival times for melphalan patients to reflect the benefit of third-line treatment. The committee expressed concerns that including third-line lenalidomide in the comparator arm had produced implausible results. The company agreed that the model produced illogical results, but only when using bortezomib as a comparator, and said that this was not the case for the comparison with melphalan. In contrast, the ERG advised that the results for retreatment with bortezomib (even though the committee no longer consider it a comparator) suggested that the company's method for adjusting for subsequent treatments was unsuitable and should not be used. The committee concluded that the company's model based on a crude indirect comparison was further limited because the adjustment for subsequent treatments gave illogical results.\n\n## The February 2016 model lacks external validity\n\nThe committee had further concerns about the external validity of the model. This was because the model predicted a mean survival benefit of 34.2\xa0months (2.7\xa0years) for lenalidomide plus dexamethasone compared with melphalan, whereas MM‑009 and MM‑010 showed a median survival benefit of only 6.4\xa0months for lenalidomide plus dexamethasone compared with dexamethasone alone. The committee was concerned that these results were not plausible because, based on clinical advice, it would be expected that the difference in survival compared with melphalan would be less than the survival benefit of lenalidomide plus dexamethasone compared with dexamethasone alone (see section\xa03.6). To explore this issue further, the committee asked the company to use its model to predict survival times with dexamethasone alone. Although dexamethasone was not a comparator, the committee used this analysis to assess the external validity of the model. The company's model predicted that the mean survival time for patients having dexamethasone (informed by MM‑009 and MM‑010) was 4.9\xa0years, compared with only 3.2\xa0years with melphalan (informed by Petrucci et al. 1989). In this analysis, the company assumed that only 48% of patients on dexamethasone had third-line lenalidomide (informed by MM‑009 and MM‑010), but that all patients on melphalan had third-line lenalidomide, which was expected to increase survival times. The committee agreed that these results were not plausible; based on clinical advice, it expected survival times with melphalan to be similar to or better than with dexamethasone, whereas these results showed the opposite effect. The committee concluded that the company's model based on a crude indirect comparison lacked external validity.\n\n## The February 2016 model implies that treatment benefit with lenalidomide continues after stopping treatment\n\nThe committee discussed the long-term survival benefit of lenalidomide plus dexamethasone compared with melphalan in the company's model based on a crude indirect comparison. It noted that the company applied the hazard ratios throughout the model, which implied that the relative survival benefit of lenalidomide continued after patients stopped treatment. The committee was concerned that there was no evidence of an ongoing survival benefit after patients stopped treatment. The committee was aware of scenarios from the company and the ERG that explored different assumptions about long-term survival. The committee agreed this was an additional uncertainty associated with this modelling approach.\n\n# The company's modelling: June 2016\n\n## The June 2016 model has limitations but assuming equivalence between melphalan and dexamethasone is preferable to the February 2016 model\n\nIn June 2016, the company submitted an alternative approach. This used the same model structure but assumed that melphalan had the same clinical effectiveness as dexamethasone. In the analyses assuming equivalence of melphalan to dexamethasone, the company used data from the dexamethasone group of MM‑009 and MM‑010 to predict clinical outcomes with melphalan. The company, ERG and committee agreed that this approach to modelling offered several advantages over the previous approach using a crude indirect comparison. Specifically, the analyses assuming equivalence:\n\nused a large, randomised data set; this meant the comparison was at low risk of bias\n\ncaptured the effect of third-line lenalidomide in the melphalan arm because 48% of patients in the dexamethasone group had subsequent lenalidomide in MM‑009 and MM‑010; this meant it was not necessary to adjust the comparator arm to reflect the benefit of third-line lenalidomide\n\ndid not need hazard ratios to be calculated using median survival times because patient-level data for both arms of the model were available from MM‑009 and MM‑010.The ERG noted that it did not have access to the Kaplan–Meier data for patients having second-line dexamethasone in MM‑009 and MM‑010. So, it was unable to assess whether the model predictions were a good fit to the mortality data from the MM‑009 and MM‑010 trials. The committee agreed that this added uncertainty to the analysis. While acknowledging this shortcoming, the committee concluded that the analysis assuming equivalence was preferable to the previous approach based on a crude indirect comparison.\n\n## The June 2016 model may underestimate the ICER for lenalidomide plus dexamethasone compared with melphalan\n\nThe company stated that the assumption of equivalence was supported by a randomised controlled trial comparing 4\xa0treatments, including melphalan plus prednisolone and including dexamethasone in patients who had not had previous treatment (Facon et al. 2006). The trial showed no difference in overall survival (the primary endpoint) between dexamethasone and melphalan. The committee was not convinced that melphalan had the same clinical effectiveness as dexamethasone because Facon et al. showed that progression-free survival was longer with melphalan. It was also aware that Facon et al. did not recruit enough patients, based on the sample size calculations, to detect a difference in survival. It also noted that clinical opinion suggested that melphalan might be more effective, in which case the analysis assuming equivalence would be biased in favour of lenalidomide plus dexamethasone. The committee concluded that the analysis assuming equivalence may have underestimated the incremental cost-effectiveness ratio (ICER) for lenalidomide plus dexamethasone compared with melphalan.\n\n## There is uncertainty about the modelling of progression-free survival, but it has a modest effect on the ICER\n\nThe ERG observed that, in the modelling of progression-free survival with dexamethasone (used as a proxy for melphalan), the company's extrapolation had a 'long tail'. This meant that some patients survived for several years without their disease progressing. The ERG advised that this extrapolation was implausible. Its analyses used the company's progression-free survival curve for the first 1.5\xa0years but, after that time, the ERG chose an exponential distribution. The committee found it difficult to identify a preferred extrapolation curve because it did not have access to the Kaplan–Meier curves from the trial that showed the number of patients at risk. Without this information, its best estimate was that the true curve was likely to be somewhere between the company's and ERG's approaches. The committee concluded that the ERG's approach was reasonable, but also noted that the cost-effectiveness results were not very sensitive to the choice of curve for progression-free survival.\n\n# Utility values\n\n## The utility values in both models are uncertain because they are based on limited evidence\n\nThe committee discussed the company's choice of utility values. It noted that the company took EQ‑5D utility values from a model by van Agthoven et al. (2004). The original source of these utility values was a 2002 PhD thesis which, to the committee's knowledge, had not been published in a peer-reviewed journal when discussed at the committee's first meeting. The committee also noted that the utility values were derived from a population younger than the population in this appraisal, and the values were higher than the average population of the same age. In addition, the company took the utility decrements for adverse events from several different sources that used different methods, were from other countries and included people with different types of cancer. The committee concluded that there was a limited evidence base to support the utility values and this added to the uncertainty in the model.\n\n# The most plausible ICER\n\n## The ICER for lenalidomide plus dexamethasone compared with melphalan may be higher than £30,000 per QALY gained\n\nThe committee preferred an analysis that included:\n\nusing data from the dexamethasone arm of the MM‑009 and MM‑010 trials as a proxy for the clinical effectiveness of melphalan (see section\xa03.14)\n\na correction of an error in the model identified by the ERG and agreed by the company.The company's ICER was between £20,000 and £30,000 per quality-adjusted life year (QALY) gained. The committee was aware that this ICER included the new, simple-discount patient access scheme (PAS) in the intervention arm and the existing complex PAS (cost capped after 26\xa0cycles) in the comparator arm to reflect the assumption that the new PAS would take effect only if NICE produces positive guidance. However, the committee was aware that, because NHS England had concerns about the operation of the complex PAS, it had renegotiated this scheme with the company. Therefore, the committee considered that there was merit in considering ICERs with the simple-discount PAS applied in both the intervention and comparator arms. The company's ICER corresponding with this scenario exceeded £30,000 per QALY gained. The committee took into account the ERG's different estimate of progression-free survival with dexamethasone (see section\xa03.16), noting that this resulted in a broadly similar ICER to the company's. The committee was aware that both the company's and ERG's analyses still assumed that melphalan had the same clinical effectiveness as dexamethasone, and the committee agreed that melphalan was likely to be more effective than dexamethasone. This meant that the ICERs were underestimated (see section\xa03.15). Therefore, the committee considered that the most plausible ICER for lenalidomide plus dexamethasone compared with melphalan was higher than the company's and ERG's ICERs, although how much higher was uncertain. It concluded that the most plausible ICER may be higher than £30,000 per QALY gained.\n\n# Innovation\n\n## Lenalidomide is not a step change in treatment and most benefits are included in the QALY calculations\n\nThe committee discussed whether lenalidomide could be defined as a step change in treatment, and whether it offered health-related benefits not captured in the modelling. The committee did not consider lenalidomide a step change in treatment because it is already offered to patients with myeloma at a later stage of the disease. However, it agreed that lenalidomide would be convenient as an oral treatment, and could save time and resources for people with multiple myeloma. It concluded that this benefit may not have been captured in the QALY calculations, but it was unlikely to alter the committee's conclusions on the cost effectiveness of lenalidomide given the high ICER.\n\n# End-of-life considerations\n\n## Lenalidomide does not meet the end-of-life criteria\n\nThe committee considered whether lenalidomide meets the end-of-life criteria for people with multiple myeloma who have had 1\xa0previous treatment including bortezomib, and for whom thalidomide and a stem cell transplant are not suitable. It was aware that the company had not presented data to support considering lenalidomide as an end-of-life therapy, and that the company did not consider that lenalidomide met the end-of-life criteria for this population. The committee noted that the model predicted that patients in the comparator arms lived longer than 24\xa0months, and therefore concluded that lenalidomide in this indication did not meet the criterion for life expectancy. Because it did not meet this criterion, the committee agreed that it did not need to discuss the end-of-life criteria further.\n\n# Conclusion\n\n## The changing treatment pathway for multiple myeloma should be taken into account in decision making\n\nThe committee was aware that there was an ongoing separate NICE appraisal for lenalidomide as a first-line treatment for multiple myeloma. It understood that the most plausible ICER for lenalidomide in this indication was within the range normally considered a cost-effective use of NHS resources for a subgroup of people who cannot have thalidomide. Recommending lenalidomide first line for people who cannot have thalidomide would change the treatment pathway, and the committee agreed that it was appropriate to take this into account when making its recommendations for lenalidomide as a second-line treatment option. The clinical experts stated that they would prefer to use lenalidomide earlier rather than later in the treatment pathway, and that retreatment with lenalidomide is unlikely. It agreed that because lenalidomide would be used as a first-line treatment option, the population likely to have lenalidomide second line (and therefore the unmet need) would decrease over time. The committee also noted that there remained an unmet need for a more effective next treatment than cytotoxic therapy for people who are currently taking bortezomib as their first treatment for multiple myeloma. It concluded that the changing multiple myeloma treatment pathway, and the potential availability of lenalidomide earlier in the treatment pathway should be taken into account in its decision making. The committee further concluded that these changes to the treatment pathway would reduce but not eliminate the unmet need for a more effective second-line treatment than cytotoxic chemotherapy for some people.\n\n## Lenalidomide plus dexamethasone is recommended in this indication despite the high ICERs\n\nThe committee noted that the most plausible ICER may be above the range usually considered a cost-effective use of NHS resources. However, when making its decision, the committee took into account:\n\nthe unmet need for an alternative treatment option to cytotoxic chemotherapy for people who had 1\xa0previous treatment, which included bortezomib\n\nthat lenalidomide is a cost-effective first-line treatment for people who cannot have thalidomide in a separate parallel appraisal\n\nthat the treatment pathway for multiple myeloma is likely to change and, if lenalidomide were to be available as a first-line treatment for people who cannot have thalidomide, fewer people would have lenalidomide as a second-line treatment after bortezomib\n\nthat, if it did not recommend lenalidomide for use after 1\xa0previous treatment including bortezomib, people currently having bortezomib first line would continue to have less effective cytotoxic chemotherapy before moving on to more effective treatments, which it agreed was inappropriate.Taking all these factors into account, the committee concluded that it was appropriate to recommend lenalidomide plus dexamethasone for treating multiple myeloma in adults who have had only 1\xa0previous therapy, which included bortezomib."}
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https://www.nice.org.uk/guidance/ta586
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Evidence-based recommendations on lenalidomide (Revlimid) plus dexamethasone for multiple myeloma after 1 treatment with bortezomib in adults.
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f96afebe00eb7a3ec00e32b195a0808fa95b1d05
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nice
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Lenalidomide plus dexamethasone for previously untreated multiple myeloma
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Lenalidomide plus dexamethasone for previously untreated multiple myeloma
Evidence-based recommendations on lenalidomide (Revlimid) plus dexamethasone for previously untreated multiple myeloma in adults.
# Recommendations
Lenalidomide plus dexamethasone is recommended as an option for previously untreated multiple myeloma in adults who are not eligible for a stem cell transplant, only if:
thalidomide is contraindicated (including for pre-existing conditions that it may aggravate) or
the person cannot tolerate thalidomide, and
the company provides lenalidomide according to the commercial arrangement.
This recommendation is not intended to affect treatment with lenalidomide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Previously untreated multiple myeloma is normally treated with thalidomide-based therapy. If people cannot take thalidomide, bortezomib-based therapy is used. There is a high unmet need for new treatment options for people who cannot take thalidomide, so that they can have newer treatments later.
Evidence from an indirect comparison suggests that lenalidomide plus dexamethasone substantially improves the length of time people live compared with bortezomib-based therapy.
The most plausible cost-effectiveness estimate for lenalidomide plus dexamethasone for people unable to take thalidomide is within the range that NICE normally considers a cost-effective use of NHS resources. Because of this and the high unmet need, lenalidomide plus dexamethasone can be recommended for people unable to take thalidomide.
Lenalidomide plus dexamethasone cannot be recommended for untreated multiple myeloma in people who could take thalidomide because this would not be cost effective. Because the definition of thalidomide intolerance in clinical practice varies, it is appropriate that NHS England clearly defines who would be eligible for treatment with lenalidomide plus dexamethasone (see section 3.2).# Information about lenalidomide
Marketing authorisation indication
Lenalidomide (Revlimid, Celgene) as combination therapy is indicated for 'the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant'.
Dosage in the marketing authorisation
The recommended starting dosage is 25 mg orally once daily on days 1 to 21 of repeated 28‑day cycles.
Price
Lenalidomide is available as a 21‑capsule pack. The cost per pack (excluding VAT; British National Formulary online, accessed April 2019) varies according to capsule size: £3,426.00 (2.5 mg), £3,570.00 (5 mg), £3,675.00 (7.5 mg), £3,780.00 (10 mg), £3,969.00 (15 mg), £4,168.50 (20 mg) and £4,368.00 (25 mg).
The company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Celgene and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Current treatments
## There is an unmet need for new effective treatments, especially for people unable to take thalidomide
Treatment for untreated multiple myeloma is either a thalidomide-based therapy or, if a person is unable to take thalidomide, a bortezomib-based therapy. Both thalidomide and bortezomib are combined with an alkylating agent and a corticosteroid. The clinical experts explained that the current treatment options can be difficult to tolerate because the combination of 3 drugs can cause substantial side effects. After disease progression, people are offered treatment depending on their initial therapy. People who have had first-line thalidomide-based therapy can have either second-line bortezomib- or carfilzomib-based therapy. People who cannot take thalidomide have first-line bortezomib-based therapy followed by second-line cytotoxic chemotherapy. After subsequent disease progression, people can have newer therapy options, including third-line lenalidomide- or panobinostat-based therapies and fourth-line pomalidomide-based therapy. The patient and clinical experts explained that cytotoxic chemotherapy is considered to be less effective than the newer therapy options. Therefore, there is an unmet need for new treatments for untreated multiple myeloma to allow people who cannot take thalidomide to have second-line bortezomib- or carfilzomib-based therapy after first progression, thereby avoiding cytotoxic chemotherapy. The committee recognised that lenalidomide plus dexamethasone, as a first-line treatment, would fulfil an unmet need for all patients, especially for those who cannot have thalidomide.
## It is unclear who cannot take thalidomide in clinical practice
The Cancer Drugs Fund clinical lead explained that it is unclear who cannot take thalidomide in clinical practice. The committee was aware that NICE's technology appraisal guidance on bortezomib and thalidomide for the first-line treatment of multiple myeloma did not define the people who cannot have thalidomide. The Cancer Drugs Fund clinical lead explained that this has led to a much wider group having bortezomib than those who cannot have thalidomide because of true contraindications or intolerance. Specifically, at least 50% of people with newly diagnosed myeloma who are not eligible for a stem cell transplant are currently having first-line bortezomib-based therapy, about 25% are having thalidomide-based therapy and about 25% are having cytotoxic chemotherapy. The clinical experts agreed that there are no standard criteria to define who cannot have thalidomide-based treatment in clinical practice, but these might include people who:
could not tolerate a 3‑drug therapy
have pre-existing neuropathy
need to use opiates because of bone involvement of myeloma
have somnolence (sleepiness or drowsiness).The committee recognised that these groups may include a high proportion of older people. It concluded that people for whom thalidomide is unsuitable can be in 1 of 2 groups:
people who cannot have thalidomide from the outset because it is contraindicated (as listed in the thalidomide summary of product characteristics), or because they have a pre-existing condition that thalidomide may aggravate (most importantly, peripheral neuropathy)
people for whom a planned course of thalidomide causes unacceptable toxicity that outweighs the benefit of continued therapy.The committee agreed that it could not define this population any further because there are no strict criteria used in clinical practice to determine who can or cannot take thalidomide. However, it expected that clinicians would exercise their judgement when deciding whether someone can take thalidomide, taking into account the contraindications in the summary of product characteristics, the person's medical history and pre-existing conditions, and the effect of toxicity on overall treatment benefit. To help clinicians do this, it would be beneficial to have clear guidance from the commissioner, NHS England.
# Company's decision problem
## The choice of comparators is suitable for decision making
The company's submission compared lenalidomide plus dexamethasone with thalidomide plus melphalan plus prednisone (MPT) for the population who can have thalidomide. For people unable to tolerate thalidomide or for whom it is contraindicated, the company compared lenalidomide plus dexamethasone with bortezomib (Velcade) plus melphalan plus prednisone (VMP). The clinical experts commented that, in clinical practice in England, the alkylating agent cyclophosphamide is more often used as part of thalidomide- or bortezomib-based therapy than melphalan. However, they explained that cyclophosphamide and melphalan are clinically equivalent, and have similar costs. The committee concluded that the comparators chosen by the company were suitable for its decision making.
## The company focuses on the population who are unable to take thalidomide
The company stated that lenalidomide would not be cost effective compared with thalidomide-based therapy, which has a low cost. Therefore, it focused on the comparison of lenalidomide plus dexamethasone with VMP in people unable to tolerate thalidomide or for whom it is contraindicated. The committee was aware that people who cannot take thalidomide have the greatest unmet need among those newly diagnosed with multiple myeloma (see section 3.1). So, it accepted the company's rationale for focusing on this group. However, it recalled that it is unclear how this group is defined in clinical practice (see section 3.2). The committee agreed that, if some people who can take thalidomide have lenalidomide instead (according to the company's argument), this would not be a cost-effective use of NHS resources. Because of this, the committee reiterated that clinicians should evaluate carefully whether people can or cannot take thalidomide.
# Clinical evidence
## The main source of clinical evidence for lenalidomide plus dexamethasone is the FIRST trial
The clinical-effectiveness evidence for lenalidomide came from the January 2017 data cut of FIRST. This was an open-label randomised controlled trial comparing lenalidomide plus dexamethasone with MPT. It included:
people randomised to have lenalidomide plus dexamethasone until progression or unacceptable toxicity and
people randomised to have MPT.The trial also included a third arm, lenalidomide plus dexamethasone for a maximum of 18 cycles. However, the company stated that this arm was not relevant to the appraisal because it did not reflect lenalidomide's marketing authorisation. The committee agreed that it did not need to consider this arm of the trial. The ERG considered that FIRST was a large, well-designed and well-conducted trial that included relevant outcome measures and had a long follow up (over 6 years of data). The committee was aware that progression-free survival was the primary end point of the trial and that overall survival was a secondary end point.
## The FIRST trial includes only people who can take thalidomide, but the results are generalisable to people who cannot take thalidomide
All patients enrolled in FIRST could, by definition, take thalidomide because the comparator arm of the trial was MPT, which is a thalidomide-based therapy. The committee queried whether the results would be relevant, given the company's focus on the population unable to take thalidomide. The clinical experts explained that being unable to take thalidomide would not be expected to change the rates of disease progression or death on lenalidomide seen in the trial. Therefore, they considered the results would be generalisable to the group who cannot have thalidomide. The committee was concerned that the main trial evidence did not reflect the relevant population in this appraisal, but accepted that the results for patients randomised to lenalidomide plus dexamethasone were unlikely to differ markedly in the group who cannot have thalidomide.
## The indirect treatment comparison includes people who are able to take thalidomide, but is suitable for decision making
Because there was no trial directly comparing lenalidomide plus dexamethasone with VMP, the company did an indirect treatment comparison to compare them. It included melphalan and prednisone to complete the network. The ERG considered that the other trials included in the network were methodologically sound, and that the company's statistical approach was appropriate, but there was uncertainty because the network included few trials overall. The committee noted that there was potential for confounding from characteristics that might differ between trials. The clinical experts explained that the main patient characteristics that might affect the clinical outcomes were age, cytogenetics, performance status, chronic kidney disease and frailty. The ERG considered that the trials were similar enough for an indirect treatment comparison. The committee noted that none of the included trials specifically recruited people who were unable to take thalidomide, but concluded that overall the indirect treatment comparison was acceptable for its decision making.
## Lenalidomide plus dexamethasone is more clinically effective than VMP
Based on the results of the indirect comparison, lenalidomide plus dexamethasone improved overall survival compared with VMP (hazard ratio 0.70, 95% credible interval 0.50 to 0.98). For progression-free survival, the hazard ratio for lenalidomide plus dexamethasone compared with VMP was 0.74 (95% CrI 0.52 to 1.05). The committee noted that the wide credible intervals reflected the small number of trials included in the network. It noted that the results for lenalidomide plus dexamethasone taken until progression or unacceptable toxicity compared with lenalidomide plus dexamethasone taken for up to 18 weeks did not differ. Based on the evidence presented, and acknowledging potential confounding, the committee concluded that lenalidomide plus dexamethasone was more clinically effective than VMP, although by how much was uncertain.
## Lenalidomide plus dexamethasone is probably well tolerated
The clinical experts explained that, in their experience of using lenalidomide plus dexamethasone, the treatment is well tolerated and associated with fewer adverse events than VMP or MPT. This is expected because lenalidomide plus dexamethasone combines 2 drugs, whereas VMP and MPT each combine 3 drugs, 1 of which is cytotoxic. Evidence from FIRST, however, showed that more people who had lenalidomide plus dexamethasone had serious adverse effects than those who had MPT. The company stated that this is because people have lenalidomide plus dexamethasone until disease progression or unacceptable toxicity whereas people have MPT and VMP for a fixed time (72 weeks for MPT and 54 weeks for VMP). Therefore, the committee agreed that lenalidomide plus dexamethasone was likely to be better tolerated in clinical practice than MPT or VMP over the same period of time.
# The company's economic model
## The company's hybrid model combines Kaplan–Meier data and constant transition probability between states
The company used a hybrid model structure. This was a partitioned survival model using the Kaplan–Meier data for the first 92 weeks, and thereafter a multi-state Markov model with a constant transition probability between the 3 states: pre-progression, progressed disease and death. The company chose this structure to account for the structural link between disease progression and mortality. The ERG noted that the company's progression-free and overall survival curves generated from the company's model fitted well to the data from FIRST. However, the committee was unclear what advantage the hybrid approach had compared with a partitioned survival model with a parametric curve fitted at week 92. This approach would have allowed different distributions to be tested and the sensitivity of the model to the extrapolation to be better explored. However, the committee acknowledged that there were over 6 years of observed data, which the company's model fitted well.
## The company's use of Kaplan–Meier data up to 92 weeks is appropriate
The committee queried why the company chose 92 weeks as the point at which to apply the Markov model, and asked the ERG if the model's results were sensitive to this cut-off time point. The company stated that it used the partitioned survival analysis for the first 92 weeks because the log-cumulative hazard plots for progression-free survival from FIRST for each treatment were parallel up to this point then diverged. This was not the case for overall survival because the log-cumulative hazard plots remained parallel. But, using a multi-state Markov model meant that the company had to model progression-free and overall survival in the same way, that is, Kaplan–Meier data up to 92 weeks followed by a constant transition probability matrix. The committee highlighted that a partitioned survival analysis would have allowed more flexible modelling because it would have been possible to model overall and progression-free survival independently. The ERG explained that the model's outputs were not sensitive to the cut-off time point, and that it considered the 92‑week cut-off appropriate. The committee concluded that the 92‑week cut-off was appropriate. However, it was unclear how sensitive the model was to the structural assumptions that the company chose.
# Assumptions used in the economic model
## A Weibull curve should be used to extrapolate time on treatment
To estimate the time on treatment beyond the end of the trial, the ERG noted that the company used different parametric curves to extrapolate the time on treatment of lenalidomide plus dexamethasone and its comparator. The ERG considered that best practice is to use the same parametric curve for both arms, and it preferred the Weibull curve. The committee acknowledged that the model was not sensitive to the change in parametric curve. It considered that using a Weibull curve to extrapolate both arms would be appropriate.
## Time on treatment for VMP should be the same as for MPT
Time on treatment for lenalidomide plus dexamethasone and MPT was collected directly in FIRST. Because there were no data on treatment duration from the clinical trial for VMP, the company assumed that time on treatment in the VMP arm equalled progression-free survival, up to the maximum treatment duration of 54 weeks. The ERG noted that this assumption would likely increase the cost of VMP because, in FIRST, progression-free survival was longer than the time on treatment. The ERG noted that the indirect comparison showed that VMP and MPT had the same progression-free survival (HR 1.00, 95% CrI 0.72 to 1.38), and both have a maximum fixed treatment duration. The ERG therefore preferred to assume time on VMP treatment was the same as time on MPT treatment up to the respective maximum treatment durations. The committee considered it plausible that the time on treatment was shorter than progression-free survival because some people would stop treatment because of adverse effects. The committee considered the ERG's change to be appropriate.
## The utility estimates should be the same after treatment has stopped
EQ‑5D data were collected directly in FIRST for lenalidomide plus dexamethasone. The company mapped EQ‑5D data for VMP from European Organisation for Research and Treatment of Cancer (EORTC) data from the clinical trial. The company assumed that there is a utility decrement during VMP treatment, which would continue even after VMP treatment has finished. The ERG considered there was no good evidence that this difference in utility estimates continued after VMP treatment stopped. The ERG therefore preferred that the utility estimates for lenalidomide plus dexamethasone and VMP to be the same after VMP treatment stops. The committee agreed with the ERG and preferred the utility estimates to be the same for lenalidomide plus dexamethasone and VMP after VMP treatment has stopped.
## Treatments taken second line and later in the company's model do not reflect NHS clinical practice, and it is unclear how this would affect the model
The ERG highlighted that the company modelled the costs and clinical effects of therapies taken second line and later based on data from FIRST. This included thalidomide-based therapies or retreatment with lenalidomide-based therapies in the company's chosen population, that is, those who cannot take thalidomide. This led the committee to conclude that thalidomide use should not be included in the model. Also, the clinical experts explained that people do not have lenalidomide more than once in clinical practice. The ERG explored removing thalidomide and lenalidomide treatments taken second line and later from the model, but cautioned that it could remove only the costs, but not the effects, of these treatment options. Also, the committee noted that the model did not reflect NHS care because the company did not include the costs and effects of NICE-recommended treatment choices including carfilzomib, panobinostat and pomalidomide-based therapies, which were not available at the time of the clinical trial. The clinical experts were unable to predict what would happen to modelled mortality rates if the model reflected therapies used in the NHS. The committee concluded that the model does not reflect clinical practice, but it was unclear what effect this had on the estimates of cost effectiveness.
# Cost-effectiveness estimates
## The most plausible ICER is the ERG's preferred ICER
The company's estimated deterministic incremental cost-effectiveness ratio (ICER) is £11,886 per quality-adjusted life year (QALY) gained for lenalidomide plus dexamethasone compared with VMP. The ERG's preferred estimated deterministic ICER is £19,654 per QALY gained, based on the following changes:
using a Weibull parametric curve to extrapolate treatment duration (see section 3.12)
assuming treatment duration was the same for VMP and MPT (see section 3.13)
assuming utility estimates were the same after VMP treatment had finished (see section 3.14)
correcting cycle length for VMP utility values and included minor additional administration costs for VMP.The committee considered the ERG's changes to be reasonable. The committee noted that the cost-effectiveness estimates included inappropriate therapies taken second line and later (see section 3.15). The ERG's exploratory analysis in which the costs of these inappropriate therapies were removed lowered the ERG's ICER. But, because the analysis did not remove their clinical effects, the committee considered this approach to be inappropriate. It concluded that the most plausible ICER was from the ERG's preferred analysis. The committee was aware that both the company's and ERG's ICERs included the new, simple-discount patient access scheme (PAS) in the intervention arm and the existing complex PAS (cost capped after 26 cycles) in the comparator arm to reflect the assumption that the new PAS would take effect only if NICE produces positive guidance. However, the committee was aware that, because NHS England had concerns about the operation of the complex PAS, it had renegotiated this scheme with the company. Therefore, the committee considered that there was merit in considering ICERs with the simple-discount PAS applied in both the intervention and comparator arms. The ERG's ICER corresponding with this scenario was £26,713 per QALY gained (the company's ICER was £18,986 per QALY gained).
## The ICER is most sensitive to varying the overall survival hazard ratio
The tornado diagram showed that the ICER was insensitive to varying most parameters, except the hazard ratio for overall survival between lenalidomide plus dexamethasone and VMP. The committee recalled that the credible interval for this parameter in the indirect comparison was wide (see section 3.8). The ERG explored a scenario in which it assumed VMP had a higher overall survival, equal to MPT. The company noted that this scenario was pessimistic because it assumed that the use of therapies second line and later remained unchanged, whereas improving overall survival would increase the use of therapies used second line and later, which would increase costs. The committee was satisfied that the most plausible ICER is reasonably robust to changes in the model parameters.
## The cost-effectiveness estimates are only valid if people are unable to take thalidomide
The company stated that lenalidomide plus dexamethasone was not cost effective compared with the thalidomide-based therapy MPT. The committee recalled that it was unclear how people who cannot take thalidomide are defined in clinical practice (see section 3.2). It reiterated that, if some people have lenalidomide who could take thalidomide, this would not be a cost-effective use of NHS resources. It recalled that people for whom thalidomide is unsuitable can fall into 1 of 2 groups (see section 3.2). The committee concluded it appropriate that these 2 groups be reflected in the recommendation.
# Other factors
## The benefit of the oral administration of lenalidomide plus dexamethasone is unlikely to make a substantial difference to the conclusions
The company considered that lenalidomide is innovative because it is taken orally, whereas people have to attend specialist treatment units to have subcutaneous or intravenous bortezomib. The patient experts explained that people would value a new oral treatment because there is a substantial burden of travelling to a specialist treatment unit for injections, particularly for older people or those who travel long distances. The committee considered that the benefit of the oral administration of lenalidomide plus dexamethasone was unlikely to have been fully captured in the QALY, but that it was unlikely to make a substantial difference to its conclusions.
# Conclusion
## Lenalidomide plus dexamethasone is recommended for routine commissioning for people unable to take thalidomide
With the committee's preferred assumptions, the ICER was £19,654 per QALY gained (using the new, simple-discount PAS in the intervention arm and the existing complex PAS in the comparator arm) or was £26,713 per QALY gained (using the new, simple-discount PAS in both the intervention and comparator arms), which is within the range NICE usually considers a cost-effective use of NHS resources. The committee considered the remaining uncertainties to lie in the model, having included evidence from trials in people who could take thalidomide and treatments in the model taken second line and later not reflecting current clinical practice. The committee recognised that there is an unmet need for new treatment options for this population, and that recommending lenalidomide plus dexamethasone as first line would allow more people to have newer treatments in subsequent lines of therapy. The committee concluded that, despite the uncertainties, lenalidomide plus dexamethasone would be a cost-effective first-line treatment option for people who are not eligible for a stem cell transplant and who cannot take thalidomide. It therefore recommended lenalidomide plus dexamethasone for routine commissioning.
|
{'Recommendations': 'Lenalidomide plus dexamethasone is recommended as an option for previously untreated multiple myeloma in adults who are not eligible for a stem cell transplant, only if:\n\nthalidomide is contraindicated (including for pre-existing conditions that it may aggravate) or\n\nthe person cannot tolerate thalidomide, and\n\nthe company provides lenalidomide according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with lenalidomide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPreviously untreated multiple myeloma is normally treated with thalidomide-based therapy. If people cannot take thalidomide, bortezomib-based therapy is used. There is a high unmet need for new treatment options for people who cannot take thalidomide, so that they can have newer treatments later.\n\nEvidence from an indirect comparison suggests that lenalidomide plus dexamethasone substantially improves the length of time people live compared with bortezomib-based therapy.\n\nThe most plausible cost-effectiveness estimate for lenalidomide plus dexamethasone for people unable to take thalidomide is within the range that NICE normally considers a cost-effective use of NHS resources. Because of this and the high unmet need, lenalidomide plus dexamethasone can be recommended for people unable to take thalidomide.\n\nLenalidomide plus dexamethasone cannot be recommended for untreated multiple myeloma in people who could take thalidomide because this would not be cost effective. Because the definition of thalidomide intolerance in clinical practice varies, it is appropriate that NHS England clearly defines who would be eligible for treatment with lenalidomide plus dexamethasone (see section\xa03.2).', 'Information about lenalidomide': "Marketing authorisation indication\n\nLenalidomide (Revlimid, Celgene) as combination therapy is indicated for 'the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant'.\n\nDosage in the marketing authorisation\n\nThe recommended starting dosage is 25\xa0mg orally once daily on days\xa01\xa0to\xa021 of repeated 28‑day cycles.\n\nPrice\n\nLenalidomide is available as a 21‑capsule pack. The cost per pack (excluding VAT; British National Formulary online, accessed April 2019) varies according to capsule size: £3,426.00 (2.5\xa0mg), £3,570.00 (5\xa0mg), £3,675.00 (7.5\xa0mg), £3,780.00 (10\xa0mg), £3,969.00 (15\xa0mg), £4,168.50 (20\xa0mg) and £4,368.00 (25\xa0mg).\n\nThe company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Celgene and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Current treatments\n\n## There is an unmet need for new effective treatments, especially for people unable to take thalidomide\n\nTreatment for untreated multiple myeloma is either a thalidomide-based therapy or, if a person is unable to take thalidomide, a bortezomib-based therapy. Both thalidomide and bortezomib are combined with an alkylating agent and a corticosteroid. The clinical experts explained that the current treatment options can be difficult to tolerate because the combination of 3\xa0drugs can cause substantial side effects. After disease progression, people are offered treatment depending on their initial therapy. People who have had first-line thalidomide-based therapy can have either second-line bortezomib- or carfilzomib-based therapy. People who cannot take thalidomide have first-line bortezomib-based therapy followed by second-line cytotoxic chemotherapy. After subsequent disease progression, people can have newer therapy options, including third-line lenalidomide- or panobinostat-based therapies and fourth-line pomalidomide-based therapy. The patient and clinical experts explained that cytotoxic chemotherapy is considered to be less effective than the newer therapy options. Therefore, there is an unmet need for new treatments for untreated multiple myeloma to allow people who cannot take thalidomide to have second-line bortezomib- or carfilzomib-based therapy after first progression, thereby avoiding cytotoxic chemotherapy. The committee recognised that lenalidomide plus dexamethasone, as a first-line treatment, would fulfil an unmet need for all patients, especially for those who cannot have thalidomide.\n\n## It is unclear who cannot take thalidomide in clinical practice\n\nThe Cancer Drugs Fund clinical lead explained that it is unclear who cannot take thalidomide in clinical practice. The committee was aware that NICE's technology appraisal guidance on bortezomib and thalidomide for the first-line treatment of multiple myeloma did not define the people who cannot have thalidomide. The Cancer Drugs Fund clinical lead explained that this has led to a much wider group having bortezomib than those who cannot have thalidomide because of true contraindications or intolerance. Specifically, at least 50% of people with newly diagnosed myeloma who are not eligible for a stem cell transplant are currently having first-line bortezomib-based therapy, about 25% are having thalidomide-based therapy and about 25% are having cytotoxic chemotherapy. The clinical experts agreed that there are no standard criteria to define who cannot have thalidomide-based treatment in clinical practice, but these might include people who:\n\ncould not tolerate a 3‑drug therapy\n\nhave pre-existing neuropathy\n\nneed to use opiates because of bone involvement of myeloma\n\nhave somnolence (sleepiness or drowsiness).The committee recognised that these groups may include a high proportion of older people. It concluded that people for whom thalidomide is unsuitable can be in 1\xa0of\xa02 groups:\n\npeople who cannot have thalidomide from the outset because it is contraindicated (as listed in the thalidomide summary of product characteristics), or because they have a pre-existing condition that thalidomide may aggravate (most importantly, peripheral neuropathy)\n\npeople for whom a planned course of thalidomide causes unacceptable toxicity that outweighs the benefit of continued therapy.The committee agreed that it could not define this population any further because there are no strict criteria used in clinical practice to determine who can or cannot take thalidomide. However, it expected that clinicians would exercise their judgement when deciding whether someone can take thalidomide, taking into account the contraindications in the summary of product characteristics, the person's medical history and pre-existing conditions, and the effect of toxicity on overall treatment benefit. To help clinicians do this, it would be beneficial to have clear guidance from the commissioner, NHS England.\n\n# Company's decision problem\n\n## The choice of comparators is suitable for decision making\n\nThe company's submission compared lenalidomide plus dexamethasone with thalidomide plus melphalan plus prednisone (MPT) for the population who can have thalidomide. For people unable to tolerate thalidomide or for whom it is contraindicated, the company compared lenalidomide plus dexamethasone with bortezomib (Velcade) plus melphalan plus prednisone (VMP). The clinical experts commented that, in clinical practice in England, the alkylating agent cyclophosphamide is more often used as part of thalidomide- or bortezomib-based therapy than melphalan. However, they explained that cyclophosphamide and melphalan are clinically equivalent, and have similar costs. The committee concluded that the comparators chosen by the company were suitable for its decision making.\n\n## The company focuses on the population who are unable to take thalidomide\n\nThe company stated that lenalidomide would not be cost effective compared with thalidomide-based therapy, which has a low cost. Therefore, it focused on the comparison of lenalidomide plus dexamethasone with VMP in people unable to tolerate thalidomide or for whom it is contraindicated. The committee was aware that people who cannot take thalidomide have the greatest unmet need among those newly diagnosed with multiple myeloma (see section\xa03.1). So, it accepted the company's rationale for focusing on this group. However, it recalled that it is unclear how this group is defined in clinical practice (see section\xa03.2). The committee agreed that, if some people who can take thalidomide have lenalidomide instead (according to the company's argument), this would not be a cost-effective use of NHS resources. Because of this, the committee reiterated that clinicians should evaluate carefully whether people can or cannot take thalidomide.\n\n# Clinical evidence\n\n## The main source of clinical evidence for lenalidomide plus dexamethasone is the FIRST trial\n\nThe clinical-effectiveness evidence for lenalidomide came from the January 2017 data cut of FIRST. This was an open-label randomised controlled trial comparing lenalidomide plus dexamethasone with MPT. It included:\n\npeople randomised to have lenalidomide plus dexamethasone until progression or unacceptable toxicity and\n\npeople randomised to have MPT.The trial also included a third arm, lenalidomide plus dexamethasone for a maximum of 18\xa0cycles. However, the company stated that this arm was not relevant to the appraisal because it did not reflect lenalidomide's marketing authorisation. The committee agreed that it did not need to consider this arm of the trial. The ERG considered that FIRST was a large, well-designed and well-conducted trial that included relevant outcome measures and had a long follow up (over 6\xa0years of data). The committee was aware that progression-free survival was the primary end point of the trial and that overall survival was a secondary end point.\n\n## The FIRST trial includes only people who can take thalidomide, but the results are generalisable to people who cannot take thalidomide\n\nAll patients enrolled in FIRST could, by definition, take thalidomide because the comparator arm of the trial was MPT, which is a thalidomide-based therapy. The committee queried whether the results would be relevant, given the company's focus on the population unable to take thalidomide. The clinical experts explained that being unable to take thalidomide would not be expected to change the rates of disease progression or death on lenalidomide seen in the trial. Therefore, they considered the results would be generalisable to the group who cannot have thalidomide. The committee was concerned that the main trial evidence did not reflect the relevant population in this appraisal, but accepted that the results for patients randomised to lenalidomide plus dexamethasone were unlikely to differ markedly in the group who cannot have thalidomide.\n\n## The indirect treatment comparison includes people who are able to take thalidomide, but is suitable for decision making\n\nBecause there was no trial directly comparing lenalidomide plus dexamethasone with VMP, the company did an indirect treatment comparison to compare them. It included melphalan and prednisone to complete the network. The ERG considered that the other trials included in the network were methodologically sound, and that the company's statistical approach was appropriate, but there was uncertainty because the network included few trials overall. The committee noted that there was potential for confounding from characteristics that might differ between trials. The clinical experts explained that the main patient characteristics that might affect the clinical outcomes were age, cytogenetics, performance status, chronic kidney disease and frailty. The ERG considered that the trials were similar enough for an indirect treatment comparison. The committee noted that none of the included trials specifically recruited people who were unable to take thalidomide, but concluded that overall the indirect treatment comparison was acceptable for its decision making.\n\n## Lenalidomide plus dexamethasone is more clinically effective than VMP\n\nBased on the results of the indirect comparison, lenalidomide plus dexamethasone improved overall survival compared with VMP (hazard ratio [HR] 0.70, 95% credible interval [CrI] 0.50\xa0to\xa00.98). For progression-free survival, the hazard ratio for lenalidomide plus dexamethasone compared with VMP was\xa00.74 (95%\xa0CrI 0.52\xa0to\xa01.05). The committee noted that the wide credible intervals reflected the small number of trials included in the network. It noted that the results for lenalidomide plus dexamethasone taken until progression or unacceptable toxicity compared with lenalidomide plus dexamethasone taken for up to 18\xa0weeks did not differ. Based on the evidence presented, and acknowledging potential confounding, the committee concluded that lenalidomide plus dexamethasone was more clinically effective than VMP, although by how much was uncertain.\n\n## Lenalidomide plus dexamethasone is probably well tolerated\n\nThe clinical experts explained that, in their experience of using lenalidomide plus dexamethasone, the treatment is well tolerated and associated with fewer adverse events than VMP or MPT. This is expected because lenalidomide plus dexamethasone combines 2\xa0drugs, whereas VMP and MPT each combine 3\xa0drugs, 1\xa0of which is cytotoxic. Evidence from FIRST, however, showed that more people who had lenalidomide plus dexamethasone had serious adverse effects than those who had MPT. The company stated that this is because people have lenalidomide plus dexamethasone until disease progression or unacceptable toxicity whereas people have MPT and VMP for a fixed time (72\xa0weeks for MPT and 54\xa0weeks for VMP). Therefore, the committee agreed that lenalidomide plus dexamethasone was likely to be better tolerated in clinical practice than MPT or VMP over the same period of time.\n\n# The company's economic model\n\n## The company's hybrid model combines Kaplan–Meier data and constant transition probability between states\n\nThe company used a hybrid model structure. This was a partitioned survival model using the Kaplan–Meier data for the first 92\xa0weeks, and thereafter a multi-state Markov model with a constant transition probability between the 3\xa0states: pre-progression, progressed disease and death. The company chose this structure to account for the structural link between disease progression and mortality. The ERG noted that the company's progression-free and overall survival curves generated from the company's model fitted well to the data from FIRST. However, the committee was unclear what advantage the hybrid approach had compared with a partitioned survival model with a parametric curve fitted at week\xa092. This approach would have allowed different distributions to be tested and the sensitivity of the model to the extrapolation to be better explored. However, the committee acknowledged that there were over 6\xa0years of observed data, which the company's model fitted well.\n\n## The company's use of Kaplan–Meier data up to 92\xa0weeks is appropriate\n\nThe committee queried why the company chose 92\xa0weeks as the point at which to apply the Markov model, and asked the ERG if the model's results were sensitive to this cut-off time point. The company stated that it used the partitioned survival analysis for the first 92\xa0weeks because the log-cumulative hazard plots for progression-free survival from FIRST for each treatment were parallel up to this point then diverged. This was not the case for overall survival because the log-cumulative hazard plots remained parallel. But, using a multi-state Markov model meant that the company had to model progression-free and overall survival in the same way, that is, Kaplan–Meier data up to 92\xa0weeks followed by a constant transition probability matrix. The committee highlighted that a partitioned survival analysis would have allowed more flexible modelling because it would have been possible to model overall and progression-free survival independently. The ERG explained that the model's outputs were not sensitive to the cut-off time point, and that it considered the 92‑week cut-off appropriate. The committee concluded that the 92‑week cut-off was appropriate. However, it was unclear how sensitive the model was to the structural assumptions that the company chose.\n\n# Assumptions used in the economic model\n\n## A Weibull curve should be used to extrapolate time on treatment\n\nTo estimate the time on treatment beyond the end of the trial, the ERG noted that the company used different parametric curves to extrapolate the time on treatment of lenalidomide plus dexamethasone and its comparator. The ERG considered that best practice is to use the same parametric curve for both arms, and it preferred the Weibull curve. The committee acknowledged that the model was not sensitive to the change in parametric curve. It considered that using a Weibull curve to extrapolate both arms would be appropriate.\n\n## Time on treatment for VMP should be the same as for MPT\n\nTime on treatment for lenalidomide plus dexamethasone and MPT was collected directly in FIRST. Because there were no data on treatment duration from the clinical trial for VMP, the company assumed that time on treatment in the VMP arm equalled progression-free survival, up to the maximum treatment duration of 54\xa0weeks. The ERG noted that this assumption would likely increase the cost of VMP because, in FIRST, progression-free survival was longer than the time on treatment. The ERG noted that the indirect comparison showed that VMP and MPT had the same progression-free survival (HR\xa01.00, 95%\xa0CrI 0.72\xa0to\xa01.38), and both have a maximum fixed treatment duration. The ERG therefore preferred to assume time on VMP treatment was the same as time on MPT treatment up to the respective maximum treatment durations. The committee considered it plausible that the time on treatment was shorter than progression-free survival because some people would stop treatment because of adverse effects. The committee considered the ERG's change to be appropriate.\n\n## The utility estimates should be the same after treatment has stopped\n\nEQ‑5D data were collected directly in FIRST for lenalidomide plus dexamethasone. The company mapped EQ‑5D data for VMP from European Organisation for Research and Treatment of Cancer (EORTC) data from the clinical trial. The company assumed that there is a utility decrement during VMP treatment, which would continue even after VMP treatment has finished. The ERG considered there was no good evidence that this difference in utility estimates continued after VMP treatment stopped. The ERG therefore preferred that the utility estimates for lenalidomide plus dexamethasone and VMP to be the same after VMP treatment stops. The committee agreed with the ERG and preferred the utility estimates to be the same for lenalidomide plus dexamethasone and VMP after VMP treatment has stopped.\n\n## Treatments taken second line and later in the company's model do not reflect NHS clinical practice, and it is unclear how this would affect the model\n\nThe ERG highlighted that the company modelled the costs and clinical effects of therapies taken second line and later based on data from FIRST. This included thalidomide-based therapies or retreatment with lenalidomide-based therapies in the company's chosen population, that is, those who cannot take thalidomide. This led the committee to conclude that thalidomide use should not be included in the model. Also, the clinical experts explained that people do not have lenalidomide more than once in clinical practice. The ERG explored removing thalidomide and lenalidomide treatments taken second line and later from the model, but cautioned that it could remove only the costs, but not the effects, of these treatment options. Also, the committee noted that the model did not reflect NHS care because the company did not include the costs and effects of NICE-recommended treatment choices including carfilzomib, panobinostat and pomalidomide-based therapies, which were not available at the time of the clinical trial. The clinical experts were unable to predict what would happen to modelled mortality rates if the model reflected therapies used in the NHS. The committee concluded that the model does not reflect clinical practice, but it was unclear what effect this had on the estimates of cost effectiveness.\n\n# Cost-effectiveness estimates\n\n## The most plausible ICER is the ERG's preferred ICER\n\nThe company's estimated deterministic incremental cost-effectiveness ratio (ICER) is £11,886 per quality-adjusted life year (QALY) gained for lenalidomide plus dexamethasone compared with VMP. The ERG's preferred estimated deterministic ICER is £19,654 per QALY gained, based on the following changes:\n\nusing a Weibull parametric curve to extrapolate treatment duration (see section\xa03.12)\n\nassuming treatment duration was the same for VMP and MPT (see section\xa03.13)\n\nassuming utility estimates were the same after VMP treatment had finished (see section\xa03.14)\n\ncorrecting cycle length for VMP utility values and included minor additional administration costs for VMP.The committee considered the ERG's changes to be reasonable. The committee noted that the cost-effectiveness estimates included inappropriate therapies taken second line and later (see section\xa03.15). The ERG's exploratory analysis in which the costs of these inappropriate therapies were removed lowered the ERG's ICER. But, because the analysis did not remove their clinical effects, the committee considered this approach to be inappropriate. It concluded that the most plausible ICER was from the ERG's preferred analysis. The committee was aware that both the company's and ERG's ICERs included the new, simple-discount patient access scheme (PAS) in the intervention arm and the existing complex PAS (cost capped after 26\xa0cycles) in the comparator arm to reflect the assumption that the new PAS would take effect only if NICE produces positive guidance. However, the committee was aware that, because NHS England had concerns about the operation of the complex PAS, it had renegotiated this scheme with the company. Therefore, the committee considered that there was merit in considering ICERs with the simple-discount PAS applied in both the intervention and comparator arms. The ERG's ICER corresponding with this scenario was £26,713 per QALY gained (the company's ICER was £18,986 per QALY gained).\n\n## The ICER is most sensitive to varying the overall survival hazard ratio\n\nThe tornado diagram showed that the ICER was insensitive to varying most parameters, except the hazard ratio for overall survival between lenalidomide plus dexamethasone and VMP. The committee recalled that the credible interval for this parameter in the indirect comparison was wide (see section\xa03.8). The ERG explored a scenario in which it assumed VMP had a higher overall survival, equal to MPT. The company noted that this scenario was pessimistic because it assumed that the use of therapies second line and later remained unchanged, whereas improving overall survival would increase the use of therapies used second line and later, which would increase costs. The committee was satisfied that the most plausible ICER is reasonably robust to changes in the model parameters.\n\n## The cost-effectiveness estimates are only valid if people are unable to take thalidomide\n\nThe company stated that lenalidomide plus dexamethasone was not cost effective compared with the thalidomide-based therapy MPT. The committee recalled that it was unclear how people who cannot take thalidomide are defined in clinical practice (see section\xa03.2). It reiterated that, if some people have lenalidomide who could take thalidomide, this would not be a cost-effective use of NHS resources. It recalled that people for whom thalidomide is unsuitable can fall into 1\xa0of\xa02 groups (see section\xa03.2). The committee concluded it appropriate that these 2\xa0groups be reflected in the recommendation.\n\n# Other factors\n\n## The benefit of the oral administration of lenalidomide plus dexamethasone is unlikely to make a substantial difference to the conclusions\n\nThe company considered that lenalidomide is innovative because it is taken orally, whereas people have to attend specialist treatment units to have subcutaneous or intravenous bortezomib. The patient experts explained that people would value a new oral treatment because there is a substantial burden of travelling to a specialist treatment unit for injections, particularly for older people or those who travel long distances. The committee considered that the benefit of the oral administration of lenalidomide plus dexamethasone was unlikely to have been fully captured in the QALY, but that it was unlikely to make a substantial difference to its conclusions.\n\n# Conclusion\n\n## Lenalidomide plus dexamethasone is recommended for routine commissioning for people unable to take thalidomide\n\nWith the committee's preferred assumptions, the ICER was £19,654 per QALY gained (using the new, simple-discount PAS in the intervention arm and the existing complex PAS in the comparator arm) or was £26,713 per QALY gained (using the new, simple-discount PAS in both the intervention and comparator arms), which is within the range NICE usually considers a cost-effective use of NHS resources. The committee considered the remaining uncertainties to lie in the model, having included evidence from trials in people who could take thalidomide and treatments in the model taken second line and later not reflecting current clinical practice. The committee recognised that there is an unmet need for new treatment options for this population, and that recommending lenalidomide plus dexamethasone as first line would allow more people to have newer treatments in subsequent lines of therapy. The committee concluded that, despite the uncertainties, lenalidomide plus dexamethasone would be a cost-effective first-line treatment option for people who are not eligible for a stem cell transplant and who cannot take thalidomide. It therefore recommended lenalidomide plus dexamethasone for routine commissioning."}
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https://www.nice.org.uk/guidance/ta587
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Evidence-based recommendations on lenalidomide (Revlimid) plus dexamethasone for previously untreated multiple myeloma in adults.
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90753f2df81907fb96752db121f8780befd7ee72
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nice
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Depression in children and young people: identification and management
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Depression in children and young people: identification and management
This guideline covers identifying and managing depression in children and young people aged 5 to 18 years. Based on the stepped-care model, it aims to improve recognition and assessment and promote effective treatments for mild and moderate to severe depression.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Care of all children and young people with depression
## Good information, informed consent and support
Children and young people and their families need good information, given as part of a collaborative and supportive relationship with healthcare professionals, and need to be able to give fully informed consent.
Healthcare professionals involved in the detection, assessment or treatment of children or young people with depression should ensure that information is provided to the patient and their parents and carers at an appropriate time. The information should be age appropriate and should cover the nature, course and treatment of depression, including the likely side effect profile of medication should this be offered.
Healthcare professionals involved in the treatment of children or young people with depression should take time to build a supportive and collaborative relationship with both the patient and the family or carers.
Healthcare professionals should make all efforts necessary to engage the child or young person and their parents or carers in treatment decisions, taking full account of patient and parental/carer expectations, so that the patient and their parents or carers can give meaningful and properly informed consent before treatment is initiated.
Families and carers should be informed of self-help groups and support groups and be encouraged to participate in such programmes where appropriate.
## Language and black, Asian and minority ethnic groups
Where possible, all services should provide written information or audiotaped material in the language of the child or young person and their family or carers, and professional interpreters should be sought for those whose preferred language is not English.
Consideration should be given to providing psychological therapies and information about medication and local services in the language of the child or young person and their family or carers where the patient's and/or their family's or carer's first language is not English. If this is not possible, an interpreter should be sought.
Healthcare professionals in primary, secondary and relevant community settings should be trained in cultural competence to aid in the diagnosis and treatment of depression in children and young people from black, Asian and minority ethnic groups. This training should take into consideration the impact of the patient's and healthcare professional's racial identity status on the patient's depression.
Healthcare professionals working with interpreters should be provided with joint training opportunities with those interpreters, to ensure that both healthcare professionals and interpreters understand the specific requirements of interpretation in a mental health setting.
The development and evaluation of services for children and young people with depression should be undertaken in collaboration with stakeholders involving patients and their families and carers, including members of black, Asian and minority ethnic groups.
## Assessment and coordination of care
When assessing a child or young person with depression, healthcare professionals should routinely consider, and record in the patient's notes, potential comorbidities, and the social, educational and family context for the patient and family members, including the quality of interpersonal relationships, both between the patient and other family members and with their friends and peers.
In the assessment of a child or young person with depression, healthcare professionals should always ask the patient and their parents or carers directly about the child or young person's alcohol and drug use, any experience of being bullied or abused, self‑harm and ideas about suicide. A young person should be offered the opportunity to discuss these issues initially in private.
If a child or young person with depression presents acutely having self‑harmed, the immediate management should follow NICE's guideline on self-harm as this applies to children and young people, paying particular attention to the guidance on consent and capacity. Further management should then follow this depression guideline.
In the assessment of a child or young person with depression, healthcare professionals should always ask the patient, and be prepared to give advice, about self‑help materials or other methods used or considered potentially helpful by the patient or their parents or carers. This may include educational leaflets, helplines, self‑diagnosis tools, peer, social and family support groups, complementary therapies and faith groups.
Healthcare professionals should only recommend self‑help materials or strategies as part of a supported and planned package of care.
For any child or young person with suspected mood disorder, a family history should be obtained to check for unipolar or bipolar depression in parents and grandparents.
When a child or young person has been diagnosed with depression, consideration should be given to the possibility of parental depression, parental substance misuse, or other mental health problems and associated problems of living, as these are often associated with depression in a child or young person and, if untreated, may have a negative impact on the success of treatment offered to the child or young person.
When the clinical progress of children and young people with depression is being monitored in secondary care, the self‑report Mood and Feelings Questionnaire (MFQ) should be considered as an adjunct to clinical judgement.
In the assessment and treatment of depression in children and young people, special attention should be paid to the issues of:
confidentiality
the young person's consent (including Gillick competence)
parental consent
child protection
the use of the Mental Health Act in young people
the use of the Mental Capacity Act in young people
the use of the Children Act.
The form of assessment should take account of cultural and ethnic variations in communication, family values and the place of the child or young person within the family.
## The organisation and planning of services
June 2019 – terminology is under revision and may change in the future in line with NHS England's Future in Mind and the Care Quality Commission's report Are we listening. We have retained the tiers terminology and will revise this when we update the 2005 recommendations.
Healthcare professionals specialising in depression in children and young people should work with local child and adolescent mental health services (CAMHS) to enhance specialist knowledge and skills regarding depression in these existing services. This work should include providing training and help with guideline implementation.
CAMHS and local healthcare commissioning organisations should consider introducing a primary mental health worker (or CAMHS link worker) into each secondary school and secondary pupil referral unit as part of tier 2 provision within the locality.
Primary mental health workers (or CAMHS link workers) should establish clear lines of communication between CAMHS and tier 1 or 2, with named contact people in each tier or service, and develop systems for the collaborative planning of services for young people with depression in tiers 1 and 2.
CAMHS and local healthcare commissioning organisations should routinely monitor the rates of detection, referral and treatment of children and young people, from all ethnic groups, with mental health problems, including those with depression, in local schools and primary care. This information should be used for planning services and made available for local, regional and national comparison.
All healthcare and CAMHS professionals should routinely use, and record in the notes, appropriate outcome measures (such as those self‑report measures used in screening for depression or generic outcome measures used by particular services, for example Health of the Nation Outcome Scale for Children and Adolescents or Strengths and Difficulties Questionnaire ), for the assessment and treatment of depression in children and young people. This information should be used for planning services, and made available for local, regional and national comparison.
## Treatment and considerations in all settings
Most children and young people with depression should be treated on an outpatient or community basis.
Before any treatment is started, healthcare professionals should assess, together with the young person, the social network around him or her. This should include a written formulation, identifying factors that may have contributed to the development and maintenance of depression, and that may impact both positively or negatively on the efficacy of the treatments offered. The formulation should also indicate ways that the healthcare professionals may work in partnership with the social and professional network of the young person.
When bullying is considered to be a factor in a child or young person's depression, CAMHS, primary care and educational professionals should work collaboratively to prevent bullying and to develop effective antibullying strategies.
Psychological therapies used in the treatment of children and young people with depression should be provided by therapists who are also trained in child and adolescent mental health.
Psychological therapies used in the treatment of children and young people with depression should be provided by healthcare professionals who have been trained to an appropriate level of competence in the specific modality of psychological therapy being offered.
Therapists should develop a treatment alliance with the family. If this proves difficult, consideration should be given to providing the family with an alternative therapist.
Comorbid diagnoses and developmental, social and educational problems should be assessed and managed, either in sequence or in parallel, with the treatment for depression. Where appropriate this should be done through consultation and alliance with a wider network of education and social care.
Attention should be paid to the possible need for parents' own psychiatric problems (particularly depression) to be treated in parallel, if the child or young person's mental health is to improve. If such a need is identified, then a plan for obtaining such treatment should be made, bearing in mind the availability of adult mental health provision and other services.
A child or young person with depression should be offered advice on the benefits of regular exercise and encouraged to consider following a structured and supervised exercise programme of typically up to 3 sessions per week of moderate duration (45 minutes to 1 hour) for between 10 and 12 weeks.
A child or young person with depression should be offered advice about sleep hygiene and anxiety management.
A child or young person with depression should be offered advice about nutrition and the benefits of a balanced diet.
# Stepped care
The stepped‑care model of depression draws attention to the different needs of children and young people with depression – depending on the characteristics of their depression and their personal and social circumstances – and the responses that are required from services. It provides a framework in which to organise the provision of services that support both healthcare professionals and patients and their parents or carers in identifying and accessing the most effective interventions (see table 1).
Focus
Action
Responsibility
Detection
Risk profiling
Tier 1
Recognition
Identification in presenting children or young people
Tiers 2 to 4
Mild depression (including dysthymia)
Watchful waiting
Digital CBT, group CBT, group IPT or group NDST
If shared decision making based on full assessment (including maturity and developmental level) indicates needs not met, individual CBT or attachment-based family therapy
Tier 1
Tier 1 or 2
Moderate to severe depression (5- to 11-year-olds)
Family-based IPT, family therapy (family-focused treatment for childhood depression and systems integrative family therapy), psychodynamic psychotherapy, or individual CBT
With or without fluoxetine
Tier 2 or 3
Moderate to severe depression (12- to 18-year-olds)
Individual CBT
With or without fluoxetine
If shared decision making based on full assessment (including maturity and developmental level) indicates needs not met, IPT‑A, family therapy (attachment-based or systemic), brief psychosocial intervention or psychodynamic psychotherapy
With or without fluoxetine
Tier 2 or 3
Depression unresponsive to treatment/recurrent depression/psychotic depression
Intensive psychological therapy
With or without fluoxetine, sertraline, citalopram, augmentation with an antipsychotic
Tier 3 or 4
Abbreviations: CBT, cognitive–behavioural therapy; IPT, interpersonal psychotherapy; IPT A, IPT for adolescents; NDST, non-directive supportive therapy.
June 2019 – terminology is under revision and may change in the future in line with NHS England's Future in Mind and the Care Quality Commission's report Are we listening. We have retained the tiers terminology and will revise this when we update the 2005 recommendations.
The guidance follows these 5 steps:
. Detection and recognition of depression and risk profiling in primary care and community settings.
. Recognition of depression in children and young people referred to Children and Young People's Mental Health Services (including CAMHS).
. Managing recognised depression in primary care and community settings – mild depression.
. Managing recognised depression in tier 2 or 3 CAMHS – moderate to severe depression.
. Managing recognised depression in tier 3 or 4 CAMHS – unresponsive, recurrent and psychotic depression, including depression needing inpatient care.
Each step introduces additional interventions; the higher steps assume interventions in the previous step.
# Step 1: Detection, risk profiling and referral
## Detection and risk profiling
See also the recommendations on psychological and social issues in children and young people in the NICE guideline on diabetes (type 1 and type 2) in children and young people.
Healthcare professionals in primary care, schools and other relevant community settings should be trained to detect symptoms of depression, and to assess children and young people who may be at risk of depression. Training should include the evaluation of recent and past psychosocial risk factors, such as age, gender, family discord, bullying, physical, sexual or emotional abuse, comorbid disorders, including drug and alcohol use, and a history of parental depression; the natural history of single loss events; the importance of multiple risk factors; ethnic and cultural factors; and factors known to be associated with a high risk of depression and other health problems, such as homelessness, refugee status and living in institutional settings.
Healthcare professionals in primary care, schools and other relevant community settings should be trained in communications skills such as 'active listening' and 'conversational technique', so that they can deal confidently with the acute sadness and distress ('situational dysphoria') that may be encountered in children and young people following recent undesirable events.
Healthcare professionals in primary care settings should be familiar with screening for mood disorders. They should have regular access to specialist supervision and consultation.
Healthcare professionals in primary care, schools and other relevant community settings who are providing support for a child or young person with situational dysphoria should consider ongoing social and environmental factors if the dysphoria becomes more persistent.
CAMHS tier 2 or 3 should work with health and social care professionals in primary care, schools and other relevant community settings to provide training and develop ethnically and culturally sensitive systems for detecting, assessing, supporting and referring children and young people who are either depressed or at significant risk of becoming depressed.
In the provision of training by CAMHS professionals for healthcare professionals in primary care, schools and relevant community settings, priority should be given to the training of pastoral support staff in schools (particularly secondary schools), community paediatricians and GPs.
When a child or young person is exposed to a single recent undesirable life event, such as bereavement, parental divorce or separation or a severely disappointing experience, healthcare professionals in primary care, schools and other relevant community settings should undertake an assessment of the risks of depression associated with the event and make contact with their parents or carers to help integrate parental/carer and professional responses. The risk profile should be recorded in the child or young person's records.
When a child or young person is exposed to a single recent undesirable life event, such as bereavement, parental divorce or separation or a severely disappointing experience, in the absence of other risk factors for depression, healthcare professionals in primary care, schools and other relevant community settings should offer support and the opportunity to talk over the event with the child or young person.
Following an undesirable event, a child or young person should not normally be referred for further assessment or treatment, as single events are unlikely to lead to a depressive illness.
A child or young person who has been exposed to a recent undesirable life event, such as bereavement, parental divorce or separation or a severely disappointing experience and is identified to be at high risk of depression (the presence of 2 or more other risk factors for depression), should be offered the opportunity to talk over their recent negative experiences with a professional in tier 1 and assessed for depression. Early referral should be considered if there is evidence of depression and/or self-harm.
When a child or young person is exposed to a recent undesirable life event, such as bereavement, parental divorce or separation or a severely disappointing experience, and where 1 or more family members (parents or children) have multiple risk histories for depression, they should be offered the opportunity to talk over their recent negative experiences with a professional in tier 1 and assessed for depression. Early referral should be considered if there is evidence of depression and/or self-harm.
If children and young people who have previously recovered from moderate or severe depression begin to show signs of a recurrence of depression, healthcare professionals in primary care, schools or other relevant community settings should refer them to CAMHS tier 2 or 3 for rapid assessment.
## Referral criteria
For children and young people, the following factors should be used by healthcare professionals as indications that management can remain at tier 1:
exposure to a single undesirable event in the absence of other risk factors for depression
exposure to a recent undesirable life event in the presence of 2 or more other risk factors with no evidence of depression and/or self‑harm
exposure to a recent undesirable life event, where 1 or more family members (parents or children) have multiple‑risk histories for depression, providing that there is no evidence of depression and/or self‑harm in the child or young person
mild depression without comorbidity.
For children and young people, the following factors should be used by healthcare professionals as criteria for referral to tier 2 or 3 CAMHS:
depression with 2 or more other risk factors for depression
depression where 1 or more family members (parents or children) have multiple‑risk histories for depression
mild depression in those who have not responded to interventions in tier 1 after 2–3 months
moderate or severe depression (including psychotic depression)
signs of a recurrence of depression in those who have recovered from previous moderate or severe depression
unexplained self‑neglect of at least 1 month's duration that could be harmful to their physical health
active suicidal ideas or plans
referral requested by a young person or their parents or carers.
For children and young people, the following factors should be used by healthcare professionals as criteria for referral to tier 4 services:
high recurrent risk of acts of self‑harm or suicide
significant ongoing self‑neglect (such as poor personal hygiene or significant reduction in eating that could be harmful to their physical health)
requirement for intensity of assessment/treatment and/or level of supervision that is not available in tier 2 or 3.
# Step 2: Recognition of depression in children and young people
Children and young people of 11 years or older referred to CAMHS without a diagnosis of depression should be routinely screened with a self‑report questionnaire for depression as part of a general assessment procedure.
Training opportunities should be made available to improve the accuracy of CAMHS professionals in diagnosing depressive conditions. The existing interviewer‑based instruments (such as Kiddie‑Sads and Child and Adolescent Psychiatric Assessment ) could be used for this purpose but will require modification for regular use in busy routine CAMHS settings.
Within tier 3 CAMHS, professionals who specialise in the treatment of depression should have been trained in interviewer‑based assessment instruments (such as K‑SADS and CAPA) and have skills in non‑verbal assessments of mood in younger children.
# Step 3: Managing mild depression
## Watchful waiting
For children and young people with diagnosed mild depression who do not want an intervention or who, in the opinion of the healthcare professional, may recover with no intervention, a further assessment should be arranged, normally within 2 weeks ('watchful waiting').
Healthcare professionals should make contact with children and young people with depression who do not attend follow‑up appointments.
## Treatments for mild depression
For children and young people with learning disabilities, see the recommendations on psychological interventions in the NICE guideline on mental health problems in people with learning disabilities.
Antidepressant medication should not be used for the initial treatment of children and young people with mild depression.
Discuss the choice of psychological therapies with children and young people with mild depression and their family members or carers (as appropriate). Explain:
what the different therapies involve
the evidence for each age group (including the limited evidence for 5- to 11‑year‑olds)
how the therapies could meet individual needs, preferences and values.
Base the choice of psychological therapy on:
a full assessment of needs, including:
the circumstances of the child or young person and their family members or carers
their clinical and personal/social history and presentation
their maturity and developmental level
the context in which treatment is to be provided
comorbidities, neurodevelopmental disorders, communication needs (language, sensory impairment) and learning disabilities
patient and carer preferences and values (as appropriate).
For 5- to 11‑year‑olds with mild depression continuing after 2 weeks of watchful waiting, and without significant comorbid problems or active suicidal ideas or plans, consider the following options adapted to developmental level as needed:
digital cognitive–behavioural therapy (CBT)
group CBT
group non-directive supportive therapy (NDST)
group interpersonal psychotherapy (IPT).If these options would not meet the child's clinical needs or are unsuitable for their circumstances, consider the following adapted to developmental level as needed:
attachment-based family therapy
individual CBT.
For 12- to 18‑year‑olds with mild depression continuing after 2 weeks of watchful waiting, and without significant comorbid problems or active suicidal ideas or plans, offer a choice of the following psychological therapies for a limited period (approximately 2 to 3 months):
digital CBT
group CBT
group NDST
group IPT.
If the options in recommendation 1.5.7 would not meet the clinical needs of a 12- to 18‑year‑old with mild depression or are unsuitable for their circumstances, consider:
attachment-based family therapy or
individual CBT.
Provide psychological therapies in settings such as schools and colleges, primary care, social services and the voluntary sector.
If mild depression in a child or young person has not responded to psychological therapy after 2 to 3 months (recommendations 1.5.6 to 1.5.8 and table 1), refer the child or young person for review by a CAMHS team.
Follow the recommendations on treating moderate to severe depression for children and young people who have continuing depression after 2 to 3 months of psychological therapy (see the section on moderate to severe depression).
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on treatments for mild depression .
Full details of the evidence and the committee's discussion are in evidence review A: Psychological interventions for the treatment of depression.
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# Steps 4 and 5: Managing moderate to severe depression
## Treatments for moderate to severe depression
For children and young people with learning disabilities, see the recommendations on psychological interventions in the NICE guideline on mental health problems in people with learning disabilities.
Children and young people presenting with moderate to severe depression should be reviewed by a CAMHS team.
Discuss the choice of psychological therapies with children and young people with moderate to severe depression and their family members or carers (as appropriate). Explain:
what the different therapies involve
the evidence for each age group (including the limited evidence for 5- to 11‑year‑olds)
how the therapies could meet individual needs, preferences and values.
Base the choice of psychological therapy on:
a full assessment of needs, including:
the circumstances of the child or young person and their family members or carers
their clinical and personal/social history and presentation
their maturity and developmental level
the context in which treatment is to be provided
comorbidities, neurodevelopmental disorders, communication needs (language, sensory impairment) and learning disabilities
patient and carer preferences and values (as appropriate).
For 5- to 11‑year‑olds with moderate to severe depression, consider the following options adapted to developmental level as needed:
family-based IPT
family therapy (family-focused treatment for childhood depression and systems integrative family therapy)
psychodynamic psychotherapy
individual CBT.
For 12- to 18‑year‑olds with moderate to severe depression, offer individual CBT for at least 3 months.
If individual CBT would not meet the clinical needs of a 12- to 18‑year‑old with moderate to severe depression or is unsuitable for their circumstances, consider the following options:
IPT-A (IPT for adolescents)
family therapy (attachment-based or systemic)
brief psychosocial intervention
psychodynamic psychotherapy.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on treatments for moderate to severe depression .
Full details of the evidence and the committee's discussion are in evidence review A: Psychological interventions for the treatment of depression.
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## Combined treatments for moderate to severe depression
Consider combined therapy (fluoxetine and psychological therapy) for initial treatment of moderate to severe depression in young people (12–18 years), as an alternative to psychological therapy followed by combined therapy and to recommendations 1.6.8 to 1.6.10. In June 2019, this was an off-label use of fluoxetine for initial combination use (fluoxetine with psychological therapy) in children and young people who have not previously had a trial of psychological therapy on its own. See NICE's information on prescribing medicines.
If moderate to severe depression in a child or young person is unresponsive to psychological therapy after 4 to 6 treatment sessions, a multidisciplinary review should be carried out.
Following multidisciplinary review, if the child or young person's depression is not responding to psychological therapy as a result of other coexisting factors such as the presence of comorbid conditions, persisting psychosocial risk factors such as family discord, or the presence of parental mental ill‑health, alternative or perhaps additional psychological therapy for the parent or other family members, or alternative psychological therapy for the patient, should be considered.
Following multidisciplinary review, offer fluoxetine if moderate to severe depression in a young person (12–18 years) is unresponsive to a specific psychological therapy after 4 to 6 sessions. In June 2019, fluoxetine was the only antidepressant with UK marketing authorisation for use in this indication for children and young people aged 8 to 18 years.
Following multidisciplinary review, cautiously consider fluoxetine if moderate to severe depression in a child (5–11 years) is unresponsive to a specific psychological therapy after 4 to 6 sessions, although the evidence for fluoxetine's effectiveness in this age group is not established. In June 2019, this was an off-label use of fluoxetine in children under the age of 8 years. See NICE's information on prescribing medicines.
## Depression unresponsive to combined treatment
If moderate to severe depression in a child or young person is unresponsive to combined treatment with a specific psychological therapy and fluoxetine after a further 6 sessions, or the patient and/or their parents or carers have declined the offer of fluoxetine, the multidisciplinary team should make a full needs and risk assessment. This should include a review of the diagnosis, examination of the possibility of comorbid diagnoses, reassessment of the possible individual, family and social causes of depression, consideration of whether there has been a fair trial of treatment, and assessment for further psychological therapy for the patient and/or additional help for the family.
Following multidisciplinary review, the following should be considered:
an alternative psychological therapy, which has not been tried previously (individual CBT, interpersonal therapy or shorter‑term family therapy, of at least 3 months' duration) or
systemic family therapy (at least 15 fortnightly sessions) or
psychodynamic psychotherapy (approximately 30 weekly sessions).
## How to use antidepressants in children and young people
Do not offer antidepressant medication to a child or young person with moderate to severe depression except in combination with a concurrent psychological therapy. Specific arrangements must be made for careful monitoring of adverse drug reactions, as well as for reviewing mental state and general progress; for example, weekly contact with the child or young person and their parents or carers for the first 4 weeks of treatment. The precise frequency will need to be decided on an individual basis, and recorded in the notes. In the event that psychological therapies are declined, medication may still be given, but as the young person will not be reviewed at psychological therapy sessions, the prescribing doctor should closely monitor the child or young person's progress on a regular basis and focus particularly on emergent adverse drug reactions.
If an antidepressant is to be prescribed this should only be following assessment and diagnosis by a child and adolescent psychiatrist.
When an antidepressant is prescribed to a child or young person with moderate to severe depression, it should be fluoxetine as this is the only antidepressant for which clinical trial evidence shows that the benefits outweigh the risks. In June 2019, this was an off-label use of fluoxetine in children under the age of 8 years. See NICE's information on prescribing medicines.
If a child or young person is started on antidepressant medication, they (and their parents or carers, as appropriate) should be informed about the rationale for the drug treatment, the delay in onset of effect, the time course of treatment, the possible side effects, and the need to take the medication as prescribed. Discussion of these issues should be supplemented by written information appropriate to the child or young person's and parents' or carers' needs that covers the issues described above and includes the latest patient information advice from the relevant regulatory authority.
A child or young person prescribed an antidepressant should be closely monitored for the appearance of suicidal behaviour, self‑harm or hostility, particularly at the beginning of treatment, by the prescribing doctor and the healthcare professional delivering the psychological therapy. Unless it is felt that medication needs to be started immediately, symptoms that might be subsequently interpreted as side effects should be monitored for 7 days before prescribing. Once medication is started the patient and their parents or carers should be informed that if there is any sign of new symptoms of these kinds, urgent contact should be made with the prescribing doctor.
When fluoxetine is prescribed for a child or young person with depression, the starting dose should be 10 mg daily. This can be increased to 20 mg daily after 1 week if clinically necessary, although lower doses should be considered in children of lower body weight. There is little evidence regarding the effectiveness of doses higher than 20 mg daily. However, higher doses may be considered in older children of higher body weight and/or when, in severe illness, an early clinical response is considered a priority. In June 2019, this was an off-label use of fluoxetine in children under the age of 8 years. See NICE's information on prescribing medicines.
When an antidepressant is prescribed in the treatment of a child or young person with depression and a self‑report rating scale is used as an adjunct to clinical judgement, this should be a recognised scale such as the MFQ.
When a child or young person responds to treatment with fluoxetine, medication should be continued for at least 6 months after remission (defined as no symptoms and full functioning for at least 8 weeks); in other words, for 6 months after this 8‑week period. In June 2019, this was an off-label use of fluoxetine in children under the age of 8 years. See NICE's information on prescribing medicines.
If treatment with fluoxetine is unsuccessful or is not tolerated because of side effects, consideration should be given to the use of another antidepressant. In this case sertraline or citalopram are the recommended second‑line treatments. In June 2019, the use in children and young people under 18 of citalopram and sertraline was off label. See NICE's information on prescribing medicines.
Sertraline or citalopram should only be used when the following criteria have been met:
The child or young person and their parents or carers have been fully involved in discussions about the likely benefits and risks of the new treatment and have been provided with appropriate written information. This information should cover the rationale for the drug treatment, the delay in onset of effect, the time course of treatment, the possible side effects, and the need to take the medication as prescribed; it should also include the latest patient information advice from the relevant regulatory authority.
The child or young person's depression is sufficiently severe and/or causing sufficiently serious symptoms (such as weight loss or suicidal behaviour) to justify a trial of another antidepressant.
There is clear evidence that there has been a fair trial of the combination of fluoxetine and a psychological therapy (in other words, that all efforts have been made to ensure adherence to the recommended treatment regimen).
There has been a reassessment of the likely causes of the depression and of treatment resistance (for example other diagnoses such as bipolar disorder or substance misuse).
There has been advice from a senior child and adolescent psychiatrist – usually a consultant.
The child or young person and/or someone with parental responsibility for the child or young person (or the young person alone, if over 16 or deemed competent) has signed an appropriate and valid consent form. See the MHRA's drug safety update on QT prolongation with citalopram and escitalopram.
When a child or young person responds to treatment with citalopram or sertraline, medication should be continued for at least 6 months after remission (defined as no symptoms and full functioning for at least 8 weeks).
When an antidepressant other than fluoxetine is prescribed for a child or young person with depression, the starting dose should be half the daily starting dose for adults. This can be gradually increased to the daily dose for adults over the next 2 to 4 weeks if clinically necessary, although lower doses should be considered in children with lower body weight. There is little evidence regarding the effectiveness of the upper daily doses for adults in children and young people, but these may be considered in older children of higher body weight and/or when, in severe illness, an early clinical response is considered a priority.
Paroxetine and venlafaxine should not be used for the treatment of depression in children and young people.
Tricyclic antidepressants should not be used for the treatment of depression in children and young people.
Where antidepressant medication is to be discontinued, the drug should be phased out over a period of 6 to 12 weeks with the exact dose being titrated against the level of discontinuation/withdrawal symptoms.
As with all other medications, consideration should be given to possible drug interactions when prescribing medication for depression in children and young people. This should include possible interactions with complementary and alternative medicines as well as with alcohol and 'recreational' drugs.
Although there is some evidence that St John's wort may be of some benefit in adults with mild to moderate depression, this cannot be assumed for children or young people, for whom there are no trials upon which to make a clinical decision. Moreover, it has an unknown side‑effect profile and is known to interact with a number of other drugs, including contraceptives. Therefore St John's wort should not be prescribed for the treatment of depression in children and young people.
A child or young person with depression who is taking St John's wort as an over-the-counter preparation should be informed of the risks and advised to discontinue treatment while being monitored for recurrence of depression and assessed for alternative treatments in accordance with this guideline.
## The treatment of psychotic depression
For children and young people with psychotic depression, augmenting the current treatment plan with a second-generation antipsychotic medication should be considered, although the optimum dose and duration of treatment are unknown. In June 2019, the use of all second-generation antipsychotics for children and young people under 18 was off label. See NICE's information on prescribing medicines.
Children and young people prescribed a second-generation antipsychotic medication should be monitored carefully for side effects.
See also the recommendations on choice of antipsychotics and how to use them in the NICE guideline on psychosis and schizophrenia in children and young people.
## Inpatient care
Inpatient treatment should be considered for children and young people who present with a high risk of suicide, high risk of serious self‑harm or high risk of self‑neglect, and/or when the intensity of treatment (or supervision) needed is not available elsewhere, or when intensive assessment is indicated.
When considering admission for a child or young person with depression, the benefits of inpatient treatment need to be balanced against potential detrimental effects, for example loss of family and community support.
When inpatient treatment is indicated, CAMHS professionals should involve the child or young person and their parents or carers in the admission and treatment process whenever possible.
Commissioners should ensure that inpatient treatment is available within reasonable travelling distance to enable the involvement of families and maintain social links.
Commissioners should ensure that inpatient services are able to admit a young person within an appropriate timescale, including immediate admission if necessary.
Inpatient services should have a range of interventions available including medication, individual and group psychological therapies and family support.
Inpatient facilities should be age appropriate and culturally enriching, with the capacity to provide appropriate educational and recreational activities.
Planning for aftercare arrangements should take place before admission or as early as possible after admission and should be based on the Care Programme Approach.
Tier 4 CAMHS professionals involved in assessing children or young people for possible inpatient admission should be specifically trained in issues of consent and capacity, the use of current mental health legislation and the use of childcare laws, as they apply to this group of patients.
## Electroconvulsive therapy
Electroconvulsive therapy (ECT) should only be considered for young people with very severe depression and either life‑threatening symptoms (such as suicidal behaviour) or intractable and severe symptoms that have not responded to other treatments.
ECT should be used extremely rarely in young people and only after careful assessment by a practitioner experienced in its use and only in a specialist environment in accordance with NICE recommendations.
ECT is not recommended in the treatment of depression in children (5–11 years).
## Discharge after a first episode
When a child or young person is in remission (fewer than 2 symptoms and full functioning for at least 8 weeks), they should be reviewed regularly for 12 months by an experienced CAMHS professional. The exact frequency of contact should be agreed between the CAMHS professional and the child or young person and/or the parents or carers and recorded in the notes. At the end of this period, if remission is maintained, the young person can be discharged to primary care.
CAMHS should keep primary care professionals up to date about progress and the need for monitoring of the child or young person in primary care. CAMHS should also inform relevant primary care professionals within 2 weeks of a patient being discharged and should provide advice about whom to contact in the event of a recurrence of depressive symptoms.
Children and young people who have been successfully treated and discharged but then re‑referred should be seen as soon as possible rather than placed on a routine waiting list.
## Recurrent depression and relapse prevention
Specific follow‑up psychological therapy sessions to reduce the likelihood of, or at least detect, a recurrence of depression should be considered for children and young people who are at a high risk of relapse (for example individuals who have already experienced 2 prior episodes, those who have high levels of subsyndromal symptoms, or those who remain exposed to multiple‑risk circumstances).
CAMHS specialists should teach recognition of illness features, early warning signs, and subthreshold disorders to tier 1 professionals, children or young people with recurrent depression and their families and carers. Self‑management techniques may help individuals to avoid and/or cope with trigger factors.
When a child or young person with recurrent depression is in remission (fewer than 2 symptoms and full functioning for at least 8 weeks), they should be reviewed regularly for 24 months by an experienced CAMHS professional. The exact frequency of contact should be agreed between the CAMHS professional and the child or young person and/or the parents or carers and recorded in the notes. At the end of this period, if remission is maintained, the young person can be discharged to primary care.
Children and young people with recurrent depression who have been successfully treated and discharged but then re‑referred should be seen as a matter of urgency.
# Transfer to adult services
See also the NICE guideline on transition from children's to adults' services for young people using health or social care services.
The CAMHS team currently providing treatment and care for a young person aged 17 who is recovering from a first episode of depression should normally continue to provide treatment until discharge is considered appropriate in accordance with this guideline, even when the person turns 18 years of age.
The CAMHS team currently providing treatment and care for a young person aged 17–18 who either has ongoing symptoms from a first episode that are not resolving or has, or is recovering from, a second or subsequent episode of depression, should normally arrange for a transfer to adult mental health services, informed by the Care Programme Approach.
A young person aged 17–18 with a history of recurrent depression who is being considered for discharge from CAMHS should be provided with comprehensive information about the treatment of depression in adults (including NICE's information for the public) and information about local services and support groups suitable for young adults with depression.
A young person aged 17–18 who has successfully recovered from a first episode of depression and is discharged from CAMHS should not normally be referred on to adult services, unless they are considered to be at high risk of relapse (for example, if they are living in multiple‑risk circumstances).
# Terms used in this guideline
## Tiers
June 2019 – The tiers terminology is under revision and may change in the future in line with NHS England's Future in Mind and the Care Quality Commission's report Are we listening. We have retained the tiers terminology and will revise this when the 2005 recommendations are updated.
The Care Quality Commission's report 'Are we listening' referred to the whole system of care and support (tiers 1 to 4) as Children and Young People's Mental Health Services. These included counselling provided through schools or GP practices, youth services, voluntary sector advice and support, and universal healthcare services like health visitors, as well as CAMHS. They used CAMHS to refer to services offering specialist care in the community (tier 3) and inpatient care (tier 4).
## Brief psychosocial intervention
This intervention is based on the brief psychosocial intervention (BPI) carried out in the IMPACT trial (Goodyer et al. 2017).
Core components of BPI include:
psychoeducation about depression and action-oriented, goal-focused, interpersonal activities as therapeutic strategies
building health habits
planning and scheduling valued activities
advice on maintaining and improving mental and physical hygiene including sleep, diet and exercise
promoting engagement with and maintaining school work and peer relations, and diminishing solitariness.
BPI does not involve cognitive or reflective analytic techniques.
## Digital CBT
Digital CBT is a form of CBT delivered using digital technology, such as a computer, tablet or phone. A variety of digital CBT programmes have been used for young people aged 12 to 18 years with mild depression. These include SPARX, Stressbusters and Grasp the Opportunity. Only Stressbusters has been tested in the UK. Some digital CBT interventions are supported by contact with a healthcare professional but in other cases there may be no additional support.
Common components of digital CBT programmes include: psychoeducation, relaxation, analysis of behaviour, behavioural activation, basic communication and interpersonal skills, emotional recognition, dealing with strong emotions, problem solving, cognitive restructuring (identifying thoughts, challenging unhelpful/negative thoughts), mindfulness and relapse prevention.# Recommendations for research
# Key recommendations for research
## Psychological therapies for children aged 5 to 11 years with mild or moderate to severe depression
What is the clinical and cost effectiveness, post-treatment and at longer-term follow‑up, of psychological therapies in children aged 5 to 11 years with mild or moderate to severe depression?
For a short explanation of why the committee made the recommendation for research, see the rationale on treatments for mild depression or moderate to severe depression .
Full details of the evidence and the committee's discussion are in evidence review A: Psychological interventions for the treatment of depression.
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## Digital cognitive–behavioural therapy
What is the clinical and cost effectiveness, post-treatment and at longer-term follow‑up, of supported digital cognitive–behavioural therapy (CBT) compared with unsupported digital CBT in young people aged 12 to 18 years with mild depression, and what are the key components of the interventions that influence effectiveness?
For a short explanation of why the committee made the recommendation for research, see the rationale on treatments for mild depression .
Full details of the evidence and the committee's discussion are in evidence review A: Psychological interventions for the treatment of depression.
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## Family therapy, interpersonal psychotherapy for adolescents and psychodynamic psychotherapy
What is the clinical and cost effectiveness, post-treatment and at longer-term follow‑up, of family therapy, psychodynamic psychotherapy and interpersonal psychotherapy for adolescents (IPT‑A) compared with each other and with individual CBT in young people aged 12 to 18 years with moderate to severe depression?
For a short explanation of why the committee made the recommendation for research, see the rationale on treatments for moderate to severe depression .
Full details of the evidence and the committee's discussion are in evidence review A: Psychological interventions for the treatment of depression.
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## Brief psychosocial intervention delivered by non-psychiatrists and in other settings
What is the clinical and cost effectiveness, post-treatment and at longer-term follow‑up, of a brief psychosocial intervention as reported by the IMPACT trial, but delivered by practitioners other than psychiatrists and in other settings, including primary care, to young people aged 12 to 18 years with mild or moderate to severe depression?
For a short explanation of why the committee made the recommendation for research, see the rationale on moderate to severe depression .
Full details of the evidence and the committee's discussion are in evidence review A: Psychological interventions for the treatment of depression.
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## Behavioural activation
What is the clinical and cost effectiveness, post treatment and at longer-term follow‑up, of behavioural activation compared with other psychological therapies in children aged 5 to 11 years and young people aged 12 to 18 years with mild or moderate to severe depression?
For a short explanation of why the committee made the recommendation for research, see the rationale for treatments for mild depression or moderate to severe depression .
Full details of the evidence and the committee's discussion are in evidence review A: Psychological interventions for the treatment of depression.
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# Other recommendations for research
## Group mindfulness
What is the clinical and cost effectiveness, post treatment and at longer-term follow‑up, of group mindfulness compared with other psychological therapies in young people aged 12 to 18 years with mild depression?
## Combination therapy (fluoxetine and psychological therapy)
An appropriately blinded, randomised controlled trial should be conducted to assess the efficacy (including measures of family and social functioning as well as depression) and the cost effectiveness of fluoxetine, psychological therapy, the combination of fluoxetine and psychological therapy compared with each other and placebo in a broadly based sample of children and young people diagnosed with moderate to severe depression (using minimal exclusion criteria).The trial should be powered to examine the effect of treatment in children and young people separately and involve a follow‑up of 12 to 18 months (but no less than 6 months).
## Care pathway experience
A qualitative study should be conducted that examines the experiences in the care pathway of children and young people and their families (and perhaps professionals) in order to inform decisions about what the most appropriate care pathway should be.
## Computer technology to assess mood and feelings
An appropriately designed study should be conducted to compare validated screening instruments for the detection of depression in children and young people. An emphasis should be placed on examining those that use computer technology and more child-friendly methods of assessing current mood and feelings, and take into account cultural and ethnic variations in communication, family values and the place of the child or young person within the family. # Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Treatments for mild depression
Recommendations 1.5.4 to 1.5.11
## Why the committee made the recommendations
To ensure that children and young people with depression and their families or carers (as appropriate) receive the best possible care and can take part in shared decision making, the committee recommended that healthcare professionals explain the treatment options, what these are like in practice and how different psychological therapies might best suit individual clinical needs, preferences and values. The discussion should also cover the evidence for the different treatments and make it clear that there is limited evidence for effective treatments for 5- to 11‑year‑olds.
The committee recognised that some children and young people have difficulties accessing treatment because of lack of transport (particularly in rural areas), chaotic family lives, being in a young offender's institute or being in care. They agreed that the healthcare professional should not only think about clinical needs, but also take into account the child or young person's personal/social history, the current environment, the setting where the treatment will be provided and individual preferences and values. In addition, certain therapies may not be suitable or may need to be adapted for use with children generally or those with comorbidities, neurodevelopmental disorders, learning disabilities or different communication needs (due to language or sensory impairment). To ensure that these factors are part of the decision-making process, the committee included them in the full assessment of needs.
The evidence for psychological therapies for 5- to 11‑year‑olds was confined to group cognitive–behavioural therapy (CBT), and although depression symptoms were reduced at the end of treatment compared with waiting list/no treatment, this was not maintained in the longer term. There were no data for other outcomes such as functional status or remission. As a result, the committee decided to recommend the same interventions that were effective in 12- to 18‑year‑olds for this age group, but adapted for their age and developmental level.
Because of the limited evidence for effective treatments for 5- to 11‑year‑olds with mild depression, the committee made a research recommendation on psychological therapies for children aged 5 to 11 years with mild or moderate to severe depression to try to stimulate research in this area.
Analysis of the evidence for 12- to 18‑year‑olds with mild depression showed that digital CBT (also known as online CBT or computer CBT), group therapies (group CBT, group interpersonal psychotherapy and group non-directive supportive therapy ), individual CBT and family therapy reduced depression symptoms or improved functional status by the end of treatment and up to 6 months later compared with a waiting list control or no treatment. In some cases, such as digital CBT, these positive effects persisted for longer than 6 months, but information on long-term effects was not always available. Digital CBT was also better than other psychological therapies at reducing depression symptoms longer term.
The committee agreed to base recommendations for psychological therapies on clinical effectiveness and cost. The average costs estimated for digital CBT and group therapy (CBT, IPT and NDST) were lower than those for individual CBT and family therapy. Taking the magnitude of effect, the estimated cost and the size of the evidence base into account, the committee agreed that a choice of digital CBT, group IPT, group NDST or group CBT should be offered first.
However, the committee recognised that digital CBT is not well defined and the evidence for effectiveness came from studies using a variety of different programmes. In addition, digital CBT can be delivered with support (from a healthcare professional) or as an unsupported intervention. It is unclear whether unsupported or supported digital CBT is more effective and which programmes would be most effective for use in the UK. As a result, the committee made a research recommendation on digital CBT to inform future guidance.
Individual CBT and family therapy were among the more expensive options. Individual CBT had a smaller effect on depression symptoms than digital CBT or group therapy (CBT, IPT or NDST). Individual CBT had a meaningful effect on functional status; this outcome was only reported in a study that recruited young people with depression and a comorbidity. Family therapy showed meaningful effects on depression symptoms, but these results were based on a single study.
The committee acknowledged that digital CBT, group CBT, group IPT and group NDST may not be suitable for everyone and that individual CBT or family therapy could be considered in these situations. They specified attachment-based family therapy in the recommendation because that was the type of family therapy used in the study.
The committee agreed not to make a recommendation for individual NDST or guided self-help because:
Individual NDST was not more effective at reducing depression symptoms at the end of treatment or at 6 months' follow‑up than control and there was no evidence for functional status or remission.
Although guided self-help reduced depression symptoms at the end of treatment compared with a waiting list control/no treatment, this was not sustained at later time points. In addition, guided self-help was no more effective at reducing depression symptoms at the end of treatment, and was either less effective or no more effective at later time points, than the recommended group therapies (group CBT, group IPT, group NDST), digital CBT, individual CBT or family therapy.
The committee made a research recommendation on behavioural activation aimed at investigating the effectiveness of behavioural activation compared with other psychological therapies. They agreed that behavioural activation may meet the needs of some children and young people with depression that are not already covered by the other recommended psychological therapies. In particular, it might suit children and young people who struggle with the concepts of CBT, and children and young people with learning disabilities or neurodevelopmental disorders. The only evidence for behavioural activation came from a single small study (60 participants) that found no difference between behavioural activation and usual care, but this may have been because of the small study size.
The committee also made a research recommendation for group mindfulness, because, although it was more effective at reducing depression symptoms post treatment and at 6 months' follow‑up than a waiting list control/no treatment, there was no evidence for other key outcomes such as functional status or later time points, and the evidence came from a single small study.
## How the recommendations might affect practice
The recommendation for digital CBT or group therapy (CBT, IPT or NDST) for children and young people with mild depression is not likely to result in increased resource use. It may even result in lower resource use if these interventions reduce the need for intensive individual therapies. Individual NDST and guided self-help are no longer recommended and the net resource impact of this change is therefore unclear.
Return to recommendations
# Treatments for moderate to severe depression
Recommendations 1.6.1 to 1.6.6
## Why the committee made the recommendations
As for mild depression, the committee agreed that children and young people and their families or carers should be empowered to take part in shared decision making. Healthcare professional should also think about a number of key factors, including history, individual circumstances, comorbidities and developmental level and maturity.
There was some evidence for psychological therapies for children aged 5 to 11 years with moderate to severe depression, but this included very few interventions. The committee agreed that the child or young person and their family or carers should be made aware of this when making decisions about treatments.
In the analysis of evidence for 5- to 11‑year‑olds with moderate to severe depression, family-based IPT and family therapy were more effective at reducing depression symptoms at the end of treatment than psychodynamic psychotherapy; but psychodynamic psychotherapy was better than family therapy at maintaining remission 6 months later. However, the evidence base was small (3 studies) and none included a control intervention. In other studies that included a control, no interventions were better than the control at reducing depression symptoms after treatment or at later time points.
Despite the limited evidence for 5- to 11‑year‑olds, the committee agreed that treatment was important for these young children. They agreed to recommend the treatments (family therapy, family-based IPT and psychodynamic psychotherapy) for which there was some evidence. They specified the types of family therapy used in the studies (family-focused treatment for childhood depression and systems integrative family therapy). They also included individual CBT in the recommendation because it was the most effective treatment for 12- to 18‑year‑olds with moderate to severe depression and they agreed that more mature children might benefit from this intervention.
Because of the limited evidence for effective treatments for 5- to 11‑year‑olds with depression, the committee made a research recommendation on psychological therapies for children aged 5 to 11 years with mild or moderate to severe depression to inform future guidance.
In an analysis of a large body of evidence for 12- to 18‑year‑olds with moderate to severe depression, individual CBT was better at reducing depression symptoms and improving functional status, quality of life and suicidal ideas compared with waiting list/no treatment, or usual care. It also increased remission at the end of treatment compared with attention control and other therapies (such as family therapy). Based on the size of these effects, the number of outcomes showing improvement and the size of the evidence base, the committee agreed to recommend individual CBT as the first-line treatment for young people with moderate to severe depression.
However, the committee recognised that individual CBT might not be suitable or meet the needs of all young people with moderate to severe depression and so they agreed that other therapies (IPT‑A , family therapy, brief psychosocial intervention and psychodynamic psychotherapy) could be considered as second-line options because there was some evidence supporting them, but this was less certain.
IPT-A and family therapy both increased functional status and depression symptoms at the end of treatment compared with waiting list/no treatment, or usual care (4 studies each). Family therapy was also better at inducing remission at the end of treatment than attention control.
The IMPACT trial could not detect a difference between BPI, psychodynamic psychotherapy and individual CBT over a range of outcomes and follow‑up times for 12- to 18‑year‑olds with moderate to severe depression. The committee agreed that BPI could be considered as an option when individual CBT is unsuitable. But they acknowledged that further research would be helpful to determine the effectiveness of BPI when delivered by a wider range of less senior practitioners and in other settings such as primary care. So they made a research recommendation on BPI delivered by non-psychiatrists and in other settings.
Psychodynamic psychotherapy increased remission at the end of treatment compared with attention control or family therapy and relaxation. However, there was no evidence for functional status and psychodynamic psychotherapy was not more effective than control at relieving depression symptoms or improving quality of life post treatment. The data for this analysis came from the IMPACT trial, which found no detectable differences between the effectiveness of psychodynamic psychotherapy and individual CBT across a range of outcomes and follow‑up times. However, a second trial of this intervention was identified with participants that spanned both age groups. It was included in the analysis for 5- to 11‑year‑olds. The committee decided not to recommend psychodynamic psychotherapy as a first-line option because it was no better than control at reducing depression symptoms at the end of treatment and there were only 2 studies including this intervention.
The committee recognised that there were fewer studies of family therapy, IPT‑A and psychodynamic psychotherapy than for individual CBT, and the existing studies either lacked data for later follow‑up times or did not cover the full range of outcomes of interest. The committee wanted more evidence to support their use in young people with moderate to severe depression and they therefore made a research recommendation on family therapy, IPT-A and psychodynamic psychotherapy to look at the relative effectiveness of these interventions compared with each other and individual CBT.
The committee agreed that behavioural activation may meet the specific needs of some children and young people with depression. In particular, it might suit those who might struggle with the concepts of CBT and children and young people with learning disabilities or neurodevelopmental disorders. They made a research recommendation on behavioural activation to inform future practice.
## How the recommendations might affect practice
Individual CBT, family therapy, psychodynamic psychotherapy and IPT‑A are already in widespread use and, as a result, the recommendations are unlikely to change resource use. Brief psychosocial intervention is not commonly delivered in current practice. Although this represents a change in practice, it is a lower intensity intervention than other individual therapies and may therefore reduce overall resource use.
Return to recommendations# Context
This guideline covers the identification and treatment of depression in children (5 to 11 years) and young people (12 to 18 years) in primary, community and secondary care. Depression is a broad diagnosis that can include different symptoms in different people. However, depressed mood or loss of pleasure in most activities, are key signs of depression. Depressive symptoms are frequently accompanied by symptoms of anxiety, but may also occur on their own.
The International Statistical Classification of Diseases (ICD‑10) uses an agreed list of 10 depressive symptoms, and divides depression into 4 categories: not depressed (fewer than 4 symptoms), mild depression (4 symptoms), moderate depression (5 to 6 symptoms), and severe depression (7 or more symptoms, with or without psychotic symptoms). For a diagnosis of depression, symptoms should be present for at least 2 weeks and every symptom should be present for most of the day.
For the purposes of this guideline, the management of depression has been divided into the following categories as defined by the ICD‑10:
mild depression
moderate and severe depression
severe depression with psychotic symptoms.
However, it is unlikely that the severity of depression can be understood in a single symptom count or visit. A child or young person may present initially with psychosomatic symptoms, and may need to be seen on more than one occasion with parents/carers and without, if appropriate, in order to gain trust. Therefore, beyond single symptom count, family context, previous history, and the degree of associated impairment are all important in helping to assess the severity of depression. Because of this, it is important to assess how the child or young person functions in different settings (for example, at school, with peers and with family), as well as asking about specific symptoms of depression.
Children and young people's mental health services are NHS priorities for care quality and outcomes improvement within the NHS Long Term Plan. As part of the plan, services will be expanded and will receive more funding. This includes the expansion of community-based mental health services to meet the needs of more children and young people and the improvement of mental health support for children and young people in school and colleges.
Remember that child maltreatment:
is common
can present anywhere, such as emergency departments and primary care or on home visits.
Be aware of or suspect abuse as a contributory factor to or cause of the symptoms or signs of depression in children. Abuse may also coexist with depression. See the NICE guideline on child maltreatment for clinical features that may be associated with maltreatment.# Finding more information and resources
You can see everything NICE says on this topic in the NICE Pathway on depression in children and young people.
To find NICE guidance on related topics, including guidance in development, see the NICE web page on depression.
For full details of the evidence and the guideline committee's discussions, see the evidence review. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Care of all children and young people with depression\n\n## Good information, informed consent and support\n\nChildren and young people and their families need good information, given as part of a collaborative and supportive relationship with healthcare professionals, and need to be able to give fully informed consent. \n\nHealthcare professionals involved in the detection, assessment or treatment of children or young people with depression should ensure that information is provided to the patient and their parents and carers at an appropriate time. The information should be age appropriate and should cover the nature, course and treatment of depression, including the likely side effect profile of medication should this be offered. \n\nHealthcare professionals involved in the treatment of children or young people with depression should take time to build a supportive and collaborative relationship with both the patient and the family or carers. \n\nHealthcare professionals should make all efforts necessary to engage the child or young person and their parents or carers in treatment decisions, taking full account of patient and parental/carer expectations, so that the patient and their parents or carers can give meaningful and properly informed consent before treatment is initiated. \n\nFamilies and carers should be informed of self-help groups and support groups and be encouraged to participate in such programmes where appropriate. \n\n## Language and black, Asian and minority ethnic groups\n\nWhere possible, all services should provide written information or audiotaped material in the language of the child or young person and their family or carers, and professional interpreters should be sought for those whose preferred language is not English. \n\nConsideration should be given to providing psychological therapies and information about medication and local services in the language of the child or young person and their family or carers where the patient's and/or their family's or carer's first language is not English. If this is not possible, an interpreter should be sought. \n\nHealthcare professionals in primary, secondary and relevant community settings should be trained in cultural competence to aid in the diagnosis and treatment of depression in children and young people from black, Asian and minority ethnic groups. This training should take into consideration the impact of the patient's and healthcare professional's racial identity status on the patient's depression. \n\nHealthcare professionals working with interpreters should be provided with joint training opportunities with those interpreters, to ensure that both healthcare professionals and interpreters understand the specific requirements of interpretation in a mental health setting. \n\nThe development and evaluation of services for children and young people with depression should be undertaken in collaboration with stakeholders involving patients and their families and carers, including members of black, Asian and minority ethnic groups. \n\n## Assessment and coordination of care\n\nWhen assessing a child or young person with depression, healthcare professionals should routinely consider, and record in the patient's notes, potential comorbidities, and the social, educational and family context for the patient and family members, including the quality of interpersonal relationships, both between the patient and other family members and with their friends and peers. \n\nIn the assessment of a child or young person with depression, healthcare professionals should always ask the patient and their parents or carers directly about the child or young person's alcohol and drug use, any experience of being bullied or abused, self‑harm and ideas about suicide. A young person should be offered the opportunity to discuss these issues initially in private. \n\nIf a child or young person with depression presents acutely having self‑harmed, the immediate management should follow NICE's guideline on self-harm as this applies to children and young people, paying particular attention to the guidance on consent and capacity. Further management should then follow this depression guideline. \n\nIn the assessment of a child or young person with depression, healthcare professionals should always ask the patient, and be prepared to give advice, about self‑help materials or other methods used or considered potentially helpful by the patient or their parents or carers. This may include educational leaflets, helplines, self‑diagnosis tools, peer, social and family support groups, complementary therapies and faith groups. \n\nHealthcare professionals should only recommend self‑help materials or strategies as part of a supported and planned package of care. \n\nFor any child or young person with suspected mood disorder, a family history should be obtained to check for unipolar or bipolar depression in parents and grandparents. \n\nWhen a child or young person has been diagnosed with depression, consideration should be given to the possibility of parental depression, parental substance misuse, or other mental health problems and associated problems of living, as these are often associated with depression in a child or young person and, if untreated, may have a negative impact on the success of treatment offered to the child or young person. \n\nWhen the clinical progress of children and young people with depression is being monitored in secondary care, the self‑report Mood and Feelings Questionnaire (MFQ) should be considered as an adjunct to clinical judgement. \n\nIn the assessment and treatment of depression in children and young people, special attention should be paid to the issues of:\n\nconfidentiality\n\nthe young person's consent (including Gillick competence)\n\nparental consent\n\nchild protection\n\nthe use of the Mental Health Act in young people\n\nthe use of the Mental Capacity Act in young people\n\nthe use of the Children Act. [2005, amended 2019]\n\nThe form of assessment should take account of cultural and ethnic variations in communication, family values and the place of the child or young person within the family. \n\n## The organisation and planning of services\n\nJune 2019 – terminology is under revision and may change in the future in line with NHS England's Future in Mind and the Care Quality Commission's report Are we listening. We have retained the tiers terminology and will revise this when we update the 2005 recommendations.\n\nHealthcare professionals specialising in depression in children and young people should work with local child and adolescent mental health services (CAMHS) to enhance specialist knowledge and skills regarding depression in these existing services. This work should include providing training and help with guideline implementation. \n\nCAMHS and local healthcare commissioning organisations should consider introducing a primary mental health worker (or CAMHS link worker) into each secondary school and secondary pupil referral unit as part of tier\xa02 provision within the locality. \n\nPrimary mental health workers (or CAMHS link workers) should establish clear lines of communication between CAMHS and tier\xa01 or\xa02, with named contact people in each tier or service, and develop systems for the collaborative planning of services for young people with depression in tiers\xa01 and\xa02. \n\nCAMHS and local healthcare commissioning organisations should routinely monitor the rates of detection, referral and treatment of children and young people, from all ethnic groups, with mental health problems, including those with depression, in local schools and primary care. This information should be used for planning services and made available for local, regional and national comparison. \n\nAll healthcare and CAMHS professionals should routinely use, and record in the notes, appropriate outcome measures (such as those self‑report measures used in screening for depression or generic outcome measures used by particular services, for example Health of the Nation Outcome Scale for Children and Adolescents [HoNOSCA] or Strengths and Difficulties Questionnaire [SDQ]), for the assessment and treatment of depression in children and young people. This information should be used for planning services, and made available for local, regional and national comparison. \n\n## Treatment and considerations in all settings\n\nMost children and young people with depression should be treated on an outpatient or community basis. \n\nBefore any treatment is started, healthcare professionals should assess, together with the young person, the social network around him or her. This should include a written formulation, identifying factors that may have contributed to the development and maintenance of depression, and that may impact both positively or negatively on the efficacy of the treatments offered. The formulation should also indicate ways that the healthcare professionals may work in partnership with the social and professional network of the young person. \n\nWhen bullying is considered to be a factor in a child or young person's depression, CAMHS, primary care and educational professionals should work collaboratively to prevent bullying and to develop effective antibullying strategies. \n\nPsychological therapies used in the treatment of children and young people with depression should be provided by therapists who are also trained in child and adolescent mental health. \n\nPsychological therapies used in the treatment of children and young people with depression should be provided by healthcare professionals who have been trained to an appropriate level of competence in the specific modality of psychological therapy being offered. \n\nTherapists should develop a treatment alliance with the family. If this proves difficult, consideration should be given to providing the family with an alternative therapist. \n\nComorbid diagnoses and developmental, social and educational problems should be assessed and managed, either in sequence or in parallel, with the treatment for depression. Where appropriate this should be done through consultation and alliance with a wider network of education and social care. \n\nAttention should be paid to the possible need for parents' own psychiatric problems (particularly depression) to be treated in parallel, if the child or young person's mental health is to improve. If such a need is identified, then a plan for obtaining such treatment should be made, bearing in mind the availability of adult mental health provision and other services. \n\nA child or young person with depression should be offered advice on the benefits of regular exercise and encouraged to consider following a structured and supervised exercise programme of typically up to 3\xa0sessions per week of moderate duration (45\xa0minutes to 1\xa0hour) for between 10\xa0and 12\xa0weeks. \n\nA child or young person with depression should be offered advice about sleep hygiene and anxiety management. \n\nA child or young person with depression should be offered advice about nutrition and the benefits of a balanced diet. \n\n# Stepped care\n\nThe stepped‑care model of depression draws attention to the different needs of children and young people with depression – depending on the characteristics of their depression and their personal and social circumstances – and the responses that are required from services. It provides a framework in which to organise the provision of services that support both healthcare professionals and patients and their parents or carers in identifying and accessing the most effective interventions (see table\xa01).\n\nFocus\n\nAction\n\nResponsibility\n\nDetection\n\nRisk profiling\n\nTier\xa01\n\nRecognition\n\nIdentification in presenting children or young people\n\nTiers\xa02 to\xa04\n\nMild depression (including dysthymia)\n\nWatchful waiting\n\nDigital CBT, group CBT, group IPT or group NDST\n\nIf shared decision making based on full assessment (including maturity and developmental level) indicates needs not met, individual CBT or attachment-based family therapy\n\nTier\xa01\n\nTier\xa01 or\xa02\n\n\n\nModerate to severe depression (5- to 11-year-olds)\n\nFamily-based IPT, family therapy (family-focused treatment for childhood depression and systems integrative family therapy), psychodynamic psychotherapy, or individual CBT\n\nWith or without fluoxetine\n\nTier\xa02 or\xa03\n\nModerate to severe depression (12- to 18-year-olds)\n\nIndividual CBT\n\nWith or without fluoxetine\n\nIf shared decision making based on full assessment (including maturity and developmental level) indicates needs not met, IPT‑A, family therapy (attachment-based or systemic), brief psychosocial intervention or psychodynamic psychotherapy\n\nWith or without fluoxetine\n\nTier\xa02 or\xa03\n\nDepression unresponsive to treatment/recurrent depression/psychotic depression\n\nIntensive psychological therapy\n\nWith or without fluoxetine, sertraline, citalopram, augmentation with an antipsychotic\n\nTier\xa03 or\xa04\n\nAbbreviations: CBT, cognitive–behavioural therapy; IPT, interpersonal psychotherapy; IPT A, IPT for adolescents; NDST, non-directive supportive therapy.\n\nJune 2019 – terminology is under revision and may change in the future in line with NHS England's Future in Mind and the Care Quality Commission's report Are we listening. We have retained the tiers terminology and will revise this when we update the 2005 recommendations.\n\nThe guidance follows these 5\xa0steps:\n\n. Detection and recognition of depression and risk profiling in primary care and community settings.\n\n. Recognition of depression in children and young people referred to Children and Young People's Mental Health Services (including CAMHS).\n\n. Managing recognised depression in primary care and community settings – mild depression.\n\n. Managing recognised depression in tier\xa02 or\xa03 CAMHS – moderate to severe depression.\n\n. Managing recognised depression in tier\xa03 or\xa04 CAMHS – unresponsive, recurrent and psychotic depression, including depression needing inpatient care.\n\nEach step introduces additional interventions; the higher steps assume interventions in the previous step.\n\n# Step 1: Detection, risk profiling and referral\n\n## Detection and risk profiling\n\nSee also the recommendations on psychological and social issues in children and young people in the NICE guideline on diabetes (type\xa01 and type\xa02) in children and young people.\n\nHealthcare professionals in primary care, schools and other relevant community settings should be trained to detect symptoms of depression, and to assess children and young people who may be at risk of depression. Training should include the evaluation of recent and past psychosocial risk factors, such as age, gender, family discord, bullying, physical, sexual or emotional abuse, comorbid disorders, including drug and alcohol use, and a history of parental depression; the natural history of single loss events; the importance of multiple risk factors; ethnic and cultural factors; and factors known to be associated with a high risk of depression and other health problems, such as homelessness, refugee status and living in institutional settings. \n\nHealthcare professionals in primary care, schools and other relevant community settings should be trained in communications skills such as 'active listening' and 'conversational technique', so that they can deal confidently with the acute sadness and distress ('situational dysphoria') that may be encountered in children and young people following recent undesirable events. \n\nHealthcare professionals in primary care settings should be familiar with screening for mood disorders. They should have regular access to specialist supervision and consultation. \n\nHealthcare professionals in primary care, schools and other relevant community settings who are providing support for a child or young person with situational dysphoria should consider ongoing social and environmental factors if the dysphoria becomes more persistent. \n\nCAMHS tier\xa02 or\xa03 should work with health and social care professionals in primary care, schools and other relevant community settings to provide training and develop ethnically and culturally sensitive systems for detecting, assessing, supporting and referring children and young people who are either depressed or at significant risk of becoming depressed. \n\nIn the provision of training by CAMHS professionals for healthcare professionals in primary care, schools and relevant community settings, priority should be given to the training of pastoral support staff in schools (particularly secondary schools), community paediatricians and GPs. \n\nWhen a child or young person is exposed to a single recent undesirable life event, such as bereavement, parental divorce or separation or a severely disappointing experience, healthcare professionals in primary care, schools and other relevant community settings should undertake an assessment of the risks of depression associated with the event and make contact with their parents or carers to help integrate parental/carer and professional responses. The risk profile should be recorded in the child or young person's records. \n\nWhen a child or young person is exposed to a single recent undesirable life event, such as bereavement, parental divorce or separation or a severely disappointing experience, in the absence of other risk factors for depression, healthcare professionals in primary care, schools and other relevant community settings should offer support and the opportunity to talk over the event with the child or young person. \n\nFollowing an undesirable event, a child or young person should not normally be referred for further assessment or treatment, as single events are unlikely to lead to a depressive illness. \n\nA child or young person who has been exposed to a recent undesirable life event, such as bereavement, parental divorce or separation or a severely disappointing experience and is identified to be at high risk of depression (the presence of 2\xa0or more other risk factors for depression), should be offered the opportunity to talk over their recent negative experiences with a professional in tier\xa01 and assessed for depression. Early referral should be considered if there is evidence of depression and/or self-harm. \n\nWhen a child or young person is exposed to a recent undesirable life event, such as bereavement, parental divorce or separation or a severely disappointing experience, and where 1\xa0or more family members (parents or children) have multiple risk histories for depression, they should be offered the opportunity to talk over their recent negative experiences with a professional in tier\xa01 and assessed for depression. Early referral should be considered if there is evidence of depression and/or self-harm. \n\nIf children and young people who have previously recovered from moderate or severe depression begin to show signs of a recurrence of depression, healthcare professionals in primary care, schools or other relevant community settings should refer them to CAMHS tier\xa02 or\xa03 for rapid assessment. \n\n## Referral criteria\n\nFor children and young people, the following factors should be used by healthcare professionals as indications that management can remain at tier\xa01:\n\nexposure to a single undesirable event in the absence of other risk factors for depression\n\nexposure to a recent undesirable life event in the presence of 2\xa0or more other risk factors with no evidence of depression and/or self‑harm\n\nexposure to a recent undesirable life event, where 1\xa0or more family members (parents or children) have multiple‑risk histories for depression, providing that there is no evidence of depression and/or self‑harm in the child or young person\n\nmild depression without comorbidity. \n\nFor children and young people, the following factors should be used by healthcare professionals as criteria for referral to tier\xa02 or\xa03 CAMHS:\n\ndepression with 2\xa0or more other risk factors for depression\n\ndepression where 1\xa0or more family members (parents or children) have multiple‑risk histories for depression\n\nmild depression in those who have not responded to interventions in tier\xa01 after 2–3\xa0months\n\nmoderate or severe depression (including psychotic depression)\n\nsigns of a recurrence of depression in those who have recovered from previous moderate or severe depression\n\nunexplained self‑neglect of at least 1\xa0month's duration that could be harmful to their physical health\n\nactive suicidal ideas or plans\n\nreferral requested by a young person or their parents or carers. \n\nFor children and young people, the following factors should be used by healthcare professionals as criteria for referral to tier\xa04 services:\n\nhigh recurrent risk of acts of self‑harm or suicide\n\nsignificant ongoing self‑neglect (such as poor personal hygiene or significant reduction in eating that could be harmful to their physical health)\n\nrequirement for intensity of assessment/treatment and/or level of supervision that is not available in tier\xa02 or\xa03. \n\n# Step 2: Recognition of depression in children and young people\n\nChildren and young people of 11\xa0years or older referred to CAMHS without a diagnosis of depression should be routinely screened with a self‑report questionnaire for depression as part of a general assessment procedure. \n\nTraining opportunities should be made available to improve the accuracy of CAMHS professionals in diagnosing depressive conditions. The existing interviewer‑based instruments (such as Kiddie‑Sads [K‑SADS] and Child and Adolescent Psychiatric Assessment [CAPA]) could be used for this purpose but will require modification for regular use in busy routine CAMHS settings. \n\nWithin tier\xa03 CAMHS, professionals who specialise in the treatment of depression should have been trained in interviewer‑based assessment instruments (such as K‑SADS and CAPA) and have skills in non‑verbal assessments of mood in younger children. \n\n# Step 3: Managing mild depression\n\n## Watchful waiting\n\nFor children and young people with diagnosed mild depression who do not want an intervention or who, in the opinion of the healthcare professional, may recover with no intervention, a further assessment should be arranged, normally within 2\xa0weeks ('watchful waiting'). \n\nHealthcare professionals should make contact with children and young people with depression who do not attend follow‑up appointments. \n\n## Treatments for mild depression\n\nFor children and young people with learning disabilities, see the recommendations on psychological interventions in the NICE guideline on mental health problems in people with learning disabilities.\n\nAntidepressant medication should not be used for the initial treatment of children and young people with mild depression. \n\nDiscuss the choice of psychological therapies with children and young people with mild depression and their family members or carers (as appropriate). Explain:\n\nwhat the different therapies involve\n\nthe evidence for each age group (including the limited evidence for 5- to 11‑year‑olds)\n\nhow the therapies could meet individual needs, preferences and values. \n\nBase the choice of psychological therapy on:\n\na full assessment of needs, including:\n\n\n\nthe circumstances of the child or young person and their family members or carers\n\ntheir clinical and personal/social history and presentation\n\ntheir maturity and developmental level\n\nthe context in which treatment is to be provided\n\ncomorbidities, neurodevelopmental disorders, communication needs (language, sensory impairment) and learning disabilities\n\n\n\npatient and carer preferences and values (as appropriate). \n\nFor 5- to 11‑year‑olds with mild depression continuing after 2\xa0weeks of watchful waiting, and without significant comorbid problems or active suicidal ideas or plans, consider the following options adapted to developmental level as needed:\n\ndigital cognitive–behavioural therapy (CBT)\n\ngroup CBT\n\ngroup non-directive supportive therapy (NDST)\n\ngroup interpersonal psychotherapy (IPT).If these options would not meet the child's clinical needs or are unsuitable for their circumstances, consider the following adapted to developmental level as needed:\n\nattachment-based family therapy\n\nindividual CBT. \n\nFor 12- to 18‑year‑olds with mild depression continuing after 2\xa0weeks of watchful waiting, and without significant comorbid problems or active suicidal ideas or plans, offer a choice of the following psychological therapies for a limited period (approximately 2\xa0to 3\xa0months):\n\ndigital CBT\n\ngroup CBT\n\ngroup NDST\n\ngroup IPT. \n\nIf the options in recommendation 1.5.7 would not meet the clinical needs of a 12- to 18‑year‑old with mild depression or are unsuitable for their circumstances, consider:\n\nattachment-based family therapy or\n\nindividual CBT. \n\nProvide psychological therapies in settings such as schools and colleges, primary care, social services and the voluntary sector. \n\nIf mild depression in a child or young person has not responded to psychological therapy after 2\xa0to 3\xa0months (recommendations 1.5.6 to 1.5.8 and table\xa01), refer the child or young person for review by a CAMHS team. \n\nFollow the recommendations on treating moderate to severe depression for children and young people who have continuing depression after 2\xa0to 3\xa0months of psychological therapy (see the section on moderate to severe depression). \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on treatments for mild depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: Psychological interventions for the treatment of depression.\n\nLoading. Please wait.\n\n# Steps 4 and 5: Managing moderate to severe depression\n\n## Treatments for moderate to severe depression\n\nFor children and young people with learning disabilities, see the recommendations on psychological interventions in the NICE guideline on mental health problems in people with learning disabilities.\n\nChildren and young people presenting with moderate to severe depression should be reviewed by a CAMHS team. \n\nDiscuss the choice of psychological therapies with children and young people with moderate to severe depression and their family members or carers (as appropriate). Explain:\n\nwhat the different therapies involve\n\nthe evidence for each age group (including the limited evidence for 5- to 11‑year‑olds)\n\nhow the therapies could meet individual needs, preferences and values. \n\nBase the choice of psychological therapy on:\n\na full assessment of needs, including:\n\n\n\nthe circumstances of the child or young person and their family members or carers\n\ntheir clinical and personal/social history and presentation\n\ntheir maturity and developmental level\n\nthe context in which treatment is to be provided\n\ncomorbidities, neurodevelopmental disorders, communication needs (language, sensory impairment) and learning disabilities\n\n\n\npatient and carer preferences and values (as appropriate). \n\nFor 5- to 11‑year‑olds with moderate to severe depression, consider the following options adapted to developmental level as needed:\n\nfamily-based IPT\n\nfamily therapy (family-focused treatment for childhood depression and systems integrative family therapy)\n\npsychodynamic psychotherapy\n\nindividual CBT. \n\nFor 12- to 18‑year‑olds with moderate to severe depression, offer individual CBT for at least 3\xa0months. \n\nIf individual CBT would not meet the clinical needs of a 12- to 18‑year‑old with moderate to severe depression or is unsuitable for their circumstances, consider the following options:\n\nIPT-A (IPT for adolescents)\n\nfamily therapy (attachment-based or systemic)\n\nbrief psychosocial intervention\n\npsychodynamic psychotherapy. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on treatments for moderate to severe depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: Psychological interventions for the treatment of depression.\n\nLoading. Please wait.\n\n## Combined treatments for moderate to severe depression\n\nConsider combined therapy (fluoxetine and psychological therapy) for initial treatment of moderate to severe depression in young people (12–18\xa0years), as an alternative to psychological therapy followed by combined therapy and to recommendations\xa01.6.8 to 1.6.10. In June 2019, this was an off-label use of fluoxetine for initial combination use (fluoxetine with psychological therapy) in children and young people who have not previously had a trial of psychological therapy on its own. See NICE's information on prescribing medicines.\n\nIf moderate to severe depression in a child or young person is unresponsive to psychological therapy after 4\xa0to\xa06\xa0treatment sessions, a multidisciplinary review should be carried out. \n\nFollowing multidisciplinary review, if the child or young person's depression is not responding to psychological therapy as a result of other coexisting factors such as the presence of comorbid conditions, persisting psychosocial risk factors such as family discord, or the presence of parental mental ill‑health, alternative or perhaps additional psychological therapy for the parent or other family members, or alternative psychological therapy for the patient, should be considered. \n\nFollowing multidisciplinary review, offer fluoxetine if moderate to severe depression in a young person (12–18\xa0years) is unresponsive to a specific psychological therapy after 4\xa0to 6\xa0sessions. In June 2019, fluoxetine was the only antidepressant with UK marketing authorisation for use in this indication for children and young people aged 8 to 18\xa0years.\n\nFollowing multidisciplinary review, cautiously consider fluoxetine if moderate to severe depression in a child (5–11\xa0years) is unresponsive to a specific psychological therapy after 4\xa0to 6\xa0sessions, although the evidence for fluoxetine's effectiveness in this age group is not established. In June 2019, this was an off-label use of fluoxetine in children under the age of 8\xa0years. See NICE's information on prescribing medicines.\n\n## Depression unresponsive to combined treatment\n\nIf moderate to severe depression in a child or young person is unresponsive to combined treatment with a specific psychological therapy and fluoxetine after a further 6\xa0sessions, or the patient and/or their parents or carers have declined the offer of fluoxetine, the multidisciplinary team should make a full needs and risk assessment. This should include a review of the diagnosis, examination of the possibility of comorbid diagnoses, reassessment of the possible individual, family and social causes of depression, consideration of whether there has been a fair trial of treatment, and assessment for further psychological therapy for the patient and/or additional help for the family. \n\nFollowing multidisciplinary review, the following should be considered:\n\nan alternative psychological therapy, which has not been tried previously (individual CBT, interpersonal therapy or shorter‑term family therapy, of at least 3\xa0months' duration) or\n\nsystemic family therapy (at least 15\xa0fortnightly sessions) or\n\npsychodynamic psychotherapy (approximately 30\xa0weekly sessions). \n\n## How to use antidepressants in children and young people\n\nDo not offer antidepressant medication to a child or young person with moderate to severe depression except in combination with a concurrent psychological therapy. Specific arrangements must be made for careful monitoring of adverse drug reactions, as well as for reviewing mental state and general progress; for example, weekly contact with the child or young person and their parents or carers for the first 4\xa0weeks of treatment. The precise frequency will need to be decided on an individual basis, and recorded in the notes. In the event that psychological therapies are declined, medication may still be given, but as the young person will not be reviewed at psychological therapy sessions, the prescribing doctor should closely monitor the child or young person's progress on a regular basis and focus particularly on emergent adverse drug reactions. \n\nIf an antidepressant is to be prescribed this should only be following assessment and diagnosis by a child and adolescent psychiatrist. \n\nWhen an antidepressant is prescribed to a child or young person with moderate to severe depression, it should be fluoxetine as this is the only antidepressant for which clinical trial evidence shows that the benefits outweigh the risks. In June 2019, this was an off-label use of fluoxetine in children under the age of 8\xa0years. See NICE's information on prescribing medicines.\n\nIf a child or young person is started on antidepressant medication, they (and their parents or carers, as appropriate) should be informed about the rationale for the drug treatment, the delay in onset of effect, the time course of treatment, the possible side effects, and the need to take the medication as prescribed. Discussion of these issues should be supplemented by written information appropriate to the child or young person's and parents' or carers' needs that covers the issues described above and includes the latest patient information advice from the relevant regulatory authority. \n\nA child or young person prescribed an antidepressant should be closely monitored for the appearance of suicidal behaviour, self‑harm or hostility, particularly at the beginning of treatment, by the prescribing doctor and the healthcare professional delivering the psychological therapy. Unless it is felt that medication needs to be started immediately, symptoms that might be subsequently interpreted as side effects should be monitored for 7\xa0days before prescribing. Once medication is started the patient and their parents or carers should be informed that if there is any sign of new symptoms of these kinds, urgent contact should be made with the prescribing doctor. \n\nWhen fluoxetine is prescribed for a child or young person with depression, the starting dose should be 10\xa0mg daily. This can be increased to 20\xa0mg daily after 1\xa0week if clinically necessary, although lower doses should be considered in children of lower body weight. There is little evidence regarding the effectiveness of doses higher than 20\xa0mg daily. However, higher doses may be considered in older children of higher body weight and/or when, in severe illness, an early clinical response is considered a priority. In June 2019, this was an off-label use of fluoxetine in children under the age of 8\xa0years. See NICE's information on prescribing medicines.\n\nWhen an antidepressant is prescribed in the treatment of a child or young person with depression and a self‑report rating scale is used as an adjunct to clinical judgement, this should be a recognised scale such as the MFQ. \n\nWhen a child or young person responds to treatment with fluoxetine, medication should be continued for at least 6\xa0months after remission (defined as no symptoms and full functioning for at least 8\xa0weeks); in other words, for 6\xa0months after this 8‑week period. In June 2019, this was an off-label use of fluoxetine in children under the age of 8\xa0years. See NICE's information on prescribing medicines.\n\nIf treatment with fluoxetine is unsuccessful or is not tolerated because of side effects, consideration should be given to the use of another antidepressant. In this case sertraline or citalopram are the recommended second‑line treatments. In June 2019, the use in children and young people under 18 of citalopram and sertraline was off label. See NICE's information on prescribing medicines.\n\nSertraline or citalopram should only be used when the following criteria have been met:\n\nThe child or young person and their parents or carers have been fully involved in discussions about the likely benefits and risks of the new treatment and have been provided with appropriate written information. This information should cover the rationale for the drug treatment, the delay in onset of effect, the time course of treatment, the possible side effects, and the need to take the medication as prescribed; it should also include the latest patient information advice from the relevant regulatory authority.\n\nThe child or young person's depression is sufficiently severe and/or causing sufficiently serious symptoms (such as weight loss or suicidal behaviour) to justify a trial of another antidepressant.\n\nThere is clear evidence that there has been a fair trial of the combination of fluoxetine and a psychological therapy (in other words, that all efforts have been made to ensure adherence to the recommended treatment regimen).\n\nThere has been a reassessment of the likely causes of the depression and of treatment resistance (for example other diagnoses such as bipolar disorder or substance misuse).\n\nThere has been advice from a senior child and adolescent psychiatrist – usually a consultant.\n\nThe child or young person and/or someone with parental responsibility for the child or young person (or the young person alone, if over\xa016 or deemed competent) has signed an appropriate and valid consent form. See the MHRA's drug safety update on QT prolongation with citalopram and escitalopram.\n\nWhen a child or young person responds to treatment with citalopram or sertraline, medication should be continued for at least 6\xa0months after remission (defined as no symptoms and full functioning for at least 8\xa0weeks). \n\nWhen an antidepressant other than fluoxetine is prescribed for a child or young person with depression, the starting dose should be half the daily starting dose for adults. This can be gradually increased to the daily dose for adults over the next 2\xa0to 4\xa0weeks if clinically necessary, although lower doses should be considered in children with lower body weight. There is little evidence regarding the effectiveness of the upper daily doses for adults in children and young people, but these may be considered in older children of higher body weight and/or when, in severe illness, an early clinical response is considered a priority. \n\nParoxetine and venlafaxine should not be used for the treatment of depression in children and young people. \n\nTricyclic antidepressants should not be used for the treatment of depression in children and young people. \n\nWhere antidepressant medication is to be discontinued, the drug should be phased out over a period of 6\xa0to 12\xa0weeks with the exact dose being titrated against the level of discontinuation/withdrawal symptoms. \n\nAs with all other medications, consideration should be given to possible drug interactions when prescribing medication for depression in children and young people. This should include possible interactions with complementary and alternative medicines as well as with alcohol and 'recreational' drugs. \n\nAlthough there is some evidence that St John's wort may be of some benefit in adults with mild to moderate depression, this cannot be assumed for children or young people, for whom there are no trials upon which to make a clinical decision. Moreover, it has an unknown side‑effect profile and is known to interact with a number of other drugs, including contraceptives. Therefore St John's wort should not be prescribed for the treatment of depression in children and young people. \n\nA child or young person with depression who is taking St John's wort as an over-the-counter preparation should be informed of the risks and advised to discontinue treatment while being monitored for recurrence of depression and assessed for alternative treatments in accordance with this guideline. \n\n## The treatment of psychotic depression\n\nFor children and young people with psychotic depression, augmenting the current treatment plan with a second-generation antipsychotic medication should be considered, although the optimum dose and duration of treatment are unknown. In June 2019, the use of all second-generation antipsychotics for children and young people under 18 was off label. See NICE's information on prescribing medicines.\n\nChildren and young people prescribed a second-generation antipsychotic medication should be monitored carefully for side effects. \n\nSee also the recommendations on choice of antipsychotics and how to use them in the NICE guideline on psychosis and schizophrenia in children and young people.\n\n## Inpatient care\n\nInpatient treatment should be considered for children and young people who present with a high risk of suicide, high risk of serious self‑harm or high risk of self‑neglect, and/or when the intensity of treatment (or supervision) needed is not available elsewhere, or when intensive assessment is indicated. \n\nWhen considering admission for a child or young person with depression, the benefits of inpatient treatment need to be balanced against potential detrimental effects, for example loss of family and community support. \n\nWhen inpatient treatment is indicated, CAMHS professionals should involve the child or young person and their parents or carers in the admission and treatment process whenever possible. \n\nCommissioners should ensure that inpatient treatment is available within reasonable travelling distance to enable the involvement of families and maintain social links. \n\nCommissioners should ensure that inpatient services are able to admit a young person within an appropriate timescale, including immediate admission if necessary. \n\nInpatient services should have a range of interventions available including medication, individual and group psychological therapies and family support. \n\nInpatient facilities should be age appropriate and culturally enriching, with the capacity to provide appropriate educational and recreational activities. \n\nPlanning for aftercare arrangements should take place before admission or as early as possible after admission and should be based on the Care Programme Approach. \n\nTier\xa04 CAMHS professionals involved in assessing children or young people for possible inpatient admission should be specifically trained in issues of consent and capacity, the use of current mental health legislation and the use of childcare laws, as they apply to this group of patients. \n\n## Electroconvulsive therapy\n\nElectroconvulsive therapy (ECT) should only be considered for young people with very severe depression and either life‑threatening symptoms (such as suicidal behaviour) or intractable and severe symptoms that have not responded to other treatments. \n\nECT should be used extremely rarely in young people and only after careful assessment by a practitioner experienced in its use and only in a specialist environment in accordance with NICE recommendations. \n\nECT is not recommended in the treatment of depression in children (5–11\xa0years). \n\n## Discharge after a first episode\n\nWhen a child or young person is in remission (fewer than 2\xa0symptoms and full functioning for at least 8\xa0weeks), they should be reviewed regularly for 12\xa0months by an experienced CAMHS professional. The exact frequency of contact should be agreed between the CAMHS professional and the child or young person and/or the parents or carers and recorded in the notes. At the end of this period, if remission is maintained, the young person can be discharged to primary care. \n\nCAMHS should keep primary care professionals up to date about progress and the need for monitoring of the child or young person in primary care. CAMHS should also inform relevant primary care professionals within 2\xa0weeks of a patient being discharged and should provide advice about whom to contact in the event of a recurrence of depressive symptoms. \n\nChildren and young people who have been successfully treated and discharged but then re‑referred should be seen as soon as possible rather than placed on a routine waiting list. \n\n## Recurrent depression and relapse prevention\n\nSpecific follow‑up psychological therapy sessions to reduce the likelihood of, or at least detect, a recurrence of depression should be considered for children and young people who are at a high risk of relapse (for example individuals who have already experienced 2\xa0prior episodes, those who have high levels of subsyndromal symptoms, or those who remain exposed to multiple‑risk circumstances). \n\nCAMHS specialists should teach recognition of illness features, early warning signs, and subthreshold disorders to tier\xa01 professionals, children or young people with recurrent depression and their families and carers. Self‑management techniques may help individuals to avoid and/or cope with trigger factors. \n\nWhen a child or young person with recurrent depression is in remission (fewer than 2\xa0symptoms and full functioning for at least 8\xa0weeks), they should be reviewed regularly for 24\xa0months by an experienced CAMHS professional. The exact frequency of contact should be agreed between the CAMHS professional and the child or young person and/or the parents or carers and recorded in the notes. At the end of this period, if remission is maintained, the young person can be discharged to primary care. \n\nChildren and young people with recurrent depression who have been successfully treated and discharged but then re‑referred should be seen as a matter of urgency. \n\n# Transfer to adult services\n\nSee also the NICE guideline on transition from children's to adults' services for young people using health or social care services.\n\nThe CAMHS team currently providing treatment and care for a young person aged\xa017 who is recovering from a first episode of depression should normally continue to provide treatment until discharge is considered appropriate in accordance with this guideline, even when the person turns 18\xa0years of age. \n\nThe CAMHS team currently providing treatment and care for a young person aged\xa017–18 who either has ongoing symptoms from a first episode that are not resolving or has, or is recovering from, a second or subsequent episode of depression, should normally arrange for a transfer to adult mental health services, informed by the Care Programme Approach. \n\nA young person aged\xa017–18 with a history of recurrent depression who is being considered for discharge from CAMHS should be provided with comprehensive information about the treatment of depression in adults (including NICE's information for the public) and information about local services and support groups suitable for young adults with depression. \n\nA young person aged\xa017–18 who has successfully recovered from a first episode of depression and is discharged from CAMHS should not normally be referred on to adult services, unless they are considered to be at high risk of relapse (for example, if they are living in multiple‑risk circumstances). \n\n# Terms used in this guideline\n\n## Tiers\n\nJune 2019 – The tiers terminology is under revision and may change in the future in line with NHS England's Future in Mind and the Care Quality Commission's report Are we listening. We have retained the tiers terminology and will revise this when the 2005 recommendations are updated.\n\nThe Care Quality Commission's report 'Are we listening' referred to the whole system of care and support (tiers\xa01 to\xa04) as Children and Young People's Mental Health Services. These included counselling provided through schools or GP practices, youth services, voluntary sector advice and support, and universal healthcare services like health visitors, as well as CAMHS. They used CAMHS to refer to services offering specialist care in the community (tier\xa03) and inpatient care (tier\xa04).\n\n## Brief psychosocial intervention\n\nThis intervention is based on the brief psychosocial intervention (BPI) carried out in the IMPACT trial (Goodyer et al. 2017).\n\nCore components of BPI include:\n\npsychoeducation about depression and action-oriented, goal-focused, interpersonal activities as therapeutic strategies\n\nbuilding health habits\n\nplanning and scheduling valued activities\n\nadvice on maintaining and improving mental and physical hygiene including sleep, diet and exercise\n\npromoting engagement with and maintaining school work and peer relations, and diminishing solitariness.\n\nBPI does not involve cognitive or reflective analytic techniques.\n\n## Digital CBT\n\nDigital CBT is a form of CBT delivered using digital technology, such as a computer, tablet or phone. A variety of digital CBT programmes have been used for young people aged 12\xa0to 18\xa0years with mild depression. These include SPARX, Stressbusters and Grasp the Opportunity. Only Stressbusters has been tested in the UK. Some digital CBT interventions are supported by contact with a healthcare professional but in other cases there may be no additional support.\n\nCommon components of digital CBT programmes include: psychoeducation, relaxation, analysis of behaviour, behavioural activation, basic communication and interpersonal skills, emotional recognition, dealing with strong emotions, problem solving, cognitive restructuring (identifying thoughts, challenging unhelpful/negative thoughts), mindfulness and relapse prevention.", 'Recommendations for research': "# Key recommendations for research\n\n## Psychological therapies for children aged 5\xa0to 11\xa0years with mild or moderate to severe depression\n\nWhat is the clinical and cost effectiveness, post-treatment and at longer-term follow‑up, of psychological therapies in children aged 5\xa0to 11\xa0years with mild or moderate to severe depression? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on treatments for mild depression\xa0 or moderate to severe depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: Psychological interventions for the treatment of depression.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\n## Digital cognitive–behavioural therapy\n\nWhat is the clinical and cost effectiveness, post-treatment and at longer-term follow‑up, of supported digital cognitive–behavioural therapy (CBT) compared with unsupported digital CBT in young people aged 12\xa0to 18\xa0years with mild depression, and what are the key components of the interventions that influence effectiveness? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on treatments for mild depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: Psychological interventions for the treatment of depression.\n\nLoading. Please wait.\n\n## Family therapy, interpersonal psychotherapy for adolescents and psychodynamic psychotherapy\n\nWhat is the clinical and cost effectiveness, post-treatment and at longer-term follow‑up, of family therapy, psychodynamic psychotherapy and interpersonal psychotherapy for adolescents (IPT‑A) compared with each other and with individual CBT in young people aged 12\xa0to 18\xa0years with moderate to severe depression? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on treatments for moderate to severe depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: Psychological interventions for the treatment of depression.\n\nLoading. Please wait.\n\n## Brief psychosocial intervention delivered by non-psychiatrists and in other settings\n\nWhat is the clinical and cost effectiveness, post-treatment and at longer-term follow‑up, of a brief psychosocial intervention as reported by the IMPACT trial, but delivered by practitioners other than psychiatrists and in other settings, including primary care, to young people aged 12\xa0to 18\xa0years with mild or moderate to severe depression? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on moderate to severe depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: Psychological interventions for the treatment of depression.\n\nLoading. Please wait.\n\n## Behavioural activation\n\nWhat is the clinical and cost effectiveness, post treatment and at longer-term follow‑up, of behavioural activation compared with other psychological therapies in children aged 5\xa0to 11\xa0years and young people aged 12\xa0to 18\xa0years with mild or moderate to severe depression? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale for treatments for mild depression\xa0 or moderate to severe depression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: Psychological interventions for the treatment of depression.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Group mindfulness\n\nWhat is the clinical and cost effectiveness, post treatment and at longer-term follow‑up, of group mindfulness compared with other psychological therapies in young people aged 12\xa0to 18\xa0years with mild depression? \n\n## Combination therapy (fluoxetine and psychological therapy)\n\nAn appropriately blinded, randomised controlled trial should be conducted to assess the efficacy (including measures of family and social functioning as well as depression) and the cost effectiveness of fluoxetine, psychological therapy, the combination of fluoxetine and psychological therapy compared with each other and placebo in a broadly based sample of children and young people diagnosed with moderate to severe depression (using minimal exclusion criteria).The trial should be powered to examine the effect of treatment in children and young people separately and involve a follow‑up of 12\xa0to 18\xa0months (but no less than 6\xa0months). \n\n## Care pathway experience\n\nA qualitative study should be conducted that examines the experiences in the care pathway of children and young people and their families (and perhaps professionals) in order to inform decisions about what the most appropriate care pathway should be. \n\n## Computer technology to assess mood and feelings\n\nAn appropriately designed study should be conducted to compare validated screening instruments for the detection of depression in children and young people. An emphasis should be placed on examining those that use computer technology and more child-friendly methods of assessing current mood and feelings, and take into account cultural and ethnic variations in communication, family values and the place of the child or young person within the family. ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Treatments for mild depression\n\nRecommendations 1.5.4 to 1.5.11\n\n## Why the committee made the recommendations\n\nTo ensure that children and young people with depression and their families or carers (as appropriate) receive the best possible care and can take part in shared decision making, the committee recommended that healthcare professionals explain the treatment options, what these are like in practice and how different psychological therapies might best suit individual clinical needs, preferences and values. The discussion should also cover the evidence for the different treatments and make it clear that there is limited evidence for effective treatments for 5- to 11‑year‑olds.\n\nThe committee recognised that some children and young people have difficulties accessing treatment because of lack of transport (particularly in rural areas), chaotic family lives, being in a young offender's institute or being in care. They agreed that the healthcare professional should not only think about clinical needs, but also take into account the child or young person's personal/social history, the current environment, the setting where the treatment will be provided and individual preferences and values. In addition, certain therapies may not be suitable or may need to be adapted for use with children generally or those with comorbidities, neurodevelopmental disorders, learning disabilities or different communication needs (due to language or sensory impairment). To ensure that these factors are part of the decision-making process, the committee included them in the full assessment of needs.\n\nThe evidence for psychological therapies for 5- to 11‑year‑olds was confined to group cognitive–behavioural therapy (CBT), and although depression symptoms were reduced at the end of treatment compared with waiting list/no treatment, this was not maintained in the longer term. There were no data for other outcomes such as functional status or remission. As a result, the committee decided to recommend the same interventions that were effective in 12- to 18‑year‑olds for this age group, but adapted for their age and developmental level.\n\nBecause of the limited evidence for effective treatments for 5- to 11‑year‑olds with mild depression, the committee made a research recommendation on psychological therapies for children aged 5 to 11 years with mild or moderate to severe depression to try to stimulate research in this area.\n\nAnalysis of the evidence for 12- to 18‑year‑olds with mild depression showed that digital CBT (also known as online CBT or computer CBT), group therapies (group CBT, group interpersonal psychotherapy [IPT] and group non-directive supportive therapy [NDST]), individual CBT and family therapy reduced depression symptoms or improved functional status by the end of treatment and up to 6\xa0months later compared with a waiting list control or no treatment. In some cases, such as digital CBT, these positive effects persisted for longer than 6\xa0months, but information on long-term effects was not always available. Digital CBT was also better than other psychological therapies at reducing depression symptoms longer term.\n\nThe committee agreed to base recommendations for psychological therapies on clinical effectiveness and cost. The average costs estimated for digital CBT and group therapy (CBT, IPT and NDST) were lower than those for individual CBT and family therapy. Taking the magnitude of effect, the estimated cost and the size of the evidence base into account, the committee agreed that a choice of digital CBT, group IPT, group NDST or group CBT should be offered first.\n\nHowever, the committee recognised that digital CBT is not well defined and the evidence for effectiveness came from studies using a variety of different programmes. In addition, digital CBT can be delivered with support (from a healthcare professional) or as an unsupported intervention. It is unclear whether unsupported or supported digital CBT is more effective and which programmes would be most effective for use in the UK. As a result, the committee made a research recommendation on digital CBT to inform future guidance.\n\nIndividual CBT and family therapy were among the more expensive options. Individual CBT had a smaller effect on depression symptoms than digital CBT or group therapy (CBT, IPT or NDST). Individual CBT had a meaningful effect on functional status; this outcome was only reported in a study that recruited young people with depression and a comorbidity. Family therapy showed meaningful effects on depression symptoms, but these results were based on a single study.\n\nThe committee acknowledged that digital CBT, group CBT, group IPT and group NDST may not be suitable for everyone and that individual CBT or family therapy could be considered in these situations. They specified attachment-based family therapy in the recommendation because that was the type of family therapy used in the study.\n\nThe committee agreed not to make a recommendation for individual NDST or guided self-help because:\n\nIndividual NDST was not more effective at reducing depression symptoms at the end of treatment or at 6\xa0months' follow‑up than control and there was no evidence for functional status or remission.\n\nAlthough guided self-help reduced depression symptoms at the end of treatment compared with a waiting list control/no treatment, this was not sustained at later time points. In addition, guided self-help was no more effective at reducing depression symptoms at the end of treatment, and was either less effective or no more effective at later time points, than the recommended group therapies (group CBT, group IPT, group NDST), digital CBT, individual CBT or family therapy.\n\nThe committee made a research recommendation on behavioural activation aimed at investigating the effectiveness of behavioural activation compared with other psychological therapies. They agreed that behavioural activation may meet the needs of some children and young people with depression that are not already covered by the other recommended psychological therapies. In particular, it might suit children and young people who struggle with the concepts of CBT, and children and young people with learning disabilities or neurodevelopmental disorders. The only evidence for behavioural activation came from a single small study (60\xa0participants) that found no difference between behavioural activation and usual care, but this may have been because of the small study size.\n\nThe committee also made a research recommendation for group mindfulness, because, although it was more effective at reducing depression symptoms post treatment and at 6\xa0months' follow‑up than a waiting list control/no treatment, there was no evidence for other key outcomes such as functional status or later time points, and the evidence came from a single small study.\n\n## How the recommendations might affect practice\n\nThe recommendation for digital CBT or group therapy (CBT, IPT or NDST) for children and young people with mild depression is not likely to result in increased resource use. It may even result in lower resource use if these interventions reduce the need for intensive individual therapies. Individual NDST and guided self-help are no longer recommended and the net resource impact of this change is therefore unclear.\n\nReturn to recommendations\n\n# Treatments for moderate to severe depression\n\nRecommendations 1.6.1 to 1.6.6\n\n## Why the committee made the recommendations\n\nAs for mild depression, the committee agreed that children and young people and their families or carers should be empowered to take part in shared decision making. Healthcare professional should also think about a number of key factors, including history, individual circumstances, comorbidities and developmental level and maturity.\n\nThere was some evidence for psychological therapies for children aged 5\xa0to 11\xa0years with moderate to severe depression, but this included very few interventions. The committee agreed that the child or young person and their family or carers should be made aware of this when making decisions about treatments.\n\nIn the analysis of evidence for 5- to 11‑year‑olds with moderate to severe depression, family-based IPT and family therapy were more effective at reducing depression symptoms at the end of treatment than psychodynamic psychotherapy; but psychodynamic psychotherapy was better than family therapy at maintaining remission 6\xa0months later. However, the evidence base was small (3\xa0studies) and none included a control intervention. In other studies that included a control, no interventions were better than the control at reducing depression symptoms after treatment or at later time points.\n\nDespite the limited evidence for 5- to 11‑year‑olds, the committee agreed that treatment was important for these young children. They agreed to recommend the treatments (family therapy, family-based IPT and psychodynamic psychotherapy) for which there was some evidence. They specified the types of family therapy used in the studies (family-focused treatment for childhood depression and systems integrative family therapy). They also included individual CBT in the recommendation because it was the most effective treatment for 12- to 18‑year‑olds with moderate to severe depression and they agreed that more mature children might benefit from this intervention.\n\nBecause of the limited evidence for effective treatments for 5- to 11‑year‑olds with depression, the committee made a research recommendation on psychological therapies for children aged 5 to 11 years with mild or moderate to severe depression to inform future guidance.\n\nIn an analysis of a large body of evidence for 12- to 18‑year‑olds with moderate to severe depression, individual CBT was better at reducing depression symptoms and improving functional status, quality of life and suicidal ideas compared with waiting list/no treatment, or usual care. It also increased remission at the end of treatment compared with attention control and other therapies (such as family therapy). Based on the size of these effects, the number of outcomes showing improvement and the size of the evidence base, the committee agreed to recommend individual CBT as the first-line treatment for young people with moderate to severe depression.\n\nHowever, the committee recognised that individual CBT might not be suitable or meet the needs of all young people with moderate to severe depression and so they agreed that other therapies (IPT‑A [IPT for adolescents], family therapy, brief psychosocial intervention [BPI] and psychodynamic psychotherapy) could be considered as second-line options because there was some evidence supporting them, but this was less certain.\n\nIPT-A and family therapy both increased functional status and depression symptoms at the end of treatment compared with waiting list/no treatment, or usual care (4\xa0studies each). Family therapy was also better at inducing remission at the end of treatment than attention control.\n\nThe IMPACT trial could not detect a difference between BPI, psychodynamic psychotherapy and individual CBT over a range of outcomes and follow‑up times for 12- to 18‑year‑olds with moderate to severe depression. The committee agreed that BPI could be considered as an option when individual CBT is unsuitable. But they acknowledged that further research would be helpful to determine the effectiveness of BPI when delivered by a wider range of less senior practitioners and in other settings such as primary care. So they made a research recommendation on BPI delivered by non-psychiatrists and in other settings.\n\nPsychodynamic psychotherapy increased remission at the end of treatment compared with attention control or family therapy and relaxation. However, there was no evidence for functional status and psychodynamic psychotherapy was not more effective than control at relieving depression symptoms or improving quality of life post treatment. The data for this analysis came from the IMPACT trial, which found no detectable differences between the effectiveness of psychodynamic psychotherapy and individual CBT across a range of outcomes and follow‑up times. However, a second trial of this intervention was identified with participants that spanned both age groups. It was included in the analysis for 5- to 11‑year‑olds. The committee decided not to recommend psychodynamic psychotherapy as a first-line option because it was no better than control at reducing depression symptoms at the end of treatment and there were only 2\xa0studies including this intervention.\n\nThe committee recognised that there were fewer studies of family therapy, IPT‑A and psychodynamic psychotherapy than for individual CBT, and the existing studies either lacked data for later follow‑up times or did not cover the full range of outcomes of interest. The committee wanted more evidence to support their use in young people with moderate to severe depression and they therefore made a research recommendation on family therapy, IPT-A and psychodynamic psychotherapy to look at the relative effectiveness of these interventions compared with each other and individual CBT.\n\nThe committee agreed that behavioural activation may meet the specific needs of some children and young people with depression. In particular, it might suit those who might struggle with the concepts of CBT and children and young people with learning disabilities or neurodevelopmental disorders. They made a research recommendation on behavioural activation to inform future practice.\n\n## How the recommendations might affect practice\n\nIndividual CBT, family therapy, psychodynamic psychotherapy and IPT‑A are already in widespread use and, as a result, the recommendations are unlikely to change resource use. Brief psychosocial intervention is not commonly delivered in current practice. Although this represents a change in practice, it is a lower intensity intervention than other individual therapies and may therefore reduce overall resource use.\n\nReturn to recommendations", 'Context': "This guideline covers the identification and treatment of depression in children (5\xa0to 11\xa0years) and young people (12\xa0to 18\xa0years) in primary, community and secondary care. Depression is a broad diagnosis that can include different symptoms in different people. However, depressed mood or loss of pleasure in most activities, are key signs of depression. Depressive symptoms are frequently accompanied by symptoms of anxiety, but may also occur on their own.\n\nThe International Statistical Classification of Diseases (ICD‑10) uses an agreed list of 10\xa0depressive symptoms, and divides depression into 4\xa0categories: not depressed (fewer than 4\xa0symptoms), mild depression (4\xa0symptoms), moderate depression (5\xa0to\xa06\xa0symptoms), and severe depression (7\xa0or more symptoms, with or without psychotic symptoms). For a diagnosis of depression, symptoms should be present for at least 2\xa0weeks and every symptom should be present for most of the day.\n\nFor the purposes of this guideline, the management of depression has been divided into the following categories as defined by the ICD‑10:\n\nmild depression\n\nmoderate and severe depression\n\nsevere depression with psychotic symptoms.\n\nHowever, it is unlikely that the severity of depression can be understood in a single symptom count or visit. A child or young person may present initially with psychosomatic symptoms, and may need to be seen on more than one occasion with parents/carers and without, if appropriate, in order to gain trust. Therefore, beyond single symptom count, family context, previous history, and the degree of associated impairment are all important in helping to assess the severity of depression. Because of this, it is important to assess how the child or young person functions in different settings (for example, at school, with peers and with family), as well as asking about specific symptoms of depression.\n\nChildren and young people's mental health services are NHS priorities for care quality and outcomes improvement within the NHS Long Term Plan. As part of the plan, services will be expanded and will receive more funding. This includes the expansion of community-based mental health services to meet the needs of more children and young people and the improvement of mental health support for children and young people in school and colleges.\n\nRemember that child maltreatment:\n\nis common\n\ncan present anywhere, such as emergency departments and primary care or on home visits.\n\nBe aware of or suspect abuse as a contributory factor to or cause of the symptoms or signs of depression in children. Abuse may also coexist with depression. See the NICE guideline on child maltreatment for clinical features that may be associated with maltreatment.", 'Finding more information and resources': "You can see everything NICE says on this topic in the NICE Pathway on depression in children and young people.\n\nTo find NICE guidance on related topics, including guidance in development, see the NICE web page on depression.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence review. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}
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https://www.nice.org.uk/guidance/ng134
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This guideline covers identifying and managing depression in children and young people aged 5 to 18 years. Based on the stepped-care model, it aims to improve recognition and assessment and promote effective treatments for mild and moderate to severe depression.
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882a321cadbd78d1547a9154f19ea1c3a8cbd229
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nice
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Urinary incontinence and pelvic organ prolapse in women: management
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Urinary incontinence and pelvic organ prolapse in women: management
This guideline covers assessing and managing urinary incontinence and pelvic organ prolapse in women aged 18 and over. It also covers complications associated with mesh surgery for these conditions.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Organisation of specialist services
## Local multidisciplinary teams
Local multidisciplinary teams (MDTs) for women with primary stress urinary incontinence, overactive bladder or primary prolapse should:
review the proposed treatment for all women offered invasive procedures for primary stress urinary incontinence, overactive bladder or primary prolapse
review the proposed management for women with primary stress urinary incontinence, overactive bladder or primary prolapse if input from a wider range of healthcare professionals is needed
work within an established clinical network that has access to a regional MDT. Note: In 2018, NHS England consulted on specialised gynaecology surgery and complex urogynaecology conditions service specifications.
Local MDTs for women with primary stress urinary incontinence, overactive bladder or primary prolapse should include:
consultants with expertise in managing urinary incontinence in women and/or pelvic organ prolapse
a urogynaecology, urology or continence specialist nurse
a pelvic floor specialist physiotherapistand may also include:
a member of the care of the elderly team
an occupational therapist
a colorectal surgeon.
Members of the local MDT (listed in recommendation 1.1.2) should attend all local MDT meetings.
## Regional multidisciplinary teams
Regional MDTs that deal with complex pelvic floor dysfunction and mesh-related problems should review the proposed treatment for women if:
they are having repeat continence surgery
they are having repeat, same-site prolapse surgery
their preferred treatment option is not available in the referring hospital
they have coexisting bowel problems that may need additional colorectal intervention
vaginal mesh for prolapse is a treatment option for them
they have mesh complications or unexplained symptoms after mesh surgery for urinary incontinence or prolapse
they are considering surgery and may wish to have children in the future.
Regional MDTs that deal with complex pelvic floor dysfunction and mesh-related problems should include:
a subspecialist in urogynaecology
a urologist with expertise in female urology
a urogynaecology, urology or continence specialist nurse
a pelvic floor specialist physiotherapist
a radiologist with expertise in pelvic floor imaging
a colorectal surgeon with expertise in pelvic floor problems
a pain specialist with expertise in managing pelvic painand may also include:
a healthcare professional trained in bowel biofeedback and trans-anal irrigation
a clinical psychologist
a member of the care of the elderly team
an occupational therapist
a surgeon skilled at operating in the obturator region
a plastic surgeon.
Regional MDTs that deal with complex pelvic floor dysfunction and mesh-related problems should have ready access to the following services:
psychology
psychosexual counselling
chronic pain management
bowel symptom management
neurology.
Members of the regional MDT (listed in recommendation 1.1.5) should attend regional MDT meetings when their specific expertise is needed.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on organisation of specialist services .
Full details of the evidence and the committee's discussion are in evidence review F: effectiveness of multidisciplinary teams for the assessment and management of urinary incontinence or pelvic organ prolapse.
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# Collecting data on surgery and surgical complications
Ask women having surgery for stress urinary incontinence or pelvic organ prolapse, or who have experienced complications related to these types of surgery, for their consent to enter the data listed in recommendation 1.2.2 in a national registry. Give each woman a copy of her data.
Providers must ensure that the following data are recorded in a national registry of surgery for urinary incontinence and pelvic organ prolapse in women:
the woman's NHS number
hospital and consultant identifiers
date and details of the procedure
for procedures involving mesh, the mesh material, manufacturer, product unique identification code and type of sutures used
for procedures involving colposuspension, the type of sutures used
for procedures involving bulking agent, the bulking material, manufacturer and product unique identification code
date and details of any investigation for complications
date and details of any surgical or non-surgical intervention for complications.
The national registry of surgery for urinary incontinence and pelvic organ prolapse in women must ensure that follow‑up data are collected on key short- and long-term (at least 5 years) outcomes, including:
validated relevant outcome measures
adverse events including pain
suspected and confirmed mesh-related complications.
The national registry of surgery for urinary incontinence and pelvic organ prolapse in women should report annually and be quality assured.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on collecting data on surgery and surgical complications .
Full details of the evidence and the committee's discussion are in evidence review E: surgical and physical management of stress urinary incontinence and evidence review I: surgical management of pelvic organ prolapse.
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# Assessing urinary incontinence
## History taking and physical examination
At the initial clinical assessment, categorise the woman's urinary incontinence as stress urinary incontinence, mixed urinary incontinence or urgency urinary incontinence/overactive bladder. Start initial treatment on this basis. In mixed urinary incontinence, direct treatment towards the predominant symptom.
If stress incontinence is the predominant symptom in mixed urinary incontinence, discuss with the woman the benefit of non-surgical management and medicines for overactive bladder before offering surgery.
During the clinical assessment seek to identify relevant predisposing and precipitating factors and other diagnoses that may require referral for additional investigation and treatment.
## Assessing pelvic floor muscles
Undertake routine digital assessment to confirm pelvic floor muscle contraction before the use of supervised pelvic floor muscle training for the treatment of urinary incontinence.
## Urine testing
Undertake a urine dipstick test in all women presenting with urinary incontinence to detect the presence of blood, glucose, protein, leucocytes and nitrites in the urine.
If women have symptoms of urinary tract infection (UTI) and their urine tests positive for both leucocytes and nitrites, send a midstream urine specimen for culture and analysis of antibiotic sensitivities. Prescribe an appropriate course of antibiotic treatment pending culture results. See the NICE guideline on urinary tract infection (lower): antimicrobial prescribing for more information.
If women have symptoms of UTI and their urine tests negative for either leucocytes or nitrites, send a midstream urine specimen for culture and analysis of antibiotic sensitivities. Consider the prescription of antibiotics pending culture results.
If women do not have symptoms of UTI, but their urine tests positive for both leucocytes and nitrites, do not offer antibiotics without the results of midstream urine culture.
If a woman does not have symptoms of UTI and her urine tests negative for either leucocytes or nitrites, do not send a urine sample for culture because she is unlikely to have UTI.
## Assessing residual urine
Measure post-void residual volume by bladder scan or catheterisation in women with symptoms suggestive of voiding dysfunction or recurrent UTI.
Use a bladder scan in preference to catheterisation on the grounds of acceptability and lower incidence of adverse events.
## Symptom scoring and quality-of-life assessment
Use a validated urinary incontinence-specific symptom and quality-of-life questionnaire when therapies are being evaluated.
## Bladder diaries
Use bladder diaries in the initial assessment of women with urinary incontinence or overactive bladder. Encourage women to complete a minimum of 3 days of the diary covering variations in their usual activities, such as both working and leisure days.
## Pad testing
Do not use pad tests in the routine assessment of women with urinary incontinence.
## Urodynamic testing
Do not perform multichannel filling and voiding cystometry before primary surgery if stress urinary incontinence or stress-predominant mixed urinary incontinence is diagnosed based on a detailed clinical history and demonstrated stress urinary incontinence at examination.
After undertaking a detailed clinical history and examination, perform multichannel filling and voiding cystometry before surgery for stress urinary incontinence in women who have any of the following:
urge-predominant mixed urinary incontinence or urinary incontinence in which the type is unclear
symptoms suggestive of voiding dysfunction
anterior or apical prolapse
a history of previous surgery for stress urinary incontinence.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on urodynamic testing .
Full details of the evidence and the committee's discussion are in evidence review A: urodynamic assessment prior to primary surgery for stress urinary incontinence.
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## Other tests of urethral competence
Do not use the Q‑tip, Bonney, Marshall and Fluid-Bridge tests in the assessment of women with urinary incontinence.
## Cystoscopy
Do not use cystoscopy in the initial assessment of women with urinary incontinence alone.
## Imaging
Do not use imaging (MRI, CT, X‑ray) for the routine assessment of women with urinary incontinence. Do not use ultrasound other than for the assessment of residual urine volume.
## Indications for referral to a specialist service
In women with urinary incontinence, indications for consideration for referral to a specialist service include:
persisting bladder or urethral pain
palpable bladder on bimanual or abdominal examination after voiding
clinically benign pelvic masses
associated faecal incontinence
suspected neurological disease
symptoms of voiding difficulty
suspected urogenital fistulae
previous continence surgery
previous pelvic cancer surgery
previous pelvic radiation therapy.
Follow the recommendations on referral for urinary tract cancer in the NICE guideline on suspected cancer, for women with haematuria or recurrent or persistent unexplained UTI.
# Non-surgical management of urinary incontinence
## Lifestyle interventions
Recommend a trial of caffeine reduction to women with overactive bladder.
Consider advising women with urinary incontinence or overactive bladder and a high or low fluid intake to modify their fluid intake.
Advise women with urinary incontinence or overactive bladder who have a BMI greater than 30 to lose weight.
## Physical therapies
Offer a trial of supervised pelvic floor muscle training of at least 3 months' duration as first-line treatment to women with stress or mixed urinary incontinence.
Pelvic floor muscle training programmes should comprise at least 8 contractions performed 3 times per day.
Do not use perineometry or pelvic floor electromyography as biofeedback as a routine part of pelvic floor muscle training.
Continue an exercise programme if pelvic floor muscle training is beneficial.
For a short explanation of why the committee made the 2019 recommendation and how it might affect practice, see the rationale and impact section on pelvic floor muscle training .
Full details of the evidence and the committee's discussion are in evidence review H: lifestyle and conservative management options for pelvic organ prolapse.
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Do not routinely use electrical stimulation in the treatment of women with overactive bladder.
Do not routinely use electrical stimulation in combination with pelvic floor muscle training.
Electrical stimulation and/or biofeedback should be considered for women who cannot actively contract pelvic floor muscles to aid motivation and adherence to therapy.
## Behavioural therapies
Offer bladder training lasting for a minimum of 6 weeks as first-line treatment to women with urgency or mixed urinary incontinence.
If women do not achieve satisfactory benefit from bladder training programmes, the combination of an overactive bladder medicine with bladder training should be considered if frequency is a troublesome symptom.
## Neurostimulation
Do not offer transcutaneous sacral nerve stimulation (surface electrodes placed above the sacrum, often known as transcutaneous electrical nerve stimulation ) to treat overactive bladder in women.
Do not offer transcutaneous posterior tibial nerve stimulation for overactive bladder.
Do not offer percutaneous posterior tibial nerve stimulation (needles inserted close to the posterior tibial nerve) for overactive bladder unless:
there has been a local MDT review and
non-surgical management including overactive bladder medicine treatment has not worked adequately and
the woman does not want botulinum toxin type A or percutaneous sacral nerve stimulation. In April 2019, most botulinum toxin type A preparations were off label for this indication. Evidence was only available for the licensed botulinum toxin type A preparation (BOTOX, Allergan).
## Absorbent containment products, urinals and toileting aids
Do not offer absorbent containment products, hand-held urinals or toileting aids to treat urinary incontinence. Offer them only:
as a coping strategy pending definitive treatment
as an adjunct to ongoing therapy
for long-term management of urinary incontinence only after treatment options have been explored.
Offer a review at least once a year to women who are using absorbent containment products for long-term management of urinary incontinence. The review should cover:
routine assessment of continence
assessment of skin integrity
changes to symptoms, comorbidities, lifestyle, mobility, medication, BMI, and social and environmental factors
the suitability of alternative treatment options
the efficacy of the absorbent containment product the woman is currently using and the quantities used.
Reviews for women who are using absorbent containment products for long-term management of urinary incontinence should be carried out by either:
a registered healthcare professional who is trained in assessing continence and making referrals to specialist services or
a non-registered healthcare worker, under the supervision of a registered healthcare professional who is trained in assessing continence and making referrals to specialist services. See indications for referral to a specialist service in this guideline.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on absorbent containment products .
Full details of the evidence and the committee's discussion are in evidence review B: treatment options for women using absorbent containment products.
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## Catheters
Bladder catheterisation (intermittent or indwelling urethral or suprapubic) should be considered for women in whom persistent urinary retention is causing incontinence, symptomatic infections or renal dysfunction, and in whom this cannot otherwise be corrected. Healthcare professionals should be aware, and explain to women, that the use of indwelling catheters in urgency urinary incontinence may not result in continence.
Offer intermittent urethral catheterisation to women with urinary retention who can be taught to self-catheterise or who have a carer who can perform the technique.
Give careful consideration to the impact of long-term indwelling urethral catheterisation. Discuss the practicalities, benefits and risks with the woman or, if appropriate, her carer. Indications for the use of long-term indwelling urethral catheters for women with urinary incontinence include:
chronic urinary retention in women who are unable to manage intermittent self-catheterisation
skin wounds, pressure ulcers or irritations that are being contaminated by urine
distress or disruption caused by bed and clothing changes
where a woman expresses a preference for this form of management.
Indwelling suprapubic catheters should be considered as an alternative to long-term urethral catheters. Be aware, and explain to women, that they may be associated with lower rates of symptomatic UTI, 'bypassing', and urethral complications than indwelling urethral catheters.
## Products to prevent leakage
Do not use intravaginal and intraurethral devices for the routine management of urinary incontinence in women. Do not advise women to consider such devices other than for occasional use when necessary to prevent leakage, for example during physical exercise.
## Complementary therapies
Do not recommend complementary therapies for the treatment of urinary incontinence or overactive bladder.
## Medicines for overactive bladder
Before starting treatment with a medicine for overactive bladder, explain to the woman:
the likelihood of the medicine being successful
the common adverse effects associated with the medicine
that some adverse effects of anticholinergic medicines, such as dry mouth and constipation, may indicate that the medicine is starting to have an effect
that she may not see substantial benefits until she has been taking the medicine for at least 4 weeks and that her symptoms may continue to improve over time
that the long-term effects of anticholinergic medicines for overactive bladder on cognitive function are uncertain.
When offering anticholinergic medicines to treat overactive bladder, take account of the woman's:
coexisting conditions (such as poor bladder emptying, cognitive impairment or dementia)
current use of other medicines that affect total anticholinergic load
risk of adverse effects, including cognitive impairment.
For women who have a diagnosis of dementia and for whom anticholinergic medicines are an option, follow the recommendations on medicines that may cause cognitive impairment in the NICE guideline on dementia.
Do not offer women flavoxate, propantheline or imipramine to treat urinary incontinence or overactive bladder.
Do not offer oxybutynin (immediate release) to older women who may be at higher risk of a sudden deterioration in their physical or mental health.
Offer the anticholinergic medicine with the lowest acquisition cost to treat overactive bladder or mixed urinary incontinence in women.
If the first medicine for overactive bladder or mixed urinary incontinence is not effective or well-tolerated, offer another medicine with a low acquisition cost (see additional information).
Offer a transdermal overactive bladder treatment to women unable to tolerate oral medicines.
For guidance on mirabegron, see the NICE technology appraisal guidance on mirabegron for treating symptoms of overactive bladder.
The use of desmopressin may be considered specifically to reduce nocturia in women with urinary incontinence or overactive bladder who find it a troublesome symptom. Use particular caution in women with cystic fibrosis and avoid in those over 65 years with cardiovascular disease or hypertension.
Do not use duloxetine as a first-line treatment for women with predominant stress urinary incontinence. Do not routinely offer duloxetine as a second-line treatment for women with stress urinary incontinence, although it may be offered as second-line therapy if women prefer pharmacological to surgical treatment or are not suitable for surgical treatment. If duloxetine is prescribed, counsel women about its adverse effects. For guidance on safe prescribing of antidepressants (such as duloxetine) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
Do not offer systemic hormone replacement therapy to treat urinary incontinence.
Offer intravaginal oestrogens to treat overactive bladder symptoms in postmenopausal women with vaginal atrophy.
Offer a face-to-face or telephone review 4 weeks after starting a new medicine for overactive bladder. Ask the woman if she is satisfied with the treatment and:
if improvement is optimal, continue treatment
if there is no or suboptimal improvement, or intolerable adverse effects, change the dose or try an alternative medicine for overactive bladder (see the recommendations for when the first medicine is not effective and offering a transdermal patch in the section on choosing medicines), and review again 4 weeks later.
Offer a review before 4 weeks if the adverse events of a medicine for overactive bladder are intolerable.
Refer women who have tried taking medicine for overactive bladder, but for whom it has not been successful or tolerated, to secondary care to consider further treatment.
Offer a further face-to-face or telephone review if a medicine for overactive bladder or urinary incontinence stops working after an initial successful 4‑week review.
Offer a review in primary care to women who remain on long-term medicine for overactive bladder or urinary incontinence every 12 months, or every 6 months if they are aged over 75.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on medicines for overactive bladder .
Full details of the evidence and the committee's discussion are in evidence review C: the risks to cognitive function for women taking anticholinergic drugs for overactive bladder.
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## Invasive procedures for overactive bladder
For women with overactive bladder that has not responded to non-surgical management or treatment with medicine and who wish to discuss further treatment options:
-ffer urodynamic investigation to determine whether detrusor overactivity is causing her overactive bladder symptoms and
if detrusor overactivity is causing her overactive bladder symptoms, offer an invasive procedure in line with the recommendation on bladder wall injection in the section on botulinum toxin type A and the recommendation in the section on urinary diversionor
if there is no detrusor overactivity, seek advice on further management from the local MDT in line with the recommendation on considering treatment with botulinum toxin type A in the section on botulinum toxin type A.
See additional information on prescribing botulinum toxin type A.
After a local MDT review, offer bladder wall injection with botulinum toxin type A to women with overactive bladder caused by detrusor overactivity that has not responded to non-surgical management, including pharmacological treatments.
Consider treatment with botulinum toxin type A after a local MDT review for women with symptoms of overactive bladder in whom urodynamic investigation has not demonstrated detrusor overactivity, if the symptoms have not responded to non-surgical management and the woman does not wish to have other invasive treatments.
After a local MDT review, discuss the benefits and risks of treatment with botulinum toxin type A with the woman and explain:
the likelihood of complete or partial symptom relief
the process of clean intermittent catheterisation, the risks, and how long it might need to be continued
the risk of adverse effects, including an increased risk of urinary tract infection
that there is not much evidence about how long the injections work for, how well they work in the long term and their long-term risks.
Start treatment with botulinum toxin type A only if the woman is willing, in the event of developing significant voiding dysfunction:
to perform clean intermittent catheterisation on a regular basis for as long as needed or
to accept a temporary indwelling catheter if she is unable to perform clean intermittent catheterisation.
Use 100 units as the initial dose of botulinum toxin type A to treat overactive bladder in women.
Offer a face-to-face or telephone review within 12 weeks of the first treatment with botulinum toxin type A to assess the response to treatment and adverse effects, and:
if there is good symptom relief, tell the woman how to self-refer for prompt specialist review if symptoms return, and offer repeat treatment as necessary
if there is inadequate symptom relief, consider increasing subsequent doses of botulinum toxin type A to 200 units and review within 12 weeks
if there was no effect, discuss with the local MDT.
If symptom relief has been adequate after injection of 100 units of botulinum toxin type A but has lasted for less than 6 months, consider increasing subsequent doses of botulinum toxin type A to 200 units and review within 12 weeks.
Do not offer botulinum toxin type B to women with overactive bladder.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on botulinum toxin type A injection .
Full details of the evidence and the committee's discussion are in evidence review D: management of overactive bladder.
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Offer percutaneous sacral nerve stimulation to women after local or regional MDT review if their overactive bladder has not responded to non-surgical management including medicines and:
their symptoms have not responded to botulinum toxin type A or
they are not prepared to accept the risks of needing catheterisation associated with botulinum toxin type A.
Discuss the long-term implications of percutaneous sacral nerve stimulation with women including:
the need for test stimulation and probability of the test's success
the risk of failure
the long-term commitment
the need for surgical revision
the adverse effects.
Tell women how to self-refer for prompt specialist review if symptoms return following a percutaneous sacral nerve stimulation procedure.
Restrict augmentation cystoplasty for the management of idiopathic detrusor overactivity to women whose condition has not responded to non-surgical management and who are willing and able to self-catheterise. Preoperative counselling for the woman or her carer should include common and serious complications: bowel disturbance, metabolic acidosis, mucus production and/or retention in the bladder, UTI and urinary retention. Discuss the small risk of malignancy occurring in the augmented bladder. Provide life-long follow‑up.
Urinary diversion should be considered for a woman with overactive bladder only when non-surgical management has failed, and if botulinum toxin type A, percutaneous sacral nerve stimulation and augmentation cystoplasty are not appropriate or are unacceptable to her. Provide life-long follow‑up. In April 2019, most botulinum toxin type A preparations were off label for this indication. Evidence was only available for the licensed botulinum toxin type A preparation (BOTOX, Allergan).
# Surgical management of stress urinary incontinence
There is public concern about the use of mesh procedures. For all of the procedures recommended in this section, including mesh procedures, there is evidence of benefit but limited evidence on the long-term adverse effects. In particular, the true prevalence of long-term complications is unknown.
If a woman is thinking about a surgical procedure for stress urinary incontinence, use the NICE patient decision aid on surgery for stress urinary incontinence to promote informed preference and shared decision making. Discussion with the woman should include:
the benefits and risks of all surgical treatment options for stress urinary incontinence that NICE recommends, whether or not they are available locally
the uncertainties about the long-term adverse effects for all procedures, particularly those involving the implantation of mesh materials
differences between procedures in the type of anaesthesia, expected length of hospital stay, surgical incisions and expected recovery period
any social or psychological factors that may affect the woman's decision.
If non-surgical management for stress urinary incontinence has failed, and the woman wishes to think about a surgical procedure, offer her the choice of:
colposuspension (open or laparoscopic) or
an autologous rectus fascial sling.Also include the option of a retropubic mid-urethral mesh sling in this choice but see the recommendations in the section on mid-urethral mesh sling procedures for additional guidance on the use of mid-urethral mesh sling procedures for stress urinary incontinence.
Consider intramural bulking agents to manage stress urinary incontinence if alternative surgical procedures are not suitable for or acceptable to the woman. Explain to the woman that:
these are permanent injectable materials
repeat injections may be needed to achieve effectiveness
limited evidence suggests that they are less effective than the surgical procedures listed in recommendation 1.5.2 and the effects wear off over time
there is limited evidence on long-term effectiveness and adverse events.
If an intramural bulking agent is injected, give the woman written information about the bulking agent, including its name, manufacturer, date of injection, and the injecting surgeon's name and contact details.
If the woman's chosen procedure for stress urinary incontinence is not available from the consulting surgeon, refer her to an alternative surgeon.
Providers must ensure that data on surgical procedures for stress urinary incontinence are recorded in a national registry, as outlined in the section on collecting data on surgery and surgical complications in this guideline.
## Mid-urethral mesh sling procedures
When offering a retropubic mid-urethral mesh sling, advise the woman that it is a permanent implant and complete removal might not be possible.
If a retropubic mid-urethral mesh sling is inserted, give the woman written information about the implant, including its name, manufacturer, date of insertion, and the implanting surgeon's name and contact details.
When planning a retropubic mid-urethral mesh sling procedure, surgeons should:
use a device manufactured from type 1 macroporous polypropylene mesh
consider using a retropubic mid-urethral mesh sling coloured for high visibility, for ease of insertion and revision.
Do not offer a transobturator approach unless there are specific clinical circumstances (for example, previous pelvic procedures) in which the retropubic approach should be avoided.
Do not use the 'top‑down' retropubic mid-urethral mesh sling approach or single-incision sub-urethral short mesh sling insertion except as part of a clinical trial.
## Artificial urinary sphincters
Do not offer women an artificial urinary sphincter to manage stress urinary incontinence unless previous surgery has failed.
For women who have had an artificial urinary sphincter inserted:
-ffer postoperative follow‑up and
ensure access to review if needed.
## Procedures that should not be offered
Do not offer women the following procedures to treat stress urinary incontinence:
anterior colporrhaphy
needle suspension
paravaginal defect repair
porcine dermis sling
the Marshall–Marchetti–Krantz procedure.
## Follow-up after surgery
Offer a follow‑up appointment within 6 months to all women who have had a surgical procedure to treat stress urinary incontinence.
For women who have had retropubic mid-urethral mesh sling surgery, the follow‑up appointment should include a vaginal examination to check for exposure or extrusion of the mesh sling.
Providers should ensure that women who have had surgery for stress urinary incontinence have access to further referral if they have recurrent symptoms or suspected complications. See also assessing complications associated with mesh surgery in this guideline.
For women whose primary surgical procedure for stress urinary incontinence has failed (including women whose symptoms have returned):
seek advice on assessment and management from a regional MDT that deals with complex pelvic floor dysfunction or
-ffer the woman advice about managing urinary symptoms if she does not wish to have another surgical procedure, and explain that she can ask for a referral if she changes her mind.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on surgical management of stress urinary incontinence .
Full details of the evidence and the committee's discussion are in evidence review E: surgical and physical management of stress urinary incontinence.
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# Assessing pelvic organ prolapse
For women presenting in primary care with symptoms or an incidental finding of vaginal prolapse:
take a history to include symptoms of prolapse, urinary, bowel and sexual function
do an examination to rule out a pelvic mass or other pathology and to document the presence of prolapse (see the recommendations in the NICE guideline on suspected cancer about ovarian cancer and bladder cancer)
discuss the woman's treatment preferences with her, and refer if needed.
For women referred to secondary care for an unrelated condition who have incidental symptoms or an incidental finding of vaginal prolapse, consider referral to a clinician with expertise in prolapse.
For women who are referred for specialist evaluation of vaginal prolapse, perform an examination to:
assess and record the presence and degree of prolapse of the anterior, central and posterior vaginal compartments of the pelvic floor, using the POP‑Q (Pelvic Organ Prolapse Quantification) system
assess the activity of the pelvic floor muscles
assess for vaginal atrophy
rule out a pelvic mass or other pathology.
For women with pelvic organ prolapse, consider using a validated pelvic floor symptom questionnaire to aid assessment and decision making.
Do not routinely perform imaging to document the presence of vaginal prolapse if a prolapse is detected by physical examination.
If the woman has symptoms of prolapse that are not explained by findings from a physical examination, consider repeating the examination with the woman standing or squatting, or at a different time.
Consider investigating the following symptoms in women with pelvic organ prolapse:
urinary symptoms that are bothersome and for which surgical intervention is an option
symptoms of obstructed defaecation or faecal incontinence (see the recommendations for baseline assessment of faecal incontinence in the NICE guideline on faecal incontinence in adults)
pain
symptoms that are not explained by examination findings.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessing pelvic organ prolapse .
Full details of the evidence and the committee's discussion are in evidence review G: assessing pelvic organ prolapse.
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# Non-surgical management of pelvic organ prolapse
Discuss management options with women who have pelvic organ prolapse, including no treatment, non-surgical treatment and surgical options, taking into account:
the woman's preferences
site of prolapse
lifestyle factors
comorbidities, including cognitive or physical impairments
age
desire for childbearing
previous abdominal or pelvic floor surgery
benefits and risks of individual procedures.
## Lifestyle modification
Consider giving advice on lifestyle to women with pelvic organ prolapse, including information on:
losing weight, if the woman has a BMI greater than 30 kg/m2
minimising heavy lifting
preventing or treating constipation.
## Topical oestrogen
Consider vaginal oestrogen for women with pelvic organ prolapse and signs of vaginal atrophy. For managing urogenital atrophy, see the recommendations in managing short-term menopausal symptoms in the NICE guideline on menopause.
Consider an oestrogen-releasing ring for women with pelvic organ prolapse and signs of vaginal atrophy who have cognitive or physical impairments that might make vaginal oestrogen pessaries or creams difficult to use.
## Pelvic floor muscle training
Consider a programme of supervised pelvic floor muscle training for at least 16 weeks as a first option for women with symptomatic POP‑Q (Pelvic Organ Prolapse Quantification) stage 1 or stage 2 pelvic organ prolapse. If the programme is beneficial, advise women to continue pelvic floor muscle training afterwards.
## Pessaries
Consider a vaginal pessary for women with symptomatic pelvic organ prolapse, alone or in conjunction with supervised pelvic floor muscle training.
Refer women who have chosen a pessary to a urogynaecology service if pessary care is not available locally.
Before starting pessary treatment:
consider treating vaginal atrophy with topical oestrogen
explain that more than 1 pessary fitting may be needed to find a suitable pessary
discuss the effect of different types of pessary on sexual intercourse
describe complications including vaginal discharge, bleeding, difficulty removing pessary and pessary expulsion
explain that the pessary should be removed at least once every 6 months to prevent serious pessary complications.
Offer women using pessaries an appointment in a pessary clinic every 6 months if they are at risk of complications, for example because of a physical or cognitive impairment that might make it difficult for them to manage their ongoing pessary care.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on non-surgical management of pelvic organ prolapse .
Full details of the evidence and the committee's discussion are in evidence review H: lifestyle and conservative management options for pelvic organ prolapse.
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# Surgical management of pelvic organ prolapse
There is public concern about the use of mesh procedures. For all of the procedures recommended in this section, including mesh procedures, there is some evidence of benefit, but limited evidence on long-term effectiveness and adverse effects. In particular, the true prevalence of long-term complications is unknown.
Offer surgery for pelvic organ prolapse to women whose symptoms have not improved with or who have declined non-surgical treatment.
If a woman is thinking about a surgical procedure for pelvic organ prolapse, use a decision aid (use the NICE patient decision aids on surgery for uterine prolapse and surgery for vaginal vault prolapse where they apply) to promote informed preference and shared decision making. Discussion with the woman should include:
the different treatment options for pelvic organ prolapse, including no treatment or continued non-surgical management
the benefits and risks of each surgical procedure, including changes in urinary, bowel and sexual function
the risk of recurrent prolapse
the uncertainties about the long-term adverse effects for all procedures, particularly those involving the implantation of mesh materials
differences between procedures in the type of anaesthesia, expected length of hospital stay, surgical incisions and expected recovery period
the role of intraoperative prolapse assessment in deciding the most appropriate surgical procedure.
Do not offer surgery to prevent incontinence in women having surgery for prolapse who do not have incontinence.
Explain to women considering surgery for anterior or apical prolapse who do not have incontinence that there is a risk of developing postoperative urinary incontinence and further treatment may be needed.
If the woman's chosen procedure for pelvic organ prolapse is not available from the consulting surgeon, refer her to an alternative surgeon.
If mesh is to be used in prolapse surgery:
explain to the woman about the type of mesh that will be used and whether or not it is permanent
ensure that details of the procedure and its subsequent short- and long-term outcomes are recorded in a national registry (see the section on collecting data on surgery and surgical complications in this guideline)
give the woman written information about the implant, including its name, manufacturer, date of insertion, and the implanting surgeon's name and contact details.
Providers must ensure that data on surgical procedures for pelvic organ prolapse are recorded in a national registry, as outlined in the section on collecting data on surgery and surgical complications in this guideline.
## Surgery for uterine prolapse
Discuss the options for treatment (see recommendation 1.8.2 on using a decision aid), including non-surgical options, hysterectomy and surgery that will preserve the uterus, with women who have uterine prolapse.
For women considering surgery for uterine prolapse:
discuss the possible complications and the lack of long-term evidence on the effectiveness of the procedures
use the NICE patient decision aid on surgery for uterine prolapse to discuss the benefits and risks of treatment, including non-surgical options.
For women with uterine prolapse who have no preference about preserving their uterus, offer a choice of:
vaginal hysterectomy, with or without vaginal sacrospinous fixation with sutures or
vaginal sacrospinous hysteropexy with sutures or
Manchester repair. Also include the option of sacro-hysteropexy with mesh (abdominal or laparoscopic) in this choice but see recommendation 1.8.6 for specific guidance on the use of mesh in prolapse surgery.
For women with uterine prolapse who wish to preserve their uterus, offer a choice of:
vaginal sacrospinous hysteropexy with sutures or
Manchester repair, unless the woman may wish to have children in the future. Also include the option of sacro-hysteropexy with mesh (abdominal or laparoscopic) in this choice but see recommendation 1.8.6 for specific guidance on the use of mesh in prolapse surgery.
If a synthetic polypropylene mesh is inserted, the details of the procedure and its subsequent short- and long-term outcomes must be collected in a national registry (see the section on collecting data on surgery and surgical complications in this guideline).
Ensure the proposed treatment is reviewed by a regional MDT (see the recommendation on MDTs reviewing proposed treatment in the section on regional multidisciplinary teams) if the woman wishes to have children in the future.
## Surgery for vault prolapse
Discuss the options for treatment (see recommendation 1.8.2 on using a decision aid), including non-surgical and surgical options, with women who have vault prolapse.
For women considering surgery for vault prolapse:
discuss the possible complications and the lack of long-term evidence on the effectiveness of the procedures
use the NICE patient decision aid on surgery for vaginal vault prolapse to discuss the benefits and risks of treatment, including non-surgical options.
Offer women with vault prolapse a choice of:
vaginal sacrospinous fixation with sutures or
sacrocolpopexy (abdominal or laparoscopic) with mesh. See recommendation 1.8.6 for specific guidance on the use of mesh in prolapse surgery.
If a synthetic polypropylene mesh is inserted, the details of the procedure and its subsequent short- and long-term outcomes must be collected in a national registry (see the section on collecting data on surgery and surgical complications in this guideline).
## Colpocleisis for vault or uterine prolapse
Consider colpocleisis for women with vault or uterine prolapse who do not intend to have penetrative vaginal sex and who have a physical condition that may put them at increased risk of operative and postoperative complications.
## Surgery for anterior prolapse
Discuss the options for treatment (see recommendation 1.8.2 on using a decision aid), including non-surgical and surgical options, with women who have anterior prolapse.
Offer anterior repair without mesh to women with anterior vaginal wall prolapse.
Recommendation withdrawn in June 2019.
Recommendation withdrawn in June 2019.
June 2019: Recommendations 1.8.21 and 1.8.22, which related to the use of synthetic polypropylene or biological mesh insertion for women with recurrent anterior vaginal wall prolapse, have been withdrawn. Instead, please see NICE interventional procedures guidance 599 on transvaginal mesh repair of anterior or posterior vaginal wall prolapse, which says:
'1.1 Current evidence on the safety of transvaginal mesh repair of anterior or posterior vaginal wall prolapse shows there are serious but well-recognised safety concerns. Evidence of long-term efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research.
'1.2 All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.
'1.3 Further research should include details of patient selection, long-term outcomes including complications, type of mesh used and method of fixation, and quality of life.'
The replacement of the guideline recommendation with a cross-reference to IPG599 is to provide clarity regarding the relation of NG123 and IPG599 and to take account of a material change since publication in the availability of products CE-marked for the indication which was referred to in the guideline recommendations.
## Surgery for posterior prolapse
Offer posterior vaginal repair without mesh to women with a posterior vaginal wall prolapse.
## Follow-up after surgery
Offer women a review 6 months after surgery for pelvic organ prolapse. Ensure that the review includes a vaginal examination and, if mesh was used, check for mesh exposure.
Providers should ensure that women who have had surgery for pelvic organ prolapse have access to further referral if they have recurrent symptoms or suspected complications. Also see the section on assessing complications associated with mesh surgery in this guideline.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on surgical management of pelvic organ prolapse .
Full details of the evidence and the committee's discussion are in evidence review I: surgical management of pelvic organ prolapse.
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# Surgery for women with both stress urinary incontinence and pelvic organ prolapse
Consider concurrent surgery for stress urinary incontinence and pelvic organ prolapse in women with anterior and/or apical prolapse and stress urinary incontinence.
When considering concurrent surgery for stress urinary incontinence and pelvic organ prolapse, discuss the options for treatment (see the recommendation on using the NICE decision aid in the section on surgical management of stress incontinence and in the section on surgical management of pelvic organ prolapse) and explain to the woman:
that there is uncertainty about whether the combined procedure is effective for treating stress urinary incontinence beyond 1 year, and that stress urinary incontinence might persist despite surgery
the risk of complications related to having surgery for stress urinary incontinence at the same time as prolapse surgery compared with the risk of complications related to having sequential surgery.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on surgery for women with both stress urinary incontinence and pelvic organ prolapse .
Full details of the evidence and the committee's discussion are in evidence review J: surgical management of pelvic organ prolapse and stress urinary incontinence.
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# Assessing complications associated with mesh surgery
For women who report new-onset symptoms after having mesh surgery for urinary incontinence or pelvic organ prolapse, evaluate whether the symptoms might be caused by a mesh-related complication. These symptoms could include:
pain or sensory change in the back, abdomen, vagina, pelvis, leg, groin or perineum that is:
either unprovoked, or provoked by movement or sexual activity and
either generalised, or in the distribution of a specific nerve, such as the obturator nerve
vaginal problems including discharge, bleeding, painful sexual intercourse, or penile trauma or pain in sexual partners
urinary problems including recurrent infection, incontinence, retention, or difficulty or pain during voiding
bowel problems including difficulty or pain on defaecation, faecal incontinence, rectal bleeding or passage of mucus
symptoms of infection, either alone or in combination with any of the symptoms outlined above.
Refer women with a suspected mesh-related complication to a urogynaecologist, urologist or colorectal surgeon for specialist assessment.
For women who are referred for specialist evaluation of a suspected mesh complication:
take a history of all past surgical procedures for prolapse or incontinence using mesh, including the dates, type of mesh and site of mesh placement and the relationship of the symptoms to the surgical procedure(s)
consider using a validated pelvic floor symptom questionnaire and a pain questionnaire to aid assessment and decision making
perform a vaginal examination to:
assess whether mesh is palpable, exposed or extruded
localise pain and its anatomical relationship to mesh
consider performing a rectal examination, if indicated, to assess for the presence of mesh perforation or fistula
consider performing a neurological assessment to assess the distribution of pain, if present, sensory alteration or muscle weakness.
For women with a confirmed mesh-related complication or unexplained symptoms after a mesh procedure:
refer to a consultant at a regional centre specialising in the diagnosis and management of mesh-related complications or
if the woman has a vaginal exposure of mesh that is smaller than 1 cm2 and no other symptoms, follow the recommendations on discussing topical oestrogen cream treatment and a follow-up appointment for those having topical oestrogen cream in the section on managing vaginal complications.
The responsible consultant should develop an individualised investigation plan for each woman with suspected or confirmed mesh-related complications, involving other members of the regional MDT if needed, and use table 1 in this guideline to inform decisions on possible investigations.
The responsible consultant must ensure that details of any confirmed mesh-related complications are:
recorded in a national registry (see the section on collecting data on surgery and surgical complications in this guideline) and
reported to the Medicines and Healthcare products Regulatory Agency (MHRA).
Investigation
Type of mesh
Indications
Benefits
Risks
Examination under anaesthesia
All types of mesh
Pain or suspected:
vaginal or rectal exposure or extrusion
sinus tract, urinary or bowel fistula
Allows diagnosis when not revealed by awake examination or when an awake, examination is not tolerated
Anaesthetic risk
Cystourethro-scopy
All types of mesh
Suspected:
urethral perforation
bladder perforation
fistula
calculus on suture or mesh material
Allows diagnosis by direct visualisation
Aids management planning
Anaesthetic risk and risk of urinary tract infection
Sigmoidoscopy
Abdominally, laparo-scopically or vaginally placed mesh for pelvic organ prolapse
Suspected bowel perforation by mesh
Allows diagnosis by direct visualisation
Aids management planning
Anaesthetic risk if carried out under anaesthesia
Risk of bowel perforation
Laparoscopy
Abdominally or laparo-scopically placed mesh for pelvic organ prolapse
Pain
Suspected bowel entrapment around mesh
Suspected adhesions secondary to mesh placement
Allows diagnosis by direct visualisation
Aids management planning
Anaesthetic risk
Risks of laparoscopy, including bowel injury
MRI, protocolled and reported by a clinician with experience in interpreting mesh complications
All types of mesh
Suspected mesh infection
Anatomical mapping of suspected fistula
Anatomical mapping and mesh localisation to guide further surgery
Back pain following abdominal mesh placement with mesh attachment to sacral promontory
Identification of discitis or osteomyelitis
Shows implanted material and complications nearby
Shows location of mesh in relation to the vaginal wall and sacrum
Generally regarded as safe, with a low risk of short- and long-term harms. Risk of contrast media injection
Ultrasound scan (transperineal, transvaginal or translabial, or 3D), performed and reported by a clinician with experience in interpreting mesh complications
Vaginally placed mesh to treat incontinence
Pain
Voiding dysfunction
Suspected infection
Suspected urethral mesh perforation
Anatomical mapping to guide excision surgery
Shows implanted material and local complications
Identifies mid-urethral slings
Shows location of mesh in relation to the vaginal wall and urethra
Discomfort
CT
All types of mesh, although CT is not commonly used to show implanted material
Suspected:
urinary tract injury
bowel injury
bowel obstruction
May be useful in assessing for urinary fistulae or bowel injury
Potential radiation-related harms and risk of contrast media injection
Fluoroscopic studies (cystography or contrast enema). Perform with water-soluble contrast media
Fluoroscopic studies and CT may be used according to local preference and expertise
All types of mesh
Suspected urinary or bowel fistula
Aids management planning
Potential radiation-related harms
Urinary flow studies and post-void residual volume assessment or cystometry
All types of mesh
Voiding dysfunction
Urinary incontinence
Aids management planning
Urinary tract infection and radiation risks if fluoroscopy is used
Neuro-physiology, including nerve conduction studies
All types of mesh
Suspected nerve injury
Allows diagnosis of impaired nerve function
Nerve conduction studies are difficult to perform and can induce more pain
Note: Individualised investigation plans may include, but are not limited to, 1 or more of these investigations.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessing complications associated with mesh surgery .
Full details of the evidence and the committee's discussion are in evidence review K: assessing mesh complications after pelvic floor mesh surgery.
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# Managing complications associated with mesh surgery
## General considerations before removing mesh
If a woman who has had a mesh procedure to treat urinary incontinence or pelvic organ prolapse is thinking about having the mesh removed, discuss the decision with her and with a regional MDT.
When discussing surgery to remove mesh, explain to the woman that:
there is limited evidence on the benefits of partial or complete removal compared with no mesh removal
surgery to remove mesh can have significant complications including organ injury, worsening pain, and urinary, bowel and sexual dysfunction
it is not certain that removing the mesh will relieve symptoms
it might not be possible to remove all of the mesh
removing only part of the mesh might be just as effective at improving symptoms as removing all of it
urinary incontinence or prolapse can recur after the mesh has been removed.
## Managing vaginal complications
Discuss non-surgical treatment with topical oestrogen cream with women who have a single area of vaginal mesh exposure that is smaller than 1 cm2.
Offer a follow‑up appointment within 3 months to women with vaginal mesh exposure who choose treatment with topical oestrogen cream.
Consider partial or complete surgical removal of the vaginal portion of mesh for women:
who do not wish to have treatment with topical oestrogen or
if the area of vaginal mesh sling exposure is 1 cm2 or larger or
if there is vaginal mesh extrusion or
if there has been no response to non-surgical treatment after a period of 3 months.
Offer imaging and further treatment to women who have signs of infection in addition to vaginal mesh exposure or extrusion.
Discuss with women who have vaginal complications after mesh sling surgery for stress urinary incontinence that:
complete removal of the vaginal portion of mesh sling is associated with a greater risk of recurrence of stress urinary incontinence than partial removal
partial removal is associated with a higher rate of further mesh sling extrusion
complete removal might not be possible.
Explain to women who have vaginal complications after vaginally placed mesh for pelvic organ prolapse that:
complete removal might not be possible
complete removal has a higher risk of urinary tract or bowel injury than partial removal
there may be a risk of recurrent prolapse.
Explain to women who have vaginal complications after abdominally placed mesh for pelvic organ prolapse that:
removal is associated with a risk of urinary tract and bowel injury
there is a risk of recurrent prolapse
they might need abdominal surgery to remove the mesh
complete removal might not be possible.
For women who have pain or painful sexual intercourse suspected to be related to previous mesh surgery:
if specialist assessment indicates a mesh-related complication, seek advice from a regional MDT
if assessment and investigation do not show a mesh abnormality such as vaginal extrusion or exposure, or an infection, consider non-surgical treatments such as pain management, vaginal oestrogen, dilators, counselling (including psychosexual counselling) and physiotherapy
if pain does not respond to initial management, seek advice from a regional MDT.
## Managing urinary complications
Refer women who have mesh perforating the lower urinary tract to a centre for mesh complications for further assessment or management.
For women with urinary symptoms after mesh surgery for stress urinary incontinence or pelvic organ prolapse who are considering mesh removal surgery, explain that:
urinary symptoms might not improve and new symptoms might occur after complete or partial removal of the mesh
stress urinary incontinence might recur after mesh removal, and the risk of this happening is higher with complete than with partial mesh removal
complete removal of the mesh might not be possible
further treatment might be needed for mesh complications, or recurrent or persistent urinary symptoms
there is a risk of adverse events such as urinary tract fistula.
Discuss division of mesh sling with women who have voiding difficulty after mesh sling surgery.
Refer women considering excision of mesh sling for persistent voiding dysfunction to a centre specialising in the diagnosis and management of mesh-related complications for assessment and management.
For women considering surgery to alleviate voiding symptoms caused by mesh surgery, explain that:
the risk of recurrent stress urinary incontinence is higher after mesh excision than mesh division
further surgery might be needed.
## Managing bowel symptoms
For women who present with functional bowel disorders after mesh surgery for pelvic organ prolapse, follow the recommendations in the NICE guideline on faecal incontinence in adults for women with faecal incontinence or locally agreed protocols for women with obstructed defecation.
For women with bowel complications that are directly related to mesh placement, such as erosion, stricture or fistula, discuss treatment with a regional MDT that has expertise in complex pelvic floor dysfunction and mesh-related problems. Use this discussion to formulate an individualised treatment plan with the woman.
Explain to women with bowel complications directly related to mesh placement that:
complete removal might not be possible
bowel symptoms might persist or recur after mesh removal
they might need a temporary or permanent stoma after mesh removal.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on managing complications associated with mesh surgery .
Full details of the evidence and the committee's discussion are in evidence review L: management of mesh complications.
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# Terms used in this guideline
This section defines some of the terms that are used in this guideline. For other definitions, see the NICE glossary.
## Anticholinergic medicine
A type of medicine used to treat overactive bladder. It reduces the activity of the bladder muscle by blocking chemical messengers to the nerves that control muscle movements.
## Augmentation cystoplasty
A procedure to treat overactive bladder. The bladder is made larger by adding a piece of tissue from the intestines to the bladder wall.
## Autologous rectus fascial sling
A type of sling used to treat stress urinary incontinence. It is made out of tissue from the woman's abdomen. The sling supports the tube that carries urine out of the body (the urethra).
## Botulinum toxin type A
A treatment used for overactive bladder. It is injected into the wall of the bladder.
## Colpocleisis
An operation to treat pelvic organ prolapse by closing the vagina.
## Colposuspension
A type of surgery used to treat stress urinary incontinence. The neck of the bladder is lifted up and stitched in this position.
## Detrusor overactivity
Involuntary bladder contractions seen during a cystometry test. They can be the cause of overactive bladder symptoms.
## Intramural bulking agents
Materials used to treat stress urinary incontinence. They are injected into the sides of the tube that carries urine out of the body (the urethra). This helps it remain closed so that urine is less likely to leak out.
## Manchester repair
An operation used to treat uterine prolapse. The neck of the womb (the cervix) is shortened. It involves shortening the cervix (neck of the womb) and supporting the womb in its natural position.
## Mesh procedure
An operation to insert plastic mesh to support tissues. Mesh procedures are used to treat stress urinary incontinence and pelvic organ prolapse in women.
## Percutaneous sacral nerve stimulation
A procedure used to treat overactive bladder. A device is implanted in the back to stimulate the nerves at the base of the spine. These nerves affect the bladder and surrounding muscles.
## Percutaneous posterior tibial nerve stimulation
A procedure used to treat overactive bladder. A mild electric current is passed through a fine needle to stimulate a nerve in the leg. This nerve controls bladder function.
## Retropubic mid-urethral mesh sling
A type of sling used to treat stress urinary incontinence. A strip of plastic is placed behind the tube that carries urine out of the body (the urethra) to support it in a sling.
## Sacrocolpopexy
A type of surgery used to treat vaginal vault prolapse. Plastic mesh is used to attach the vagina to a bone at the bottom of the spine.
## Sacro-hysteropexy
An operation to treat uterine prolapse. Plastic mesh is used to attach the womb (the uterus) to a bone at the bottom of the spine.
## Urinary diversion
A type of surgery used to treat stress urinary incontinence. It causes urine to flow through an opening in the abdomen into an external bag, instead of into the bladder.
## Vaginal sacrospinous fixation
A type of surgery used to treat vaginal vault or uterine prolapse. The top of the vagina is stitched to a ligament in the pelvis. It is done through a cut on the inside of the vagina.
## Vaginal sacrospinous hysteropexy
An operation used to treat uterine prolapse. The cervix is stitched to a ligament in the pelvis. It is done through a cut on the inside of the vagina.
# Additional information
## Recommendation 1.4.31
This could be any medicine with the lowest acquisition cost from any of the medicines reviewed in 2013. The evidence review considered the following medicines: darifenacin, fesoterodine, oxybutynin (immediate release), oxybutynin (extended release), oxybutynin (transdermal), oxybutynin (topical gel), propiverine, propiverine (extended release), solifenacin, tolterodine (immediate release), tolterodine (extended release), trospium and trospium (extended release). See chapter 6 of the 2013 full guideline.
## Recommendations 1.4.44 to 1.4.50
In April 2019, only 1 preparation of botulinum toxin type A (BOTOX, Allergan) had a UK marketing authorisation for overactive bladder. The licensed dose was 100 units.
One preparation of botulinum toxin type A (BOTOX, Allergan) had a UK marketing authorisation for use at a dose of 200 units, for treating neurogenic detrusor overactivity with urinary incontinence due to subcervical spinal cord injury (traumatic or non-traumatic) or multiple sclerosis.
Note that units of botulinum toxin type A are not interchangeable between preparations. If prescribing outside the marketing authorisation ('off label'), see NICE's information on prescribing medicines.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Anticholinergic medicines
What is the effectiveness and safety of anticholinergic medicines for overactive bladder in older women?
For a short explanation of why the committee made the recommendation for research, see the rationale on medicines for overactive bladder .
Full details of the evidence and the committee's discussion are in evidence review C: the risks to cognitive function for women taking anticholinergic drugs for overactive bladder.
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## Colpocleisis compared with sacrospinous fixation for pelvic organ prolapse
What is the effectiveness of colpocleisis compared with sacrospinous fixation for pelvic organ prolapse in elderly women?
For a short explanation of why the committee made the recommendation for research, see the rationale on surgical management of pelvic organ prolapse .
Full details of the evidence and the committee's discussion are in evidence review I: surgical management of pelvic organ prolapse.
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## Assessing complications associated with mesh surgery
What is the effectiveness of ultrasound-guided visualisation compared with clinical assessment to identify complications after mesh surgery for stress urinary incontinence or pelvic organ prolapse in women?
For a short explanation of why the committee made the recommendation for research, see the rationale on assessing complications associated with mesh surgery .
Full details of the evidence and the committee's discussion are in evidence review K: assessing mesh complications after pelvic floor mesh surgery.
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## Pessaries or surgery for pelvic organ prolapse
What are the long-term outcomes, including patient satisfaction, from the use of pessaries compared with surgery for pelvic organ prolapse in women?
For a short explanation of why the committee made the recommendation for research, see the rationale on non-surgical management of pelvic organ prolapse .
Full details of the evidence and the committee's discussion are in evidence review H: lifestyle and conservative management options for pelvic organ prolapse.
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## Long-term risks of surgery with and without mesh
What are the long-term risks of mesh surgery compared with non-mesh surgery for stress urinary incontinence and pelvic organ prolapse in women?
For a short explanation of why the committee made the recommendation for research, see the rationale on surgical management of stress urinary incontinence and surgical management of pelvic organ prolapse .
Full details of the evidence and the committee's discussion are in:
evidence review E: surgical and physical management of stress urinary incontinence
evidence review I: surgical management of pelvic organ prolapse.
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# Other recommendations for research
## Long-term effectiveness of botulinum toxin type A for overactive bladder
What is the long-term effectiveness of bladder wall injection with botulinum toxin type A for overactive bladder in women?
For a short explanation of why the committee made the recommendation for research, see the rationale on botulinum toxin type A injection .
Full details of the evidence and the committee's discussion are in evidence review D: management of overactive bladder.
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## Surgery for stress urinary incontinence and pelvic organ prolapse
What is the most effective surgical management for women with both stress urinary incontinence and pelvic organ prolapse, including the sequence of interventions?
For a short explanation of why the committee made the recommendation for research, see the rationale on surgery for women with both stress urinary incontinence and pelvic organ prolapse .
Full details of the evidence and the committee's discussion are in evidence review J: surgical management of pelvic organ prolapse and stress urinary incontinence.
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## Pain management after mesh surgery
What is the effectiveness of pain management for women who present with chronic pain 3 months after mesh surgery for stress urinary incontinence or pelvic organ prolapse?
For a short explanation of why the committee made the recommendation for research, see the rationale on managing complications associated with mesh surgery .
Full details of the evidence and the committee's discussion are in evidence review L: management of mesh complications.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the 2019 recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Organisation of specialist services
Recommendations 1.1.1 to 1.1.7
## Why the committee made the 2019 recommendations
The committee agreed, based on their experience, that women with stress urinary incontinence, overactive bladder or primary prolapse would benefit from the broad range of expertise provided by a local multidisciplinary team (MDT). They agreed that a local MDT working within a regional clinical network could refer women to other services within the network for treatments that are not available locally, thus providing a broader choice of treatments.
The committee thought that women with complications related to mesh surgery, or with complex pelvic floor problems, should have access to a specialist MDT working at the regional level. The regional MDT could provide expert assessment and ensure that women are offered all available treatment options.
The committee acknowledged that membership of local and regional MDTs needs to be flexible and will vary in line with local and regional arrangements.
## How the recommendations might affect practice
The recommendations on the different levels of MDTs, their composition, and how they should work together might affect how local and regional MDTs are commissioned and how services are currently organised.
Return to recommendations
# Collecting data on surgery and surgical complications
Recommendations 1.2.1 to 1.2.4
## Why the committee made the 2019 recommendations
The committee were concerned about the lack of reliable evidence on adverse events after surgery for urinary incontinence and pelvic organ prolapse, especially those that occur 2 years or more after surgery. They were also aware of the widespread public concern about the use of synthetic mesh to treat these conditions in women. The wording of the recommendations reflects the committee's strong support for the collection of data in a national registry of surgery for urinary incontinence and pelvic organ prolapse in women.
The committee agreed that it would be helpful to provide a broad indication of the types of information that should be included in the registry, rather than specifying this in detail. The data in the registry will be analysed in the future to provide more reliable evidence than is available currently on the use of the various procedures in England and Wales and their long-term effects. This could be used to inform future guidance. The recommendations support the findings of the Mesh Oversight Group Report on reporting procedures in a national database.
The committee also agreed to highlight the importance of obtaining consent from women to include their data in the registry, and giving women a copy of their own data.
## How the recommendations might affect practice
The recommendations are likely to have an impact on healthcare professionals and providers who are not already doing this because additional time and resource will be needed to report data to the registry and because of the cost of maintaining the registry and analysing the data.
Return to recommendations
# Urodynamic testing
Recommendations 1.3.15 and 1.3.16
## Why the committee made the 2019 recommendations
The evidence did not show any benefit from urodynamic testing to assess stress urinary incontinence or stress-predominant mixed urinary incontinence in women who have demonstrable stress urinary incontinence before primary surgery. The committee concluded that urodynamic testing is not necessary for most women in this situation.
However, based on their experience the committee agreed that urodynamic testing can be beneficial if the diagnosis is unclear or if the woman has symptoms of voiding dysfunction, anterior or apical prolapse, or a history of surgery for stress urinary incontinence.
## How the recommendations might affect practice
The recommendations are likely to reduce variation in practice, which is largely caused by uncertainty about the clinical value of urodynamic testing before surgery. They are also expected to reduce the number of women having urodynamic testing before surgery, and avoid unnecessary use of a procedure that some women find unpleasant.
Return to recommendations
# Pelvic floor muscle training
Recommendation 1.4.4
## Why the committee made the 2019 recommendation
Although there was some good evidence showing that surgery is more effective than pelvic floor muscle training to manage stress urinary incontinence, the committee also took into account the risks associated with surgery and the absence of side effects from pelvic floor muscle training. They noted that the 2006 guideline committee had recommended pelvic floor muscle training, and had looked at evidence on both stress urinary incontinence and mixed urinary incontinence. The 2019 committee looked at evidence on stress urinary incontinence alone. The evidence showed that pelvic floor muscle training is just as effective as surgery for around half of women with stress urinary incontinence. The committee therefore decided to retain the 2006 recommendation for pelvic floor muscle training as a first-line treatment for stress urinary incontinence.
## How the recommendation might affect practice
The 2019 recommendation is unchanged from 2006 and so should not lead to changes in clinical practice in most services. However, there might still be services in which pelvic floor muscle training is not routinely offered, so the recommendation might lead to a change in practice in those areas.
Return to recommendations
# Absorbent containment products
Recommendations 1.4.16 to 1.4.18
## Why the committee made the 2019 recommendations
There was no evidence available on the use of absorbent containment products to manage urinary incontinence. In the committee's experience, these products are often used for long-term management, with no review of their ongoing suitability or discussion of other possible management options. The committee were particularly concerned about the effect that long-term use of these products can have on skin integrity if urine absorption is not adequate, noting that breakdown of vulval skin is uncomfortable and distressing. They agreed that a review of absorbent containment products should be done at least once a year to ensure that problems are identified more promptly and management can be tailored to women's changing clinical and lifestyle needs.
The committee noted that standard medical reviews often do not include absorbent containment product use, and therefore agreed that reviews of absorbent containment products should be conducted or overseen by a continence-trained healthcare professional. They thought this would ensure that reviews are consistent and thorough, and offer women a full range of management options, including referral to specialist services if needed.
## How the recommendations might affect practice
The recommendations will result in an increase in reviews for women using absorbent containment products. This might reduce the overall use of these products and lead to more referrals for alternative treatment. Although short‑term costs might rise, long-term costs can be expected to fall through reduction in the use of absorbent containment products.
Return to recommendations
# Medicines for overactive bladder
Recommendations 1.4.25 to 1.4.27 and 1.4.30
## Why the committee made the 2019 recommendations
The committee noted that there is very little evidence about how anticholinergic medicines prescribed for overactive bladder affect cognitive function in women. They were aware that some anticholinergic medicines have been associated with dementia and Alzheimer's disease. They also noted that large numbers of women are prescribed anticholinergic medicines, with some estimates suggesting that one‑third of women aged over 65 have some degree of incontinence. Because the long-term effects of anticholinergic medicines are uncertain, the committee stressed the importance of a full discussion with the woman, taking account of the woman's total anticholinergic load and carrying out regular reviews. They also decided to make a research recommendation on anticholinergic medicines to inform future guidance.
The effectiveness of anticholinergic and other medicines for overactive bladder was not reviewed in this guideline update.
## How the recommendations might affect practice
The recommendations might raise awareness of the potential adverse effects of anticholinergic medicines, especially on cognitive function, and result in women being able to make better informed choices about managing their overactive bladder. The recommendations should also ensure that healthcare professionals regularly review women who remain on long-term medication.
Return to recommendations
# Botulinum toxin type A injection
Recommendations 1.4.44 to 1.4.51
## Why the committee made the 2019 recommendations
The evidence on botulinum toxin type A injections for overactive bladder was limited, especially on the long-term effectiveness, dosage and frequency of injections, and the risks of adverse effects. The committee decided to make a research recommendation on the long-term effectiveness of botulinum toxin type A to inform future guidance.
The committee discussed starting doses and agreed that there was not enough evidence on the benefits and risks to recommend starting treatment with a higher dose than 100 units. The committee were aware from their own experience that there may be an increased risk of self-catheterisation with 200 units and that women usually wish to avoid this if possible. Although starting with the lower dose (100 units) may result in some women needing more injections, the committee agreed that there was not enough evidence to support starting at the higher dose.
Despite the limited evidence, the committee agreed that increasing the dose to 200 units might be effective for women who have not had a satisfactory response to 100 units. The committee also agreed that an increase in dose to 200 units should be considered for women who had a response to 100 units that lasted less than 6 months. These recommendations were based on the committee's clinical experience.
The committee discussed follow‑up in clinical practice. They noted that the 2013 guideline recommended follow‑up at 6 months, or sooner if symptoms return. However, based on their experience, the committee agreed that 6 months might be too late for some women, and recommended a telephone call or a clinic appointment within 12 weeks of their first injection.
## How the recommendations might affect practice
The recommendations are expected to reduce variation in practice by giving clear guidance on the initial dose of botulinum toxin A for treating women with idiopathic overactive bladder.
Changes in practice are unlikely because services are already in place to support botulinum toxin type A treatment. There will be a cost saving by having a starting dose of 100 units. There may also be savings because the recommendations no longer specify that women need training in self-catheterisation before treatment.
Return to recommendations
# Surgical management of stress urinary incontinence
Recommendations 1.5.1 to 1.5.18
## Why the committee made the 2019 recommendations
The evidence showed that there were no important differences in the short- and medium-term effectiveness of colposuspension, retropubic mid-urethral mesh slings and autologous rectus fascial slings, so the committee agreed that women should be offered a choice of these 3 procedures.
However, they emphasised that there is substantial uncertainty about the long-term complications associated with each procedure, and agreed that women should be made aware of this when choosing a procedure. They also made a research recommendation on the long-term risks of surgery with and without mesh to help inform future guidance.
The committee acknowledged the public concern about the risks of these procedures, especially those involving the insertion of mesh products. However, they agreed that women should not be denied effective surgical options. Instead, women should be fully informed and supported by their doctor to make the right decision about their treatment, taking into account the benefits and risks of all the options as well as any individual social or psychological factors that might affect their decision. The committee agreed that a patient decision aid could help women better understand the different surgical options and promote shared decision making.
The committee also noted variation in the amount of information and level of detail given to women before surgery and agreed that key information should be included in the recommendations, with more detailed information provided in the patient decision aid. The committee noted the importance of giving women full information about the benefits and risks of these procedures.
Evidence showed that open and laparoscopic colposuspension were equally effective procedures. Although there is a slightly increased risk of bladder injury with the laparoscopic approach, the committee thought this risk was not sufficient to exclude this option.
The committee recommended the retropubic, rather than the transobturator, route because the evidence showed that retropubic mesh slings are more likely to cure incontinence in the short term and less likely to cause complications in the medium and short term. In addition, the committee agreed that the retropubic mesh slings are easier to remove if complications do occur. However, there is evidence of a greater risk of bladder injury and need for temporary catheterisation with a retropubic procedure.
The committee agreed that porcine dermis slings should not be offered because they are less likely to result in a cure and more likely to lead to repeat surgery than a retropubic mesh sling.
The committee noted the lack of evidence on the long-term use of intramural bulking agents and uncertainty about the risks. However, in the committee's experience, some women, particularly those who are older or frail, find them beneficial. The committee agreed that intramural bulking agents should be considered if other surgery is unsuitable for, or unacceptable to, the woman. They emphasised that women who choose an intramural bulking agent should be fully advised of the risks, the lack of evidence for long-term effectiveness and adverse events, and that other surgical procedures may be more effective.
## How the recommendations might affect practice
More thorough and detailed discussion with women before they have surgery for stress urinary incontinence is likely to moderately increase the time spent in consultations.
Synthetic mesh slings, colposuspension, autologous rectus fascial slings and intramural bulking agents are offered in current practice. However, all surgical options are not available at every hospital and women may require referral to another centre (regional centre) if they choose to have a procedure that is not available locally. Regional centres may require extra resources to meet this need. There might also be an increase in the number of colposuspensions and autologous rectus fascial sling procedures carried out.
Return to recommendations
# Assessing pelvic organ prolapse
Recommendations 1.6.1 to 1.6.7
## Why the committee made the 2019 recommendations
The evidence indicated that self-reported symptoms can accurately identify pelvic organ prolapse, although the committee noted that prolapse is often an incidental finding. They agreed, based on the evidence and their clinical experience, that accurate assessment of suspected pelvic organ prolapse depends on a thorough clinical history and examination.
The committee thought that secondary care clinicians who suspect or identify vaginal prolapse could consider referral to a clinician with expertise in prolapse.
Evidence showed that the POP‑Q (Pelvic Organ Prolapse Quantification) system produces an accurate assessment of pelvic organ prolapse, and the committee agreed that it provides an objective and standardised measure that will ensure consistency of assessment.
Based on their experience, the committee agreed that it is important to assess pelvic floor muscles and vaginal atrophy, and to rule out a pelvic mass or other pathology. They also agreed that a validated pelvic floor symptom questionnaire could aid assessment.
The committee noted evidence showing that imaging does not provide any additional benefit in the assessment of vaginal prolapse diagnosed by physical examination. They agreed that imaging would delay management, and should not be routinely carried out in this situation.
Based on their experience, the committee agreed that symptoms of pelvic floor prolapse can become more prominent when the woman is straining or changes her position. They concluded that repeating the physical examination with the woman in a different position could be helpful if her symptoms are not explained by the physical examination. They also agreed, based on their experience, that other pelvic floor symptoms, including symptoms that remain unexplained after physical examination, should also be investigated.
## How the recommendations might affect practice
The recommendations reflect current good practice, so the committee agreed there should be little change in practice.
Return to recommendations
# Non-surgical management of pelvic organ prolapse
Recommendations 1.7.1 to 1.7.9
## Why the committee made the 2019 recommendations
Based on their experience, the committee agreed that there should be an initial discussion of the management options with women who have pelvic organ prolapse, including no treatment, non-surgical treatment and all surgical options.
There was no evidence available on lifestyle modification to manage pelvic organ prolapse, so the committee used their knowledge and clinical experience to make this recommendation. They thought that advice on aspects of lifestyle that directly affect the pelvic organs is most useful for women with pelvic organ prolapse. The committee agreed that obesity, heavy lifting and constipation all exacerbate the symptoms of pelvic organ prolapse by increasing intra-abdominal pressure.
There was no evidence available on topical oestrogen to manage pelvic organ prolapse. In the committee's experience, women with urogenital atrophy have more pronounced symptoms of pelvic organ prolapse. Treatment with a vaginal oestrogen reduces the effect of the atrophy and improves symptoms. The committee noted that vaginal oestrogen is available in a pessary, a cream or an oestrogen-releasing ring.
A small amount of evidence suggests that pelvic floor muscle training is beneficial for women with pelvic organ prolapse.
Limited evidence suggests that pessaries are an important alternative to surgical intervention for women with all stages of prolapse including advanced prolapse. The committee agreed that pessaries are an easily available option for women and that many women prefer them as an alternative to surgery. However, there is little evidence so the committee made a research recommendation on pessaries or surgery for pelvic organ prolapse to inform future practice.
The committee discussed the complications that can develop with pessary use and agreed that women should be advised of these, and of the importance of the pessary being removed at regular intervals. Serious complications such as pessary incarceration necessitating removal under anaesthetic, or the development of fistulae, can occur if pessaries are not changed regularly. The committee noted that women who have difficulty managing long-term pessary care because of physical or cognitive impairments are at higher risk of these complications. They therefore recommended regular appointments for these women.
## How the recommendations might affect practice
The recommendation generally reflects current practice, so the committee agreed there should be no major impact on practice.
The committee concluded that these recommendations can be expected to increase the use of vaginal oestrogen, especially in primary care, and decrease the number of referrals for specialist advice and use of other interventions.
The recommendation is current practice in some services but not all, and the committee suspects that the recommendation may result in the need for some increase in resources.
The recommendations are current practice in some services and the committee does not expect it to result in significant resource increases.
Return to recommendations
# Surgical management of pelvic organ prolapse
Recommendations 1.8.1 to 1.8.25
## Why the committee made the 2019 recommendations
The evidence on surgery for pelvic organ prolapse was limited, making it difficult for the committee to draw definite conclusions about the benefits and risks of the different types of surgery. In particular, they noted a lack of long-term evidence on the effectiveness of different types of mesh surgery. In view of this, the committee agreed that it is important to give women information on all the treatment options, including no treatment, physiotherapy, pessaries and the range of surgical options, so that they can decide which is their preferred treatment.
The committee emphasised that there is substantial uncertainty about the long-term success and complications associated with each procedure, and agreed that women should be made aware of this when choosing a procedure. They also made a research recommendation on the long-term risks of surgery with and without mesh to help inform future guidance.
The committee acknowledged the public concern about the risks of procedures involving the insertion of mesh products. However, they agreed that women should not be denied effective surgical options. Instead, they should be fully informed and supported by their doctor to make the right decision about their treatment. They agreed that a patient decision aid could help women better understand the benefits and risks of the different treatment options and promote shared decision making.
The committee agreed informed choice is of great importance in making decisions about surgery, and that a woman should be provided with information on all her potential options for management. The committee were aware that multiple factors (for example, comorbidities and lifestyle) affect the choice of treatment, many of which were not captured by the evidence, and that these should be taken into account when discussing surgery with women.
The committee also noted variation in the amount of information and level of detail given to women before surgery and agreed that key information should be included in the recommendations, with more detailed information provided in the NICE patient decision aids. The committee noted the importance of providing full information about the benefits and risks of these procedures.
The committee noted that for some women, the full extent of prolapse in all compartments can only be evaluated during surgery. Therefore it is important to discuss with women the surgical plan if prolapse is found to be more severe than anticipated from clinic examination.
The committee agreed that surgical options, including surgery that will preserve the uterus, should be discussed with the woman.
Based on their clinical experience, they agreed that women who wish to preserve their uterus should be offered a choice of 3 types of surgery. There was no evidence available that compared these 3 procedures.
For women who have no preference about preserving their uterus, the committee used their clinical experience to agree that women should be offered a choice of 4 surgical options. There was a very small amount of evidence showing that vaginal hysterectomy might be slightly better than sacrospinous hysteropexy, but there was not enough evidence to justify a preference for any of the 4 options.
The committee noted that the evidence showed no difference in cure and quality of life between sacrocolpopexy and sacrospinous fixation. Based on the evidence and their clinical experience, the committee agreed that women with vault prolapse should be offered a choice of 2 types of surgery. The committee noted that sacrocolpopexy can be performed either as open surgery or laparoscopically.
Based on their clinical experience, the committee agreed that colpocleisis should be considered a potential surgical option for managing symptoms of vault or uterine prolapse in some groups of women. There was no evidence comparing colpocleisis with other management options. However, the committee thought that colpocleisis should be considered for women who have no other surgical options or for whom the other procedures would carry a higher risk of a serious complication. They made a research recommendation on colpocleisis compared with sacrospinous fixation for pelvic organ prolapse to help inform future guidance.
The evidence suggested that mesh surgery has higher cure rates, fewer repeat surgeries for pelvic organ prolapse, and lower recurrence rates compared with anterior colporrhaphy. However, the committee were aware of the potential complications associated with mesh exposure and erosion, and that these may increase over time. This is particularly relevant for younger women having surgery, but there was no evidence specifically for these women. Based on the evidence of risks associated with mesh surgery, the committee agreed that anterior repair without mesh should be offered.
They agreed that mesh surgery could be considered, but only for recurrent prolapse in a very limited number of women for whom there is no alternative treatment. The committee noted that evidence supports the effectiveness of mesh placement for anterior prolapse. They discussed the balance between the risks associated with mesh surgery and the potential harms of no treatment, which include persistent prolapse, problems with bladder emptying, ulceration of vaginal skin, recurrent urinary tract infections, pain and discomfort, sexual dysfunction, and problems with working and social life. The committee agreed that some women with recurrent prolapse after a non-mesh repair might be prepared to accept the risks associated with mesh surgery, and that these women should have the option to make an informed choice.
There was no evidence showing that mesh surgery is better than non-mesh surgery for posterior prolapse, and mesh surgery is associated with an increased risk of complications. The committee therefore agreed that vaginal repair without mesh should be offered to women with posterior prolapse.
Based on their experience, the committee agreed that a review 6 months after any type of surgery for prolapse will help to establish the effectiveness and rate of short-term complications. In view of the concern regarding long-term complications, the committee considered that it was important that women should be referred for specialist advice if they experience recurrent symptoms or complications after 6 months.
## How the recommendations might affect practice
More thorough and detailed discussion with women before they have surgery for pelvic organ prolapse is likely to moderately increase time spent in consultations. Sacro-hysteropexy with mesh is not available at all centres so this might increase referrals between centres. However, because fewer women are choosing mesh surgery, the increase in this type of referral is likely to be negligible. Similarly, there could be a small increase in referrals for laparoscopic sacrocolpopexy and colpocleisis, but this is not expected to have a significant impact on practice.
Return to recommendations
# Surgery for women with both stress urinary incontinence and pelvic organ prolapse
Recommendations 1.9.1 and 1.9.2
## Why the committee made the 2019 recommendations
The evidence did not show any clear benefits for concurrent surgery for stress urinary incontinence and pelvic organ prolapse, but the committee agreed that it should be considered in women with anterior and/or apical prolapse and stress urinary incontinence. They agreed that women should be told about the uncertainty of the benefits and risks of concurrent surgery compared with sequential surgery, to ensure that they are equipped to make an informed decision. The committee made a research recommendation on the most effective surgical management for women with both stress urinary incontinence and pelvic organ prolapse.
## How the recommendations might affect practice
The committee expect these recommendations to reduce variations in care and improve the information women are given when choosing between sequential and concurrent surgery for stress urinary incontinence and pelvic organ prolapse.
Return to recommendations
# Assessing complications associated with mesh surgery
Recommendations 1.10.1 to 1.10.6
## Why the committee made the 2019 recommendations
The committee noted, based on their experience, that there can be delays in the diagnosis of mesh-related complications. They therefore highlighted the importance of considering mesh as a possible cause of pain, vaginal problems, or urinary or bowel problems in women who have had mesh inserted.
The committee were unable to make generalised recommendations on assessing possible mesh-related complications because of the wide variety of procedures and implanted materials used, and the many different complications that might result from these. They therefore agreed that women with suspected mesh-related complications should be referred to a specialist centre unless they have an uncomplicated, small mesh exposure that can be treated with topical oestrogen.
There was little evidence available on the use of specific investigations to assess suspected mesh-related complications, so the committee decided to outline a range of possible investigations. They also made a research recommendation on assessing complications associated with mesh surgery to inform future guidance.
## How the recommendations might affect practice
The recommendations reflect current good practice and the committee did not expect them to result in changes in practice.
Return to recommendations
# Managing complications associated with mesh surgery
Recommendations 1.11.1 to 1.11.18
## Why the committee made the 2019 recommendations
The available evidence was very limited and so the committee made recommendations based on their experience. They noted that women often have multiple complications from mesh surgery and that these complications can be long lasting. They also noted that the success of mesh removal varies widely depending on the specific mesh-related complication. In addition, some women who have complete mesh removal will have further complications and recurrence of stress urinary incontinence, pelvic organ prolapse, or both. The committee therefore agreed that healthcare professionals should have a full discussion with women who are considering having partial or complete mesh removal. They also agreed that mesh should be removed only after a review by the regional MDT.
Based on their experience, the committee agreed that topical oestrogen is only likely to be effective for small exposures of mesh and should be discussed with the woman as an option that could be tried before surgery is considered. They noted that some women who present with mesh exposure or extrusion with vaginal discharge may have a mesh infection, and imaging should be considered to assist in the diagnosis.
The committee acknowledged the impact that mesh perforation in the lower urinary tract has on women's quality of life, and agreed that women with this complication should be referred for further assessment. Similarly, women who have pain or painful sexual intercourse should be offered specialist assessment. The committee reiterated the need to tell women about the possible benefits and risks of mesh removal surgery. The committee also noted the lack of evidence in this area and made a recommendation for research on pain management after mesh surgery.
## How the recommendations might affect practice
The committee thought that these recommendations will reduce delays in treatment for mesh-related complications, although they might increase the number of referrals.
Return to recommendations# Context
Urinary incontinence is a common symptom that can affect women of all ages, with a wide range of severity and nature. Although it is rarely life-threatening, urinary incontinence can be very detrimental to the physical, psychological and social wellbeing of the women it affects. The impact on families and carers can also be profound, and the resource implications for the health service are considerable. Urinary incontinence is defined by the International Continence Society as 'the complaint of any involuntary leakage of urine'.
Urinary incontinence can be a result of functional abnormalities in the lower urinary tract or of illnesses. Stress urinary incontinence is involuntary urine leakage on effort, exertion, sneezing or coughing. Urgency urinary incontinence is involuntary urine leakage accompanied or immediately preceded by urgency (a sudden compelling desire to urinate that is difficult to delay). Mixed urinary incontinence is involuntary urine leakage associated with both urgency and exertion, effort, sneezing or coughing. Overactive bladder (OAB) is defined as urgency that occurs with or without urgency urinary incontinence and usually with frequency and nocturia. OAB that occurs with incontinence is known as 'OAB wet'. OAB that occurs without incontinence is known as 'OAB dry'. These combinations of symptoms are suggestive of the urodynamic finding of detrusor overactivity, but can be the result of other forms of urethrovesical dysfunction.
Pelvic organ prolapse is defined as symptomatic descent of 1 or more of: the anterior vaginal wall, the posterior vaginal wall, the cervix or uterus, or the apex of the vagina (vault or cuff). Symptoms include a vaginal bulge or sensation of something coming down, urinary, bowel and sexual symptoms, and pelvic and back pain. These symptoms affect women's quality of life.
The prevalence of pelvic organ prolapse is high; in primary care in the UK, 8.4% of women reported vaginal bulge or lump, and on examination prolapse is present in up to 50% of women. One in 10 women will need at least 1 surgical procedure, and the rate of re‑operation is as high as 19%. There is likely to be an increasing need for surgery for urinary incontinence and pelvic organ prolapse because of the ageing population.
The NHS England Mesh Working Group report published in December 2015 raised a number of concerns about the safety and efficacy of surgery for stress urinary incontinence and pelvic organ prolapse using mesh devices. The report made the following recommendations for NICE:
to produce a clinical guideline that describes, holistically, care for women with pelvic organ prolapse
to review the 2013 NICE guideline on urinary incontinence in women (CG171)
to review evidence on complications arising from surgery for stress urinary incontinence and pelvic organ prolapse.
NICE accepted these recommendations and has reviewed the evidence on complications arising from surgery for stress urinary incontinence and managing pelvic organ prolapse and updated this guideline.# Finding more information and resources
To find NICE guidance on related topics, including guidance in development, see the NICE topic pages on gynaecological conditions and urological conditions.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Organisation of specialist services\n\n## Local multidisciplinary teams\n\nLocal multidisciplinary teams (MDTs) for women with primary stress urinary incontinence, overactive bladder or primary prolapse should:\n\nreview the proposed treatment for all women offered invasive procedures for primary stress urinary incontinence, overactive bladder or primary prolapse\n\nreview the proposed management for women with primary stress urinary incontinence, overactive bladder or primary prolapse if input from a wider range of healthcare professionals is needed\n\nwork within an established clinical network that has access to a regional MDT. Note: In 2018, NHS England consulted on specialised gynaecology surgery and complex urogynaecology conditions service specifications.\n\nLocal MDTs for women with primary stress urinary incontinence, overactive bladder or primary prolapse should include:\n\nconsultants with expertise in managing urinary incontinence in women and/or pelvic organ prolapse\n\na urogynaecology, urology or continence specialist nurse\n\na pelvic floor specialist physiotherapistand may also include:\n\na member of the care of the elderly team\n\nan occupational therapist\n\na colorectal surgeon. \n\nMembers of the local MDT (listed in recommendation\xa01.1.2) should attend all local MDT meetings. \n\n## Regional multidisciplinary teams\n\nRegional MDTs that deal with complex pelvic floor dysfunction and mesh-related problems should review the proposed treatment for women if:\n\nthey are having repeat continence surgery\n\nthey are having repeat, same-site prolapse surgery\n\ntheir preferred treatment option is not available in the referring hospital\n\nthey have coexisting bowel problems that may need additional colorectal intervention\n\nvaginal mesh for prolapse is a treatment option for them\n\nthey have mesh complications or unexplained symptoms after mesh surgery for urinary incontinence or prolapse\n\nthey are considering surgery and may wish to have children in the future. \n\nRegional MDTs that deal with complex pelvic floor dysfunction and mesh-related problems should include:\n\na subspecialist in urogynaecology\n\na urologist with expertise in female urology\n\na urogynaecology, urology or continence specialist nurse\n\na pelvic floor specialist physiotherapist\n\na radiologist with expertise in pelvic floor imaging\n\na colorectal surgeon with expertise in pelvic floor problems\n\na pain specialist with expertise in managing pelvic painand may also include:\n\na healthcare professional trained in bowel biofeedback and trans-anal irrigation\n\na clinical psychologist\n\na member of the care of the elderly team\n\nan occupational therapist\n\na surgeon skilled at operating in the obturator region\n\na plastic surgeon. \n\nRegional MDTs that deal with complex pelvic floor dysfunction and mesh-related problems should have ready access to the following services:\n\npsychology\n\npsychosexual counselling\n\nchronic pain management\n\nbowel symptom management\n\nneurology. \n\nMembers of the regional MDT (listed in recommendation\xa01.1.5) should attend regional MDT meetings when their specific expertise is needed. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on organisation of specialist services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: effectiveness of multidisciplinary teams for the assessment and management of urinary incontinence or pelvic organ prolapse.\n\nLoading. Please wait.\n\n# Collecting data on surgery and surgical complications\n\nAsk women having surgery for stress urinary incontinence or pelvic organ prolapse, or who have experienced complications related to these types of surgery, for their consent to enter the data listed in recommendation\xa01.2.2 in a national registry. Give each woman a copy of her data. \n\nProviders must ensure that the following data are recorded in a national registry of surgery for urinary incontinence and pelvic organ prolapse in women:\n\nthe woman's NHS number\n\nhospital and consultant identifiers\n\ndate and details of the procedure\n\nfor procedures involving mesh, the mesh material, manufacturer, product unique identification code and type of sutures used\n\nfor procedures involving colposuspension, the type of sutures used\n\nfor procedures involving bulking agent, the bulking material, manufacturer and product unique identification code\n\ndate and details of any investigation for complications\n\ndate and details of any surgical or non-surgical intervention for complications. \n\nThe national registry of surgery for urinary incontinence and pelvic organ prolapse in women must ensure that follow‑up data are collected on key short- and long-term (at least 5\xa0years) outcomes, including:\n\nvalidated relevant outcome measures\n\nadverse events including pain\n\nsuspected and confirmed mesh-related complications. \n\nThe national registry of surgery for urinary incontinence and pelvic organ prolapse in women should report annually and be quality assured. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on collecting data on surgery and surgical complications\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: surgical and physical management of stress urinary incontinence and evidence review I: surgical management of pelvic organ prolapse.\n\nLoading. Please wait.\n\n# Assessing urinary incontinence\n\n## History taking and physical examination\n\nAt the initial clinical assessment, categorise the woman's urinary incontinence as stress urinary incontinence, mixed urinary incontinence or urgency urinary incontinence/overactive bladder. Start initial treatment on this basis. In mixed urinary incontinence, direct treatment towards the predominant symptom. \n\nIf stress incontinence is the predominant symptom in mixed urinary incontinence, discuss with the woman the benefit of non-surgical management and medicines for overactive bladder before offering surgery. [2013, amended 2019]\n\nDuring the clinical assessment seek to identify relevant predisposing and precipitating factors and other diagnoses that may require referral for additional investigation and treatment. \n\n## Assessing pelvic floor muscles\n\nUndertake routine digital assessment to confirm pelvic floor muscle contraction before the use of supervised pelvic floor muscle training for the treatment of urinary incontinence. [2006, amended 2013]\n\n## Urine testing\n\nUndertake a urine dipstick test in all women presenting with urinary incontinence to detect the presence of blood, glucose, protein, leucocytes and nitrites in the urine. \n\nIf women have symptoms of urinary tract infection (UTI) and their urine tests positive for both leucocytes and nitrites, send a midstream urine specimen for culture and analysis of antibiotic sensitivities. Prescribe an appropriate course of antibiotic treatment pending culture results. See the NICE guideline on urinary tract infection (lower): antimicrobial prescribing for more information. [2006, amended 2019]\n\nIf women have symptoms of UTI and their urine tests negative for either leucocytes or nitrites, send a midstream urine specimen for culture and analysis of antibiotic sensitivities. Consider the prescription of antibiotics pending culture results. \n\nIf women do not have symptoms of UTI, but their urine tests positive for both leucocytes and nitrites, do not offer antibiotics without the results of midstream urine culture. \n\nIf a woman does not have symptoms of UTI and her urine tests negative for either leucocytes or nitrites, do not send a urine sample for culture because she is unlikely to have UTI. \n\n## Assessing residual urine\n\nMeasure post-void residual volume by bladder scan or catheterisation in women with symptoms suggestive of voiding dysfunction or recurrent UTI. \n\nUse a bladder scan in preference to catheterisation on the grounds of acceptability and lower incidence of adverse events. \n\n## Symptom scoring and quality-of-life assessment\n\nUse a validated urinary incontinence-specific symptom and quality-of-life questionnaire when therapies are being evaluated. [2006, amended 2019]\n\n## Bladder diaries\n\nUse bladder diaries in the initial assessment of women with urinary incontinence or overactive bladder. Encourage women to complete a minimum of 3\xa0days of the diary covering variations in their usual activities, such as both working and leisure days. \n\n## Pad testing\n\nDo not use pad tests in the routine assessment of women with urinary incontinence. \n\n## Urodynamic testing\n\nDo not perform multichannel filling and voiding cystometry before primary surgery if stress urinary incontinence or stress-predominant mixed urinary incontinence is diagnosed based on a detailed clinical history and demonstrated stress urinary incontinence at examination. \n\nAfter undertaking a detailed clinical history and examination, perform multichannel filling and voiding cystometry before surgery for stress urinary incontinence in women who have any of the following:\n\nurge-predominant mixed urinary incontinence or urinary incontinence in which the type is unclear\n\nsymptoms suggestive of voiding dysfunction\n\nanterior or apical prolapse\n\na history of previous surgery for stress urinary incontinence. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on urodynamic testing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: urodynamic assessment prior to primary surgery for stress urinary incontinence.\n\nLoading. Please wait.\n\n## Other tests of urethral competence\n\nDo not use the Q‑tip, Bonney, Marshall and Fluid-Bridge tests in the assessment of women with urinary incontinence. \n\n## Cystoscopy\n\nDo not use cystoscopy in the initial assessment of women with urinary incontinence alone. \n\n## Imaging\n\nDo not use imaging (MRI, CT, X‑ray) for the routine assessment of women with urinary incontinence. Do not use ultrasound other than for the assessment of residual urine volume. \n\n## Indications for referral to a specialist service\n\nIn women with urinary incontinence, indications for consideration for referral to a specialist service include:\n\npersisting bladder or urethral pain\n\npalpable bladder on bimanual or abdominal examination after voiding\n\nclinically benign pelvic masses\n\nassociated faecal incontinence\n\nsuspected neurological disease\n\nsymptoms of voiding difficulty\n\nsuspected urogenital fistulae\n\nprevious continence surgery\n\nprevious pelvic cancer surgery\n\nprevious pelvic radiation therapy. \n\nFollow the recommendations on referral for urinary tract cancer in the NICE guideline on suspected cancer, for women with haematuria or recurrent or persistent unexplained UTI. [2006, amended 2019]\n\n# Non-surgical management of urinary incontinence\n\n## Lifestyle interventions\n\nRecommend a trial of caffeine reduction to women with overactive bladder. \n\nConsider advising women with urinary incontinence or overactive bladder and a high or low fluid intake to modify their fluid intake. \n\nAdvise women with urinary incontinence or overactive bladder who have a BMI greater than\xa030 to lose weight. \n\n## Physical therapies\n\nOffer a trial of supervised pelvic floor muscle training of at least 3\xa0months' duration as first-line treatment to women with stress or mixed urinary incontinence. \n\nPelvic floor muscle training programmes should comprise at least 8\xa0contractions performed 3\xa0times per day. \n\nDo not use perineometry or pelvic floor electromyography as biofeedback as a routine part of pelvic floor muscle training. \n\nContinue an exercise programme if pelvic floor muscle training is beneficial. \n\nFor a short explanation of why the committee made the 2019 recommendation and how it might affect practice, see the rationale and impact section on pelvic floor muscle training\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: lifestyle and conservative management options for pelvic organ prolapse.\n\nLoading. Please wait.\n\nDo not routinely use electrical stimulation in the treatment of women with overactive bladder. \n\nDo not routinely use electrical stimulation in combination with pelvic floor muscle training. \n\nElectrical stimulation and/or biofeedback should be considered for women who cannot actively contract pelvic floor muscles to aid motivation and adherence to therapy. \n\n## Behavioural therapies\n\nOffer bladder training lasting for a minimum of 6\xa0weeks as first-line treatment to women with urgency or mixed urinary incontinence. \n\nIf women do not achieve satisfactory benefit from bladder training programmes, the combination of an overactive bladder medicine with bladder training should be considered if frequency is a troublesome symptom. \n\n## Neurostimulation\n\nDo not offer transcutaneous sacral nerve stimulation (surface electrodes placed above the sacrum, often known as transcutaneous electrical nerve stimulation [TENS]) to treat overactive bladder in women. \n\nDo not offer transcutaneous posterior tibial nerve stimulation for overactive bladder. \n\nDo not offer percutaneous posterior tibial nerve stimulation (needles inserted close to the posterior tibial nerve) for overactive bladder unless:\n\nthere has been a local MDT review and\n\nnon-surgical management including overactive bladder medicine treatment has not worked adequately and\n\nthe woman does not want botulinum toxin type\xa0A or percutaneous sacral nerve stimulation. [2013, amended 2019]In April 2019, most botulinum toxin type\xa0A preparations were off label for this indication. Evidence was only available for the licensed botulinum toxin type\xa0A preparation (BOTOX, Allergan).\n\n## Absorbent containment products, urinals and toileting aids\n\nDo not offer absorbent containment products, hand-held urinals or toileting aids to treat urinary incontinence. Offer them only:\n\nas a coping strategy pending definitive treatment\n\nas an adjunct to ongoing therapy\n\nfor long-term management of urinary incontinence only after treatment options have been explored. \n\nOffer a review at least once a year to women who are using absorbent containment products for long-term management of urinary incontinence. The review should cover:\n\nroutine assessment of continence\n\nassessment of skin integrity\n\nchanges to symptoms, comorbidities, lifestyle, mobility, medication, BMI, and social and environmental factors\n\nthe suitability of alternative treatment options\n\nthe efficacy of the absorbent containment product the woman is currently using and the quantities used. \n\nReviews for women who are using absorbent containment products for long-term management of urinary incontinence should be carried out by either:\n\na registered healthcare professional who is trained in assessing continence and making referrals to specialist services or\n\na non-registered healthcare worker, under the supervision of a registered healthcare professional who is trained in assessing continence and making referrals to specialist services. See indications for referral to a specialist service in this guideline. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on absorbent containment products\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: treatment options for women using absorbent containment products.\n\nLoading. Please wait.\n\n## Catheters\n\nBladder catheterisation (intermittent or indwelling urethral or suprapubic) should be considered for women in whom persistent urinary retention is causing incontinence, symptomatic infections or renal dysfunction, and in whom this cannot otherwise be corrected. Healthcare professionals should be aware, and explain to women, that the use of indwelling catheters in urgency urinary incontinence may not result in continence. \n\nOffer intermittent urethral catheterisation to women with urinary retention who can be taught to self-catheterise or who have a carer who can perform the technique. \n\nGive careful consideration to the impact of long-term indwelling urethral catheterisation. Discuss the practicalities, benefits and risks with the woman or, if appropriate, her carer. Indications for the use of long-term indwelling urethral catheters for women with urinary incontinence include:\n\nchronic urinary retention in women who are unable to manage intermittent self-catheterisation\n\nskin wounds, pressure ulcers or irritations that are being contaminated by urine\n\ndistress or disruption caused by bed and clothing changes\n\nwhere a woman expresses a preference for this form of management. \n\nIndwelling suprapubic catheters should be considered as an alternative to long-term urethral catheters. Be aware, and explain to women, that they may be associated with lower rates of symptomatic UTI, 'bypassing', and urethral complications than indwelling urethral catheters. \n\n## Products to prevent leakage\n\nDo not use intravaginal and intraurethral devices for the routine management of urinary incontinence in women. Do not advise women to consider such devices other than for occasional use when necessary to prevent leakage, for example during physical exercise. \n\n## Complementary therapies\n\nDo not recommend complementary therapies for the treatment of urinary incontinence or overactive bladder. \n\n## Medicines for overactive bladder\n\nBefore starting treatment with a medicine for overactive bladder, explain to the woman:\n\nthe likelihood of the medicine being successful\n\nthe common adverse effects associated with the medicine\n\nthat some adverse effects of anticholinergic medicines, such as dry mouth and constipation, may indicate that the medicine is starting to have an effect\n\nthat she may not see substantial benefits until she has been taking the medicine for at least 4\xa0weeks and that her symptoms may continue to improve over time\n\nthat the long-term effects of anticholinergic medicines for overactive bladder on cognitive function are uncertain. \n\nWhen offering anticholinergic medicines to treat overactive bladder, take account of the woman's:\n\ncoexisting conditions (such as poor bladder emptying, cognitive impairment or dementia)\n\ncurrent use of other medicines that affect total anticholinergic load\n\nrisk of adverse effects, including cognitive impairment. \n\nFor women who have a diagnosis of dementia and for whom anticholinergic medicines are an option, follow the recommendations on medicines that may cause cognitive impairment in the NICE guideline on dementia. \n\nDo not offer women flavoxate, propantheline or imipramine to treat urinary incontinence or overactive bladder. \n\nDo not offer oxybutynin (immediate release) to older women who may be at higher risk of a sudden deterioration in their physical or mental health. [2013, amended 2019]\n\nOffer the anticholinergic medicine with the lowest acquisition cost to treat overactive bladder or mixed urinary incontinence in women. \n\nIf the first medicine for overactive bladder or mixed urinary incontinence is not effective or well-tolerated, offer another medicine with a low acquisition cost (see additional information). \n\nOffer a transdermal overactive bladder treatment to women unable to tolerate oral medicines. \n\nFor guidance on mirabegron, see the NICE technology appraisal guidance on mirabegron for treating symptoms of overactive bladder. \n\nThe use of desmopressin may be considered specifically to reduce nocturia in women with urinary incontinence or overactive bladder who find it a troublesome symptom. Use particular caution in women with cystic fibrosis and avoid in those over 65\xa0years with cardiovascular disease or hypertension. \n\nDo not use duloxetine as a first-line treatment for women with predominant stress urinary incontinence. Do not routinely offer duloxetine as a second-line treatment for women with stress urinary incontinence, although it may be offered as second-line therapy if women prefer pharmacological to surgical treatment or are not suitable for surgical treatment. If duloxetine is prescribed, counsel women about its adverse effects. For guidance on safe prescribing of antidepressants (such as duloxetine) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nDo not offer systemic hormone replacement therapy to treat urinary incontinence. \n\nOffer intravaginal oestrogens to treat overactive bladder symptoms in postmenopausal women with vaginal atrophy. \n\nOffer a face-to-face or telephone review 4\xa0weeks after starting a new medicine for overactive bladder. Ask the woman if she is satisfied with the treatment and:\n\nif improvement is optimal, continue treatment\n\nif there is no or suboptimal improvement, or intolerable adverse effects, change the dose or try an alternative medicine for overactive bladder (see the recommendations for when the first medicine is not effective and offering a transdermal patch in the section on choosing medicines), and review again 4\xa0weeks later. \n\nOffer a review before 4\xa0weeks if the adverse events of a medicine for overactive bladder are intolerable. \n\nRefer women who have tried taking medicine for overactive bladder, but for whom it has not been successful or tolerated, to secondary care to consider further treatment. \n\nOffer a further face-to-face or telephone review if a medicine for overactive bladder or urinary incontinence stops working after an initial successful 4‑week review. \n\nOffer a review in primary care to women who remain on long-term medicine for overactive bladder or urinary incontinence every 12\xa0months, or every 6\xa0months if they are aged over\xa075. [2013, amended 2019]\n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on medicines for overactive bladder\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: the risks to cognitive function for women taking anticholinergic drugs for overactive bladder.\n\nLoading. Please wait.\n\n## Invasive procedures for overactive bladder\n\nFor women with overactive bladder that has not responded to non-surgical management or treatment with medicine and who wish to discuss further treatment options:\n\noffer urodynamic investigation to determine whether detrusor overactivity is causing her overactive bladder symptoms and\n\nif detrusor overactivity is causing her overactive bladder symptoms, offer an invasive procedure in line with the recommendation on bladder wall injection in the section on botulinum toxin type\xa0A and the recommendation in the section on urinary diversionor\n\nif there is no detrusor overactivity, seek advice on further management from the local MDT in line with the recommendation on considering treatment with botulinum toxin type\xa0A in the section on botulinum toxin type\xa0A. [2013, amended 2019]\n\nSee additional information on prescribing botulinum toxin type\xa0A.\n\nAfter a local MDT review, offer bladder wall injection with botulinum toxin type\xa0A to women with overactive bladder caused by detrusor overactivity that has not responded to non-surgical management, including pharmacological treatments. \n\nConsider treatment with botulinum toxin type\xa0A after a local MDT review for women with symptoms of overactive bladder in whom urodynamic investigation has not demonstrated detrusor overactivity, if the symptoms have not responded to non-surgical management and the woman does not wish to have other invasive treatments. \n\nAfter a local MDT review, discuss the benefits and risks of treatment with botulinum toxin type\xa0A with the woman and explain:\n\nthe likelihood of complete or partial symptom relief\n\nthe process of clean intermittent catheterisation, the risks, and how long it might need to be continued\n\nthe risk of adverse effects, including an increased risk of urinary tract infection\n\nthat there is not much evidence about how long the injections work for, how well they work in the long term and their long-term risks. \n\nStart treatment with botulinum toxin type\xa0A only if the woman is willing, in the event of developing significant voiding dysfunction:\n\nto perform clean intermittent catheterisation on a regular basis for as long as needed or\n\nto accept a temporary indwelling catheter if she is unable to perform clean intermittent catheterisation. [2013, amended 2019]\n\nUse 100\xa0units as the initial dose of botulinum toxin type\xa0A to treat overactive bladder in women. \n\nOffer a face-to-face or telephone review within 12\xa0weeks of the first treatment with botulinum toxin type\xa0A to assess the response to treatment and adverse effects, and:\n\nif there is good symptom relief, tell the woman how to self-refer for prompt specialist review if symptoms return, and offer repeat treatment as necessary\n\nif there is inadequate symptom relief, consider increasing subsequent doses of botulinum toxin type\xa0A to 200\xa0units and review within 12\xa0weeks\n\nif there was no effect, discuss with the local MDT. \n\nIf symptom relief has been adequate after injection of 100\xa0units of botulinum toxin type\xa0A but has lasted for less than 6\xa0months, consider increasing subsequent doses of botulinum toxin type\xa0A to 200\xa0units and review within 12\xa0weeks. \n\nDo not offer botulinum toxin type\xa0B to women with overactive bladder. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on botulinum toxin type\xa0A injection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: management of overactive bladder.\n\nLoading. Please wait.\n\nOffer percutaneous sacral nerve stimulation to women after local or regional MDT review if their overactive bladder has not responded to non-surgical management including medicines and:\n\ntheir symptoms have not responded to botulinum toxin type\xa0A or\n\nthey are not prepared to accept the risks of needing catheterisation associated with botulinum toxin type\xa0A. [2013, amended 2019]\n\nDiscuss the long-term implications of percutaneous sacral nerve stimulation with women including:\n\nthe need for test stimulation and probability of the test's success\n\nthe risk of failure\n\nthe long-term commitment\n\nthe need for surgical revision\n\nthe adverse effects. \n\nTell women how to self-refer for prompt specialist review if symptoms return following a percutaneous sacral nerve stimulation procedure. \n\nRestrict augmentation cystoplasty for the management of idiopathic detrusor overactivity to women whose condition has not responded to non-surgical management and who are willing and able to self-catheterise. Preoperative counselling for the woman or her carer should include common and serious complications: bowel disturbance, metabolic acidosis, mucus production and/or retention in the bladder, UTI and urinary retention. Discuss the small risk of malignancy occurring in the augmented bladder. Provide life-long follow‑up. [2006, amended 2013]\n\nUrinary diversion should be considered for a woman with overactive bladder only when non-surgical management has failed, and if botulinum toxin type\xa0A, percutaneous sacral nerve stimulation and augmentation cystoplasty are not appropriate or are unacceptable to her. Provide life-long follow‑up. [2006, amended 2013]In April 2019, most botulinum toxin\xa0type A preparations were off label for this indication. Evidence was only available for the licensed botulinum toxin type\xa0A preparation (BOTOX, Allergan).\n\n# Surgical management of stress urinary incontinence\n\nThere is public concern about the use of mesh procedures. For all of the procedures recommended in this section, including mesh procedures, there is evidence of benefit but limited evidence on the long-term adverse effects. In particular, the true prevalence of long-term complications is unknown.\n\nIf a woman is thinking about a surgical procedure for stress urinary incontinence, use the NICE patient decision aid on surgery for stress urinary incontinence to promote informed preference and shared decision making. Discussion with the woman should include:\n\nthe benefits and risks of all surgical treatment options for stress urinary incontinence that NICE recommends, whether or not they are available locally\n\nthe uncertainties about the long-term adverse effects for all procedures, particularly those involving the implantation of mesh materials\n\ndifferences between procedures in the type of anaesthesia, expected length of hospital stay, surgical incisions and expected recovery period\n\nany social or psychological factors that may affect the woman's decision. [2013, amended 2019]\n\nIf non-surgical management for stress urinary incontinence has failed, and the woman wishes to think about a surgical procedure, offer her the choice of:\n\ncolposuspension (open or laparoscopic) or\n\nan autologous rectus fascial sling.Also include the option of a retropubic mid-urethral mesh sling in this choice but see the recommendations in the section on mid-urethral mesh sling procedures for additional guidance on the use of mid-urethral mesh sling procedures for stress urinary incontinence. \n\nConsider intramural bulking agents to manage stress urinary incontinence if alternative surgical procedures are not suitable for or acceptable to the woman. Explain to the woman that:\n\nthese are permanent injectable materials\n\nrepeat injections may be needed to achieve effectiveness\n\nlimited evidence suggests that they are less effective than the surgical procedures listed in recommendation\xa01.5.2 and the effects wear off over time\n\nthere is limited evidence on long-term effectiveness and adverse events. \n\nIf an intramural bulking agent is injected, give the woman written information about the bulking agent, including its name, manufacturer, date of injection, and the injecting surgeon's name and contact details. \n\nIf the woman's chosen procedure for stress urinary incontinence is not available from the consulting surgeon, refer her to an alternative surgeon. \n\nProviders must ensure that data on surgical procedures for stress urinary incontinence are recorded in a national registry, as outlined in the section on collecting data on surgery and surgical complications in this guideline. \n\n## Mid-urethral mesh sling procedures\n\nWhen offering a retropubic mid-urethral mesh sling, advise the woman that it is a permanent implant and complete removal might not be possible. \n\nIf a retropubic mid-urethral mesh sling is inserted, give the woman written information about the implant, including its name, manufacturer, date of insertion, and the implanting surgeon's name and contact details. \n\nWhen planning a retropubic mid-urethral mesh sling procedure, surgeons should:\n\nuse a device manufactured from type\xa01 macroporous polypropylene mesh\n\nconsider using a retropubic mid-urethral mesh sling coloured for high visibility, for ease of insertion and revision. [2013, amended 2019]\n\nDo not offer a transobturator approach unless there are specific clinical circumstances (for example, previous pelvic procedures) in which the retropubic approach should be avoided. \n\nDo not use the 'top‑down' retropubic mid-urethral mesh sling approach or single-incision sub-urethral short mesh sling insertion except as part of a clinical trial. \n\n## Artificial urinary sphincters\n\nDo not offer women an artificial urinary sphincter to manage stress urinary incontinence unless previous surgery has failed. [2006, amended 2019]\n\nFor women who have had an artificial urinary sphincter inserted:\n\noffer postoperative follow‑up and\n\nensure access to review if needed. [2006, amended 2019]\n\n## Procedures that should not be offered\n\nDo not offer women the following procedures to treat stress urinary incontinence:\n\nanterior colporrhaphy\n\nneedle suspension\n\nparavaginal defect repair\n\nporcine dermis sling\n\nthe Marshall–Marchetti–Krantz procedure. \n\n## Follow-up after surgery\n\nOffer a follow‑up appointment within 6\xa0months to all women who have had a surgical procedure to treat stress urinary incontinence. \n\nFor women who have had retropubic mid-urethral mesh sling surgery, the follow‑up appointment should include a vaginal examination to check for exposure or extrusion of the mesh sling. \n\nProviders should ensure that women who have had surgery for stress urinary incontinence have access to further referral if they have recurrent symptoms or suspected complications. See also assessing complications associated with mesh surgery in this guideline. \n\nFor women whose primary surgical procedure for stress urinary incontinence has failed (including women whose symptoms have returned):\n\nseek advice on assessment and management from a regional MDT that deals with complex pelvic floor dysfunction or\n\noffer the woman advice about managing urinary symptoms if she does not wish to have another surgical procedure, and explain that she can ask for a referral if she changes her mind. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on surgical management of stress urinary incontinence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: surgical and physical management of stress urinary incontinence.\n\nLoading. Please wait.\n\n# Assessing pelvic organ prolapse\n\nFor women presenting in primary care with symptoms or an incidental finding of vaginal prolapse:\n\ntake a history to include symptoms of prolapse, urinary, bowel and sexual function\n\ndo an examination to rule out a pelvic mass or other pathology and to document the presence of prolapse (see the recommendations in the NICE guideline on suspected cancer about ovarian cancer and bladder cancer)\n\ndiscuss the woman's treatment preferences with her, and refer if needed. \n\nFor women referred to secondary care for an unrelated condition who have incidental symptoms or an incidental finding of vaginal prolapse, consider referral to a clinician with expertise in prolapse. \n\nFor women who are referred for specialist evaluation of vaginal prolapse, perform an examination to:\n\nassess and record the presence and degree of prolapse of the anterior, central and posterior vaginal compartments of the pelvic floor, using the POP‑Q (Pelvic Organ Prolapse Quantification) system\n\nassess the activity of the pelvic floor muscles\n\nassess for vaginal atrophy\n\nrule out a pelvic mass or other pathology. \n\nFor women with pelvic organ prolapse, consider using a validated pelvic floor symptom questionnaire to aid assessment and decision making. \n\nDo not routinely perform imaging to document the presence of vaginal prolapse if a prolapse is detected by physical examination. \n\nIf the woman has symptoms of prolapse that are not explained by findings from a physical examination, consider repeating the examination with the woman standing or squatting, or at a different time. \n\nConsider investigating the following symptoms in women with pelvic organ prolapse:\n\nurinary symptoms that are bothersome and for which surgical intervention is an option\n\nsymptoms of obstructed defaecation or faecal incontinence (see the recommendations for baseline assessment of faecal incontinence in the NICE guideline on faecal incontinence in adults)\n\npain\n\nsymptoms that are not explained by examination findings. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessing pelvic organ prolapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: assessing pelvic organ prolapse.\n\nLoading. Please wait.\n\n# Non-surgical management of pelvic organ prolapse\n\nDiscuss management options with women who have pelvic organ prolapse, including no treatment, non-surgical treatment and surgical options, taking into account:\n\nthe woman's preferences\n\nsite of prolapse\n\nlifestyle factors\n\ncomorbidities, including cognitive or physical impairments\n\nage\n\ndesire for childbearing\n\nprevious abdominal or pelvic floor surgery\n\nbenefits and risks of individual procedures. \n\n## Lifestyle modification\n\nConsider giving advice on lifestyle to women with pelvic organ prolapse, including information on:\n\nlosing weight, if the woman has a BMI greater than 30\xa0kg/m2\n\nminimising heavy lifting\n\npreventing or treating constipation. \n\n## Topical oestrogen\n\nConsider vaginal oestrogen for women with pelvic organ prolapse and signs of vaginal atrophy. For managing urogenital atrophy, see the recommendations in managing short-term menopausal symptoms in the NICE guideline on menopause. \n\nConsider an oestrogen-releasing ring for women with pelvic organ prolapse and signs of vaginal atrophy who have cognitive or physical impairments that might make vaginal oestrogen pessaries or creams difficult to use. \n\n## Pelvic floor muscle training\n\nConsider a programme of supervised pelvic floor muscle training for at least 16\xa0weeks as a first option for women with symptomatic POP‑Q (Pelvic Organ Prolapse Quantification) stage\xa01 or stage\xa02 pelvic organ prolapse. If the programme is beneficial, advise women to continue pelvic floor muscle training afterwards. \n\n## Pessaries\n\nConsider a vaginal pessary for women with symptomatic pelvic organ prolapse, alone or in conjunction with supervised pelvic floor muscle training. \n\nRefer women who have chosen a pessary to a urogynaecology service if pessary care is not available locally. \n\nBefore starting pessary treatment:\n\nconsider treating vaginal atrophy with topical oestrogen\n\nexplain that more than 1\xa0pessary fitting may be needed to find a suitable pessary\n\ndiscuss the effect of different types of pessary on sexual intercourse\n\ndescribe complications including vaginal discharge, bleeding, difficulty removing pessary and pessary expulsion\n\nexplain that the pessary should be removed at least once every 6\xa0months to prevent serious pessary complications. \n\nOffer women using pessaries an appointment in a pessary clinic every 6\xa0months if they are at risk of complications, for example because of a physical or cognitive impairment that might make it difficult for them to manage their ongoing pessary care. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on non-surgical management of pelvic organ prolapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: lifestyle and conservative management options for pelvic organ prolapse.\n\nLoading. Please wait.\n\n# Surgical management of pelvic organ prolapse\n\nThere is public concern about the use of mesh procedures. For all of the procedures recommended in this section, including mesh procedures, there is some evidence of benefit, but limited evidence on long-term effectiveness and adverse effects. In particular, the true prevalence of long-term complications is unknown.\n\nOffer surgery for pelvic organ prolapse to women whose symptoms have not improved with or who have declined non-surgical treatment. \n\nIf a woman is thinking about a surgical procedure for pelvic organ prolapse, use a decision aid (use the NICE patient decision aids on surgery for uterine prolapse and surgery for vaginal vault prolapse where they apply) to promote informed preference and shared decision making. Discussion with the woman should include:\n\nthe different treatment options for pelvic organ prolapse, including no treatment or continued non-surgical management\n\nthe benefits and risks of each surgical procedure, including changes in urinary, bowel and sexual function\n\nthe risk of recurrent prolapse\n\nthe uncertainties about the long-term adverse effects for all procedures, particularly those involving the implantation of mesh materials\n\ndifferences between procedures in the type of anaesthesia, expected length of hospital stay, surgical incisions and expected recovery period\n\nthe role of intraoperative prolapse assessment in deciding the most appropriate surgical procedure. \n\nDo not offer surgery to prevent incontinence in women having surgery for prolapse who do not have incontinence. \n\nExplain to women considering surgery for anterior or apical prolapse who do not have incontinence that there is a risk of developing postoperative urinary incontinence and further treatment may be needed. \n\nIf the woman's chosen procedure for pelvic organ prolapse is not available from the consulting surgeon, refer her to an alternative surgeon. \n\nIf mesh is to be used in prolapse surgery:\n\nexplain to the woman about the type of mesh that will be used and whether or not it is permanent\n\nensure that details of the procedure and its subsequent short- and long-term outcomes are recorded in a national registry (see the section on collecting data on surgery and surgical complications in this guideline)\n\ngive the woman written information about the implant, including its name, manufacturer, date of insertion, and the implanting surgeon's name and contact details. \n\nProviders must ensure that data on surgical procedures for pelvic organ prolapse are recorded in a national registry, as outlined in the section on collecting data on surgery and surgical complications in this guideline. \n\n## Surgery for uterine prolapse\n\nDiscuss the options for treatment (see recommendation 1.8.2 on using a decision aid), including non-surgical options, hysterectomy and surgery that will preserve the uterus, with women who have uterine prolapse. \n\nFor women considering surgery for uterine prolapse:\n\ndiscuss the possible complications and the lack of long-term evidence on the effectiveness of the procedures\n\nuse the NICE patient decision aid on surgery for uterine prolapse to discuss the benefits and risks of treatment, including non-surgical options. \n\nFor women with uterine prolapse who have no preference about preserving their uterus, offer a choice of:\n\nvaginal hysterectomy, with or without vaginal sacrospinous fixation with sutures or\n\nvaginal sacrospinous hysteropexy with sutures or\n\nManchester repair. Also include the option of sacro-hysteropexy with mesh (abdominal or laparoscopic) in this choice but see recommendation 1.8.6 for specific guidance on the use of mesh in prolapse surgery. \n\nFor women with uterine prolapse who wish to preserve their uterus, offer a choice of:\n\nvaginal sacrospinous hysteropexy with sutures or\n\nManchester repair, unless the woman may wish to have children in the future. Also include the option of sacro-hysteropexy with mesh (abdominal or laparoscopic) in this choice but see recommendation\xa01.8.6 for specific guidance on the use of mesh in prolapse surgery. \n\nIf a synthetic polypropylene mesh is inserted, the details of the procedure and its subsequent short- and long-term outcomes must be collected in a national registry (see the section on collecting data on surgery and surgical complications in this guideline). \n\nEnsure the proposed treatment is reviewed by a regional MDT (see the recommendation on MDTs reviewing proposed treatment in the section on regional multidisciplinary teams) if the woman wishes to have children in the future. \n\n## Surgery for vault prolapse\n\nDiscuss the options for treatment (see recommendation 1.8.2 on using a decision aid), including non-surgical and surgical options, with women who have vault prolapse. \n\nFor women considering surgery for vault prolapse:\n\ndiscuss the possible complications and the lack of long-term evidence on the effectiveness of the procedures\n\nuse the NICE patient decision aid on surgery for vaginal vault prolapse to discuss the benefits and risks of treatment, including non-surgical options. \n\nOffer women with vault prolapse a choice of:\n\nvaginal sacrospinous fixation with sutures or\n\nsacrocolpopexy (abdominal or laparoscopic) with mesh. See recommendation\xa01.8.6 for specific guidance on the use of mesh in prolapse surgery. \n\nIf a synthetic polypropylene mesh is inserted, the details of the procedure and its subsequent short- and long-term outcomes must be collected in a national registry (see the section on collecting data on surgery and surgical complications in this guideline). \n\n## Colpocleisis for vault or uterine prolapse\n\nConsider colpocleisis for women with vault or uterine prolapse who do not intend to have penetrative vaginal sex and who have a physical condition that may put them at increased risk of operative and postoperative complications. \n\n## Surgery for anterior prolapse\n\nDiscuss the options for treatment (see recommendation 1.8.2 on using a decision aid), including non-surgical and surgical options, with women who have anterior prolapse. \n\nOffer anterior repair without mesh to women with anterior vaginal wall prolapse. \n\nRecommendation withdrawn in June 2019.\n\nRecommendation withdrawn in June 2019.\n\nJune 2019: Recommendations 1.8.21 and 1.8.22, which related to the use of synthetic polypropylene or biological mesh insertion for women with recurrent anterior vaginal wall prolapse, have been withdrawn. Instead, please see NICE interventional procedures guidance 599 on transvaginal mesh repair of anterior or posterior vaginal wall prolapse, which says:\n\n'1.1 Current evidence on the safety of transvaginal mesh repair of anterior or posterior vaginal wall prolapse shows there are serious but well-recognised safety concerns. Evidence of long-term efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research.\n\n'1.2 All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.\n\n'1.3 Further research should include details of patient selection, long-term outcomes including complications, type of mesh used and method of fixation, and quality of life.'\n\nThe replacement of the guideline recommendation with a cross-reference to IPG599 is to provide clarity regarding the relation of NG123 and IPG599 and to take account of a material change since publication in the availability of products CE-marked for the indication which was referred to in the guideline recommendations.\n\n## Surgery for posterior prolapse\n\nOffer posterior vaginal repair without mesh to women with a posterior vaginal wall prolapse. \n\n## Follow-up after surgery\n\nOffer women a review 6\xa0months after surgery for pelvic organ prolapse. Ensure that the review includes a vaginal examination and, if mesh was used, check for mesh exposure. \n\nProviders should ensure that women who have had surgery for pelvic organ prolapse have access to further referral if they have recurrent symptoms or suspected complications. Also see the section on assessing complications associated with mesh surgery in this guideline. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on surgical management of pelvic organ prolapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: surgical management of pelvic organ prolapse.\n\nLoading. Please wait.\n\n# Surgery for women with both stress urinary incontinence and pelvic organ prolapse\n\nConsider concurrent surgery for stress urinary incontinence and pelvic organ prolapse in women with anterior and/or apical prolapse and stress urinary incontinence. \n\nWhen considering concurrent surgery for stress urinary incontinence and pelvic organ prolapse, discuss the options for treatment (see the recommendation on using the NICE decision aid in the section on surgical management of stress incontinence and in the section on surgical management of pelvic organ prolapse) and explain to the woman:\n\nthat there is uncertainty about whether the combined procedure is effective for treating stress urinary incontinence beyond 1\xa0year, and that stress urinary incontinence might persist despite surgery\n\nthe risk of complications related to having surgery for stress urinary incontinence at the same time as prolapse surgery compared with the risk of complications related to having sequential surgery. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on surgery for women with both stress urinary incontinence and pelvic organ prolapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: surgical management of pelvic organ prolapse and stress urinary incontinence.\n\nLoading. Please wait.\n\n# Assessing complications associated with mesh surgery\n\nFor women who report new-onset symptoms after having mesh surgery for urinary incontinence or pelvic organ prolapse, evaluate whether the symptoms might be caused by a mesh-related complication. These symptoms could include:\n\npain or sensory change in the back, abdomen, vagina, pelvis, leg, groin or perineum that is:\n\n\n\neither unprovoked, or provoked by movement or sexual activity and\n\neither generalised, or in the distribution of a specific nerve, such as the obturator nerve\n\n\n\nvaginal problems including discharge, bleeding, painful sexual intercourse, or penile trauma or pain in sexual partners\n\nurinary problems including recurrent infection, incontinence, retention, or difficulty or pain during voiding\n\nbowel problems including difficulty or pain on defaecation, faecal incontinence, rectal bleeding or passage of mucus\n\nsymptoms of infection, either alone or in combination with any of the symptoms outlined above. \n\nRefer women with a suspected mesh-related complication to a urogynaecologist, urologist or colorectal surgeon for specialist assessment. \n\nFor women who are referred for specialist evaluation of a suspected mesh complication:\n\ntake a history of all past surgical procedures for prolapse or incontinence using mesh, including the dates, type of mesh and site of mesh placement and the relationship of the symptoms to the surgical procedure(s)\n\nconsider using a validated pelvic floor symptom questionnaire and a pain questionnaire to aid assessment and decision making\n\nperform a vaginal examination to:\n\n\n\nassess whether mesh is palpable, exposed or extruded\n\nlocalise pain and its anatomical relationship to mesh\n\n\n\nconsider performing a rectal examination, if indicated, to assess for the presence of mesh perforation or fistula\n\nconsider performing a neurological assessment to assess the distribution of pain, if present, sensory alteration or muscle weakness. \n\nFor women with a confirmed mesh-related complication or unexplained symptoms after a mesh procedure:\n\nrefer to a consultant at a regional centre specialising in the diagnosis and management of mesh-related complications or\n\nif the woman has a vaginal exposure of mesh that is smaller than 1\xa0cm2 and no other symptoms, follow the recommendations on discussing topical oestrogen cream treatment and a follow-up appointment for those having topical oestrogen cream in the section on managing vaginal complications. \n\nThe responsible consultant should develop an individualised investigation plan for each woman with suspected or confirmed mesh-related complications, involving other members of the regional MDT if needed, and use table\xa01 in this guideline to inform decisions on possible investigations. \n\nThe responsible consultant must ensure that details of any confirmed mesh-related complications are:\n\nrecorded in a national registry (see the section on collecting data on surgery and surgical complications in this guideline) and\n\nreported to the Medicines and Healthcare products Regulatory Agency (MHRA). \n\nInvestigation\n\nType of mesh\n\nIndications\n\nBenefits\n\nRisks\n\nExamination under anaesthesia\n\nAll types of mesh\n\nPain or suspected:\n\nvaginal or rectal exposure or extrusion\n\nsinus tract, urinary or bowel fistula\n\nAllows diagnosis when not revealed by awake examination or when an awake, examination is not tolerated\n\nAnaesthetic risk\n\nCystourethro-scopy\n\nAll types of mesh\n\nSuspected:\n\nurethral perforation\n\nbladder perforation\n\nfistula\n\ncalculus on suture or mesh material\n\nAllows diagnosis by direct visualisation\n\nAids management planning\n\nAnaesthetic risk and risk of urinary tract infection\n\nSigmoidoscopy\n\nAbdominally, laparo-scopically or vaginally placed mesh for pelvic organ prolapse\n\nSuspected bowel perforation by mesh\n\nAllows diagnosis by direct visualisation\n\nAids management planning\n\nAnaesthetic risk if carried out under anaesthesia\n\nRisk of bowel perforation\n\nLaparoscopy\n\nAbdominally or laparo-scopically placed mesh for pelvic organ prolapse\n\nPain\n\nSuspected bowel entrapment around mesh\n\nSuspected adhesions secondary to mesh placement\n\nAllows diagnosis by direct visualisation\n\nAids management planning\n\n\n\nAnaesthetic risk\n\nRisks of laparoscopy, including bowel injury\n\nMRI, protocolled and reported by a clinician with experience in interpreting mesh complications\n\nAll types of mesh\n\nSuspected mesh infection\n\nAnatomical mapping of suspected fistula\n\nAnatomical mapping and mesh localisation to guide further surgery\n\nBack pain following abdominal mesh placement with mesh attachment to sacral promontory\n\nIdentification of discitis or osteomyelitis\n\nShows implanted material and complications nearby\n\nShows location of mesh in relation to the vaginal wall and sacrum\n\nGenerally regarded as safe, with a low risk of short- and long-term harms. Risk of contrast media injection\n\nUltrasound scan (transperineal, transvaginal or translabial, or 3D), performed and reported by a clinician with experience in interpreting mesh complications\n\nVaginally placed mesh to treat incontinence\n\nPain\n\nVoiding dysfunction\n\nSuspected infection\n\nSuspected urethral mesh perforation\n\nAnatomical mapping to guide excision surgery\n\nShows implanted material and local complications\n\nIdentifies mid-urethral slings\n\nShows location of mesh in relation to the vaginal wall and urethra\n\nDiscomfort\n\nCT\n\nAll types of mesh, although CT is not commonly used to show implanted material\n\nSuspected:\n\nurinary tract injury\n\nbowel injury\n\nbowel obstruction\n\nMay be useful in assessing for urinary fistulae or bowel injury\n\nPotential radiation-related harms and risk of contrast media injection\n\nFluoroscopic studies (cystography or contrast enema). Perform with water-soluble contrast media\n\nFluoroscopic studies and CT may be used according to local preference and expertise\n\nAll types of mesh\n\nSuspected urinary or bowel fistula\n\nAids management planning\n\nPotential radiation-related harms\n\nUrinary flow studies and post-void residual volume assessment or cystometry\n\nAll types of mesh\n\nVoiding dysfunction\n\nUrinary incontinence\n\nAids management planning\n\n\n\nUrinary tract infection and radiation risks if fluoroscopy is used\n\nNeuro-physiology, including nerve conduction studies\n\nAll types of mesh\n\nSuspected nerve injury\n\nAllows diagnosis of impaired nerve function\n\nNerve conduction studies are difficult to perform and can induce more pain\n\nNote: Individualised investigation plans may include, but are not limited to, 1\xa0or more of these investigations.\n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessing complications associated with mesh surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: assessing mesh complications after pelvic floor mesh surgery.\n\nLoading. Please wait.\n\n# Managing complications associated with mesh surgery\n\n## General considerations before removing mesh\n\nIf a woman who has had a mesh procedure to treat urinary incontinence or pelvic organ prolapse is thinking about having the mesh removed, discuss the decision with her and with a regional MDT. \n\nWhen discussing surgery to remove mesh, explain to the woman that:\n\nthere is limited evidence on the benefits of partial or complete removal compared with no mesh removal\n\nsurgery to remove mesh can have significant complications including organ injury, worsening pain, and urinary, bowel and sexual dysfunction\n\nit is not certain that removing the mesh will relieve symptoms\n\nit might not be possible to remove all of the mesh\n\nremoving only part of the mesh might be just as effective at improving symptoms as removing all of it\n\nurinary incontinence or prolapse can recur after the mesh has been removed. \n\n## Managing vaginal complications\n\nDiscuss non-surgical treatment with topical oestrogen cream with women who have a single area of vaginal mesh exposure that is smaller than 1\xa0cm2. \n\nOffer a follow‑up appointment within 3\xa0months to women with vaginal mesh exposure who choose treatment with topical oestrogen cream. \n\nConsider partial or complete surgical removal of the vaginal portion of mesh for women:\n\nwho do not wish to have treatment with topical oestrogen or\n\nif the area of vaginal mesh sling exposure is 1\xa0cm2 or larger or\n\nif there is vaginal mesh extrusion or\n\nif there has been no response to non-surgical treatment after a period of 3\xa0months. \n\nOffer imaging and further treatment to women who have signs of infection in addition to vaginal mesh exposure or extrusion. \n\nDiscuss with women who have vaginal complications after mesh sling surgery for stress urinary incontinence that:\n\ncomplete removal of the vaginal portion of mesh sling is associated with a greater risk of recurrence of stress urinary incontinence than partial removal\n\npartial removal is associated with a higher rate of further mesh sling extrusion\n\ncomplete removal might not be possible. \n\nExplain to women who have vaginal complications after vaginally placed mesh for pelvic organ prolapse that:\n\ncomplete removal might not be possible\n\ncomplete removal has a higher risk of urinary tract or bowel injury than partial removal\n\nthere may be a risk of recurrent prolapse. \n\nExplain to women who have vaginal complications after abdominally placed mesh for pelvic organ prolapse that:\n\nremoval is associated with a risk of urinary tract and bowel injury\n\nthere is a risk of recurrent prolapse\n\nthey might need abdominal surgery to remove the mesh\n\ncomplete removal might not be possible. \n\nFor women who have pain or painful sexual intercourse suspected to be related to previous mesh surgery:\n\nif specialist assessment indicates a mesh-related complication, seek advice from a regional MDT\n\nif assessment and investigation do not show a mesh abnormality such as vaginal extrusion or exposure, or an infection, consider non-surgical treatments such as pain management, vaginal oestrogen, dilators, counselling (including psychosexual counselling) and physiotherapy\n\nif pain does not respond to initial management, seek advice from a regional MDT. \n\n## Managing urinary complications\n\nRefer women who have mesh perforating the lower urinary tract to a centre for mesh complications for further assessment or management. \n\nFor women with urinary symptoms after mesh surgery for stress urinary incontinence or pelvic organ prolapse who are considering mesh removal surgery, explain that:\n\nurinary symptoms might not improve and new symptoms might occur after complete or partial removal of the mesh\n\nstress urinary incontinence might recur after mesh removal, and the risk of this happening is higher with complete than with partial mesh removal\n\ncomplete removal of the mesh might not be possible\n\nfurther treatment might be needed for mesh complications, or recurrent or persistent urinary symptoms\n\nthere is a risk of adverse events such as urinary tract fistula. \n\nDiscuss division of mesh sling with women who have voiding difficulty after mesh sling surgery. \n\nRefer women considering excision of mesh sling for persistent voiding dysfunction to a centre specialising in the diagnosis and management of mesh-related complications for assessment and management. \n\nFor women considering surgery to alleviate voiding symptoms caused by mesh surgery, explain that:\n\nthe risk of recurrent stress urinary incontinence is higher after mesh excision than mesh division\n\nfurther surgery might be needed. \n\n## Managing bowel symptoms\n\nFor women who present with functional bowel disorders after mesh surgery for pelvic organ prolapse, follow the recommendations in the NICE guideline on faecal incontinence in adults for women with faecal incontinence or locally agreed protocols for women with obstructed defecation. \n\nFor women with bowel complications that are directly related to mesh placement, such as erosion, stricture or fistula, discuss treatment with a regional MDT that has expertise in complex pelvic floor dysfunction and mesh-related problems. Use this discussion to formulate an individualised treatment plan with the woman. \n\nExplain to women with bowel complications directly related to mesh placement that:\n\ncomplete removal might not be possible\n\nbowel symptoms might persist or recur after mesh removal\n\nthey might need a temporary or permanent stoma after mesh removal. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on managing complications associated with mesh surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: management of mesh complications.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines some of the terms that are used in this guideline. For other definitions, see the NICE glossary.\n\n## Anticholinergic medicine\n\nA type of medicine used to treat overactive bladder. It reduces the activity of the bladder muscle by blocking chemical messengers to the nerves that control muscle movements.\n\n## Augmentation cystoplasty\n\nA procedure to treat overactive bladder. The bladder is made larger by adding a piece of tissue from the intestines to the bladder wall.\n\n## Autologous rectus fascial sling\n\nA type of sling used to treat stress urinary incontinence. It is made out of tissue from the woman's abdomen. The sling supports the tube that carries urine out of the body (the urethra).\n\n## Botulinum toxin type\xa0A\n\nA treatment used for overactive bladder. It is injected into the wall of the bladder.\n\n## Colpocleisis\n\nAn operation to treat pelvic organ prolapse by closing the vagina.\n\n## Colposuspension\n\nA type of surgery used to treat stress urinary incontinence. The neck of the bladder is lifted up and stitched in this position.\n\n## Detrusor overactivity\n\nInvoluntary bladder contractions seen during a cystometry test. They can be the cause of overactive bladder symptoms.\n\n## Intramural bulking agents\n\nMaterials used to treat stress urinary incontinence. They are injected into the sides of the tube that carries urine out of the body (the urethra). This helps it remain closed so that urine is less likely to leak out.\n\n## Manchester repair\n\nAn operation used to treat uterine prolapse. The neck of the womb (the cervix) is shortened. It involves shortening the cervix (neck of the womb) and supporting the womb in its natural position.\n\n## Mesh procedure\n\nAn operation to insert plastic mesh to support tissues. Mesh procedures are used to treat stress urinary incontinence and pelvic organ prolapse in women.\n\n## Percutaneous sacral nerve stimulation\n\nA procedure used to treat overactive bladder. A device is implanted in the back to stimulate the nerves at the base of the spine. These nerves affect the bladder and surrounding muscles.\n\n## Percutaneous posterior tibial nerve stimulation\n\nA procedure used to treat overactive bladder. A mild electric current is passed through a fine needle to stimulate a nerve in the leg. This nerve controls bladder function.\n\n## Retropubic mid-urethral mesh sling\n\nA type of sling used to treat stress urinary incontinence. A strip of plastic is placed behind the tube that carries urine out of the body (the urethra) to support it in a sling.\n\n## Sacrocolpopexy\n\nA type of surgery used to treat vaginal vault prolapse. Plastic mesh is used to attach the vagina to a bone at the bottom of the spine.\n\n## Sacro-hysteropexy\n\nAn operation to treat uterine prolapse. Plastic mesh is used to attach the womb (the uterus) to a bone at the bottom of the spine.\n\n## Urinary diversion\n\nA type of surgery used to treat stress urinary incontinence. It causes urine to flow through an opening in the abdomen into an external bag, instead of into the bladder.\n\n## Vaginal sacrospinous fixation\n\nA type of surgery used to treat vaginal vault or uterine prolapse. The top of the vagina is stitched to a ligament in the pelvis. It is done through a cut on the inside of the vagina.\n\n## Vaginal sacrospinous hysteropexy\n\nAn operation used to treat uterine prolapse. The cervix is stitched to a ligament in the pelvis. It is done through a cut on the inside of the vagina.\n\n# Additional information\n\n## Recommendation 1.4.31\n\nThis could be any medicine with the lowest acquisition cost from any of the medicines reviewed in 2013. The evidence review considered the following medicines: darifenacin, fesoterodine, oxybutynin (immediate release), oxybutynin (extended release), oxybutynin (transdermal), oxybutynin (topical gel), propiverine, propiverine (extended release), solifenacin, tolterodine (immediate release), tolterodine (extended release), trospium and trospium (extended release). See chapter 6 of the 2013 full guideline.\n\n## Recommendations 1.4.44 to 1.4.50\n\nIn April 2019, only 1 preparation of botulinum toxin type\xa0A (BOTOX, Allergan) had a UK marketing authorisation for overactive bladder. The licensed dose was 100\xa0units.\n\nOne preparation of botulinum toxin type\xa0A (BOTOX, Allergan) had a UK marketing authorisation for use at a dose of 200\xa0units, for treating neurogenic detrusor overactivity with urinary incontinence due to subcervical spinal cord injury (traumatic or non-traumatic) or multiple sclerosis.\n\nNote that units of botulinum toxin type\xa0A are not interchangeable between preparations. If prescribing outside the marketing authorisation ('off label'), see NICE's information on prescribing medicines.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Anticholinergic medicines\n\nWhat is the effectiveness and safety of anticholinergic medicines for overactive bladder in older women? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on medicines for overactive bladder\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: the risks to cognitive function for women taking anticholinergic drugs for overactive bladder.\n\nLoading. Please wait.\n\n## Colpocleisis compared with sacrospinous fixation for pelvic organ prolapse\n\nWhat is the effectiveness of colpocleisis compared with sacrospinous fixation for pelvic organ prolapse in elderly women? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on surgical management of pelvic organ prolapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: surgical management of pelvic organ prolapse.\n\nLoading. Please wait.\n\n## Assessing complications associated with mesh surgery\n\nWhat is the effectiveness of ultrasound-guided visualisation compared with clinical assessment to identify complications after mesh surgery for stress urinary incontinence or pelvic organ prolapse in women? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on assessing complications associated with mesh surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: assessing mesh complications after pelvic floor mesh surgery.\n\nLoading. Please wait.\n\n## Pessaries or surgery for pelvic organ prolapse\n\nWhat are the long-term outcomes, including patient satisfaction, from the use of pessaries compared with surgery for pelvic organ prolapse in women? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on non-surgical management of pelvic organ prolapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: lifestyle and conservative management options for pelvic organ prolapse.\n\nLoading. Please wait.\n\n## Long-term risks of surgery with and without mesh\n\nWhat are the long-term risks of mesh surgery compared with non-mesh surgery for stress urinary incontinence and pelvic organ prolapse in women? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on surgical management of stress urinary incontinence\xa0 and surgical management of pelvic organ prolapse\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E: surgical and physical management of stress urinary incontinence\n\nevidence review\xa0I: surgical management of pelvic organ prolapse.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Long-term effectiveness of botulinum toxin type\xa0A for overactive bladder\n\nWhat is the long-term effectiveness of bladder wall injection with botulinum toxin type\xa0A for overactive bladder in women? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on botulinum toxin type\xa0A injection\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: management of overactive bladder.\n\nLoading. Please wait.\n\n## Surgery for stress urinary incontinence and pelvic organ prolapse\n\nWhat is the most effective surgical management for women with both stress urinary incontinence and pelvic organ prolapse, including the sequence of interventions? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on surgery for women with both stress urinary incontinence and pelvic organ prolapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: surgical management of pelvic organ prolapse and stress urinary incontinence.\n\nLoading. Please wait.\n\n## Pain management after mesh surgery\n\nWhat is the effectiveness of pain management for women who present with chronic pain 3\xa0months after mesh surgery for stress urinary incontinence or pelvic organ prolapse? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on managing complications associated with mesh surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: management of mesh complications.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the 2019 recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Organisation of specialist services\n\nRecommendations 1.1.1 to 1.1.7\n\n## Why the committee made the 2019 recommendations\n\nThe committee agreed, based on their experience, that women with stress urinary incontinence, overactive bladder or primary prolapse would benefit from the broad range of expertise provided by a local multidisciplinary team (MDT). They agreed that a local MDT working within a regional clinical network could refer women to other services within the network for treatments that are not available locally, thus providing a broader choice of treatments.\n\nThe committee thought that women with complications related to mesh surgery, or with complex pelvic floor problems, should have access to a specialist MDT working at the regional level. The regional MDT could provide expert assessment and ensure that women are offered all available treatment options.\n\nThe committee acknowledged that membership of local and regional MDTs needs to be flexible and will vary in line with local and regional arrangements.\n\n## How the recommendations might affect practice\n\nThe recommendations on the different levels of MDTs, their composition, and how they should work together might affect how local and regional MDTs are commissioned and how services are currently organised.\n\nReturn to recommendations\n\n# Collecting data on surgery and surgical complications\n\nRecommendations 1.2.1 to 1.2.4\n\n## Why the committee made the 2019 recommendations\n\nThe committee were concerned about the lack of reliable evidence on adverse events after surgery for urinary incontinence and pelvic organ prolapse, especially those that occur 2\xa0years or more after surgery. They were also aware of the widespread public concern about the use of synthetic mesh to treat these conditions in women. The wording of the recommendations reflects the committee's strong support for the collection of data in a national registry of surgery for urinary incontinence and pelvic organ prolapse in women.\n\nThe committee agreed that it would be helpful to provide a broad indication of the types of information that should be included in the registry, rather than specifying this in detail. The data in the registry will be analysed in the future to provide more reliable evidence than is available currently on the use of the various procedures in England and Wales and their long-term effects. This could be used to inform future guidance. The recommendations support the findings of the Mesh Oversight Group Report on reporting procedures in a national database.\n\nThe committee also agreed to highlight the importance of obtaining consent from women to include their data in the registry, and giving women a copy of their own data.\n\n## How the recommendations might affect practice\n\nThe recommendations are likely to have an impact on healthcare professionals and providers who are not already doing this because additional time and resource will be needed to report data to the registry and because of the cost of maintaining the registry and analysing the data.\n\nReturn to recommendations\n\n# Urodynamic testing\n\nRecommendations 1.3.15 and 1.3.16\n\n## Why the committee made the 2019 recommendations\n\nThe evidence did not show any benefit from urodynamic testing to assess stress urinary incontinence or stress-predominant mixed urinary incontinence in women who have demonstrable stress urinary incontinence before primary surgery. The committee concluded that urodynamic testing is not necessary for most women in this situation.\n\nHowever, based on their experience the committee agreed that urodynamic testing can be beneficial if the diagnosis is unclear or if the woman has symptoms of voiding dysfunction, anterior or apical prolapse, or a history of surgery for stress urinary incontinence.\n\n## How the recommendations might affect practice\n\nThe recommendations are likely to reduce variation in practice, which is largely caused by uncertainty about the clinical value of urodynamic testing before surgery. They are also expected to reduce the number of women having urodynamic testing before surgery, and avoid unnecessary use of a procedure that some women find unpleasant.\n\nReturn to recommendations\n\n# Pelvic floor muscle training\n\nRecommendation 1.4.4\n\n## Why the committee made the 2019 recommendation\n\nAlthough there was some good evidence showing that surgery is more effective than pelvic floor muscle training to manage stress urinary incontinence, the committee also took into account the risks associated with surgery and the absence of side effects from pelvic floor muscle training. They noted that the 2006 guideline committee had recommended pelvic floor muscle training, and had looked at evidence on both stress urinary incontinence and mixed urinary incontinence. The 2019 committee looked at evidence on stress urinary incontinence alone. The evidence showed that pelvic floor muscle training is just as effective as surgery for around half of women with stress urinary incontinence. The committee therefore decided to retain the 2006 recommendation for pelvic floor muscle training as a first-line treatment for stress urinary incontinence.\n\n## How the recommendation might affect practice\n\nThe 2019 recommendation is unchanged from 2006 and so should not lead to changes in clinical practice in most services. However, there might still be services in which pelvic floor muscle training is not routinely offered, so the recommendation might lead to a change in practice in those areas.\n\nReturn to recommendations\n\n# Absorbent containment products\n\nRecommendations 1.4.16 to 1.4.18\n\n## Why the committee made the 2019 recommendations\n\nThere was no evidence available on the use of absorbent containment products to manage urinary incontinence. In the committee's experience, these products are often used for long-term management, with no review of their ongoing suitability or discussion of other possible management options. The committee were particularly concerned about the effect that long-term use of these products can have on skin integrity if urine absorption is not adequate, noting that breakdown of vulval skin is uncomfortable and distressing. They agreed that a review of absorbent containment products should be done at least once a year to ensure that problems are identified more promptly and management can be tailored to women's changing clinical and lifestyle needs.\n\nThe committee noted that standard medical reviews often do not include absorbent containment product use, and therefore agreed that reviews of absorbent containment products should be conducted or overseen by a continence-trained healthcare professional. They thought this would ensure that reviews are consistent and thorough, and offer women a full range of management options, including referral to specialist services if needed.\n\n## How the recommendations might affect practice\n\nThe recommendations will result in an increase in reviews for women using absorbent containment products. This might reduce the overall use of these products and lead to more referrals for alternative treatment. Although short‑term costs might rise, long-term costs can be expected to fall through reduction in the use of absorbent containment products.\n\nReturn to recommendations\n\n# Medicines for overactive bladder\n\nRecommendations 1.4.25 to 1.4.27 and 1.4.30\n\n## Why the committee made the 2019 recommendations\n\nThe committee noted that there is very little evidence about how anticholinergic medicines prescribed for overactive bladder affect cognitive function in women. They were aware that some anticholinergic medicines have been associated with dementia and Alzheimer's disease. They also noted that large numbers of women are prescribed anticholinergic medicines, with some estimates suggesting that one‑third of women aged over\xa065 have some degree of incontinence. Because the long-term effects of anticholinergic medicines are uncertain, the committee stressed the importance of a full discussion with the woman, taking account of the woman's total anticholinergic load and carrying out regular reviews. They also decided to make a research recommendation on anticholinergic medicines to inform future guidance.\n\nThe effectiveness of anticholinergic and other medicines for overactive bladder was not reviewed in this guideline update.\n\n## How the recommendations might affect practice\n\nThe recommendations might raise awareness of the potential adverse effects of anticholinergic medicines, especially on cognitive function, and result in women being able to make better informed choices about managing their overactive bladder. The recommendations should also ensure that healthcare professionals regularly review women who remain on long-term medication.\n\nReturn to recommendations\n\n# Botulinum toxin type\xa0A injection\n\nRecommendations 1.4.44 to 1.4.51\n\n## Why the committee made the 2019 recommendations\n\nThe evidence on botulinum toxin type\xa0A injections for overactive bladder was limited, especially on the long-term effectiveness, dosage and frequency of injections, and the risks of adverse effects. The committee decided to make a research recommendation on the long-term effectiveness of botulinum toxin type\xa0A to inform future guidance.\n\nThe committee discussed starting doses and agreed that there was not enough evidence on the benefits and risks to recommend starting treatment with a higher dose than 100\xa0units. The committee were aware from their own experience that there may be an increased risk of self-catheterisation with 200\xa0units and that women usually wish to avoid this if possible. Although starting with the lower dose (100\xa0units) may result in some women needing more injections, the committee agreed that there was not enough evidence to support starting at the higher dose.\n\nDespite the limited evidence, the committee agreed that increasing the dose to 200\xa0units might be effective for women who have not had a satisfactory response to 100\xa0units. The committee also agreed that an increase in dose to 200\xa0units should be considered for women who had a response to 100\xa0units that lasted less than 6\xa0months. These recommendations were based on the committee's clinical experience.\n\nThe committee discussed follow‑up in clinical practice. They noted that the 2013 guideline recommended follow‑up at 6\xa0months, or sooner if symptoms return. However, based on their experience, the committee agreed that 6\xa0months might be too late for some women, and recommended a telephone call or a clinic appointment within 12\xa0weeks of their first injection.\n\n## How the recommendations might affect practice\n\nThe recommendations are expected to reduce variation in practice by giving clear guidance on the initial dose of botulinum toxin\xa0A for treating women with idiopathic overactive bladder.\n\nChanges in practice are unlikely because services are already in place to support botulinum toxin type\xa0A treatment. There will be a cost saving by having a starting dose of 100\xa0units. There may also be savings because the recommendations no longer specify that women need training in self-catheterisation before treatment.\n\nReturn to recommendations\n\n# Surgical management of stress urinary incontinence\n\nRecommendations 1.5.1 to 1.5.18\n\n## Why the committee made the 2019 recommendations\n\nThe evidence showed that there were no important differences in the short- and medium-term effectiveness of colposuspension, retropubic mid-urethral mesh slings and autologous rectus fascial slings, so the committee agreed that women should be offered a choice of these 3\xa0procedures.\n\nHowever, they emphasised that there is substantial uncertainty about the long-term complications associated with each procedure, and agreed that women should be made aware of this when choosing a procedure. They also made a research recommendation on the long-term risks of surgery with and without mesh to help inform future guidance.\n\nThe committee acknowledged the public concern about the risks of these procedures, especially those involving the insertion of mesh products. However, they agreed that women should not be denied effective surgical options. Instead, women should be fully informed and supported by their doctor to make the right decision about their treatment, taking into account the benefits and risks of all the options as well as any individual social or psychological factors that might affect their decision. The committee agreed that a patient decision aid could help women better understand the different surgical options and promote shared decision making.\n\nThe committee also noted variation in the amount of information and level of detail given to women before surgery and agreed that key information should be included in the recommendations, with more detailed information provided in the patient decision aid. The committee noted the importance of giving women full information about the benefits and risks of these procedures.\n\nEvidence showed that open and laparoscopic colposuspension were equally effective procedures. Although there is a slightly increased risk of bladder injury with the laparoscopic approach, the committee thought this risk was not sufficient to exclude this option.\n\nThe committee recommended the retropubic, rather than the transobturator, route because the evidence showed that retropubic mesh slings are more likely to cure incontinence in the short term and less likely to cause complications in the medium and short term. In addition, the committee agreed that the retropubic mesh slings are easier to remove if complications do occur. However, there is evidence of a greater risk of bladder injury and need for temporary catheterisation with a retropubic procedure.\n\nThe committee agreed that porcine dermis slings should not be offered because they are less likely to result in a cure and more likely to lead to repeat surgery than a retropubic mesh sling.\n\nThe committee noted the lack of evidence on the long-term use of intramural bulking agents and uncertainty about the risks. However, in the committee's experience, some women, particularly those who are older or frail, find them beneficial. The committee agreed that intramural bulking agents should be considered if other surgery is unsuitable for, or unacceptable to, the woman. They emphasised that women who choose an intramural bulking agent should be fully advised of the risks, the lack of evidence for long-term effectiveness and adverse events, and that other surgical procedures may be more effective.\n\n## How the recommendations might affect practice\n\nMore thorough and detailed discussion with women before they have surgery for stress urinary incontinence is likely to moderately increase the time spent in consultations.\n\nSynthetic mesh slings, colposuspension, autologous rectus fascial slings and intramural bulking agents are offered in current practice. However, all surgical options are not available at every hospital and women may require referral to another centre (regional centre) if they choose to have a procedure that is not available locally. Regional centres may require extra resources to meet this need. There might also be an increase in the number of colposuspensions and autologous rectus fascial sling procedures carried out.\n\nReturn to recommendations\n\n# Assessing pelvic organ prolapse\n\nRecommendations 1.6.1 to 1.6.7\n\n## Why the committee made the 2019 recommendations\n\nThe evidence indicated that self-reported symptoms can accurately identify pelvic organ prolapse, although the committee noted that prolapse is often an incidental finding. They agreed, based on the evidence and their clinical experience, that accurate assessment of suspected pelvic organ prolapse depends on a thorough clinical history and examination.\n\nThe committee thought that secondary care clinicians who suspect or identify vaginal prolapse could consider referral to a clinician with expertise in prolapse.\n\nEvidence showed that the POP‑Q (Pelvic Organ Prolapse Quantification) system produces an accurate assessment of pelvic organ prolapse, and the committee agreed that it provides an objective and standardised measure that will ensure consistency of assessment.\n\nBased on their experience, the committee agreed that it is important to assess pelvic floor muscles and vaginal atrophy, and to rule out a pelvic mass or other pathology. They also agreed that a validated pelvic floor symptom questionnaire could aid assessment.\n\nThe committee noted evidence showing that imaging does not provide any additional benefit in the assessment of vaginal prolapse diagnosed by physical examination. They agreed that imaging would delay management, and should not be routinely carried out in this situation.\n\nBased on their experience, the committee agreed that symptoms of pelvic floor prolapse can become more prominent when the woman is straining or changes her position. They concluded that repeating the physical examination with the woman in a different position could be helpful if her symptoms are not explained by the physical examination. They also agreed, based on their experience, that other pelvic floor symptoms, including symptoms that remain unexplained after physical examination, should also be investigated.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current good practice, so the committee agreed there should be little change in practice.\n\nReturn to recommendations\n\n# Non-surgical management of pelvic organ prolapse\n\nRecommendations 1.7.1 to 1.7.9\n\n## Why the committee made the 2019 recommendations\n\nBased on their experience, the committee agreed that there should be an initial discussion of the management options with women who have pelvic organ prolapse, including no treatment, non-surgical treatment and all surgical options.\n\nThere was no evidence available on lifestyle modification to manage pelvic organ prolapse, so the committee used their knowledge and clinical experience to make this recommendation. They thought that advice on aspects of lifestyle that directly affect the pelvic organs is most useful for women with pelvic organ prolapse. The committee agreed that obesity, heavy lifting and constipation all exacerbate the symptoms of pelvic organ prolapse by increasing intra-abdominal pressure.\n\nThere was no evidence available on topical oestrogen to manage pelvic organ prolapse. In the committee's experience, women with urogenital atrophy have more pronounced symptoms of pelvic organ prolapse. Treatment with a vaginal oestrogen reduces the effect of the atrophy and improves symptoms. The committee noted that vaginal oestrogen is available in a pessary, a cream or an oestrogen-releasing ring.\n\nA small amount of evidence suggests that pelvic floor muscle training is beneficial for women with pelvic organ prolapse.\n\nLimited evidence suggests that pessaries are an important alternative to surgical intervention for women with all stages of prolapse including advanced prolapse. The committee agreed that pessaries are an easily available option for women and that many women prefer them as an alternative to surgery. However, there is little evidence so the committee made a research recommendation on pessaries or surgery for pelvic organ prolapse to inform future practice.\n\nThe committee discussed the complications that can develop with pessary use and agreed that women should be advised of these, and of the importance of the pessary being removed at regular intervals. Serious complications such as pessary incarceration necessitating removal under anaesthetic, or the development of fistulae, can occur if pessaries are not changed regularly. The committee noted that women who have difficulty managing long-term pessary care because of physical or cognitive impairments are at higher risk of these complications. They therefore recommended regular appointments for these women.\n\n## How the recommendations might affect practice\n\nThe recommendation generally reflects current practice, so the committee agreed there should be no major impact on practice.\n\nThe committee concluded that these recommendations can be expected to increase the use of vaginal oestrogen, especially in primary care, and decrease the number of referrals for specialist advice and use of other interventions.\n\nThe recommendation is current practice in some services but not all, and the committee suspects that the recommendation may result in the need for some increase in resources.\n\nThe recommendations are current practice in some services and the committee does not expect it to result in significant resource increases.\n\nReturn to recommendations\n\n# Surgical management of pelvic organ prolapse\n\nRecommendations 1.8.1 to 1.8.25\n\n## Why the committee made the 2019 recommendations\n\nThe evidence on surgery for pelvic organ prolapse was limited, making it difficult for the committee to draw definite conclusions about the benefits and risks of the different types of surgery. In particular, they noted a lack of long-term evidence on the effectiveness of different types of mesh surgery. In view of this, the committee agreed that it is important to give women information on all the treatment options, including no treatment, physiotherapy, pessaries and the range of surgical options, so that they can decide which is their preferred treatment.\n\nThe committee emphasised that there is substantial uncertainty about the long-term success and complications associated with each procedure, and agreed that women should be made aware of this when choosing a procedure. They also made a research recommendation on the long-term risks of surgery with and without mesh to help inform future guidance.\n\nThe committee acknowledged the public concern about the risks of procedures involving the insertion of mesh products. However, they agreed that women should not be denied effective surgical options. Instead, they should be fully informed and supported by their doctor to make the right decision about their treatment. They agreed that a patient decision aid could help women better understand the benefits and risks of the different treatment options and promote shared decision making.\n\nThe committee agreed informed choice is of great importance in making decisions about surgery, and that a woman should be provided with information on all her potential options for management. The committee were aware that multiple factors (for example, comorbidities and lifestyle) affect the choice of treatment, many of which were not captured by the evidence, and that these should be taken into account when discussing surgery with women.\n\nThe committee also noted variation in the amount of information and level of detail given to women before surgery and agreed that key information should be included in the recommendations, with more detailed information provided in the NICE patient decision aids. The committee noted the importance of providing full information about the benefits and risks of these procedures.\n\nThe committee noted that for some women, the full extent of prolapse in all compartments can only be evaluated during surgery. Therefore it is important to discuss with women the surgical plan if prolapse is found to be more severe than anticipated from clinic examination.\n\nThe committee agreed that surgical options, including surgery that will preserve the uterus, should be discussed with the woman.\n\nBased on their clinical experience, they agreed that women who wish to preserve their uterus should be offered a choice of 3\xa0types of surgery. There was no evidence available that compared these 3\xa0procedures.\n\nFor women who have no preference about preserving their uterus, the committee used their clinical experience to agree that women should be offered a choice of 4\xa0surgical options. There was a very small amount of evidence showing that vaginal hysterectomy might be slightly better than sacrospinous hysteropexy, but there was not enough evidence to justify a preference for any of the 4\xa0options.\n\nThe committee noted that the evidence showed no difference in cure and quality of life between sacrocolpopexy and sacrospinous fixation. Based on the evidence and their clinical experience, the committee agreed that women with vault prolapse should be offered a choice of 2\xa0types of surgery. The committee noted that sacrocolpopexy can be performed either as open surgery or laparoscopically.\n\nBased on their clinical experience, the committee agreed that colpocleisis should be considered a potential surgical option for managing symptoms of vault or uterine prolapse in some groups of women. There was no evidence comparing colpocleisis with other management options. However, the committee thought that colpocleisis should be considered for women who have no other surgical options or for whom the other procedures would carry a higher risk of a serious complication. They made a research recommendation on colpocleisis compared with sacrospinous fixation for pelvic organ prolapse to help inform future guidance.\n\nThe evidence suggested that mesh surgery has higher cure rates, fewer repeat surgeries for pelvic organ prolapse, and lower recurrence rates compared with anterior colporrhaphy. However, the committee were aware of the potential complications associated with mesh exposure and erosion, and that these may increase over time. This is particularly relevant for younger women having surgery, but there was no evidence specifically for these women. Based on the evidence of risks associated with mesh surgery, the committee agreed that anterior repair without mesh should be offered.\n\nThey agreed that mesh surgery could be considered, but only for recurrent prolapse in a very limited number of women for whom there is no alternative treatment. The committee noted that evidence supports the effectiveness of mesh placement for anterior prolapse. They discussed the balance between the risks associated with mesh surgery and the potential harms of no treatment, which include persistent prolapse, problems with bladder emptying, ulceration of vaginal skin, recurrent urinary tract infections, pain and discomfort, sexual dysfunction, and problems with working and social life. The committee agreed that some women with recurrent prolapse after a non-mesh repair might be prepared to accept the risks associated with mesh surgery, and that these women should have the option to make an informed choice.\n\nThere was no evidence showing that mesh surgery is better than non-mesh surgery for posterior prolapse, and mesh surgery is associated with an increased risk of complications. The committee therefore agreed that vaginal repair without mesh should be offered to women with posterior prolapse.\n\nBased on their experience, the committee agreed that a review 6\xa0months after any type of surgery for prolapse will help to establish the effectiveness and rate of short-term complications. In view of the concern regarding long-term complications, the committee considered that it was important that women should be referred for specialist advice if they experience recurrent symptoms or complications after 6\xa0months.\n\n## How the recommendations might affect practice\n\nMore thorough and detailed discussion with women before they have surgery for pelvic organ prolapse is likely to moderately increase time spent in consultations. Sacro-hysteropexy with mesh is not available at all centres so this might increase referrals between centres. However, because fewer women are choosing mesh surgery, the increase in this type of referral is likely to be negligible. Similarly, there could be a small increase in referrals for laparoscopic sacrocolpopexy and colpocleisis, but this is not expected to have a significant impact on practice.\n\nReturn to recommendations\n\n# Surgery for women with both stress urinary incontinence and pelvic organ prolapse\n\nRecommendations 1.9.1 and 1.9.2\n\n## Why the committee made the 2019 recommendations\n\nThe evidence did not show any clear benefits for concurrent surgery for stress urinary incontinence and pelvic organ prolapse, but the committee agreed that it should be considered in women with anterior and/or apical prolapse and stress urinary incontinence. They agreed that women should be told about the uncertainty of the benefits and risks of concurrent surgery compared with sequential surgery, to ensure that they are equipped to make an informed decision. The committee made a research recommendation on the most effective surgical management for women with both stress urinary incontinence and pelvic organ prolapse.\n\n## How the recommendations might affect practice\n\nThe committee expect these recommendations to reduce variations in care and improve the information women are given when choosing between sequential and concurrent surgery for stress urinary incontinence and pelvic organ prolapse.\n\nReturn to recommendations\n\n# Assessing complications associated with mesh surgery\n\nRecommendations 1.10.1 to 1.10.6\n\n## Why the committee made the 2019 recommendations\n\nThe committee noted, based on their experience, that there can be delays in the diagnosis of mesh-related complications. They therefore highlighted the importance of considering mesh as a possible cause of pain, vaginal problems, or urinary or bowel problems in women who have had mesh inserted.\n\nThe committee were unable to make generalised recommendations on assessing possible mesh-related complications because of the wide variety of procedures and implanted materials used, and the many different complications that might result from these. They therefore agreed that women with suspected mesh-related complications should be referred to a specialist centre unless they have an uncomplicated, small mesh exposure that can be treated with topical oestrogen.\n\nThere was little evidence available on the use of specific investigations to assess suspected mesh-related complications, so the committee decided to outline a range of possible investigations. They also made a research recommendation on assessing complications associated with mesh surgery to inform future guidance.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current good practice and the committee did not expect them to result in changes in practice.\n\nReturn to recommendations\n\n# Managing complications associated with mesh surgery\n\nRecommendations 1.11.1 to 1.11.18\n\n## Why the committee made the 2019 recommendations\n\nThe available evidence was very limited and so the committee made recommendations based on their experience. They noted that women often have multiple complications from mesh surgery and that these complications can be long lasting. They also noted that the success of mesh removal varies widely depending on the specific mesh-related complication. In addition, some women who have complete mesh removal will have further complications and recurrence of stress urinary incontinence, pelvic organ prolapse, or both. The committee therefore agreed that healthcare professionals should have a full discussion with women who are considering having partial or complete mesh removal. They also agreed that mesh should be removed only after a review by the regional MDT.\n\nBased on their experience, the committee agreed that topical oestrogen is only likely to be effective for small exposures of mesh and should be discussed with the woman as an option that could be tried before surgery is considered. They noted that some women who present with mesh exposure or extrusion with vaginal discharge may have a mesh infection, and imaging should be considered to assist in the diagnosis.\n\nThe committee acknowledged the impact that mesh perforation in the lower urinary tract has on women's quality of life, and agreed that women with this complication should be referred for further assessment. Similarly, women who have pain or painful sexual intercourse should be offered specialist assessment. The committee reiterated the need to tell women about the possible benefits and risks of mesh removal surgery. The committee also noted the lack of evidence in this area and made a recommendation for research on pain management after mesh surgery.\n\n## How the recommendations might affect practice\n\nThe committee thought that these recommendations will reduce delays in treatment for mesh-related complications, although they might increase the number of referrals.\n\nReturn to recommendations", 'Context': "Urinary incontinence is a common symptom that can affect women of all ages, with a wide range of severity and nature. Although it is rarely life-threatening, urinary incontinence can be very detrimental to the physical, psychological and social wellbeing of the women it affects. The impact on families and carers can also be profound, and the resource implications for the health service are considerable. Urinary incontinence is defined by the International Continence Society as 'the complaint of any involuntary leakage of urine'.\n\nUrinary incontinence can be a result of functional abnormalities in the lower urinary tract or of illnesses. Stress urinary incontinence is involuntary urine leakage on effort, exertion, sneezing or coughing. Urgency urinary incontinence is involuntary urine leakage accompanied or immediately preceded by urgency (a sudden compelling desire to urinate that is difficult to delay). Mixed urinary incontinence is involuntary urine leakage associated with both urgency and exertion, effort, sneezing or coughing. Overactive bladder (OAB) is defined as urgency that occurs with or without urgency urinary incontinence and usually with frequency and nocturia. OAB that occurs with incontinence is known as 'OAB wet'. OAB that occurs without incontinence is known as 'OAB dry'. These combinations of symptoms are suggestive of the urodynamic finding of detrusor overactivity, but can be the result of other forms of urethrovesical dysfunction.\n\nPelvic organ prolapse is defined as symptomatic descent of 1\xa0or more of: the anterior vaginal wall, the posterior vaginal wall, the cervix or uterus, or the apex of the vagina (vault or cuff). Symptoms include a vaginal bulge or sensation of something coming down, urinary, bowel and sexual symptoms, and pelvic and back pain. These symptoms affect women's quality of life.\n\nThe prevalence of pelvic organ prolapse is high; in primary care in the UK, 8.4% of women reported vaginal bulge or lump, and on examination prolapse is present in up to 50% of women. One in 10\xa0women will need at least 1\xa0surgical procedure, and the rate of re‑operation is as high as\xa019%. There is likely to be an increasing need for surgery for urinary incontinence and pelvic organ prolapse because of the ageing population.\n\nThe NHS England Mesh Working Group report published in December 2015 raised a number of concerns about the safety and efficacy of surgery for stress urinary incontinence and pelvic organ prolapse using mesh devices. The report made the following recommendations for NICE:\n\nto produce a clinical guideline that describes, holistically, care for women with pelvic organ prolapse\n\nto review the 2013 NICE guideline on urinary incontinence in women (CG171)\n\nto review evidence on complications arising from surgery for stress urinary incontinence and pelvic organ prolapse.\n\nNICE accepted these recommendations and has reviewed the evidence on complications arising from surgery for stress urinary incontinence and managing pelvic organ prolapse and updated this guideline.", 'Finding more information and resources': "To find NICE guidance on related topics, including guidance in development, see the NICE topic pages on gynaecological conditions and urological conditions.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice."}
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https://www.nice.org.uk/guidance/ng123
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This guideline covers assessing and managing urinary incontinence and pelvic organ prolapse in women aged 18 and over. It also covers complications associated with mesh surgery for these conditions.
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889134c8e3d48f2387a024b4dd22cc5400621864
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nice
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Ambu aScope4 Broncho for use in unexpected difficult airways
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Ambu aScope4 Broncho for use in unexpected difficult airways
Evidence-based recommendations on Ambu aScope4 Broncho for use in unexpected difficult airways.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.
The case for adopting the Ambu aScope4 Broncho for use in people with unexpected difficult airways needing emergency intubation is supported by the evidence. This shows that the Ambu aScope4 Broncho is an acceptable alternative, where a multiple-use fibre optic endoscope is unavailable. There are also advantages during replacement of dislodged tracheostomy tubes in the intensive care setting. Making the Ambu aScope4 Broncho available for use across settings is likely to improve outcomes and patient safety.
Adoption of the Ambu aScope4 Broncho is supported by cost modelling for a range of common clinical settings in which there is no multiple-use endoscope or where existing multiple-use endoscopes are not available. These settings are: isolated units, operating theatre units, and intensive care units, where the uses include the repositioning of displaced tracheostomy tubes. Although there were some uncertainties in the cost modelling, cost savings are likely in all settings modelled. The amount saved will depend on the number of intubations performed and on the number (if any) of existing multiple-use fibre optic endoscopes in use.
The details of the cost modelling and estimated cost savings for each clinical setting are described in sections 5.16 to 5.20. Section 5.21 presents the details of the revised cost modelling. As an example of the clinical area where savings could be greatest, using the Ambu aScope4 Broncho in the intensive care setting is estimated to be cost saving (£6,632 per year) when more than 700 intubations are conducted each year, when there are 2 or fewer existing multiple-use fibre optic endoscopes, and assuming that 5% of intubations are difficult. # The technology
# Description of the technology
The Ambu aScope4 Broncho (Ambu Ltd) is a sterile, flexible, disposable device available in 3 sizes (slim, regular and large) of which the slim and regular sizes are indicated for difficulties with endotracheal intubation in patients with difficult airways. It is used to visualise the airway and then to aid in the placement of an endotracheal tube, either directly or through an intubating laryngeal mask. It is a portable device that can be used wherever a flexible fibre optic endoscope is needed for airway management. This may be in anaesthetic rooms, critical care or emergency departments or in other areas of hospitals where emergency airway management is undertaken. The Ambu aScope4 Broncho can also be used to aid percutaneous dilatational tracheostomy and to check the position and patency of airway devices such as endotracheal tubes, double lumen tubes and tracheostomy tubes. The slim version of the Ambu aScope4 Broncho can pass through an Aintree intubating catheter if one is being used.
The Ambu aScope4 Broncho system consists of 2 components – a single‑use aScope (endoscope) and an accompanying aScope monitor for displaying the images. These are supplied together. The Ambu aScope4 Broncho uses video camera technology to create the image which is displayed on the 800×480 pixel aScope monitor. The portable monitor indicates the rechargeable battery capacity (claimed minimum of 3 hours) and also has a video output to transfer images to a larger monitor or recording device. The 2 components are used together and must therefore be available in the same location for the system to be effective. The single-use endoscopes are supplied sterile and ready for use. The monitor is re-usable. During procedures, the monitor can be powered by either battery or mains and is designed to be connected to the mains to recharge at other times.
The Ambu aScope4 Broncho has a working channel of 1.2 mm to 2.6 mm diameter, depending on size, that can be used for instillation of fluids (saline and topical anaesthesia), suction and insertion of endoscopic accessories. The suction port is designed to remove secretions.
The cost of Ambu aScope4 Broncho stated in the sponsor's submission was £179 (including VAT) per single-use endoscope. The monitor had a list price of £799 but was provided to NHS organisations free of charge with 5 Ambu aScope4 Broncho devices. Each monitor has a 12-month warranty and each single-use Ambu aScope4 Broncho has a 3-year shelf life.
The claimed benefits of Ambu aScope4 Broncho in the case for adoption presented by the sponsor are:
Improved outcomes in emergencies and unexpected scenarios of difficult airway management due to the immediate availability of a sterile fibre optic endoscope that does not need calibration.
Improved safety for patients with tracheostomies due to a reduction in morbidity and mortality associated with the failure to re-establish ventilation if the tracheostomy tube is displaced in a patient with a difficult airway.
Reduced risk of cross-infection from contaminated multiple-use fibre optic endoscopes.
Reduced costs associated with an improvement in clinical outcomes in emergencies and unexpected scenarios of difficult airway management including patients with tracheostomies.
Reduced costs associated with a reduction in the incidence of cross-infection.
Reduced time and resources spent on cleaning and repair and internal transfer between hospital departments as the Ambu aScope4 Broncho is delivered sterile and ready to use.
# Current management
Placement of an endotracheal tube guided by a multiple-use fibre optic endoscope is the gold standard for managing difficult intubation. Using a fibre optic endoscope or a video scope allows visualisation of the vocal cords followed by accurate placement of an endotracheal tube.
The Difficult Airways Society guidelines (Henderson et al. 2004) outline the clinical pathway for unexpected difficult tracheal intubation during routine induction of anaesthesia in adults. The guidelines describe the initial tracheal intubation plan (Plan A) and the secondary tracheal intubation plan (Plan B). Plan A describes direct laryngoscopy as the initial standard technique for intubation. Plan B is recommended after 4 failed attempts at intubation. This involves placement of a supraglottic airway device: if that is successfully achieved and the patient can be ventilated, then ventilation may be maintained via the supraglottic airway device, or else tracheal intubation can be attempted with the aid of a multiple-use fibre optic endoscope.
Tracheostomy is a surgical procedure performed on a patient's neck to create an airway directly into the trachea. The placement of a percutaneous tracheostomy tube can be guided by a multiple-use fibre optic endoscope. Percutaneous tracheostomy has now replaced the traditional open operation and is considered standard technique in many intensive care units worldwide. The use of an endoscope during percutaneous tracheostomy enables the user to visualise the procedure from within the trachea, and so prevent the needle and dilators from penetrating the back of the trachea as well as ensuring that the tracheostomy tube is correctly placed.# Clinical evidence
# Summary of clinical evidence
Full details of all clinical outcomes considered by the Committee are available in the assessment report overview.
The key clinical outcomes presented in the decision problem for the Ambu aScope4 Broncho in patients undergoing emergency intubation with difficult airways were:
incidence of delayed or failed intubation
clinical consequences associated with delayed or failed intubation:
death
hypoxic brain injury
intensive care unit length of stay
hospital length of stay
incidence of contamination and cross-infection
device-related adverse events.
The clinical evidence for the Ambu aScope4 Broncho was based on 11 studies. These comprised 4 published and 2 unpublished randomised controlled trials and 5 published case series reports. Three of the studies evaluated the Ambu aScope4 Broncho and 8 evaluated the Ambu aScope, which is the immediate predecessor device.
## Patient-based randomised studies
In a randomised controlled trial, Kristensen (2013) compared the Ambu aScope against a multiple-use fibre optic endoscope in 60 patients with expected normal airways and expected difficult airways. All patients were successfully intubated. The median total intubation time, including the administration of local anaesthetic, was 278 seconds for the Ambu aScope and 234 seconds for the multiple-use endoscope. Although this was statistically significant in favour of the multiple-use fibre scope (p<0.03), the investigators concluded that it was not clinically important because the difference was likely to be less than the hypothesised non-inferiority margin of 120 seconds.
In a randomised controlled trial Schoettker et al. (2012) compared Ambu aScope4 Broncho against a multiple-use fibre optic endoscope in 100 patients with difficult airways (simulated by a semi-rigid cervical collar). The use of the Ambu aScope4 Broncho was associated with a longer time to intubation compared with the fibre optic endoscope (69.5 versus 49.5 seconds, mean difference of 20 seconds, p<0.05). Overall, the image quality provided by the Ambu aScope4 Broncho was lower than with the fibre optic endoscope although the quality was judged subjectively to be excellent in 24 out of 50 cases and acceptable in another 22 out of the 50 cases. Two attempts were needed in 4 out of 50 cases with the Ambu aScope4 Broncho compared against 8 out of 50 for the multiple-use fibre optic endoscopes. There was a 100% intubation success rate in less than 4 minutes for both devices.
## Manikin-based studies
Piepho et al. (2010) conducted a randomised controlled trial that compared the Ambu aScope against a multiple-use fibre optic endoscope by examining the performance of 21 anaesthetists during an easy and a difficult intubation simulation in a manikin. The mean time to intubation for difficult airways was 63 seconds with the Ambu aScope compared against 56 seconds for the comparator (mean difference 7 seconds; 95% confidence interval −11.66 to 25.66), which was statistically non-significant. In the difficult intubation scenario, the intubation success rate was lower when using the Ambu aScope compared against using the fibre optic endoscope (67% versus 81%, p=0.02), which the authors concluded was mainly caused by the low image quality. Overall the Ambu aScope scored a rating of 'satisfactory' compared against a rating of 'good' for the multiple-use fibre optic endoscope.
Vijayakumar et al. (2011) conducted a randomised controlled trial that compared the manoeuvrability and ease of use of the Ambu aScope against a multiple-use fibre optic endoscope in manikins set to simulate difficult fibre optic endoscope placement of an endotracheal tube. The mean time to task completion was 63 seconds for the Ambu aScope compared against 53 seconds for the fibre optic endoscope (p=0.08). The estimated 95% CI (1.26 to 18.74) did not overlap with a difference of more than 30 seconds between the Ambu aScope and the multiple-use fibre optic endoscope (which was considered to be a clinically important difference). The mean number of tip surface collisions was slightly higher with the Ambu aScope at 2.7 compared against the fibre optic endoscope at 2.5. The ease of use impression was rated at 65 for the Ambu aScope compared against 77 for the fibre optic endoscope (100 being extremely easy to use).
A study by Scutt et al. (2011) compared the Ambu aScope against a multiple-use fibre optic endoscope in 2 simulated settings. In the first setting, 22 participants (all who were familiar with, or skilled in, fibre optic intubation) performed paired oral and nasal fibre optic intubations in 3 different airway training manikins (a total of 264 intubations). In the second setting 21 participants intubated 1 airway trainer manikin using 3 supraglottic airway devices: classic and intubating laryngeal mask airways, and i‑gel (a total of 66 intubations). For each intubation the time to intubate was recorded from starting the endoscopy with a preloaded tracheal tube to the first lung ventilation. In both settings, time to intubation was similar between the Ambu aScope and the multiple-use fibre optic endoscope (p=0.18). Use of the Ambu aScope was associated with more reported problems than the multiple-use fibre optic endoscope (32% versus 17% respectively, p=0.04), including difficulties with manipulation, railroading tubes and picture quality. The Ambu aScope was rated a mean score of 7.7 versus 8.5 for the multiple-use endoscope (10 being the highest in terms of ease of use and image quality). In the first setting, 88% of intubations were successful on the initial attempt. In the second setting, there were 4 failures at the first intubation attempt in 126 attempts (3%).
## Small case series
Piepho et al. (2010) described a case series in which the Ambu aScope was used in 5 patients with expected and unexpected difficult airways. Typical landmarks such as the uvula, tongue, epiglottis and larynx were adequately identified in all 5 patients using the Ambu aScope. Intubations via a nasal route were performed in 3 awake patients and advancing the tracheal tube was smooth and easy in these patients. The Ambu aScope was also used in 2 patients via an oral route and in 1 of these patients, airway secretions obstructed vision on the monitor. This was resolved following suctioning and cleaning of the Ambu aScope lens using a sterile swab. Tracheal intubation was successfully achieved in all 5 patients.
In a case series of 10 patients by Pujol et al. (2010), 9 of 10 intubations with the Ambu aScope were performed and completed without incident. Intubation could not be accomplished in 1 patient. Tube insertion was considered easy in 8 patients, easy but with some manoeuvres needed in 1 patient and impossible in 1 patient. In all 10 patients, a complete view of the glottis was obtained. The image quality was considered adequate in 5 patients and poor in another 5 patients. Fogging of the lens occurred in 6 patients and was cleared easily by gently touching the airway mucosa in 4 patients and by removing the endoscope and cleaning the tip in the other 2 patients. In 2 cases there were secretions that could not be suctioned but they did not result in difficult tube insertion.
Jamadarkhana et al. (2011) described a case series of 10 patients in whom Ambu aScope4 Broncho was used to perform percutaneous dilatational tracheostomy. The average time to set up the endoscope and monitor was less than 5 minutes. The procedure time from needle puncture of the trachea to tracheostomy tube placement ranged from 5 to 10 minutes. All the anaesthetists reported easy handling and manoeuvrability because Ambu aScope4 Broncho was light-weight. They scored the clarity and quality of endoscopic view to be between 8 and 10 out of a maximum of 10. No complications were reported during use of the Ambu aScope4 Broncho.
In a case series of 10 patients needing a percutaneous tracheostomy, Perbet et al. (2011) found that 7 of the 10 operators rated the Ambu aScope 'very satisfactory', and 3 rated it as 'satisfactory' across all parameters. The presence of the screen was deemed useful in all of the cases.
Vincent et al. (2011) described a case series of 8 patients with expected difficult airways. All 8 patients were successfully intubated while awake using the Ambu aScope4 Broncho; 7 by the nasal route and 1 orally. The mean time it took to position the endoscope to visualise the carina was 254.5 seconds, with the shortest time taken being 62 seconds. The mean time for confirming the position of the tube in the trachea after visualising the carina was 51.5 seconds. Of the 8 operators, 6 reported an excellent view of anatomical landmarks, and 2 reported the view as poor, but adequate for intubating the trachea. The mean score for manoeuvrability was 6.8 (range 3–9 with 10 classed as extremely manoeuvrable) and the mean score for usefulness of the endoscope was 7.4 (3–10 with 10 classed as extremely useful).
## Unpublished patient-based study
A study by Lenhardt et al. (2011) has been published as a poster presentation but the Committee considered detailed findings presented as academic-in-confidence data. The randomised controlled trial compared the Ambu aScope against a pre-formed stylet (multiple-use fibre optic endoscope) in 140 patients with expected difficult airways. All patients were successfully intubated and no serious complications were encountered. The time to intubation was similar for the use of the Ambu aScope and a pre-formed rigid stylet (95±63 seconds versus 104±100 seconds, p=0.6). The rating for ease of use was found to be similar for the Ambu aScope and the pre-formed stylet.
## Adverse events
No adverse event reports relating to the Ambu aScope were reported in a search of the US Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. The Medicines and Healthcare products Regulatory Agency (MHRA) has not received any reports of adverse events relating to the Ambu aScope4 Broncho.
## Committee considerations
The Committee noted that the clinical evidence was from studies in manikins or patients with expected (or simulated) difficult airways. There were no controlled trials in patients with unexpected difficult airways but the Committee recognised the considerable difficulties of conducting such studies.
The Committee judged that the studies provided evidence that the Ambu aScope4 Broncho was an acceptable alternative to multiple-use fibre optic endoscopes. In addition, the Committee received expert advice that although the Ambu aScope4 Broncho has poorer image quality than standard multiple-use fibre optic endoscopes and its lens needs cleaning during use, it is an acceptable alternative in situations in which a multiple-use fibre optic endoscope is not available.
The Committee noted that in the studies in which manikins were used, the anaesthetists had previous experience of using standard multiple-use fibre optic endoscopes, but lacked experience of using the Ambu aScope. Therefore, the longer time to intubation observed for the Ambu aScope might have been influenced by the anaesthetists' lack of experience in using the device.
The Committee was mindful that potential consequences of failed intubation include severe brain injury and death. It accepted that the immediate availability of the Ambu aScope4 Broncho in situations where multiple-use fibre optic endoscopes are not available may lower the risk of these consequences occurring. The Committee noted that clinical evidence on these outcomes was not available.
The Committee considered the fact that the Ambu aScope (the predecessor of the Ambu aScope4 Broncho) was used in 8 of the 11 studies presented. It judged that the data derived from these studies were relevant and valid for this submission because the Ambu aScope4 Broncho has the same mode of action and design as the Ambu aScope, but with certain modifications which were likely to improve, rather than impair, its performance.# NHS considerations
# System impact
The sponsor claimed that using the Ambu aScope4 Broncho would lead to an improvement in clinical outcomes. This may be relevant in emergencies and unexpected scenarios of difficult airway management, including those patients with tracheostomies.
The sponsor claimed that an improvement in clinical outcomes by reducing the risk of severe brain injury and death may lead to overall costs being reduced.
The sponsor claimed that because the Ambu aScope4 Broncho is single use, there would be a decrease in costs associated with a reduction in the incidence of cross-infection.
The sponsor claimed that using the Ambu aScope4 Broncho would reduce the time and resources spent on cleaning and repair of multiple-use fibre optic endoscopes, and on their internal transfer between hospital departments, because the Ambu aScope4 Broncho is delivered sterile and ready to use.
## Committee considerations
The Committee noted that multiple-use fibre optic endoscopes may be located on a different floor or in a different building to that in which emergency airway management is needed. Therefore, it may not be possible to obtain a fibre optic endoscope in time to use it in an emergency. The Committee considered that the main potential benefit of the Ambu aScope4 Broncho was its immediate availability for use in locations remote from fibre optic endoscopes. The Committee noted that the Ambu aScope4 Broncho may therefore be of particular value in a variety of clinical settings such as accident and emergency departments, isolated units within large hospitals and remote hospitals that have no fibre optic endoscopes.
The Committee received expert advice that multiple-use fibre optic endoscopes are often damaged in the intensive care unit when they are being used during percutaneous tracheostomy; costly repair or even replacement is then necessary. Use of the Ambu aScope4 Broncho has advantages in this scenario because the scopes are single use and damage to them is therefore of significantly less consequence.
The Committee received expert advice that in clinical settings where difficult intubations may be encountered but multiple-use fibre optic endoscopes are not available, a delay in accessing a fibre optic endoscope may have important clinical consequences including brain injury or death. The Committee noted that no published evidence or clinical studies had been submitted to support this.
The Committee considered that using the Ambu aScope4 Broncho in the clinical settings described in 4.7 could lead to an improvement in clinical outcomes but it noted that no evidence had been submitted that overall costs would be reduced.
The Committee noted that no evidence was presented to support the claim that there would be a decrease in costs associated with a reduction in the incidence of cross-infection.
The Committee acknowledged the possibility that using the Ambu aScope4 Broncho would reduce the time and resources spent on cleaning and repair of multiple-use fibre optic endoscopes, but limited evidence was submitted to support this claim.# Cost considerations
# Cost evidence
## Published evidence
The sponsor identified 3 published economic studies that focused on estimating the cost of the Ambu aScope or the multiple-use fibre optic endoscope. No modelling of the cost consequences of adoption was included in the studies.
## Sponsor cost model
The sponsor submitted a de novo cost analysis for Ambu aScope4 Broncho that estimated the costs and consequences associated with the use of the Ambu aScope4 Broncho and multiple-use fibre optic endoscopes. The analysis was from an NHS and personal social services perspective. Full details of all cost evidence and modelling considered by the Committee are available in the assessment report overview.
The sponsor submitted a base-case analysis for 3 scenarios: unexpected difficult intubation in the operating theatre units, unexpected difficult intubation in the intensive care unit, and replacing a dislodged tracheostomy tube in the intensive care unit. The model for unexpected difficult airways needing emergency intubation separated patients according to those who had successful intubations and those who had delayed or failed intubations; the latter group were separated further according to those who survived and had no brain injury, and those with brain injury or who died. A separate model was designed for replacing dislodged tracheostomy tubes because this is not managed in the same way as an intubation and is associated with different costs and outcomes. The model for dislodged tracheostomy tubes separated patients into those who were successfully managed, those who had extended intensive care unit stay and those with brain injury or who died. The analysis reported the costs associated with equipment and clinical outcomes, which were delayed or failed intubation and the replacement of dislodged tracheostomy tubes.
The sponsor's base-case analysis included several key assumptions:
The number of procedures performed per year with multiple-use fibre optic endoscopes was 150.
The number of multiple-use endoscopes available was 5.
The multiple-use fibre optic endoscope cost (including weighted costs including stack systems, cameras and so on) was £12,105.
The Ambu aScope4 Broncho cost per endoscope with monitor was £179 (including VAT).
The rate of intensive care unit admission or prolongation of stay was 74% for people who have had a failed intubation and 75% for people who have had a dislodged tracheostomy tube replaced.
The cost of the intensive care unit per day was £1,321.
The model for unexpected difficult intubations had the following assumptions:
The rate of delayed or failed intubation when using multiple-use fibre optic endoscopes in the operating theatre units was 6.25%.
The rate of delayed or failed intubation when using multiple-use fibre optic endoscopes in the intensive care unit was 16.6%.
The average intensive care unit length of stay was 6.2 days.
The rate of brain injury or death in patients who had difficult intubations and in whom intubation has failed was 28%.
The reduction in risk of delayed or failed intubation leading to patient harm with the Ambu aScope4 Broncho was 10%.
The model for dislodged tracheostomies had the following assumptions:
The rate of brain injury or death because of dislodged tracheostomy was 13%.
The average intensive care unit length of stay was 15.4 days.
The reduction in risk of dislodged tracheostomy leading to patient harm with Ambu aScope4 Broncho was 10%.
The sponsor's base-case analysis estimated the incremental cost saving of the Ambu aScope4 Broncho compared against multiple-use fibre optic endoscopes to be £30 per intubation for equipment and staff costs only. This was consistent across the 3 settings. If the Ambu aScope4 Broncho was used instead of a multiple-use endoscope and if the equipment and staff costs and the modelled costs associated with hospitalisations were included, then:
for unexpected and difficult intubation in the operating theatre units there are potential incremental cost savings of £68 per patient
for unexpected difficult airways in the intensive care unit there are potential incremental cost savings of £130.70 per patient
for dislodged tracheostomy there are potential incremental cost savings of £1,555.80 per patient.
A deterministic sensitivity analysis explored parameter uncertainty and the effect of these changes on the cost of the Ambu aScope4 Broncho. The parameters included the failure rate of intubation, the reduced risk rates of failed intubation with the Ambu aScope4 Broncho, the length of hospitalisation and the costs associated with multiple-use fibre optic endoscopes. The sensitivity analysis showed that the findings were responsive to the parameter changes in all 3 clinical settings. The Ambu aScope4 Broncho remained cost saving in most scenarios, with the exceptions being long equipment lifetime or a substantially low equipment cost for the multiple-use fibre optic endoscope
The External Assessment Centre carried out additional analyses to examine the impact of changing the following parameters of the sponsor's base case:
Rate of delayed intubation in patients with unexpected difficult intubations in the operating theatre units and intensive care units for multiple-use fibre optic endoscopes (10%).
Rate of harm needing extended hospital stay in patients with difficult intubations when intubation was delayed (50%).
The External Assessment Centre's base-case analysis in unexpected difficult intubation in an operating theatre unit indicated a cost saving of £401 when using the Ambu aScope4 Broncho. In unexpected difficult intubation in an intensive care unit, the mean cost per patient when using the Ambu aScope4 Broncho was £1,185 and the mean cost of a multiple-use fibre optic endoscope was £1,524. This indicates a cost saving of £339 when using an Ambu aScope4 Broncho in this scenario. The External Assessment Centre stated that the results were based on clinical expert opinion and the sponsor's assumptions, and the model was subject to uncertainty. After reviewing the sponsor's de novo model (see section 5.21), the Committee asked for further information on the cost consequences using a different model structure, assumptions and parameters.
## External Assessment Centre cost model
The sponsor's de novo cost analysis modelled a scenario in which multiple-use fibre optic endoscopes were completely replaced by the Ambu aScope4 Broncho. It did not consider the cost consequences of using the Ambu aScope4 Broncho if both multiple-use fibre optic endoscopes and the Ambu aScope4 Broncho were available. The External Assessment Centre was therefore asked to carry out additional analyses to estimate any potential cost savings of purchasing the Ambu aScope4 Broncho in different settings:
in small hospital units that do not have access to any multiple-use fibre optic endoscopes for unexpected difficult airway management
in addition to the existing stock of multiple-use fibre optic endoscopes in operating theatre units and intensive care units for unexpected difficult intubations and displaced tracheostomy tubes.
The External Assessment Centre modelled costs in 5 clinical settings:
an isolated hospital unit
an obstetric unit
an operating theatre unit
an intensive care unit
displaced tracheostomy tubes (in an intensive care unit). All of the above settings are of indeterminate size. For example, an operating theatre unit is likely to consist of more than 1 operating theatre but the modelling is based on the number of intubations within each unit rather than of the size of the unit. A displaced tracheostomy tube is not a clinical setting and is not specific to an intensive care unit but for the purposes of the cost modelling this procedure has been classed as a clinical setting.Potential cost savings were considered from purchasing:
-r more Ambu aScope4 Broncho devices for use in managing unexpected difficult intubation in a specified clinical setting with no multiple-use fibre optic endoscopes available
-r more Ambu aScope4 Broncho devices for use in managing unexpected difficult intubation in a specified clinical setting with 1 or more multiple-use fibre optic endoscopes available
-r more Ambu aScope4 Broncho devices for use in managing displaced tracheostomy tubes in an intensive care unit with 1 or more multiple-use fibre optic endoscopes, but where none of these endoscopes may be immediately available.
The economic model was used to evaluate the cost savings of purchasing the Ambu aScope4 Broncho for hospital units that do not have access to multiple-use fibre optic endoscopes. In these hospital units, it was assumed that, if an Ambu aScope4 Broncho was available, it would be used if and only if an unexpected difficult intubation occurred. Unexpected difficult intubations were therefore the entry point into the decision tree. The model was also used to evaluate purchasing the Ambu aScope4 Broncho as an addition for those hospital units that do have access to multiple-use endoscopes. These hospital units are likely to have a high throughput of patients needing intubation (for example, a busy operating theatre) and/or a high probability of expected difficult intubations. For modelling purposes, the number of multiple-use endoscopes was considered fixed for each clinical setting to allow the model to focus on the benefit of purchasing Ambu aScope4 Bronchos as an addition to existing multiple-use endoscopes. The number of unexpectedly difficult intubations arising for which there was no multiple-use endoscope available was modelled as a function of the number of multiple-use endoscopes, numbers of intubations carried out in the unit, and multiple-use endoscope non-availability (which was modelled using a queuing simulation). Difficult intubation events occurred at random intervals according to a Poisson process.
There were uncertainties in several parameters used in the cost modelling, often caused by there being limited or no clinical data to support the assumptions. Cost savings were considered likely in all the clinical settings that were modelled, but these depended on the number of intubations performed and on the number (if any) of existing multiple-use fibre optic endoscopes.
The base-case analysis of all of the clinical settings showed that the potential cost savings from purchasing the Ambu aScope4 Broncho came from using it when multiple-use fibre optic endoscopes were not available, therefore avoiding the consequences of failed intubation such as severe brain injury. It was assumed that an unexpected difficult intubation arises on average 6 times per 1,000 intubations.
The base-case analysis of using the Ambu aScope4 Broncho in an isolated hospital unit assumed 300 intubations per year and that no multiple-use fibre optic endoscopes were available. The cost saving per year was £749 per unit if the cost of the monitor was excluded and £653 if it was included. The number of intubations per year above which purchasing a bundle of 5 Ambu aScope4 Bronchos was cost saving was 95 if the monitor was excluded and 115 if the monitor was included.
Two base-case analyses were performed for using the Ambu aScope4 Broncho in an obstetrics unit: one assumed 400 intubations per year and no multiple-use fibre optic endoscopes, and the second analysis assumed 400 intubations per year and 1 multiple-use endoscope. If there were no multiple-use endoscopes, the cost saving per annum was £1,452 if the cost of the monitor was excluded and £1,356 if it was included. If there were no multiple-use endoscopes, the number of intubations per year above which purchasing a bundle of 5 Ambu aScope4 Bronchos was cost saving was 80. If a multiple-use endoscope was available then the Ambu aScope4 Broncho was estimated to be cost incurring unless a minimum of 500 intubations per year were done in the unit.
The base-case analysis for using the Ambu aScope4 Broncho in operating theatre units assumed that there were 2 multiple-use fibre optic endoscopes and that 1,000 intubations per year were conducted. Based on this, the Ambu aScope4 Broncho was considered to be cost incurring by £203 per unit per year if the cost of the monitor was excluded and £299 if it was included. The number of intubations per year above which purchasing a bundle of 5 Ambu aScope4 Bronchos was cost saving was 1,250 if the monitor was excluded and 1,350 if the monitor was included.
The base-case analysis for using the Ambu aScope4 Broncho in intensive care units assumed that there were 2 multiple-use fibre optic endoscopes and 700 intubations per year. Two assumptions considering the probability of difficult intubation were presented: 20% and 5%. If the probability of difficult intubation was 20%, the cost saving per year was £3,219 if the cost of the monitor was excluded and £3,123 if it was included. If the probability of difficult intubation was 5%, the cost saving per year was £3,128 if the cost of the monitor was excluded and £3,031 if it was included. The number of intubations per year above which purchasing a bundle of 5 Ambu aScope4 Bronchos was cost saving was 50–100 with 20% probability and 250–300 with 5% probability.
The base-case analysis for using the Ambu aScope4 Broncho to aid the replacement of displaced tracheostomy tubes assumed a displacement rate of 15% per year for an intensive care unit with 2 multiple-use fibre optic endoscopes. For a base case of 200 tracheostomies per year, the cost saving per year was £5,281 per unit if the cost of the monitor was excluded and £5,185 if it was included. The number of tracheostomies per year above which purchasing a bundle of 5 Ambu aScope4 Bronchos was cost saving was 70.
## Committee considerations
The Committee considered the sponsor's economic analysis in which the Ambu aScope4 Broncho completely replaced multiple-use fibre optic endoscopes in operating theatre units and intensive care units. It noted that the sponsor's model did not consider the cost consequences of using the Ambu aScope4 Broncho if both the multiple-use endoscopes and the Ambu aScope4 Broncho are available. The Committee received advice from several clinical experts that a multiple-use endoscope would, where available, be preferred by clinicians, and concluded that the sponsor's model was not realistic. The Committee also considered that there were too many uncertainties in the sponsor's economic model to use the outcomes as the basis to make recommendations.
The Committee requested further modelling, which was carried out by the External Assessment Centre, to establish any potential cost savings of purchasing the Ambu aScope4 Broncho in 5 clinical settings. This modelling considered the cost consequences for 2 scenarios: using the Ambu aScope4 Broncho where multiple-use endoscopes are not available for use in a clinical setting; and using the Ambu aScope4 Broncho where multiple-use endoscopes are normally available in a clinical setting but for some reason are inaccessible. The Committee judged that if the Ambu aScope4 Broncho was available for use, there are likely to be cost savings in all the settings modelled, based on the following assumptions about the number of intubations or tracheostomies performed each year:
Isolated hospital unit with no multiple-use endoscopes: 95 intubations.
Obstetrics unit with no multiple-use endoscopes: 80 intubations.
Obstetrics unit with 1 multiple-use endoscope: 500 intubations.
Operating theatre unit with 2 multiple-use endoscopes: 1,250 intubations.
Intensive care units with 2 multiple-use endoscopes: 50 intubations (20% difficult intubation probability) and 250 intubations (5% difficult intubation probability).
Replacement of displaced tracheostomy tubes (assuming a 15% per year displacement rate) in an intensive care unit with 2 multiple-use endoscopes: 70 tracheostomies.
The Committee noted that the analyses showed specific advantages for the Ambu aScope4 Broncho in the replacement of displaced tracheostomy tubes (see section 4.6). The Committee accepted expert advice that multiple-use fibre optic endoscopes are often damaged in the intensive care unit when they are used during tracheostomy replacement. The modelling assumed that there were 2 existing multiple-use endoscopes and that the Ambu aScope4 Broncho is used when a multiple-use endoscope is unavailable. Combining the described advantages with its other use in intensive care units, the Committee judged that the Ambu aScope4 Broncho has the potential for most cost savings in intensive care units.
The Committee recognised uncertainties in a number of the parameters in the External Assessment Centre's economic model. The Committee noted that adverse events are rare but that some of these events, such as hypoxic brain damage, may result in considerable costs. It accepted that the cost modelling provided by the External Assessment Centre took account of this. The cost modelling was based on overall risks in the NHS and it should be noted that cost consequences may vary between units.
The Committee noted that the External Assessment Centre's economic model was based on assumptions of a certain number of intubations per year. It recognised that most hospitals in England have been designed with several operating theatres adjacent to each other (that is, operating theatre units) with shared availability of multiple-use fibre optic endoscopes. The numbers of intubations performed annually in these operating theatre units typically far exceeds the threshold number determined from the cost modelling. The Committee therefore considered that, when this is the case, the cost savings will be greater than those estimated.
The Committee was also advised that in certain situations in which a multiple-use fibre optic endoscope is not available, planned operations may be cancelled. This can result in unused operating theatre unit time, and increased length of stay or readmission for patients, leading to additional costs. The Committee considered this was an additional reason that the cost savings associated with introducing the Ambu aScope4 Broncho to operating theatre units may have been underestimated.
For the guidance review, the External Assessment Centre revised the model to reflect 2018 costs. Further details of the cost parameter changes are in the costing review report. The External Assessment Centre applied the revised cost of the device and other costs to the cost model for settings with no multiple-use fibre optic endoscopes available and reported that net savings doubled to £1,638 (previously £749) with the cost of the monitor included and £1,433 (previously £653) when the cost of the monitor was deducted. This increase in cost savings is because of the increase in the cost of harms. It is also considered plausible that these savings will be achieved at lower thresholds than the 95–115 intubations noted in section 5.16. The External Assessment Centre also applied the revised costs to an intensive care unit setting. It reported that the cost saving in this setting also doubled to £6,632. # Conclusions
The Committee concluded that the evidence shows that the Ambu aScope4 Broncho is an acceptable alternative when a multiple-use fibre optic endoscope is not available to manage unexpected difficult endotracheal intubation and displaced tracheostomies.
The Committee concluded that, although some cost model parameters were uncertain, the availability of the Ambu aScope4 Broncho in isolated hospital units, obstetric units, operating theatre units and intensive care units is likely to be cost saving.
The Committee considered that use of the Ambu aScope4 Broncho has particular advantages for replacing dislodged tracheostomy tubes in intensive care units, with potential for significant cost savings in this setting.
The Committee considered that, because of the serious clinical consequences of inadequate management of unplanned difficult airways, patient safety would be improved by the adoption of the Ambu aScope4 Broncho in all clinical settings studied, particularly in isolated hospital units where there is currently no access to any endoscope.
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{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.\n\nThe case for adopting the Ambu\xa0aScope4 Broncho for use in people with unexpected difficult airways needing emergency intubation is supported by the evidence. This shows that the Ambu\xa0aScope4 Broncho is an acceptable alternative, where a multiple-use fibre optic endoscope is unavailable. There are also advantages during replacement of dislodged tracheostomy tubes in the intensive care setting. Making the Ambu\xa0aScope4 Broncho available for use across settings is likely to improve outcomes and patient safety.\n\nAdoption of the Ambu\xa0aScope4 Broncho is supported by cost modelling for a range of common clinical settings in which there is no multiple-use endoscope or where existing multiple-use endoscopes are not available. These settings are: isolated units, operating theatre units, and intensive care units, where the uses include the repositioning of displaced tracheostomy tubes. Although there were some uncertainties in the cost modelling, cost savings are likely in all settings modelled. The amount saved will depend on the number of intubations performed and on the number (if any) of existing multiple-use fibre optic endoscopes in use.\n\nThe details of the cost modelling and estimated cost savings for each clinical setting are described in sections 5.16 to 5.20. Section\xa05.21 presents the details of the revised cost modelling. As an example of the clinical area where savings could be greatest, using the Ambu\xa0aScope4 Broncho in the intensive care setting is estimated to be cost saving (£6,632\xa0per year) when more than 700\xa0intubations are conducted each year, when there are 2\xa0or fewer existing multiple-use fibre optic endoscopes, and assuming that 5% of intubations are difficult. ", 'The technology': "# Description of the technology\n\nThe Ambu\xa0aScope4 Broncho (Ambu Ltd) is a sterile, flexible, disposable device available in 3\xa0sizes (slim, regular and large) of which the slim and regular sizes are indicated for difficulties with endotracheal intubation in patients with difficult airways. It is used to visualise the airway and then to aid in the placement of an endotracheal tube, either directly or through an intubating laryngeal mask. It is a portable device that can be used wherever a flexible fibre optic endoscope is needed for airway management. This may be in anaesthetic rooms, critical care or emergency departments or in other areas of hospitals where emergency airway management is undertaken. The Ambu\xa0aScope4 Broncho can also be used to aid percutaneous dilatational tracheostomy and to check the position and patency of airway devices such as endotracheal tubes, double lumen tubes and tracheostomy tubes. The slim version of the Ambu\xa0aScope4 Broncho can pass through an Aintree intubating catheter if one is being used. \n\nThe Ambu\xa0aScope4 Broncho system consists of 2\xa0components – a single‑use aScope (endoscope) and an accompanying aScope monitor for displaying the images. These are supplied together. The Ambu\xa0aScope4 Broncho uses video camera technology to create the image which is displayed on the 800×480\xa0pixel aScope monitor. The portable monitor indicates the rechargeable battery capacity (claimed minimum of 3\xa0hours) and also has a video output to transfer images to a larger monitor or recording device. The 2\xa0components are used together and must therefore be available in the same location for the system to be effective. The single-use endoscopes are supplied sterile and ready for use. The monitor is re-usable. During procedures, the monitor can be powered by either battery or mains and is designed to be connected to the mains to recharge at other times. \n\nThe Ambu\xa0aScope4 Broncho has a working channel of 1.2\xa0mm to 2.6\xa0mm diameter, depending on size, that can be used for instillation of fluids (saline and topical anaesthesia), suction and insertion of endoscopic accessories. The suction port is designed to remove secretions. \n\nThe cost of Ambu\xa0aScope4 Broncho stated in the sponsor's submission was £179\xa0(including VAT) per single-use endoscope. The monitor had a list price of £799\xa0but was provided to NHS organisations free of charge with 5\xa0Ambu\xa0aScope4 Broncho devices. Each monitor has a 12-month warranty and each single-use Ambu\xa0aScope4 Broncho has a 3-year shelf life.\n\nThe claimed benefits of Ambu\xa0aScope4 Broncho in the case for adoption presented by the sponsor are:\n\nImproved outcomes in emergencies and unexpected scenarios of difficult airway management due to the immediate availability of a sterile fibre optic endoscope that does not need calibration.\n\nImproved safety for patients with tracheostomies due to a reduction in morbidity and mortality associated with the failure to re-establish ventilation if the tracheostomy tube is displaced in a patient with a difficult airway.\n\nReduced risk of cross-infection from contaminated multiple-use fibre optic endoscopes.\n\nReduced costs associated with an improvement in clinical outcomes in emergencies and unexpected scenarios of difficult airway management including patients with tracheostomies.\n\nReduced costs associated with a reduction in the incidence of cross-infection.\n\nReduced time and resources spent on cleaning and repair and internal transfer between hospital departments as the Ambu\xa0aScope4 Broncho is delivered sterile and ready to use.\n\n# Current management\n\nPlacement of an endotracheal tube guided by a multiple-use fibre optic endoscope is the gold standard for managing difficult intubation. Using a fibre optic endoscope or a video scope allows visualisation of the vocal cords followed by accurate placement of an endotracheal tube.\n\nThe Difficult Airways Society guidelines (Henderson et al. 2004) outline the clinical pathway for unexpected difficult tracheal intubation during routine induction of anaesthesia in adults. The guidelines describe the initial tracheal intubation plan (Plan A) and the secondary tracheal intubation plan (Plan B). Plan A describes direct laryngoscopy as the initial standard technique for intubation. Plan B is recommended after 4\xa0failed attempts at intubation. This involves placement of a supraglottic airway device: if that is successfully achieved and the patient can be ventilated, then ventilation may be maintained via the supraglottic airway device, or else tracheal intubation can be attempted with the aid of a multiple-use fibre optic endoscope.\n\nTracheostomy is a surgical procedure performed on a patient's neck to create an airway directly into the trachea. The placement of a percutaneous tracheostomy tube can be guided by a multiple-use fibre optic endoscope. Percutaneous tracheostomy has now replaced the traditional open operation and is considered standard technique in many intensive care units worldwide. The use of an endoscope during percutaneous tracheostomy enables the user to visualise the procedure from within the trachea, and so prevent the needle and dilators from penetrating the back of the trachea as well as ensuring that the tracheostomy tube is correctly placed.", 'Clinical evidence': "# Summary of clinical evidence\n\nFull details of all clinical outcomes considered by the Committee are available in the assessment report overview.\n\nThe key clinical outcomes presented in the decision problem for the Ambu\xa0aScope4 Broncho in patients undergoing emergency intubation with difficult airways were:\n\nincidence of delayed or failed intubation\n\nclinical consequences associated with delayed or failed intubation:\n\n\n\ndeath\n\nhypoxic brain injury\n\nintensive care unit length of stay\n\nhospital length of stay\n\n\n\nincidence of contamination and cross-infection\n\ndevice-related adverse events.\n\nThe clinical evidence for the Ambu\xa0aScope4 Broncho was based on 11\xa0studies. These comprised 4\xa0published and 2\xa0unpublished randomised controlled trials and 5\xa0published case series reports. Three of the studies evaluated the Ambu\xa0aScope4 Broncho and 8\xa0evaluated the Ambu\xa0aScope, which is the immediate predecessor device.\n\n## Patient-based randomised studies\n\nIn a randomised controlled trial, Kristensen (2013) compared the Ambu\xa0aScope against a multiple-use fibre optic endoscope in 60\xa0patients with expected normal airways and expected difficult airways. All patients were successfully intubated. The median total intubation time, including the administration of local anaesthetic, was 278\xa0seconds for the Ambu\xa0aScope and 234\xa0seconds for the multiple-use endoscope. Although this was statistically significant in favour of the multiple-use fibre scope (p<0.03), the investigators concluded that it was not clinically important because the difference was likely to be less than the hypothesised non-inferiority margin of 120\xa0seconds.\n\nIn a randomised controlled trial Schoettker et al. (2012) compared Ambu\xa0aScope4 Broncho against a multiple-use fibre optic endoscope in 100\xa0patients with difficult airways (simulated by a semi-rigid cervical collar). The use of the Ambu\xa0aScope4 Broncho was associated with a longer time to intubation compared with the fibre optic endoscope (69.5\xa0versus 49.5\xa0seconds, mean difference of 20\xa0seconds, p<0.05). Overall, the image quality provided by the Ambu\xa0aScope4 Broncho was lower than with the fibre optic endoscope although the quality was judged subjectively to be excellent in 24\xa0out of 50\xa0cases and acceptable in another 22\xa0out of the 50\xa0cases. Two attempts were needed in 4\xa0out of 50\xa0cases with the Ambu\xa0aScope4 Broncho compared against 8\xa0out of 50\xa0for the multiple-use fibre optic endoscopes. There was a 100% intubation success rate in less than 4\xa0minutes for both devices.\n\n## Manikin-based studies\n\nPiepho et al. (2010) conducted a randomised controlled trial that compared the Ambu\xa0aScope against a multiple-use fibre optic endoscope by examining the performance of 21\xa0anaesthetists during an easy and a difficult intubation simulation in a manikin. The mean time to intubation for difficult airways was 63\xa0seconds with the Ambu\xa0aScope compared against 56\xa0seconds for the comparator (mean difference 7\xa0seconds; 95% confidence interval [CI] −11.66\xa0to 25.66), which was statistically non-significant. In the difficult intubation scenario, the intubation success rate was lower when using the Ambu\xa0aScope compared against using the fibre optic endoscope (67% versus 81%, p=0.02), which the authors concluded was mainly caused by the low image quality. Overall the Ambu\xa0aScope scored a rating of 'satisfactory' compared against a rating of 'good' for the multiple-use fibre optic endoscope.\n\nVijayakumar et al. (2011) conducted a randomised controlled trial that compared the manoeuvrability and ease of use of the Ambu\xa0aScope against a multiple-use fibre optic endoscope in manikins set to simulate difficult fibre optic endoscope placement of an endotracheal tube. The mean time to task completion was 63\xa0seconds for the Ambu\xa0aScope compared against 53\xa0seconds for the fibre optic endoscope (p=0.08). The estimated 95% CI (1.26\xa0to 18.74) did not overlap with a difference of more than 30\xa0seconds between the Ambu\xa0aScope and the multiple-use fibre optic endoscope (which was considered to be a clinically important difference). The mean number of tip surface collisions was slightly higher with the Ambu\xa0aScope at 2.7\xa0compared against the fibre optic endoscope at 2.5. The ease of use impression was rated at 65\xa0for the Ambu\xa0aScope compared against 77\xa0for the fibre optic endoscope (100\xa0being extremely easy to use).\n\nA study by Scutt et al. (2011) compared the Ambu\xa0aScope against a multiple-use fibre optic endoscope in 2\xa0simulated settings. In the first setting, 22\xa0participants (all who were familiar with, or skilled in, fibre optic intubation) performed paired oral and nasal fibre optic intubations in 3\xa0different airway training manikins (a total of 264\xa0intubations). In the second setting 21\xa0participants intubated 1\xa0airway trainer manikin using 3\xa0supraglottic airway devices: classic and intubating laryngeal mask airways, and i‑gel (a total of 66\xa0intubations). For each intubation the time to intubate was recorded from starting the endoscopy with a preloaded tracheal tube to the first lung ventilation. In both settings, time to intubation was similar between the Ambu\xa0aScope and the multiple-use fibre optic endoscope (p=0.18). Use of the Ambu\xa0aScope was associated with more reported problems than the multiple-use fibre optic endoscope (32% versus 17% respectively, p=0.04), including difficulties with manipulation, railroading tubes and picture quality. The Ambu\xa0aScope was rated a mean score of 7.7\xa0versus 8.5\xa0for the multiple-use endoscope (10\xa0being the highest in terms of ease of use and image quality). In the first setting, 88% of intubations were successful on the initial attempt. In the second setting, there were 4\xa0failures at the first intubation attempt in 126\xa0attempts (3%).\n\n## Small case series\n\nPiepho et al. (2010) described a case series in which the Ambu\xa0aScope was used in 5\xa0patients with expected and unexpected difficult airways. Typical landmarks such as the uvula, tongue, epiglottis and larynx were adequately identified in all 5\xa0patients using the Ambu\xa0aScope. Intubations via a nasal route were performed in 3\xa0awake patients and advancing the tracheal tube was smooth and easy in these patients. The Ambu\xa0aScope was also used in 2\xa0patients via an oral route and in 1\xa0of these patients, airway secretions obstructed vision on the monitor. This was resolved following suctioning and cleaning of the Ambu\xa0aScope lens using a sterile swab. Tracheal intubation was successfully achieved in all 5\xa0patients.\n\nIn a case series of 10\xa0patients by Pujol et al. (2010), 9\xa0of 10\xa0intubations with the Ambu\xa0aScope were performed and completed without incident. Intubation could not be accomplished in 1\xa0patient. Tube insertion was considered easy in 8\xa0patients, easy but with some manoeuvres needed in 1\xa0patient and impossible in 1\xa0patient. In all 10\xa0patients, a complete view of the glottis was obtained. The image quality was considered adequate in 5\xa0patients and poor in another 5\xa0patients. Fogging of the lens occurred in 6\xa0patients and was cleared easily by gently touching the airway mucosa in 4\xa0patients and by removing the endoscope and cleaning the tip in the other 2\xa0patients. In 2\xa0cases there were secretions that could not be suctioned but they did not result in difficult tube insertion.\n\nJamadarkhana et al. (2011) described a case series of 10\xa0patients in whom Ambu\xa0aScope4 Broncho was used to perform percutaneous dilatational tracheostomy. The average time to set up the endoscope and monitor was less than 5\xa0minutes. The procedure time from needle puncture of the trachea to tracheostomy tube placement ranged from 5\xa0to 10\xa0minutes. All the anaesthetists reported easy handling and manoeuvrability because Ambu\xa0aScope4 Broncho was light-weight. They scored the clarity and quality of endoscopic view to be between 8\xa0and 10\xa0out of a maximum of 10. No complications were reported during use of the Ambu\xa0aScope4 Broncho.\n\nIn a case series of 10\xa0patients needing a percutaneous tracheostomy, Perbet et al. (2011) found that 7\xa0of the 10\xa0operators rated the Ambu\xa0aScope 'very satisfactory', and 3\xa0rated it as 'satisfactory' across all parameters. The presence of the screen was deemed useful in all of the cases.\n\nVincent et al. (2011) described a case series of 8\xa0patients with expected difficult airways. All 8\xa0patients were successfully intubated while awake using the Ambu\xa0aScope4 Broncho; 7\xa0by the nasal route and 1\xa0orally. The mean time it took to position the endoscope to visualise the carina was 254.5\xa0seconds, with the shortest time taken being 62\xa0seconds. The mean time for confirming the position of the tube in the trachea after visualising the carina was 51.5\xa0seconds. Of the 8\xa0operators, 6\xa0reported an excellent view of anatomical landmarks, and 2\xa0reported the view as poor, but adequate for intubating the trachea. The mean score for manoeuvrability was 6.8\xa0(range 3–9\xa0with 10\xa0classed as extremely manoeuvrable) and the mean score for usefulness of the endoscope was 7.4\xa0(3–10\xa0with 10\xa0classed as extremely useful).\n\n## Unpublished patient-based study\n\nA study by Lenhardt et al. (2011) has been published as a poster presentation but the Committee considered detailed findings presented as academic-in-confidence data. The randomised controlled trial compared the Ambu\xa0aScope against a pre-formed stylet (multiple-use fibre optic endoscope) in 140\xa0patients with expected difficult airways. All patients were successfully intubated and no serious complications were encountered. The time to intubation was similar for the use of the Ambu\xa0aScope and a pre-formed rigid stylet (95±63\xa0seconds versus 104±100\xa0seconds, p=0.6). The rating for ease of use was found to be similar for the Ambu\xa0aScope and the pre-formed stylet.\n\n## Adverse events\n\nNo adverse event reports relating to the Ambu\xa0aScope were reported in a search of the US Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. The Medicines and Healthcare products Regulatory Agency (MHRA) has not received any reports of adverse events relating to the Ambu\xa0aScope4 Broncho.\n\n## Committee considerations\n\nThe Committee noted that the clinical evidence was from studies in manikins or patients with expected (or simulated) difficult airways. There were no controlled trials in patients with unexpected difficult airways but the Committee recognised the considerable difficulties of conducting such studies.\n\nThe Committee judged that the studies provided evidence that the Ambu\xa0aScope4 Broncho was an acceptable alternative to multiple-use fibre optic endoscopes. In addition, the Committee received expert advice that although the Ambu\xa0aScope4 Broncho has poorer image quality than standard multiple-use fibre optic endoscopes and its lens needs cleaning during use, it is an acceptable alternative in situations in which a multiple-use fibre optic endoscope is not available.\n\nThe Committee noted that in the studies in which manikins were used, the anaesthetists had previous experience of using standard multiple-use fibre optic endoscopes, but lacked experience of using the Ambu\xa0aScope. Therefore, the longer time to intubation observed for the Ambu\xa0aScope might have been influenced by the anaesthetists' lack of experience in using the device.\n\nThe Committee was mindful that potential consequences of failed intubation include severe brain injury and death. It accepted that the immediate availability of the Ambu\xa0aScope4 Broncho in situations where multiple-use fibre optic endoscopes are not available may lower the risk of these consequences occurring. The Committee noted that clinical evidence on these outcomes was not available.\n\nThe Committee considered the fact that the Ambu\xa0aScope (the predecessor of the Ambu\xa0aScope4 Broncho) was used in 8\xa0of the 11\xa0studies presented. It judged that the data derived from these studies were relevant and valid for this submission because the Ambu\xa0aScope4 Broncho has the same mode of action and design as the Ambu\xa0aScope, but with certain modifications which were likely to improve, rather than impair, its performance.", 'NHS considerations': '# System impact\n\nThe sponsor claimed that using the Ambu\xa0aScope4 Broncho would lead to an improvement in clinical outcomes. This may be relevant in emergencies and unexpected scenarios of difficult airway management, including those patients with tracheostomies.\n\nThe sponsor claimed that an improvement in clinical outcomes by reducing the risk of severe brain injury and death may lead to overall costs being reduced.\n\nThe sponsor claimed that because the Ambu\xa0aScope4 Broncho is single use, there would be a decrease in costs associated with a reduction in the incidence of cross-infection.\n\nThe sponsor claimed that using the Ambu\xa0aScope4 Broncho would reduce the time and resources spent on cleaning and repair of multiple-use fibre optic endoscopes, and on their internal transfer between hospital departments, because the Ambu\xa0aScope4 Broncho is delivered sterile and ready to use.\n\n## Committee considerations\n\nThe Committee noted that multiple-use fibre optic endoscopes may be located on a different floor or in a different building to that in which emergency airway management is needed. Therefore, it may not be possible to obtain a fibre optic endoscope in time to use it in an emergency. The Committee considered that the main potential benefit of the Ambu\xa0aScope4 Broncho was its immediate availability for use in locations remote from fibre optic endoscopes. The Committee noted that the Ambu\xa0aScope4 Broncho may therefore be of particular value in a variety of clinical settings such as accident and emergency departments, isolated units within large hospitals and remote hospitals that have no fibre optic endoscopes.\n\nThe Committee received expert advice that multiple-use fibre optic endoscopes are often damaged in the intensive care unit when they are being used during percutaneous tracheostomy; costly repair or even replacement is then necessary. Use of the Ambu\xa0aScope4 Broncho has advantages in this scenario because the scopes are single use and damage to them is therefore of significantly less consequence.\n\nThe Committee received expert advice that in clinical settings where difficult intubations may be encountered but multiple-use fibre optic endoscopes are not available, a delay in accessing a fibre optic endoscope may have important clinical consequences including brain injury or death. The Committee noted that no published evidence or clinical studies had been submitted to support this.\n\nThe Committee considered that using the Ambu\xa0aScope4 Broncho in the clinical settings described in 4.7\xa0could lead to an improvement in clinical outcomes but it noted that no evidence had been submitted that overall costs would be reduced.\n\nThe Committee noted that no evidence was presented to support the claim that there would be a decrease in costs associated with a reduction in the incidence of cross-infection.\n\nThe Committee acknowledged the possibility that using the Ambu\xa0aScope4 Broncho would reduce the time and resources spent on cleaning and repair of multiple-use fibre optic endoscopes, but limited evidence was submitted to support this claim.', 'Cost considerations': "# Cost evidence\n\n## Published evidence\n\nThe sponsor identified 3\xa0published economic studies that focused on estimating the cost of the Ambu\xa0aScope or the multiple-use fibre optic endoscope. No modelling of the cost consequences of adoption was included in the studies.\n\n## Sponsor cost model\n\nThe sponsor submitted a de novo cost analysis for Ambu\xa0aScope4 Broncho that estimated the costs and consequences associated with the use of the Ambu\xa0aScope4 Broncho and multiple-use fibre optic endoscopes. The analysis was from an NHS and personal social services perspective. Full details of all cost evidence and modelling considered by the Committee are available in the assessment report overview.\n\nThe sponsor submitted a base-case analysis for 3\xa0scenarios: unexpected difficult intubation in the operating theatre units, unexpected difficult intubation in the intensive care unit, and replacing a dislodged tracheostomy tube in the intensive care unit. The model for unexpected difficult airways needing emergency intubation separated patients according to those who had successful intubations and those who had delayed or failed intubations; the latter group were separated further according to those who survived and had no brain injury, and those with brain injury or who died. A separate model was designed for replacing dislodged tracheostomy tubes because this is not managed in the same way as an intubation and is associated with different costs and outcomes. The model for dislodged tracheostomy tubes separated patients into those who were successfully managed, those who had extended intensive care unit stay and those with brain injury or who died. The analysis reported the costs associated with equipment and clinical outcomes, which were delayed or failed intubation and the replacement of dislodged tracheostomy tubes.\n\nThe sponsor's base-case analysis included several key assumptions:\n\nThe number of procedures performed per year with multiple-use fibre optic endoscopes was 150.\n\nThe number of multiple-use endoscopes available was 5.\n\nThe multiple-use fibre optic endoscope cost (including weighted costs including stack systems, cameras and so on) was £12,105.\n\nThe Ambu\xa0aScope4 Broncho cost per endoscope with monitor was £179\xa0(including VAT).\n\nThe rate of intensive care unit admission or prolongation of stay was 74% for people who have had a failed intubation and 75% for people who have had a dislodged tracheostomy tube replaced.\n\nThe cost of the intensive care unit per day was £1,321.\n\nThe model for unexpected difficult intubations had the following assumptions:\n\nThe rate of delayed or failed intubation when using multiple-use fibre optic endoscopes in the operating theatre units was 6.25%.\n\nThe rate of delayed or failed intubation when using multiple-use fibre optic endoscopes in the intensive care unit was 16.6%.\n\nThe average intensive care unit length of stay was 6.2\xa0days.\n\nThe rate of brain injury or death in patients who had difficult intubations and in whom intubation has failed was 28%.\n\nThe reduction in risk of delayed or failed intubation leading to patient harm with the Ambu\xa0aScope4 Broncho was 10%.\n\nThe model for dislodged tracheostomies had the following assumptions:\n\nThe rate of brain injury or death because of dislodged tracheostomy was 13%.\n\nThe average intensive care unit length of stay was 15.4\xa0days.\n\nThe reduction in risk of dislodged tracheostomy leading to patient harm with Ambu\xa0aScope4 Broncho was 10%.\n\nThe sponsor's base-case analysis estimated the incremental cost saving of the Ambu\xa0aScope4 Broncho compared against multiple-use fibre optic endoscopes to be £30\xa0per intubation for equipment and staff costs only. This was consistent across the 3\xa0settings. If the Ambu\xa0aScope4 Broncho was used instead of a multiple-use endoscope and if the equipment and staff costs and the modelled costs associated with hospitalisations were included, then:\n\nfor unexpected and difficult intubation in the operating theatre units there are potential incremental cost savings of £68\xa0per patient\n\nfor unexpected difficult airways in the intensive care unit there are potential incremental cost savings of £130.70\xa0per patient\n\nfor dislodged tracheostomy there are potential incremental cost savings of £1,555.80\xa0per patient.\n\nA deterministic sensitivity analysis explored parameter uncertainty and the effect of these changes on the cost of the Ambu\xa0aScope4 Broncho. The parameters included the failure rate of intubation, the reduced risk rates of failed intubation with the Ambu\xa0aScope4 Broncho, the length of hospitalisation and the costs associated with multiple-use fibre optic endoscopes. The sensitivity analysis showed that the findings were responsive to the parameter changes in all 3\xa0clinical settings. The Ambu\xa0aScope4 Broncho remained cost saving in most scenarios, with the exceptions being long equipment lifetime or a substantially low equipment cost for the multiple-use fibre optic endoscope\n\nThe External Assessment Centre carried out additional analyses to examine the impact of changing the following parameters of the sponsor's base case:\n\nRate of delayed intubation in patients with unexpected difficult intubations in the operating theatre units and intensive care units for multiple-use fibre optic endoscopes (10%).\n\nRate of harm needing extended hospital stay in patients with difficult intubations when intubation was delayed (50%).\n\nThe External Assessment Centre's base-case analysis in unexpected difficult intubation in an operating theatre unit indicated a cost saving of £401\xa0when using the Ambu\xa0aScope4 Broncho. In unexpected difficult intubation in an intensive care unit, the mean cost per patient when using the Ambu\xa0aScope4 Broncho was £1,185\xa0and the mean cost of a multiple-use fibre optic endoscope was £1,524. This indicates a cost saving of £339\xa0when using an Ambu\xa0aScope4 Broncho in this scenario. The External Assessment Centre stated that the results were based on clinical expert opinion and the sponsor's assumptions, and the model was subject to uncertainty. After reviewing the sponsor's de novo model (see section\xa05.21), the Committee asked for further information on the cost consequences using a different model structure, assumptions and parameters.\n\n## External Assessment Centre cost model\n\nThe sponsor's de novo cost analysis modelled a scenario in which multiple-use fibre optic endoscopes were completely replaced by the Ambu\xa0aScope4 Broncho. It did not consider the cost consequences of using the Ambu\xa0aScope4 Broncho if both multiple-use fibre optic endoscopes and the Ambu\xa0aScope4 Broncho were available. The External Assessment Centre was therefore asked to carry out additional analyses to estimate any potential cost savings of purchasing the Ambu\xa0aScope4 Broncho in different settings:\n\nin small hospital units that do not have access to any multiple-use fibre optic endoscopes for unexpected difficult airway management\n\nin addition to the existing stock of multiple-use fibre optic endoscopes in operating theatre units and intensive care units for unexpected difficult intubations and displaced tracheostomy tubes.\n\nThe External Assessment Centre modelled costs in 5\xa0clinical settings:\n\nan isolated hospital unit\n\nan obstetric unit\n\nan operating theatre unit\n\nan intensive care unit\n\ndisplaced tracheostomy tubes (in an intensive care unit). All of the above settings are of indeterminate size. For example, an operating theatre unit is likely to consist of more than 1\xa0operating theatre but the modelling is based on the number of intubations within each unit rather than of the size of the unit. A displaced tracheostomy tube is not a clinical setting and is not specific to an intensive care unit but for the purposes of the cost modelling this procedure has been classed as a clinical setting.Potential cost savings were considered from purchasing:\n\nor more Ambu\xa0aScope4 Broncho devices for use in managing unexpected difficult intubation in a specified clinical setting with no multiple-use fibre optic endoscopes available\n\nor more Ambu\xa0aScope4 Broncho devices for use in managing unexpected difficult intubation in a specified clinical setting with 1\xa0or more multiple-use fibre optic endoscopes available\n\nor more Ambu\xa0aScope4 Broncho devices for use in managing displaced tracheostomy tubes in an intensive care unit with 1\xa0or more multiple-use fibre optic endoscopes, but where none of these endoscopes may be immediately available.\n\nThe economic model was used to evaluate the cost savings of purchasing the Ambu\xa0aScope4 Broncho for hospital units that do not have access to multiple-use fibre optic endoscopes. In these hospital units, it was assumed that, if an Ambu\xa0aScope4 Broncho was available, it would be used if and only if an unexpected difficult intubation occurred. Unexpected difficult intubations were therefore the entry point into the decision tree. The model was also used to evaluate purchasing the Ambu\xa0aScope4 Broncho as an addition for those hospital units that do have access to multiple-use endoscopes. These hospital units are likely to have a high throughput of patients needing intubation (for example, a busy operating theatre) and/or a high probability of expected difficult intubations. For modelling purposes, the number of multiple-use endoscopes was considered fixed for each clinical setting to allow the model to focus on the benefit of purchasing Ambu\xa0aScope4 Bronchos as an addition to existing multiple-use endoscopes. The number of unexpectedly difficult intubations arising for which there was no multiple-use endoscope available was modelled as a function of the number of multiple-use endoscopes, numbers of intubations carried out in the unit, and multiple-use endoscope non-availability (which was modelled using a queuing simulation). Difficult intubation events occurred at random intervals according to a Poisson process.\n\nThere were uncertainties in several parameters used in the cost modelling, often caused by there being limited or no clinical data to support the assumptions. Cost savings were considered likely in all the clinical settings that were modelled, but these depended on the number of intubations performed and on the number (if any) of existing multiple-use fibre optic endoscopes.\n\nThe base-case analysis of all of the clinical settings showed that the potential cost savings from purchasing the Ambu\xa0aScope4 Broncho came from using it when multiple-use fibre optic endoscopes were not available, therefore avoiding the consequences of failed intubation such as severe brain injury. It was assumed that an unexpected difficult intubation arises on average 6\xa0times per 1,000\xa0intubations.\n\nThe base-case analysis of using the Ambu\xa0aScope4 Broncho in an isolated hospital unit assumed 300\xa0intubations per year and that no multiple-use fibre optic endoscopes were available. The cost saving per year was £749\xa0per unit if the cost of the monitor was excluded and £653\xa0if it was included. The number of intubations per year above which purchasing a bundle of 5\xa0Ambu\xa0aScope4 Bronchos was cost saving was 95\xa0if the monitor was excluded and 115\xa0if the monitor was included.\n\nTwo base-case analyses were performed for using the Ambu\xa0aScope4 Broncho in an obstetrics unit: one assumed 400\xa0intubations per year and no multiple-use fibre optic endoscopes, and the second analysis assumed 400\xa0intubations per year and 1\xa0multiple-use endoscope. If there were no multiple-use endoscopes, the cost saving per annum was £1,452\xa0if the cost of the monitor was excluded and £1,356\xa0if it was included. If there were no multiple-use endoscopes, the number of intubations per year above which purchasing a bundle of 5\xa0Ambu\xa0aScope4 Bronchos was cost saving was 80. If a multiple-use endoscope was available then the Ambu\xa0aScope4 Broncho was estimated to be cost incurring unless a minimum of 500\xa0intubations per year were done in the unit.\n\nThe base-case analysis for using the Ambu\xa0aScope4 Broncho in operating theatre units assumed that there were 2\xa0multiple-use fibre optic endoscopes and that 1,000\xa0intubations per year were conducted. Based on this, the Ambu\xa0aScope4 Broncho was considered to be cost incurring by £203\xa0per unit per year if the cost of the monitor was excluded and £299\xa0if it was included. The number of intubations per year above which purchasing a bundle of 5\xa0Ambu\xa0aScope4 Bronchos was cost saving was 1,250\xa0if the monitor was excluded and 1,350\xa0if the monitor was included.\n\nThe base-case analysis for using the Ambu\xa0aScope4 Broncho in intensive care units assumed that there were 2\xa0multiple-use fibre optic endoscopes and 700\xa0intubations per year. Two assumptions considering the probability of difficult intubation were presented: 20% and 5%. If the probability of difficult intubation was 20%, the cost saving per year was £3,219\xa0if the cost of the monitor was excluded and £3,123\xa0if it was included. If the probability of difficult intubation was 5%, the cost saving per year was £3,128\xa0if the cost of the monitor was excluded and £3,031\xa0if it was included. The number of intubations per year above which purchasing a bundle of 5\xa0Ambu\xa0aScope4 Bronchos was cost saving was 50–100\xa0with 20% probability and 250–300\xa0with 5% probability.\n\nThe base-case analysis for using the Ambu\xa0aScope4 Broncho to aid the replacement of displaced tracheostomy tubes assumed a displacement rate of 15% per year for an intensive care unit with 2\xa0multiple-use fibre optic endoscopes. For a base case of 200\xa0tracheostomies per year, the cost saving per year was £5,281\xa0per unit if the cost of the monitor was excluded and £5,185\xa0if it was included. The number of tracheostomies per year above which purchasing a bundle of 5\xa0Ambu\xa0aScope4 Bronchos was cost saving was 70.\n\n## Committee considerations\n\nThe Committee considered the sponsor's economic analysis in which the Ambu\xa0aScope4 Broncho completely replaced multiple-use fibre optic endoscopes in operating theatre units and intensive care units. It noted that the sponsor's model did not consider the cost consequences of using the Ambu\xa0aScope4 Broncho if both the multiple-use endoscopes and the Ambu\xa0aScope4 Broncho are available. The Committee received advice from several clinical experts that a multiple-use endoscope would, where available, be preferred by clinicians, and concluded that the sponsor's model was not realistic. The Committee also considered that there were too many uncertainties in the sponsor's economic model to use the outcomes as the basis to make recommendations.\n\nThe Committee requested further modelling, which was carried out by the External Assessment Centre, to establish any potential cost savings of purchasing the Ambu\xa0aScope4 Broncho in 5\xa0clinical settings. This modelling considered the cost consequences for 2\xa0scenarios: using the Ambu\xa0aScope4 Broncho where multiple-use endoscopes are not available for use in a clinical setting; and using the Ambu\xa0aScope4 Broncho where multiple-use endoscopes are normally available in a clinical setting but for some reason are inaccessible. The Committee judged that if the Ambu\xa0aScope4 Broncho was available for use, there are likely to be cost savings in all the settings modelled, based on the following assumptions about the number of intubations or tracheostomies performed each year:\n\nIsolated hospital unit with no multiple-use endoscopes: 95\xa0intubations.\n\nObstetrics unit with no multiple-use endoscopes: 80\xa0intubations.\n\nObstetrics unit with 1\xa0multiple-use endoscope: 500\xa0intubations.\n\nOperating theatre unit with 2\xa0multiple-use endoscopes: 1,250\xa0intubations.\n\nIntensive care units with 2\xa0multiple-use endoscopes: 50\xa0intubations (20% difficult intubation probability) and 250\xa0intubations (5% difficult intubation probability).\n\nReplacement of displaced tracheostomy tubes (assuming a 15% per year displacement rate) in an intensive care unit with 2\xa0multiple-use endoscopes: 70\xa0tracheostomies.\n\nThe Committee noted that the analyses showed specific advantages for the Ambu\xa0aScope4 Broncho in the replacement of displaced tracheostomy tubes (see section\xa04.6). The Committee accepted expert advice that multiple-use fibre optic endoscopes are often damaged in the intensive care unit when they are used during tracheostomy replacement. The modelling assumed that there were 2\xa0existing multiple-use endoscopes and that the Ambu\xa0aScope4 Broncho is used when a multiple-use endoscope is unavailable. Combining the described advantages with its other use in intensive care units, the Committee judged that the Ambu\xa0aScope4 Broncho has the potential for most cost savings in intensive care units.\n\nThe Committee recognised uncertainties in a number of the parameters in the External Assessment Centre's economic model. The Committee noted that adverse events are rare but that some of these events, such as hypoxic brain damage, may result in considerable costs. It accepted that the cost modelling provided by the External Assessment Centre took account of this. The cost modelling was based on overall risks in the NHS and it should be noted that cost consequences may vary between units.\n\nThe Committee noted that the External Assessment Centre's economic model was based on assumptions of a certain number of intubations per year. It recognised that most hospitals in England have been designed with several operating theatres adjacent to each other (that is, operating theatre units) with shared availability of multiple-use fibre optic endoscopes. The numbers of intubations performed annually in these operating theatre units typically far exceeds the threshold number determined from the cost modelling. The Committee therefore considered that, when this is the case, the cost savings will be greater than those estimated.\n\nThe Committee was also advised that in certain situations in which a multiple-use fibre optic endoscope is not available, planned operations may be cancelled. This can result in unused operating theatre unit time, and increased length of stay or readmission for patients, leading to additional costs. The Committee considered this was an additional reason that the cost savings associated with introducing the Ambu\xa0aScope4 Broncho to operating theatre units may have been underestimated.\n\nFor the guidance review, the External Assessment Centre revised the model to reflect 2018 costs. Further details of the cost parameter changes are in the costing review report. The External Assessment Centre applied the revised cost of the device and other costs to the cost model for settings with no multiple-use fibre optic endoscopes available and reported that net savings doubled to £1,638 (previously £749) with the cost of the monitor included and £1,433 (previously £653) when the cost of the monitor was deducted. This increase in cost savings is because of the increase in the cost of harms. It is also considered plausible that these savings will be achieved at lower thresholds than the 95–115\xa0intubations noted in section\xa05.16. The External Assessment Centre also applied the revised costs to an intensive care unit setting. It reported that the cost saving in this setting also doubled to £6,632. ", 'Conclusions': 'The Committee concluded that the evidence shows that the Ambu\xa0aScope4 Broncho\xa0is an acceptable alternative when a multiple-use fibre optic endoscope is not available to manage unexpected difficult endotracheal intubation and displaced tracheostomies.\n\nThe Committee concluded that, although some cost model parameters were uncertain, the availability of the Ambu\xa0aScope4 Broncho\xa0in isolated hospital units, obstetric units, operating theatre units and intensive care units is likely to be cost saving.\n\nThe Committee considered that use of the Ambu\xa0aScope4 Broncho\xa0has particular advantages for replacing dislodged tracheostomy tubes in intensive care units, with potential for significant cost savings in this setting.\n\nThe Committee considered that, because of the serious clinical consequences of inadequate management of unplanned difficult airways, patient safety would be improved by the adoption of the Ambu\xa0aScope4 Broncho\xa0in all clinical settings studied, particularly in isolated hospital units where there is currently no access to any endoscope.'}
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https://www.nice.org.uk/guidance/mtg14
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Evidence-based recommendations on Ambu aScope4 Broncho for use in unexpected difficult airways.
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ee35e0e352c2a2ce9e9d3899b8473a294403918c
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nice
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Percutaneous mechanical thrombectomy for acute deep vein thrombosis of the leg
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Percutaneous mechanical thrombectomy for acute deep vein thrombosis of the leg
Evidence-based recommendations on percutaneous mechanical thrombectomy for acute deep vein thrombosis of the leg in adults. This involves removing the clot through a catheter inserted into the vein.
# Recommendations
Current evidence on the safety of percutaneous mechanical thrombectomy for acute deep vein thrombosis (DVT) of the leg shows there are well-recognised but infrequent complications.
For acute iliofemoral DVT, the evidence on efficacy is limited in quality and quantity, therefore this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
For distal DVT that does not extend into the common femoral vein, the evidence on efficacy is inconclusive, therefore this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Clinicians wishing to do percutaneous mechanical thrombectomy for acute iliofemoral DVT should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.
Clinicians should enter details of all patients who have the procedure onto the British Society of Interventional Radiology Venous Registry.
Further research should report the patient selection criteria including the site of the clot, symptom severity and age of patients.# The condition, current treatments and procedure
# The condition
Deep vein thrombosis (DVT) is a blood clot that develops within a deep vein, usually in the leg. It can cause pain, swelling, tenderness and red skin but sometimes there are no symptoms. Risk factors for DVT include surgery, immobility, malignancy, hypercoagulability, pregnancy and dehydration.
DVT may lead to complications because the blood flow in the leg is being affected. Chronic venous insufficiency can cause post‑thrombotic syndrome in the affected leg with pain, swelling, and sometimes chronic ulceration. Raised venous pressure can rarely cause phlegmasia cerulean dolens with oedema of the leg, cyanosis, blistering and ischemia. If the clot becomes dislodged it can travel through the veins to the lungs and cause a pulmonary embolus, which is potentially life‑threatening.
# Current treatments
A DVT is usually treated with anticoagulation. Extensive DVT is sometimes treated with systemic thrombolysis, or by endovascular interventions such as catheter‑directed thrombolysis. Thrombolysis is associated with a risk of haemorrhagic complications including stroke. Surgical thrombectomy is an option when a DVT is refractory to thrombolytic therapy, or in people for whom thrombolysis is contraindicated, but it is rarely used.
# The procedure
Percutaneous mechanical thrombectomy for acute DVT of the leg is usually done together with direct infusion of a thrombolytic drug into the thrombus. However, it can be done by itself if thrombolytic drugs are contraindicated. It can also be done before thrombolysis to reduce the size of the clot, or after thrombolysis if the thrombus persists.
The procedure is done using local anaesthesia. Imaging is used to determine the appropriate venous access, which is usually the popliteal or femoral vein. A catheter is advanced through the vein into the thrombus using fluoroscopic guidance. There are a range of mechanical thrombectomy devices that use different principles. The objective is mechanical disruption and aspiration of the thrombus. A temporary inferior vena cava filter may be used during the procedure to reduce the risk of pulmonary embolism from a displaced clot.
Anticoagulant drugs are usually taken for at least 3 months after the procedure and sometimes longer if clinically indicated, to prevent recurrence. Early ambulation and use of compression stockings are advised.
Adjuvant angioplasty or stenting of the vein may be needed if thrombus removal reveals an anatomical lesion that contributed to the formation of the DVT or that increases the risk of recurrence.
|
{'Recommendations': "Current evidence on the safety of percutaneous mechanical thrombectomy for acute deep vein thrombosis (DVT) of the leg shows there are well-recognised but infrequent complications.\n\nFor acute iliofemoral DVT, the evidence on efficacy is limited in quality and quantity, therefore this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFor distal DVT that does not extend into the common femoral vein, the evidence on efficacy is inconclusive, therefore this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wishing to do percutaneous mechanical thrombectomy for acute iliofemoral DVT should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.\n\nClinicians should enter details of all patients who have the procedure onto the British Society of Interventional Radiology Venous Registry.\n\nFurther research should report the patient selection criteria including the site of the clot, symptom severity and age of patients.", 'The condition, current treatments and procedure': '# The condition\n\nDeep vein thrombosis (DVT) is a blood clot that develops within a deep vein, usually in the leg. It can cause pain, swelling, tenderness and red skin but sometimes there are no symptoms. Risk factors for DVT include surgery, immobility, malignancy, hypercoagulability, pregnancy and dehydration.\n\nDVT may lead to complications because the blood flow in the leg is being affected. Chronic venous insufficiency can cause post‑thrombotic syndrome in the affected leg with pain, swelling, and sometimes chronic ulceration. Raised venous pressure can rarely cause phlegmasia cerulean dolens with oedema of the leg, cyanosis, blistering and ischemia. If the clot becomes dislodged it can travel through the veins to the lungs and cause a pulmonary embolus, which is potentially life‑threatening.\n\n# Current treatments\n\nA DVT is usually treated with anticoagulation. Extensive DVT is sometimes treated with systemic thrombolysis, or by endovascular interventions such as catheter‑directed thrombolysis. Thrombolysis is associated with a risk of haemorrhagic complications including stroke. Surgical thrombectomy is an option when a DVT is refractory to thrombolytic therapy, or in people for whom thrombolysis is contraindicated, but it is rarely used.\n\n# The procedure\n\nPercutaneous mechanical thrombectomy for acute DVT of the leg is usually done together with direct infusion of a thrombolytic drug into the thrombus. However, it can be done by itself if thrombolytic drugs are contraindicated. It can also be done before thrombolysis to reduce the size of the clot, or after thrombolysis if the thrombus persists.\n\nThe procedure is done using local anaesthesia. Imaging is used to determine the appropriate venous access, which is usually the popliteal or femoral vein. A catheter is advanced through the vein into the thrombus using fluoroscopic guidance. There are a range of mechanical thrombectomy devices that use different principles. The objective is mechanical disruption and aspiration of the thrombus. A temporary inferior vena cava filter may be used during the procedure to reduce the risk of pulmonary embolism from a displaced clot.\n\nAnticoagulant drugs are usually taken for at least 3\xa0months after the procedure and sometimes longer if clinically indicated, to prevent recurrence. Early ambulation and use of compression stockings are advised.\n\nAdjuvant angioplasty or stenting of the vein may be needed if thrombus removal reveals an anatomical lesion that contributed to the formation of the DVT or that increases the risk of recurrence.'}
|
https://www.nice.org.uk/guidance/ipg651
|
Evidence-based recommendations on percutaneous mechanical thrombectomy for acute deep vein thrombosis of the leg in adults. This involves removing the clot through a catheter inserted into the vein.
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ffc1603dc27b6e2e9a6f74140392024799974398
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nice
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Bronchoscopic thermal vapour ablation for upper-lobe emphysema
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Bronchoscopic thermal vapour ablation for upper-lobe emphysema
Evidence-based recommendations on bronchoscopic thermal vapour ablation for upper-lobe emphysema in adults. This involves passing a bronchoscope (a tube with a camera on the end) through the mouth or nose into the lungs. This then delivers steam which destroys the diseased part of the lung, allowing the healthy parts to work better.
# Recommendations
Current evidence on the safety and efficacy of bronchoscopic thermal vapour ablation for upper-lobe emphysema is inadequate in quantity and quality. Therefore, the procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should evaluate safety and efficacy in the short and long term and include details of patient selection. NICE may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Emphysema is a chronic lung disease that typically happens with chronic obstructive pulmonary disease. In emphysema, the walls of the air sacs (alveoli) in the lungs weaken and disintegrate. This leaves behind abnormally large air spaces that stay filled with air even when the patient breathes out. The most common symptoms of emphysema are shortness of breath, coughing, fatigue and weight loss. Recurrent illnesses (such as chest infections) often lead to exacerbations, for which patients may need hospitalisation. Emphysema is usually related to smoking, but other risk factors include air pollution and an inherited alpha-1-antitrypsin deficiency.
# Current treatments
Treatment options include pulmonary rehabilitation (exercise training, breathing retraining, and patient and carer education), stopping smoking, and using inhaled or oral bronchodilators and corticosteroids. Oxygen therapy may also be needed in more severe cases. Lung volume reduction surgery is an option for patients who experience breathlessness, and whose pulmonary function tests and CT scans show severe disease and enlarged air spaces. Surgery can be done thoracoscopically or using an open approach. Endoscopic lung volume reduction techniques include implanting valves or coils. The aim is to reduce the morbidity and mortality associated with conventional surgery.
# The procedure
Bronchoscopic thermal vapour (steam) ablation for upper-lobe emphysema is usually done using general anaesthesia. A bronchoscope is passed down the airway to the diseased areas of the lung. The most severely affected and hyper-inflated lung segments are targeted for treatment. A catheter is used to deliver a patient-specific predetermined dose of thermal vapour through the bronchoscope. A balloon at the tip of the catheter is inflated to seal off the targeted area. The dose of thermal vapour depends on the mass, volume and diseased state of the affected area. The thermal vapour ablates the diseased tissue, which the body removes through the natural healing process. Multiple treatments can be done over time, targeting different segments as the patient's disease progresses. This procedure is not done when there is proven active infection in the lung. The removal of disease tissue results in a reduction of lung volume and subsequent remodelling of the lung. Lung volume reduction typically happens gradually over a 4- to 6‑week period. Respiratory symptoms may worsen in the first 2 to 4 weeks after treatment.
|
{'Recommendations': 'Current evidence on the safety and efficacy of bronchoscopic thermal vapour ablation for upper-lobe emphysema is inadequate in quantity and quality. Therefore, the procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should evaluate safety and efficacy in the short and long term and include details of patient selection. NICE may update the guidance on publication of further evidence.', 'The condition, current treatments and procedure': "# The condition\n\nEmphysema is a chronic lung disease that typically happens with chronic obstructive pulmonary disease. In emphysema, the walls of the air sacs (alveoli) in the lungs weaken and disintegrate. This leaves behind abnormally large air spaces that stay filled with air even when the patient breathes out. The most common symptoms of emphysema are shortness of breath, coughing, fatigue and weight loss. Recurrent illnesses (such as chest infections) often lead to exacerbations, for which patients may need hospitalisation. Emphysema is usually related to smoking, but other risk factors include air pollution and an inherited alpha-1-antitrypsin deficiency.\n\n# Current treatments\n\nTreatment options include pulmonary rehabilitation (exercise training, breathing retraining, and patient and carer education), stopping smoking, and using inhaled or oral bronchodilators and corticosteroids. Oxygen therapy may also be needed in more severe cases. Lung volume reduction surgery is an option for patients who experience breathlessness, and whose pulmonary function tests and CT scans show severe disease and enlarged air spaces. Surgery can be done thoracoscopically or using an open approach. Endoscopic lung volume reduction techniques include implanting valves or coils. The aim is to reduce the morbidity and mortality associated with conventional surgery.\n\n# The procedure\n\nBronchoscopic thermal vapour (steam) ablation for upper-lobe emphysema is usually done using general anaesthesia. A bronchoscope is passed down the airway to the diseased areas of the lung. The most severely affected and hyper-inflated lung segments are targeted for treatment. A catheter is used to deliver a patient-specific predetermined dose of thermal vapour through the bronchoscope. A balloon at the tip of the catheter is inflated to seal off the targeted area. The dose of thermal vapour depends on the mass, volume and diseased state of the affected area. The thermal vapour ablates the diseased tissue, which the body removes through the natural healing process. Multiple treatments can be done over time, targeting different segments as the patient's disease progresses. This procedure is not done when there is proven active infection in the lung. The removal of disease tissue results in a reduction of lung volume and subsequent remodelling of the lung. Lung volume reduction typically happens gradually over a 4-\xa0to 6‑week period. Respiratory symptoms may worsen in the first 2\xa0to 4\xa0weeks after treatment."}
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https://www.nice.org.uk/guidance/ipg652
|
Evidence-based recommendations on bronchoscopic thermal vapour ablation for upper-lobe emphysema in adults. This involves passing a bronchoscope (a tube with a camera on the end) through the mouth or nose into the lungs. This then delivers steam which destroys the diseased part of the lung, allowing the healthy parts to work better.
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c4a227729d6d6e3754dfee7cd03340fd846eb2f5
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nice
|
Percutaneous insertion of a cerebral protection device to prevent cerebral embolism during TAVI
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Percutaneous insertion of a cerebral protection device to prevent cerebral embolism during TAVI
Evidence-based recommendations on percutaneous insertion of a cerebral protection device to prevent cerebral embolism during TAVI in adults. This involves placing a device inside an artery near the heart.
# Recommendations
The evidence on percutaneous insertion of a cerebral protection device to prevent cerebral embolism during transcatheter aortic valve implantation (TAVI) raises no major safety concerns other than those associated with the TAVI procedure. However, the evidence on efficacy for preventing TAVI-related stroke is inconclusive. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do percutaneous insertion of a cerebral protection device to prevent cerebral embolism during TAVI should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients and their carers understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.
Details of all patients should be entered into the UK TAVI registry.
Patient selection for this procedure should be done by the multidisciplinary team that is considering the suitability of TAVI.
This procedure should only be done in specialised centres, and only by clinicians and teams with specific training and experience in complex endovascular interventions. Centres doing this procedure should have both cardiac and vascular surgical support for the emergency treatment of complications and subsequent patient care.
NICE encourages further research on percutaneous insertion of a cerebral protection device to prevent cerebral embolism during TAVI. This should include details of patient selection and risk stratification for TAVI-related stroke. NICE may update the guidance on publication of further evidence.# The condition and procedure
# The condition
Transcatheter aortic valve implantation (TAVI) aims to provide a less invasive alternative to open cardiac surgery for treating aortic stenosis, avoiding the need for sternotomy and cardiopulmonary bypass. However, debris may be dislodged during the TAVI procedure. This can enter the cerebral circulation and embolise, causing cerebral ischaemic events including a stroke.
# The procedure
Percutaneous insertion of a cerebral protection device aims to prevent debris dislodged during TAVI from passing into the cerebral circulation. The aim is to reduce the risk of cerebral ischaemic events including a stroke.
During the TAVI procedure, before the valve is inserted, a cerebral protection device is inserted percutaneously through the radial or femoral artery. Depending on the type of device used, it is placed into the aortic arch or into the brachiocephalic (innominate) and left common carotid arteries. It is deployed to protect the ostia of the brachiocephalic (innominate) artery and the left common carotid artery. It may also protect the left subclavian artery, depending on the type of device used. It works either by filtering dislodged debris from the blood, or by deflecting dislodged debris away from the cerebral circulation to the systemic circulation. The device is removed at the end of the TAVI procedure.
The evidence review identified 3 types of cerebral protection devices. One is a deflector system that covers all 3 main branches of the aortic arch. The 2 other types cover the brachiocephalic trunk and the left common carotid artery; 1 is a filter system, the other is a deflector system.
|
{'Recommendations': "The evidence on percutaneous insertion of a cerebral protection device to prevent cerebral embolism during transcatheter aortic valve implantation (TAVI) raises no major safety concerns other than those associated with the TAVI procedure. However, the evidence on efficacy for preventing TAVI-related stroke is inconclusive. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do percutaneous insertion of a cerebral protection device to prevent cerebral embolism during TAVI should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients and their carers understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.\n\nDetails of all patients should be entered into the UK TAVI registry.\n\nPatient selection for this procedure should be done by the multidisciplinary team that is considering the suitability of TAVI.\n\nThis procedure should only be done in specialised centres, and only by clinicians and teams with specific training and experience in complex endovascular interventions. Centres doing this procedure should have both cardiac and vascular surgical support for the emergency treatment of complications and subsequent patient care.\n\nNICE encourages further research on percutaneous insertion of a cerebral protection device to prevent cerebral embolism during TAVI. This should include details of patient selection and risk stratification for TAVI-related stroke. NICE may update the guidance on publication of further evidence.", 'The condition and procedure': '# The condition\n\nTranscatheter aortic valve implantation (TAVI) aims to provide a less invasive alternative to open cardiac surgery for treating aortic stenosis, avoiding the need for sternotomy and cardiopulmonary bypass. However, debris may be dislodged during the TAVI procedure. This can enter the cerebral circulation and embolise, causing cerebral ischaemic events including a stroke.\n\n# The procedure\n\nPercutaneous insertion of a cerebral protection device aims to prevent debris dislodged during TAVI from passing into the cerebral circulation. The aim is to reduce the risk of cerebral ischaemic events including a stroke.\n\nDuring the TAVI procedure, before the valve is inserted, a cerebral protection device is inserted percutaneously through the radial or femoral artery. Depending on the type of device used, it is placed into the aortic arch or into the brachiocephalic (innominate) and left common carotid arteries. It is deployed to protect the ostia of the brachiocephalic (innominate) artery and the left common carotid artery. It may also protect the left subclavian artery, depending on the type of device used. It works either by filtering dislodged debris from the blood, or by deflecting dislodged debris away from the cerebral circulation to the systemic circulation. The device is removed at the end of the TAVI procedure.\n\nThe evidence review identified 3\xa0types of cerebral protection devices. One is a deflector system that covers all 3\xa0main branches of the aortic arch. The 2\xa0other types cover the brachiocephalic trunk and the left common carotid artery; 1\xa0is a filter system, the other is a deflector system.'}
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https://www.nice.org.uk/guidance/ipg650
|
Evidence-based recommendations on percutaneous insertion of a cerebral protection device to prevent cerebral embolism during TAVI in adults. This involves placing a device inside an artery near the heart.
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ea593142754e07317bd3cfcb80a99058ef409875
|
nice
|
Ocrelizumab for treating primary progressive multiple sclerosis
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Ocrelizumab for treating primary progressive multiple sclerosis
Evidence-based recommendations on ocrelizumab (Ocrevus) for treating primary progressive multiple sclerosis in adults.
# Recommendations
Ocrelizumab is recommended, within its marketing authorisation, as an option for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
There are currently no disease-modifying treatments available for primary progressive multiple sclerosis. Results of 1 clinical trial show that ocrelizumab can slow the worsening of disability, although the size and duration of this effect are uncertain.
Given the unmet clinical need, the most plausible cost-effectiveness estimates for ocrelizumab at the agreed price compared with best supportive care alone are in the range that NICE considers an acceptable use of NHS resources. Because of this, ocrelizumab is recommended for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults.# Information about ocrelizumab
Marketing authorisation indication
Ocrelizumab (Ocrevus, Roche) has a marketing authorisation in the UK 'for the treatment of adult patients with early primary progressive multiple sclerosis in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity'.
Dosage in the marketing authorisation
Ocrelizumab is administered by intravenous infusion. The first dose is administered as 2×300 mg infusions 2 weeks apart; subsequent doses are administered as a single 600 mg infusion every 6 months. There should be a minimum interval of 5 months between each dose.
Price
The list price for ocrelizumab is £4,790 per 300‑mg vial (company submission).
The company has a commercial arrangement. This makes ocrelizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# The condition and current care pathway
## Primary progressive multiple sclerosis has a substantial effect on the lives of people with the condition and their families
Other than ocrelizumab, there are currently no disease-modifying treatments with a marketing authorisation for primary progressive multiple sclerosis. So, unlike for relapsing–remitting multiple sclerosis, clinicians can only offer interventions that manage symptoms. The patient experts explained that having a diagnosis of primary progressive multiple sclerosis often helps people understand the cause of their symptoms, but learning that there are no treatment options to slow the disease process can cause anxiety. The experts further commented that people with the condition often have to reduce work commitments and may be unable to continue their usual daily activities. They highlighted the loss of confidence and depression that this causes, and that people feel the condition reduces what they are able to contribute to society. The committee noted the submissions it had received from patient and carer organisations, and comments received at consultation. These detailed how many people with primary progressive multiple sclerosis eventually need support and care from family members or friends, and that ocrelizumab has provided hope of slowing disability progression for people diagnosed with the condition. The committee concluded that primary progressive multiple sclerosis can substantially affect the lives of people with the condition and their families, and that disease-modifying treatments would be welcome.
## Slowing disability progression and preserving upper limb function allow people to continue working, and to engage in everyday activities and self-care
A patient expert explained that, after starting treatment with ocrelizumab, his condition had improved. This had allowed him to keep working, particularly because of the treatment's effect on his upper limb function. In addition, patient experts and clinical experts explained that preserving upper limb function is important because it allows people to continue to care for themselves and reduces their reliance on others. The clinical experts noted that it is important to preserve upper limb function in all forms of multiple sclerosis. The committee noted that slowing disability progression allows people to stay in work and engage in everyday activities for longer than they may have done without treatment. It concluded that slowing disability progression and preserving upper limb function will allow people with primary progressive multiple sclerosis, as with other forms of multiple sclerosis, to continue working, engage in everyday activities and care for themselves for longer.
## Diagnosing the condition is difficult and identifying who will benefit from ocrelizumab could increase demand for MRI scans
The clinical experts explained that diagnosing primary progressive multiple sclerosis is difficult because of the gradual, progressive nature of the condition, and the non-specific symptoms. In addition, it is hard to determine the time since onset of the condition because there is often no clear initial event. NICE must appraise drugs within the confines of the marketing authorisation determined by the regulators; the committee noted that the marketing authorisation limits treatment to early primary progressive multiple sclerosis with imaging features that are characteristic of inflammatory activity. The committee was aware that this needs either a single T1 MRI scan with a contrast agent (gadolinium) to identify acute inflammatory lesions, or at least 2 T2 MRI scans to identify new or enlarging lesions. A clinical expert explained that use of gadolinium is reducing because of concerns over longer-term safety, but that T2 scans could be used to identify inflammatory activity and to monitor change, and that they do not rely on an active lesion at the time of imaging. The company included the cost of an MRI scan, without contrast, per person having ocrelizumab in the economic model, and the cost of a further MRI scan, without contrast, for 70% of people (assuming that 30% of people with primary progressive multiple sclerosis would already have had a suitable MRI scan). A patient expert commented that repeated MRI scans are not currently done to monitor inflammatory activity because no disease-modifying treatments are available for primary progressive multiple sclerosis. The committee concluded that the use of ocrelizumab could result in increased demand for MRI scans.
# Clinical effectiveness
## It is appropriate to use data from the 'MRI-active' subgroup rather than from everyone in the ORATORIO trial
The company used the ORATORIO trial to provide evidence of the efficacy of ocrelizumab to treat primary progressive multiple sclerosis. ORATORIO was a double-blind, placebo-controlled trial including 732 people from 29 countries. The committee noted that it did not enrol people aged over 55 years. A clinical expert commented that this is generally the case for trials in multiple sclerosis, and that the results could be considered generalisable to people in this age group. The committee further noted that the marketing authorisation for ocrelizumab was narrower than the inclusion criteria for the ORATORIO trial (that is, the entire or intention-to-treat population). The company explained that it had provided a post-hoc subgroup analysis of people in the ORATORIO trial with gadolinium-enhancing T1 lesions at screening or baseline, or with new T2 lesions between screening and baseline, to match the specification in the marketing authorisation for 'imaging features characteristic of inflammatory activity' (MRI-active subgroup). The committee noted that the trial was not powered for this group, so the real difference in treatment may have been missed. The clinical experts explained that the company's method of identifying people with imaging features characteristic of inflammatory activity met accepted definitions. The committee concluded that it was appropriate to use data from the MRI-active subgroup from ORATORIO for decision making.
## Defining early primary progressive multiple sclerosis is difficult in NHS practice
The marketing authorisation for ocrelizumab includes restricting treatment to primary progressive multiple sclerosis that is 'early' in terms of duration and level of disability. The company considered that everyone enrolled in the ORATORIO trial met this definition; specifically, the trial included only people who, at screening, had:
an expanded disability status scale (EDSS) score from 3.0 to 6.5 points
a time since onset of symptoms of:
less than 15 years if the EDSS score was more than 5.0 or
less than 10 years if the EDSS score was 5.0 or less.The committee noted that the European Medicines Agency (EMA) had defined early primary progressive multiple sclerosis in the summary of product characteristics with reference to the main inclusion criteria of the ORATORIO trial. The clinical experts considered this to be too long to reflect 'early' disease, but also noted that there is no clear definition of early disease. The ERG commented that the clinical experts it had consulted suggested that they would define early disease as being within 5 years of symptom onset. The committee concluded that defining 'early' disease in NHS practice is difficult but that, for the purpose of this appraisal, early primary progressive multiple sclerosis is as defined by the EMA for the marketing authorisation.
## It is not appropriate to limit estimates of clinical and cost effectiveness, and this guidance to people aged 50 years or under
The company provided clinical data from a subgroup of the MRI-active subgroup limited to people aged 50 years or under (that is, younger than the inclusion criteria of the trial), and modelled the cost effectiveness of ocrelizumab for this subgroup. The committee noted that the marketing authorisation does not specify an age threshold for treatment. It concluded that, in the absence of a clear biological rationale to exclude data from patients aged 50 to 55 years, it was not appropriate to define an age limit in this guidance.
## Confirmed disability progression at 24 weeks is preferable to that at 12 weeks
The primary end point in the ORATORIO trial was time to disability progression confirmed after 12 weeks ('confirmed disability progression', CDP‑12). Time to disability progression confirmed after 24 weeks (CDP‑24) was a secondary end point. In the MRI-active subgroup, the treatment effect was slightly larger for CDP‑12 (hazard ratio 0.68; 95% confidence interval 0.46 to 0.99) than for CDP‑24 (hazard ratio 0.71; 95% confidence interval 0.47 to 1.06). The clinical experts commented that there is no consensus on what a 'clinically significant' effect is because there is no precedent for treating primary progressive multiple sclerosis. The committee noted that, in previous appraisals for relapsing–remitting multiple sclerosis, disability confirmed at 24 weeks (6 months) had been preferred because of higher specificity than disability confirmed at 12 weeks (3 months). The committee considered whether there were reasons why this should differ for primary progressive multiple sclerosis. A clinical expert commented that confirming disability after a longer period would be more reliable than after a shorter period in primary progressive multiple sclerosis, as it is in relapsing–remitting multiple sclerosis. The committee concluded that it preferred analyses using CDP after 24 weeks to after 12 weeks.
## The treatment effect size estimated from the double-blind ORATORIO trial is preferable to using data from the open-label extension study
In response to consultation, the company provided estimates of treatment effectiveness that included data from an ongoing open-label extension of the ORATORIO trial combined with data from the double-blind treatment period. During the open-label extension, patients were made aware of their treatment allocation and those who had had placebo were able to switch to ocrelizumab. To calculate the treatment effect including the open-label data, the company used the Rank Preserving Structural Failure Time model to adjust for treatment switching. These data are academic in confidence so cannot be reported here. This resulted in estimated treatment effects for CDP‑12 and CDP‑24 that were greater than the effects estimated using data from the double-blind treatment period only. The ERG commented that using unblinded data increased the risk of both performance and detection bias and, acknowledging this, the committee questioned why these data had been used. The company explained that the data decreased uncertainty by providing longer follow‑up, which captured a 'lag time' to maximum treatment effect. The committee noted that, unlike results from the double-blind period alone, the treatment effect was larger for CDP‑24 than for CDP‑12 when the open-label extension data were incorporated. The committee was aware that, in other NICE appraisals, observational follow‑up provides information on objective measures, such as death. However, it noted that disability progression is a subjective outcome and, compared with a double-blind study, an open-label study increases the risk of misclassifying outcomes. The committee concluded that using data from the open-label extension increased uncertainty about the size of the treatment effect. It further concluded that it preferred to use analyses that incorporated data from only the double-blind period of the ORATORIO trial, so it did not need to consider the methods that the company used to adjust for crossover.
# Cost effectiveness
## It is appropriate to include costs, disutilities and a treatment effect associated with relapses in the economic model
The clinical experts explained that relapses occur in primary progressive multiple sclerosis but do not characterise the condition in the way that they do for relapsing–remitting multiple sclerosis. The company excluded costs, disutilities and a treatment effect associated with ocrelizumab for relapses in its base-case model. The committee concluded that it would have been appropriate for the company to include costs, disutilities and a treatment effect associated with relapses in its base-case analysis. It noted that the company had done this in its revised base-case analysis submitted at consultation.
# Adverse events
## Infections and progressive multifocal leukoencephalopathy (PML) are possible adverse events associated with ocrelizumab
The committee questioned why the company had not included adverse events related to infection in the model, given that a high proportion of people in both the treatment (70%) and placebo (68%) arms of the ORATORIO trial had experienced infections. The company explained that it had focused on a specific infection (upper respiratory tract infection), which occurred with the largest difference in frequencies between the ocrelizumab and placebo arms. The company explained that it could assign specific costs and utility values to upper respiratory tract infections, but not to aggregated infections. The committee also questioned why the company had not included PML in its model, noting that this had been considered as relevant in the then ongoing appraisal of ocrelizumab for relapsing–remitting multiple sclerosis. The company commented that it had included PML as an adverse event in an updated model for the relapsing–remitting multiple sclerosis appraisal, but only because it can be attributed to previous disease-modifying treatments. The company excluded it from the model for primary progressive multiple sclerosis because there have not yet been any recorded cases of PML after treatment with ocrelizumab in people with this condition. The clinical experts commented that PML is related to the treatment rather than the condition, and it would be inconsistent to consider that PML could occur in 1 type of multiple sclerosis, but not another. The committee concluded that ORATORIO was far too small and short to identify the real risk of PML. The committee concluded that there may be a risk of PML after treatment with ocrelizumab and that, if so, the economic model should include this. At consultation, the company submitted a revised base-case analysis that included PML as an adverse event.
## It is appropriate to use registry data to inform baseline transitions between EDSS states
To inform the progression of disability between EDSS states in the absence of treatment, the company chose not to use data from the placebo group of the ORATORIO trial but instead to use data from a disease registry (MSBase) in its model. The company explained that it had used registry data because they reflect a larger population over a longer follow-up period. It also explained that it had chosen not to use registries that have been used in previous relapsing–remitting multiple sclerosis appraisals, such as the London Ontario registry, because these included few people with primary progressive multiple sclerosis. The ERG highlighted that MSBase was not restricted to people with primary progressive multiple sclerosis who had MRI scans showing inflammatory activity. The company acknowledged that limited MRI data are available from the MSBase registry, and the clinical experts confirmed this. Moreover, the clinical experts commented that many patients represented in the MSBase registry come from Eastern Europe, where the definition of primary progressive multiple sclerosis may differ from the UK. However, at consultation, the company commented that 80% of patients represented in the MSBase dataset came from Canada, Spain, Italy, the Netherlands and Australia. The committee also noted that there were few data available to inform estimates of transition probabilities between all EDSS states from the ORATORIO trial. It therefore concluded that it was appropriate to use the MSBase registry to inform baseline transitions between EDSS states in the absence of treatment in the company's model.
# Waning of treatment efficacy
## Treatment efficacy may wane over time with ocrelizumab, but the absolute rate of waning is uncertain
The company assumed in its original base case that the relative treatment effect of ocrelizumab did not wane over time (that is, it worked equally well early and late in the course of treatment). It assumed this because ocrelizumab generates few neutralising antibodies, and because there was a sustained treatment effect in an open-label extension of a trial in relapsing–remitting multiple sclerosis. The company also assumed that people would stop taking ocrelizumab if they no longer gained benefit from it. Therefore, the company considered that including all-cause stopping of treatment in the economic model (see section 3.13) would act as a proxy for any waning of treatment effect in its original base-case analysis. The ERG considered it implausible that there is no waning of treatment effect and applied a decline in treatment effect from year 5. The ERG did this because treatment effect fluctuated over the course of the ORATORIO trial, and there was no evidence to show a long-term sustained effect. At consultation, the company submitted data from the most recent data cut of an ongoing open-label extension to the ORATORIO trial, which provided almost 6.5 years of data. The company used these to support a revised base-case analysis, which assumed a treatment waning effect from 10 years. The ERG commented that data from the open-label extension were reasonable evidence to support the absence of a treatment waning effect beyond 5 years, and revised its base-case analysis to assume a decline in treatment efficacy from 7 years. The committee noted that, in an appraisal for ocrelizumab for relapsing–remitting multiple sclerosis, the committee considered that treatment efficacy likely wanes over time. The committee concluded that the company's original assumption of no waning of treatment effect was too optimistic but that, acknowledging the issues of the open-label extension (see section 3.8), the ERG's approach may still be too pessimistic. It concluded that the true waning of treatment effect is likely to lie between the company's and ERG's updated approaches, and that exploring assumptions of treatment waning from between 7 years and 10 years is reasonable.
# Stopping treatment
## There is considerable uncertainty about how long people would take ocrelizumab
The company modelled stopping of treatment (because of adverse events or because it does not work) by fitting a Gompertz distribution to data from the whole population rather than the MRI-active subgroup in ORATORIO. However, the company stated that 'clinical opinion' considered the average treatment duration predicted by this model to be too high (about 7.0 years). It provided what it considered a more realistic scenario analysis with a higher and constant treatment withdrawal rate, which predicted an average treatment duration of about 4.5 years. The ERG also used a Gompertz model in its base case, and considered that the rate of stopping treatment would rise as the effect of ocrelizumab waned (after 5.0 years in its original base case and 7.0 years in its revised base case; see section 3.12), adding this to its base case. The company's revised base case assumed an increase in the rate of stopping treatment at 5.0 years, to match the ERG's original base case. The ERG commented that this did not match its approach because it preferred to link treatment waning (by applying a reduced treatment effect) and an increased rate of stopping treatment. The committee considered that this approach may be too conservative because people remaining on the drug would be expected to show a good response, and would potentially not experience a reduced treatment effect. It concluded that there is considerable uncertainty about how long people would take ocrelizumab, but that the ERG's base case is likely to have overestimated the rate of stopping treatment.
## There is considerable uncertainty about an appropriate stopping rule for disease-modifying therapies for primary progressive multiple sclerosis
Both the company and ERG assumed in their original base cases that people whose disease progressed to EDSS state 8.0 would stop ocrelizumab. The clinical experts commented that this was later than when people stop disease-modifying treatments in relapsing–remitting multiple sclerosis, which is when a person's condition reaches and stays at EDSS state 7.0 for more than 6 months. Both the company and ERG assumed that treatment would stop when a person's condition reached EDSS state 7.0 in their revised base cases. The clinical experts commented that an argument can be made for continuing treatment to EDSS state 8.0 because preserving upper limb function is particularly important once people are unable to walk. This was supported by comments from a patient group received during consultation. However, the committee and experts considered that this argument would apply equally to people with relapsing–remitting multiple sclerosis. The clinical experts noted that the ORATORIO trial enrolled people with multiple sclerosis with an EDSS only up to state 6.5, so there is no evidence for efficacy when starting treatment beyond this state, and that the ORATORIO trial did not have a stopping rule. The committee discussed the need for better disease models in multiple sclerosis. It concluded that, although there is considerable uncertainty, it had not been presented with any evidence to support a stopping rule that differed by type of multiple sclerosis.
# Utility values
## It is appropriate to use utility values from the ORATORIO study for EDSS states, supplemented by values from the literature
The company used utility values derived from the ORATORIO trial for most EDSS states in its base case. For EDSS states (0, 1, 8 and 9) for which ORATORIO offered no data, the company used utility values specific to primary progressive multiple sclerosis from Multiple Sclerosis Trust survey data (Orme et al. 2007). The committee noted that the utility values from ORATORIO were higher than those from Orme et al. and another study in primary progressive multiple sclerosis (Hawton and Green, 2016). The company suggested that the utility values from ORATORIO were higher because people in the ORATORIO trial were younger (mean age 44 years) than in the other studies. The committee noted that the population for which NICE's recommendations apply include people aged over 55 years, who are not represented in ORATORIO. It also commented that a more recent publication than Orme et al. was available. At consultation, the company clarified, to the satisfaction of the committee, an issue of what appeared to be higher utility values for higher states of disability. The company also commented that people with inflammatory activity would be younger, and that few patients aged over 55 years would be eligible for ocrelizumab, based on data from the ORATORIO trial. The company believed that utility values from ORATORIO were a better match for the population within the marketing authorisation for ocrelizumab. The committee concluded that using different sources of utility data was acceptable when there were no trial data for EDSS states.
## It is not appropriate to include additional utility decrements for upper limb dysfunction and fatigue
In addition to applying utility values for each EDSS state, in its original base-case model, the company also applied a utility decrement to each EDSS state for people with upper limb dysfunction and those with 'clinically meaningful fatigue'. The committee noted that upper limb function and fatigue were among 17 exploratory end points included in the protocol for ORATORIO. It questioned why the company had selected these outcomes to include in the model rather than the many other exploratory end points measured. The committee was aware of statistical principles for clinical trials from the regulators, which deem results only from planned analyses to be confirmatory. The company explained that they did this because its analysis on data from ORATORIO showed that these factors affected health-related quality of life independent of EDSS state. The ERG disagreed with including additional utility decrements in the model, and did not include them in its own base case. It noted that ocrelizumab did not reduce fatigue (based on change in baseline score) in the MRI-active subgroup. It also noted that the company defined people as having clinically meaningful fatigue using cut-offs on the Modified Fatigue Impact Scale (MFIS). However, the ERG noted that cut-offs are not normally used with fatigue scores, and that most people entering the ORATORIO trial had fatigue based on the company's definition. The ERG also highlighted that previous appraisals for multiple sclerosis had not used specific utility decrements for symptoms associated with multiple sclerosis. The clinical experts commented that fatigue and upper limb function are equally important for people with relapsing–remitting multiple sclerosis. The committee noted that the company's approach would double-count disutilities incorporated within the EQ‑5D because the MFIS and EQ‑5D questionnaires overlap in some domains. At consultation, the company submitted a revised base case that excluded a utility decrement for fatigue, but still included a decrement for upper limb dysfunction. The ERG commented that the measure of upper limb function used in ORATORIO (changes in time to complete the 9‑hole peg test) may not reflect changes in upper limb function that matter to people, such as reduced ability to wash, dress and feed themselves. The committee objected to using chosen selected exploratory end points in the modelling without considering the risk of false-positive findings. The committee still considered at its second meeting that including decrements for upper limb function, decreasing utilities as people progressed through EDSS states, and carer disutilities likely overestimated the effect of ocrelizumab on slowing disability progression. It therefore concluded that it was inappropriate to include utility decrements from upper limb dysfunction and fatigue in the economic model.
# Cost-effectiveness estimates
## Ocrelizumab is a cost-effective use of NHS resources
In a second revised base case, the company estimated the incremental cost-effectiveness ratio (ICER) for the MRI-active subgroup with an updated commercial arrangement. The company's model for this base case included the committee's preferred changes to the company's original submission, and to its first revision. These were:
including costs, disutilities and a treatment effect associated with relapses (see section 3.9)
including the risk of PML (see section 3.10)
using CDP‑24 to estimate treatment effect (see section 3.7)
removing a utility decrement for fatigue and for upper limb dysfunction (see section 3.16)
using data from the double-blind period of the ORATORIO trial to estimate treatment effect (see section 3.8).The company also provided 2 versions of its second revised base-case model, with treatment waning from either 7 or 10 years (see section 3.12). The ERG confirmed that the company's revised model reflected the committee's preferences. The ERG also re-ran the company's probabilistic analyses. The discount and the ICERs are confidential and the exact values cannot be reported here. The committee, in its third meeting, acknowledged that uncertainties remained about the true rate of treatment waning (see section 3.12) and how long people would continue to take ocrelizumab (see section 3.13). It again acknowledged that there is an unmet need for disease-modifying treatment for this condition (see section 3.1). The committee concluded that the most plausible ICER for ocrelizumab compared with best supportive care alone was within the range generally considered to reflect good value for treating conditions without any other treatment options. It further concluded that ocrelizumab, with the commercial arrangement, was cost effective for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults.
# Innovation
## Ocrelizumab is an innovative treatment for primary progressive multiple sclerosis
The company stated that ocrelizumab is an innovative treatment because it is the only approved disease-modifying treatment for use in primary progressive multiple sclerosis. The committee noted that there is a considerable unmet need for treatment (see section 3.1) for this condition, so ocrelizumab reflects a 'step change' in treatment. The company stated that it believed its model captured all quality-adjusted life year (QALY) benefits. The committee agreed that ocrelizumab is a 'step change' in the treatment of primary progressive multiple sclerosis, and that it had not been presented with evidence of any additional benefits not captured in the QALY measurements.
# Conclusion
## Ocrelizumab is recommended for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults
Ocrelizumab slows disability progression compared with placebo, although the size and duration of the effect are uncertain. There is a large unmet need for treating primary progressive multiple sclerosis because no disease-modifying treatments are currently available (see section 3.1). The committee concluded that the ICERs generated by the economic model for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults represented a cost-effective use of NHS resources at the price reflected within the commercial arrangement.
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{'Recommendations': 'Ocrelizumab is recommended, within its marketing authorisation, as an option for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThere are currently no disease-modifying treatments available for primary progressive multiple sclerosis. Results of 1\xa0clinical trial show that ocrelizumab can slow the worsening of disability, although the size and duration of this effect are uncertain.\n\nGiven the unmet clinical need, the most plausible cost-effectiveness estimates for ocrelizumab at the agreed price compared with best supportive care alone are in the range that NICE considers an acceptable use of NHS resources. Because of this, ocrelizumab is recommended for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults.', 'Information about ocrelizumab': "Marketing authorisation indication\n\nOcrelizumab (Ocrevus, Roche) has a marketing authorisation in the UK 'for the treatment of adult patients with early primary progressive multiple sclerosis in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity'.\n\nDosage in the marketing authorisation\n\nOcrelizumab is administered by intravenous infusion. The first dose is administered as\xa02×300\xa0mg infusions 2\xa0weeks apart; subsequent doses are administered as a single 600\xa0mg infusion every 6\xa0months. There should be a minimum interval of 5\xa0months between each dose.\n\nPrice\n\nThe list price for ocrelizumab is £4,790 per 300‑mg vial (company submission).\n\nThe company has a commercial arrangement. This makes ocrelizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# The condition and current care pathway\n\n## Primary progressive multiple sclerosis has a substantial effect on the lives of people with the condition and their families\n\nOther than ocrelizumab, there are currently no disease-modifying treatments with a marketing authorisation for primary progressive multiple sclerosis. So, unlike for relapsing–remitting multiple sclerosis, clinicians can only offer interventions that manage symptoms. The patient experts explained that having a diagnosis of primary progressive multiple sclerosis often helps people understand the cause of their symptoms, but learning that there are no treatment options to slow the disease process can cause anxiety. The experts further commented that people with the condition often have to reduce work commitments and may be unable to continue their usual daily activities. They highlighted the loss of confidence and depression that this causes, and that people feel the condition reduces what they are able to contribute to society. The committee noted the submissions it had received from patient and carer organisations, and comments received at consultation. These detailed how many people with primary progressive multiple sclerosis eventually need support and care from family members or friends, and that ocrelizumab has provided hope of slowing disability progression for people diagnosed with the condition. The committee concluded that primary progressive multiple sclerosis can substantially affect the lives of people with the condition and their families, and that disease-modifying treatments would be welcome.\n\n## Slowing disability progression and preserving upper limb function allow people to continue working, and to engage in everyday activities and self-care\n\nA patient expert explained that, after starting treatment with ocrelizumab, his condition had improved. This had allowed him to keep working, particularly because of the treatment's effect on his upper limb function. In addition, patient experts and clinical experts explained that preserving upper limb function is important because it allows people to continue to care for themselves and reduces their reliance on others. The clinical experts noted that it is important to preserve upper limb function in all forms of multiple sclerosis. The committee noted that slowing disability progression allows people to stay in work and engage in everyday activities for longer than they may have done without treatment. It concluded that slowing disability progression and preserving upper limb function will allow people with primary progressive multiple sclerosis, as with other forms of multiple sclerosis, to continue working, engage in everyday activities and care for themselves for longer.\n\n## Diagnosing the condition is difficult and identifying who will benefit from ocrelizumab could increase demand for MRI scans\n\nThe clinical experts explained that diagnosing primary progressive multiple sclerosis is difficult because of the gradual, progressive nature of the condition, and the non-specific symptoms. In addition, it is hard to determine the time since onset of the condition because there is often no clear initial event. NICE must appraise drugs within the confines of the marketing authorisation determined by the regulators; the committee noted that the marketing authorisation limits treatment to early primary progressive multiple sclerosis with imaging features that are characteristic of inflammatory activity. The committee was aware that this needs either a single T1\xa0MRI scan with a contrast agent (gadolinium) to identify acute inflammatory lesions, or at least 2\xa0T2\xa0MRI scans to identify new or enlarging lesions. A clinical expert explained that use of gadolinium is reducing because of concerns over longer-term safety, but that T2\xa0scans could be used to identify inflammatory activity and to monitor change, and that they do not rely on an active lesion at the time of imaging. The company included the cost of an MRI scan, without contrast, per person having ocrelizumab in the economic model, and the cost of a further MRI scan, without contrast, for 70% of people (assuming that 30% of people with primary progressive multiple sclerosis would already have had a suitable MRI scan). A patient expert commented that repeated MRI scans are not currently done to monitor inflammatory activity because no disease-modifying treatments are available for primary progressive multiple sclerosis. The committee concluded that the use of ocrelizumab could result in increased demand for MRI scans.\n\n# Clinical effectiveness\n\n## It is appropriate to use data from the 'MRI-active' subgroup rather than from everyone in the ORATORIO trial\n\nThe company used the ORATORIO trial to provide evidence of the efficacy of ocrelizumab to treat primary progressive multiple sclerosis. ORATORIO was a double-blind, placebo-controlled trial including 732\xa0people from 29\xa0countries. The committee noted that it did not enrol people aged over 55\xa0years. A clinical expert commented that this is generally the case for trials in multiple sclerosis, and that the results could be considered generalisable to people in this age group. The committee further noted that the marketing authorisation for ocrelizumab was narrower than the inclusion criteria for the ORATORIO trial (that is, the entire or intention-to-treat population). The company explained that it had provided a post-hoc subgroup analysis of people in the ORATORIO trial with gadolinium-enhancing T1\xa0lesions at screening or baseline, or with new T2\xa0lesions between screening and baseline, to match the specification in the marketing authorisation for 'imaging features characteristic of inflammatory activity' (MRI-active subgroup). The committee noted that the trial was not powered for this group, so the real difference in treatment may have been missed. The clinical experts explained that the company's method of identifying people with imaging features characteristic of inflammatory activity met accepted definitions. The committee concluded that it was appropriate to use data from the MRI-active subgroup from ORATORIO for decision making.\n\n## Defining early primary progressive multiple sclerosis is difficult in NHS practice\n\nThe marketing authorisation for ocrelizumab includes restricting treatment to primary progressive multiple sclerosis that is 'early' in terms of duration and level of disability. The company considered that everyone enrolled in the ORATORIO trial met this definition; specifically, the trial included only people who, at screening, had:\n\nan expanded disability status scale (EDSS) score from 3.0 to 6.5\xa0points\n\na time since onset of symptoms of:\n\n\n\nless than 15\xa0years if the EDSS score was more than\xa05.0 or\n\nless than 10\xa0years if the EDSS score was\xa05.0 or less.The committee noted that the European Medicines Agency (EMA) had defined early primary progressive multiple sclerosis in the summary of product characteristics with reference to the main inclusion criteria of the ORATORIO trial. The clinical experts considered this to be too long to reflect 'early' disease, but also noted that there is no clear definition of early disease. The ERG commented that the clinical experts it had consulted suggested that they would define early disease as being within 5\xa0years of symptom onset. The committee concluded that defining 'early' disease in NHS practice is difficult but that, for the purpose of this appraisal, early primary progressive multiple sclerosis is as defined by the EMA for the marketing authorisation.\n\n\n\n## It is not appropriate to limit estimates of clinical and cost effectiveness, and this guidance to people aged 50\xa0years or under\n\nThe company provided clinical data from a subgroup of the MRI-active subgroup limited to people aged 50\xa0years or under (that is, younger than the inclusion criteria of the trial), and modelled the cost effectiveness of ocrelizumab for this subgroup. The committee noted that the marketing authorisation does not specify an age threshold for treatment. It concluded that, in the absence of a clear biological rationale to exclude data from patients aged 50\xa0to 55\xa0years, it was not appropriate to define an age limit in this guidance.\n\n## Confirmed disability progression at 24\xa0weeks is preferable to that at 12\xa0weeks\n\nThe primary end point in the ORATORIO trial was time to disability progression confirmed after 12\xa0weeks ('confirmed disability progression', CDP‑12). Time to disability progression confirmed after 24\xa0weeks (CDP‑24) was a secondary end point. In the MRI-active subgroup, the treatment effect was slightly larger for CDP‑12 (hazard ratio\xa00.68; 95%\xa0confidence interval 0.46 to 0.99) than for CDP‑24 (hazard ratio\xa00.71; 95%\xa0confidence interval 0.47 to 1.06). The clinical experts commented that there is no consensus on what a 'clinically significant' effect is because there is no precedent for treating primary progressive multiple sclerosis. The committee noted that, in previous appraisals for relapsing–remitting multiple sclerosis, disability confirmed at 24\xa0weeks (6\xa0months) had been preferred because of higher specificity than disability confirmed at 12\xa0weeks (3\xa0months). The committee considered whether there were reasons why this should differ for primary progressive multiple sclerosis. A clinical expert commented that confirming disability after a longer period would be more reliable than after a shorter period in primary progressive multiple sclerosis, as it is in relapsing–remitting multiple sclerosis. The committee concluded that it preferred analyses using CDP after 24\xa0weeks to after 12\xa0weeks.\n\n## The treatment effect size estimated from the double-blind ORATORIO trial is preferable to using data from the open-label extension study\n\nIn response to consultation, the company provided estimates of treatment effectiveness that included data from an ongoing open-label extension of the ORATORIO trial combined with data from the double-blind treatment period. During the open-label extension, patients were made aware of their treatment allocation and those who had had placebo were able to switch to ocrelizumab. To calculate the treatment effect including the open-label data, the company used the Rank Preserving Structural Failure Time model to adjust for treatment switching. These data are academic in confidence so cannot be reported here. This resulted in estimated treatment effects for CDP‑12 and CDP‑24 that were greater than the effects estimated using data from the double-blind treatment period only. The ERG commented that using unblinded data increased the risk of both performance and detection bias and, acknowledging this, the committee questioned why these data had been used. The company explained that the data decreased uncertainty by providing longer follow‑up, which captured a 'lag time' to maximum treatment effect. The committee noted that, unlike results from the double-blind period alone, the treatment effect was larger for CDP‑24 than for CDP‑12 when the open-label extension data were incorporated. The committee was aware that, in other NICE appraisals, observational follow‑up provides information on objective measures, such as death. However, it noted that disability progression is a subjective outcome and, compared with a double-blind study, an open-label study increases the risk of misclassifying outcomes. The committee concluded that using data from the open-label extension increased uncertainty about the size of the treatment effect. It further concluded that it preferred to use analyses that incorporated data from only the double-blind period of the ORATORIO trial, so it did not need to consider the methods that the company used to adjust for crossover.\n\n# Cost effectiveness\n\n## It is appropriate to include costs, disutilities and a treatment effect associated with relapses in the economic model\n\nThe clinical experts explained that relapses occur in primary progressive multiple sclerosis but do not characterise the condition in the way that they do for relapsing–remitting multiple sclerosis. The company excluded costs, disutilities and a treatment effect associated with ocrelizumab for relapses in its base-case model. The committee concluded that it would have been appropriate for the company to include costs, disutilities and a treatment effect associated with relapses in its base-case analysis. It noted that the company had done this in its revised base-case analysis submitted at consultation.\n\n# Adverse events\n\n## Infections and progressive multifocal leukoencephalopathy (PML) are possible adverse events associated with ocrelizumab\n\nThe committee questioned why the company had not included adverse events related to infection in the model, given that a high proportion of people in both the treatment (70%) and placebo (68%) arms of the ORATORIO trial had experienced infections. The company explained that it had focused on a specific infection (upper respiratory tract infection), which occurred with the largest difference in frequencies between the ocrelizumab and placebo arms. The company explained that it could assign specific costs and utility values to upper respiratory tract infections, but not to aggregated infections. The committee also questioned why the company had not included PML in its model, noting that this had been considered as relevant in the then ongoing appraisal of ocrelizumab for relapsing–remitting multiple sclerosis. The company commented that it had included PML as an adverse event in an updated model for the relapsing–remitting multiple sclerosis appraisal, but only because it can be attributed to previous disease-modifying treatments. The company excluded it from the model for primary progressive multiple sclerosis because there have not yet been any recorded cases of PML after treatment with ocrelizumab in people with this condition. The clinical experts commented that PML is related to the treatment rather than the condition, and it would be inconsistent to consider that PML could occur in 1\xa0type of multiple sclerosis, but not another. The committee concluded that ORATORIO was far too small and short to identify the real risk of PML. The committee concluded that there may be a risk of PML after treatment with ocrelizumab and that, if so, the economic model should include this. At consultation, the company submitted a revised base-case analysis that included PML as an adverse event.\n\n## It is appropriate to use registry data to inform baseline transitions between EDSS states\n\nTo inform the progression of disability between EDSS states in the absence of treatment, the company chose not to use data from the placebo group of the ORATORIO trial but instead to use data from a disease registry (MSBase) in its model. The company explained that it had used registry data because they reflect a larger population over a longer follow-up period. It also explained that it had chosen not to use registries that have been used in previous relapsing–remitting multiple sclerosis appraisals, such as the London Ontario registry, because these included few people with primary progressive multiple sclerosis. The ERG highlighted that MSBase was not restricted to people with primary progressive multiple sclerosis who had MRI scans showing inflammatory activity. The company acknowledged that limited MRI data are available from the MSBase registry, and the clinical experts confirmed this. Moreover, the clinical experts commented that many patients represented in the MSBase registry come from Eastern Europe, where the definition of primary progressive multiple sclerosis may differ from the UK. However, at consultation, the company commented that 80% of patients represented in the MSBase dataset came from Canada, Spain, Italy, the Netherlands and Australia. The committee also noted that there were few data available to inform estimates of transition probabilities between all EDSS states from the ORATORIO trial. It therefore concluded that it was appropriate to use the MSBase registry to inform baseline transitions between EDSS states in the absence of treatment in the company's model.\n\n# Waning of treatment efficacy\n\n## Treatment efficacy may wane over time with ocrelizumab, but the absolute rate of waning is uncertain\n\nThe company assumed in its original base case that the relative treatment effect of ocrelizumab did not wane over time (that is, it worked equally well early and late in the course of treatment). It assumed this because ocrelizumab generates few neutralising antibodies, and because there was a sustained treatment effect in an open-label extension of a trial in relapsing–remitting multiple sclerosis. The company also assumed that people would stop taking ocrelizumab if they no longer gained benefit from it. Therefore, the company considered that including all-cause stopping of treatment in the economic model (see section\xa03.13) would act as a proxy for any waning of treatment effect in its original base-case analysis. The ERG considered it implausible that there is no waning of treatment effect and applied a decline in treatment effect from year\xa05. The ERG did this because treatment effect fluctuated over the course of the ORATORIO trial, and there was no evidence to show a long-term sustained effect. At consultation, the company submitted data from the most recent data cut of an ongoing open-label extension to the ORATORIO trial, which provided almost 6.5\xa0years of data. The company used these to support a revised base-case analysis, which assumed a treatment waning effect from 10\xa0years. The ERG commented that data from the open-label extension were reasonable evidence to support the absence of a treatment waning effect beyond 5\xa0years, and revised its base-case analysis to assume a decline in treatment efficacy from 7\xa0years. The committee noted that, in an appraisal for ocrelizumab for relapsing–remitting multiple sclerosis, the committee considered that treatment efficacy likely wanes over time. The committee concluded that the company's original assumption of no waning of treatment effect was too optimistic but that, acknowledging the issues of the open-label extension (see section\xa03.8), the ERG's approach may still be too pessimistic. It concluded that the true waning of treatment effect is likely to lie between the company's and ERG's updated approaches, and that exploring assumptions of treatment waning from between 7\xa0years and 10\xa0years is reasonable.\n\n# Stopping treatment\n\n## There is considerable uncertainty about how long people would take ocrelizumab\n\nThe company modelled stopping of treatment (because of adverse events or because it does not work) by fitting a Gompertz distribution to data from the whole population rather than the MRI-active subgroup in ORATORIO. However, the company stated that 'clinical opinion' considered the average treatment duration predicted by this model to be too high (about 7.0\xa0years). It provided what it considered a more realistic scenario analysis with a higher and constant treatment withdrawal rate, which predicted an average treatment duration of about 4.5\xa0years. The ERG also used a Gompertz model in its base case, and considered that the rate of stopping treatment would rise as the effect of ocrelizumab waned (after 5.0\xa0years in its original base case and 7.0\xa0years in its revised base case; see section\xa03.12), adding this to its base case. The company's revised base case assumed an increase in the rate of stopping treatment at 5.0\xa0years, to match the ERG's original base case. The ERG commented that this did not match its approach because it preferred to link treatment waning (by applying a reduced treatment effect) and an increased rate of stopping treatment. The committee considered that this approach may be too conservative because people remaining on the drug would be expected to show a good response, and would potentially not experience a reduced treatment effect. It concluded that there is considerable uncertainty about how long people would take ocrelizumab, but that the ERG's base case is likely to have overestimated the rate of stopping treatment.\n\n## There is considerable uncertainty about an appropriate stopping rule for disease-modifying therapies for primary progressive multiple sclerosis\n\nBoth the company and ERG assumed in their original base cases that people whose disease progressed to EDSS state\xa08.0 would stop ocrelizumab. The clinical experts commented that this was later than when people stop disease-modifying treatments in relapsing–remitting multiple sclerosis, which is when a person's condition reaches and stays at EDSS state\xa07.0 for more than 6\xa0months. Both the company and ERG assumed that treatment would stop when a person's condition reached EDSS state\xa07.0 in their revised base cases. The clinical experts commented that an argument can be made for continuing treatment to EDSS state\xa08.0 because preserving upper limb function is particularly important once people are unable to walk. This was supported by comments from a patient group received during consultation. However, the committee and experts considered that this argument would apply equally to people with relapsing–remitting multiple sclerosis. The clinical experts noted that the ORATORIO trial enrolled people with multiple sclerosis with an EDSS only up to state\xa06.5, so there is no evidence for efficacy when starting treatment beyond this state, and that the ORATORIO trial did not have a stopping rule. The committee discussed the need for better disease models in multiple sclerosis. It concluded that, although there is considerable uncertainty, it had not been presented with any evidence to support a stopping rule that differed by type of multiple sclerosis.\n\n# Utility values\n\n## It is appropriate to use utility values from the ORATORIO study for EDSS states, supplemented by values from the literature\n\nThe company used utility values derived from the ORATORIO trial for most EDSS states in its base case. For EDSS states (0,\xa01,\xa08 and\xa09) for which ORATORIO offered no data, the company used utility values specific to primary progressive multiple sclerosis from Multiple Sclerosis\xa0Trust survey data (Orme et al. 2007). The committee noted that the utility values from ORATORIO were higher than those from Orme et al. and another study in primary progressive multiple sclerosis (Hawton and Green, 2016). The company suggested that the utility values from ORATORIO were higher because people in the ORATORIO trial were younger (mean age 44\xa0years) than in the other studies. The committee noted that the population for which NICE's recommendations apply include people aged over 55\xa0years, who are not represented in ORATORIO. It also commented that a more recent publication than Orme et al. was available. At consultation, the company clarified, to the satisfaction of the committee, an issue of what appeared to be higher utility values for higher states of disability. The company also commented that people with inflammatory activity would be younger, and that few patients aged over 55\xa0years would be eligible for ocrelizumab, based on data from the ORATORIO trial. The company believed that utility values from ORATORIO were a better match for the population within the marketing authorisation for ocrelizumab. The committee concluded that using different sources of utility data was acceptable when there were no trial data for EDSS states.\n\n## It is not appropriate to include additional utility decrements for upper limb dysfunction and fatigue\n\nIn addition to applying utility values for each EDSS state, in its original base-case model, the company also applied a utility decrement to each EDSS state for people with upper limb dysfunction and those with 'clinically meaningful fatigue'. The committee noted that upper limb function and fatigue were among 17\xa0exploratory end points included in the protocol for ORATORIO. It questioned why the company had selected these outcomes to include in the model rather than the many other exploratory end points measured. The committee was aware of statistical principles for clinical trials from the regulators, which deem results only from planned analyses to be confirmatory. The company explained that they did this because its analysis on data from ORATORIO showed that these factors affected health-related quality of life independent of EDSS state. The ERG disagreed with including additional utility decrements in the model, and did not include them in its own base case. It noted that ocrelizumab did not reduce fatigue (based on change in baseline score) in the MRI-active subgroup. It also noted that the company defined people as having clinically meaningful fatigue using cut-offs on the Modified Fatigue Impact Scale (MFIS). However, the ERG noted that cut-offs are not normally used with fatigue scores, and that most people entering the ORATORIO trial had fatigue based on the company's definition. The ERG also highlighted that previous appraisals for multiple sclerosis had not used specific utility decrements for symptoms associated with multiple sclerosis. The clinical experts commented that fatigue and upper limb function are equally important for people with relapsing–remitting multiple sclerosis. The committee noted that the company's approach would double-count disutilities incorporated within the EQ‑5D because the MFIS and EQ‑5D questionnaires overlap in some domains. At consultation, the company submitted a revised base case that excluded a utility decrement for fatigue, but still included a decrement for upper limb dysfunction. The ERG commented that the measure of upper limb function used in ORATORIO (changes in time to complete the 9‑hole peg test) may not reflect changes in upper limb function that matter to people, such as reduced ability to wash, dress and feed themselves. The committee objected to using chosen selected exploratory end points in the modelling without considering the risk of false-positive findings. The committee still considered at its second meeting that including decrements for upper limb function, decreasing utilities as people progressed through EDSS states, and carer disutilities likely overestimated the effect of ocrelizumab on slowing disability progression. It therefore concluded that it was inappropriate to include utility decrements from upper limb dysfunction and fatigue in the economic model.\n\n# Cost-effectiveness estimates\n\n## Ocrelizumab is a cost-effective use of NHS resources\n\nIn a second revised base case, the company estimated the incremental cost-effectiveness ratio (ICER) for the MRI-active subgroup with an updated commercial arrangement. The company's model for this base case included the committee's preferred changes to the company's original submission, and to its first revision. These were:\n\nincluding costs, disutilities and a treatment effect associated with relapses (see section\xa03.9)\n\nincluding the risk of PML (see section\xa03.10)\n\nusing CDP‑24 to estimate treatment effect (see section\xa03.7)\n\nremoving a utility decrement for fatigue and for upper limb dysfunction (see section\xa03.16)\n\nusing data from the double-blind period of the ORATORIO trial to estimate treatment effect (see section 3.8).The company also provided 2\xa0versions of its second revised base-case model, with treatment waning from either 7\xa0or 10\xa0years (see section\xa03.12). The ERG confirmed that the company's revised model reflected the committee's preferences. The ERG also re-ran the company's probabilistic analyses. The discount and the ICERs are confidential and the exact values cannot be reported here. The committee, in its third meeting, acknowledged that uncertainties remained about the true rate of treatment waning (see section\xa03.12) and how long people would continue to take ocrelizumab (see section\xa03.13). It again acknowledged that there is an unmet need for disease-modifying treatment for this condition (see section\xa03.1). The committee concluded that the most plausible ICER for ocrelizumab compared with best supportive care alone was within the range generally considered to reflect good value for treating conditions without any other treatment options. It further concluded that ocrelizumab, with the commercial arrangement, was cost effective for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults.\n\n# Innovation\n\n## Ocrelizumab is an innovative treatment for primary progressive multiple sclerosis\n\nThe company stated that ocrelizumab is an innovative treatment because it is the only approved disease-modifying treatment for use in primary progressive multiple sclerosis. The committee noted that there is a considerable unmet need for treatment (see section\xa03.1) for this condition, so ocrelizumab reflects a 'step change' in treatment. The company stated that it believed its model captured all quality-adjusted life year (QALY) benefits. The committee agreed that ocrelizumab is a 'step change' in the treatment of primary progressive multiple sclerosis, and that it had not been presented with evidence of any additional benefits not captured in the QALY measurements.\n\n# Conclusion\n\n## Ocrelizumab is recommended for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults\n\nOcrelizumab slows disability progression compared with placebo, although the size and duration of the effect are uncertain. There is a large unmet need for treating primary progressive multiple sclerosis because no disease-modifying treatments are currently available (see section\xa03.1). The committee concluded that the ICERs generated by the economic model for treating early primary progressive multiple sclerosis with imaging features characteristic of inflammatory activity in adults represented a cost-effective use of NHS resources at the price reflected within the commercial arrangement."}
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https://www.nice.org.uk/guidance/ta585
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Evidence-based recommendations on ocrelizumab (Ocrevus) for treating primary progressive multiple sclerosis in adults.
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afb9efc4b2fcda8f86dae432f9c475954634a244
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nice
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Endocuff Vision for assisting visualisation during colonoscopy
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Endocuff Vision for assisting visualisation during colonoscopy
Evidence-based recommendations on Endocuff Vision for assisting visualisation during colonoscopy.
# Recommendations
Evidence supports the case for adopting Endocuff Vision in the NHS because it improves the adenoma detection rate during colonoscopy, particularly for people having a colonoscopy as part of bowel cancer screening.
Endocuff Vision should be considered as an option for people having a colonoscopy as part of bowel cancer screening following a positive stool test. There is limited evidence for the benefits of Endocuff Vision in a non-screening population.
Cost modelling shows that for people having a colonoscopy as part of bowel cancer screening, using Endocuff Vision is cost saving. Savings are related to the adenoma detection rate; for a colonoscopist with a baseline adenoma detection rate of 51%, using Endocuff Vision saves £53 per patient over 10 years compared with standard colonoscopy.
Why the committee made these recommendations
The bowel cancer screening programme is an NHS service that offers tests (including colonoscopy) to people who are at risk of bowel cancer. Colonoscopy is used to detect bowel cancer but also to identify and remove adenomas that could develop into cancerous lesions if left untreated.
Endocuff Vision is a disposable sleeve that fits over the end of most colonoscopes. It is designed to improve visualisation of the bowel during colonoscopy.
Clinical evidence shows that for people having a colonoscopy as part of bowel cancer screening, using Endocuff Vision improves the adenoma detection rate without increasing how long the procedure takes. Better detection of adenomas is likely to reduce the incidence of subsequent cancers. Cost analyses in this population also suggest that Endocuff Vision is cost saving if the adenoma detection rate is improved by more than 3%.
The clinical and cost effectiveness of Endocuff Vision in other populations (such as people having a colonoscopy unrelated to bowel screening) is less certain because of the limited evidence available.# The technology
Technology
Endocuff Vision (Norgine Pharmaceuticals) is a single-use, disposable device which fits over the end of most conventional colonoscopes. It has a row of flexible arms, hinged at the base, which are retracted during insertion and spread out during withdrawal. These arms push out the mucosal folds of the colon, allowing more of the mucosal surface to be viewed. This helps with identifying colonic polyps, specifically adenomas and adenocarcinomas, and increases the likelihood of complete resection, as well as helping post-resection scar examination. Endocuff Vision received a CE mark in August 2016 as a class I sterile medical device.
Innovative aspects
The row of flexible arms is designed to increase the diagnostic sensitivity of colonoscopy investigation by increasing the total surface area of the visual field. The company claims that using Endocuff Vision can also improve the stability of the colonoscope and control of the tip.
Intended use
Endocuff Vision is intended to be used as an add-on to a standard colonoscope for people having a colonoscopy:
for an unexplained change in bowel habit, iron deficiency or bleeding from the bowel (including those with positive faecal occult blood test or faecal immunochemical test result)
to remove known polyps, which may be difficult to find, remove or ablate because of their size, position, or previous incomplete removal
for surveillance, after previous adenoma removal
as part of bowel screening investigations following a positive faecal occult blood test.
Endocuff Vision is not intended for deep ileal intubation. It should not be used in people with acute, severe colitis or if there is known colonic stricture. It should not be used for complex sub-mucosal dissection when a separate distal attachment is needed.
Costs
The cost of an Endocuff Vision sleeve is £12.05 (excluding VAT) per unit. Endocuff Vision has been selected for the NHS Innovation and Technology (ITP) Payment 2018/19 scheme.
For more details, see the ITP product information for Endocuff Vision.# Evidence
# Clinical evidence
## Relevant evidence comes from 4 studies, 2 of which are randomised controlled trials
Of the 4 studies that met the inclusion criteria in the scope, 2 were randomised controlled trials (ADENOMA and E‑Cap) and 2 were non-randomised prospective cohort studies (Rameshshanker et al. 2016 and Tsiamoulos et al. 2018).
## A multicentre trial shows that Endocuff Vision increases adenoma detection rates
ADENOMA was a UK-based, multicentre, single-blind randomised controlled trial (n=1,772) that compared Endocuff Vision-assisted colonoscopy with standard colonoscopy (Ngu et al. 2018). The population comprised adults having a colonoscopy after presenting with clinical symptoms of bowel cancer, for post-polypectomy surveillance, or after a positive faecal occult blood test as part of bowel cancer screening. The results showed that for the whole study population, Endocuff Vision-assisted colonoscopy led to a significant increase in adenoma detection rates compared with standard colonoscopy (p=0.02). Subgroup analyses showed that this was mainly driven by a 10.8% improvement in the screening population, which comprised about 45% of the whole study population; there was no statistically significant improvement in adenoma detection rates in the other patient subgroups.
## The 3 single-centre studies are potentially biased by local expertise and so may not be representative of UK practice
The other randomised controlled trial (E-Cap) was a single-blind, single-centre study (n=531) comparing Endocuff Vision-assisted colonoscopy with standard colonoscopy in adults who had a positive faecal occult blood test as part of bowel cancer screening. Tsiamoulos (2018) was a single-centre pilot service evaluation of Endocuff Vision, set up as a before-after study (n=410) in adults who had a positive faecal occult blood test as part of bowel cancer screening. Rameshshanker (2016) was a single-centre study (n=96) that prospectively compared Endocuff Vision-assisted colonoscopy with standard colonoscopy. These 3 single-centre studies showed various levels of improvement in adenoma detection rates with Endocuff Vision-assisted colonoscopies. The external assessment centre (EAC) noted that the level of improvement was inversely related to the expertise of the colonoscopists involved; that is, more benefits were seen with Endocuff Vision when used by colonoscopists with less expertise. Because of this, results of the single-centre studies are likely to be biased by local expertise and so may not be representative of NHS practice. For full details of the clinical evidence, see section 3 of the assessment report.
# Cost evidence
## The company's model shows that Endocuff Vision is cost saving in people having colonoscopies as part of bowel cancer screening
The company submitted a de novo cost model which compared Endocuff Vision-assisted colonoscopy with standard colonoscopy in patients having colonoscopies after a positive faecal occult blood test as part of bowel cancer screening. The model comprised a number of interlinked decision trees and Markov models based on an established model of colorectal cancer. The model results showed that over 10 years, using Endocuff Vision in this patient population would save £12 per patient. Sensitivity analyses showed that the cost savings were driven by how much Endocuff Vision improved the adenoma detection rate, because a higher adenoma detection and resection rate is likely to result in a lower incidence of colorectal cancer (see section 4.5).
## The EAC's revised model shows that Endocuff Vision is cost saving if it improves the adenoma detection rate by over 3%
The EAC considered the model structure, use of 1‑year cycles and a 10‑year time horizon to be appropriate. However, it revised the model to include more appropriate parameters based on data from the bowel cancer screening programme, including the stage distribution of screen-detected and symptomatic-detected colorectal cancer (Sagar et al. 2015) and the success rate for standard colonoscopy (Lee et al. 2012). The EAC's revised model showed that over 10 years, using Endocuff Vision in a screening population would save around £53 per patient. Sensitivity analyses showed similar results to the company's analyses, with the cost savings mainly driven by how much Endocuff Vision improved the adenoma detection rate. Specifically, the EAC's revised model showed that Endocuff Vision was cost saving when it improved the adenoma detection rate by over 3%.
## Endocuff Vision is unlikely to be cost saving for a non-screening population
The company did not submit an analysis of Endocuff Vision in people having treatment unrelated to bowel cancer screening. The EAC did additional analyses and concluded that Endocuff Vision was unlikely to be cost saving in this population because of the modest gain in adenoma detection rates seen with Endocuff Vision in the ADENOMA trial. For full details of the cost evidence, see section 4 of the assessment report.# Committee discussion
# Clinical-effectiveness overview
## Endocuff Vision improves the adenoma detection rate in people having colonoscopies as part of bowel cancer screening
The committee noted that 3 of the 4 studies showed that Endocuff Vision improved the adenoma detection rate in people having colonoscopies as part of bowel cancer screening. The ADENOMA trial was the only study powered to detect a difference in adenoma detection rates and the results showed a statistically significant improvement with Endocuff Vision of almost 11%. The external assessment centre (EAC) concluded that ADENOMA was a high-quality study with a low risk of bias. The clinical experts confirmed that the trial accurately represented NHS clinical practice. The committee considered the E‑Cap study which was the only trial that showed no improvement in adenoma detection rates with Endocuff Vision. It understood that this study included only 4 colonoscopists who already had baseline adenoma detection rates for standard colonoscopy that were much higher than the reported average of 46.5% (Lee et al. 2012). The committee noted that the benefits of Endocuff Vision may have been less apparent in this study because of the colonoscopists' relatively high level of expertise. Having considered all the clinical evidence, the committee concluded that using Endocuff Vision increases the adenoma detection rate in people having colonoscopies as part of bowel cancer screening and noted that the UK National Screening Committee is responsible for deciding if new technologies, such as Endocuff Vision, should be included in relevant screening pathway service specifications.
## Using Endocuff Vision may increase the detection of cancers during bowel cancer screening
The committee noted that secondary outcomes from ADENOMA included a statistically significant increase in the number of detected cancers with Endocuff Vison. The study was not powered to detect differences in cancer detection rates, but the committee considered this secondary outcome to be promising. The committee concluded that more evidence on the detection of cancers during bowel cancer screening with Endocuff Vision would be helpful.
## There is limited evidence for the benefits of Endocuff Vision in a non-screening population
Only 2 of the 4 studies (E-Cap and ADENOMA) included patients having colonoscopies unrelated to bowel cancer screening (n=1,135). E‑Cap also included patients who were under surveillance after having polyps removed, but ADENOMA was the only study that involved both symptomatic and surveillance populations. The clinical experts explained that the baseline adenoma detection rate was much lower in people having colonoscopies unrelated to bowel cancer screening, because this population is more heterogeneous in terms of patient age and presenting symptoms than the bowel cancer screening population. Results from the ADENOMA trial showed that use of Endocuff Vision in a non-screening population (n=975) was associated with a marginal (0.4%) improvement in adenoma detection rate from a baseline rate of 23.9% in the standard colonoscopy group. The committee therefore concluded that the benefits of Endocuff Vision are less certain in these patients.
# Outcome measures
## Adenoma detection rate is the best available surrogate quality indicator for diagnostic colonoscopy but it is influenced by a number of factors
The committee noted that adenoma detection rate is the most widely used quality indicator for diagnostic colonoscopy: it is used by the Joint Advisory Group on Gastrointestinal Endoscopy (JAG) and the NHS bowel cancer screening programme to monitor colonoscopy standards. The clinical experts, including a representative from the bowel cancer screening programme, explained that the minimum rate is 40% but that centres aspire to 50%. The clinical experts agreed that the average adenoma detection rate in a screening population was around 50%, and that anything above 65% would be considered exceptional. However, they noted that adenoma detection rates vary in both screening and non-screening populations. The clinical experts also explained that the adenoma detection rate is influenced by a number of factors, including how long the colonoscopist spends inspecting the walls of the bowel, how well the bowel is cleansed, levels of colonoscopist fatigue and the resolution of the colonoscope.
## Increased adenoma detection with Endocuff Vision may lead to a reduced risk of interval cancers
The clinical experts explained that people having bowel cancer screening may develop subsequent cancers that are referred to as 'interval cancers' (that is, cancers that are diagnosed in the intervals between tests). The clinical experts noted that the incidence of interval cancers varies across the UK from 2% to 13%. Detecting and removing more adenomas may lead to a subsequent reduction in the risk of interval cancers (because some adenomas may progress to cancerous lesions). The EAC and clinical experts explained that increases in adenoma detection and resection rates are associated with a reduced risk of interval cancers. They referred to 2 studies that evaluated this relationship:
In Kaminski et al. (2010), people who had colonoscopies done by colonoscopists with an adenoma detection rate of less than 20% were at a higher risk of developing interval cancers than people who had colonoscopies done by colonoscopists with an adenoma detection rate of over 20%.
In Corley et al. (2014), an increase in the adenoma detection rate of 1% resulted in a decrease in the risk of developing interval cancers of 3%.The clinical experts cautioned that a plateau effect is likely for the adenoma detection rate, above which there would be diminishing effects on interval cancer risk. Because these studies only evaluated baseline adenoma detection rates of up to 50%, it is uncertain if and at what level this plateau would become apparent. The clinical experts were uncertain as to what effect the increase in adenoma detection rate from 50% to 60% (as seen with Endocuff Vison in the ADENOMA trial) would have on interval cancer risk. However, they were not aware of any evidence to suggest that the increase would not be clinically useful. Consequently, the committee concluded that the adenoma detection rate could be considered a predictor of interval cancer risk, and so it is plausible that Endocuff Vision may reduce the incidence of interval cancers.
# Side effects and adverse events
## Adverse events are about as common with Endocuff Vision-assisted colonoscopy as with standard colonoscopy
The committee noted that some rare adverse events have been reported with the predecessor device, Endocuff, including colon perforation. The clinical experts explained that Endocuff Vision has been designed to avoid these problems. The committee noted that the incidence of adverse events with Endocuff Vision was comparable to that of standard colonoscopy.
# Patient selection
## Use of Endocuff Vision should be decided on a case-by-case basis
The clinical experts explained that the priority in colonoscopy is to achieve a complete procedure (with a high caecal intubation rate) with minimal discomfort to the patient. They noted that the use of Endocuff Vision may cause a small amount of pain and discomfort when inserting the colonoscope, but this is usually temporary and no additional sedation is needed. The clinical experts emphasised that the decision to use Endocuff Vision should be based on clinical judgement taking into consideration patients' comorbidities, physical presentation, symptoms and age.
## Use of Endocuff Vision may not be suitable for some patient groups
The clinical experts described certain circumstances when Endocuff Vision is unlikely to provide benefits. These included: investigation in patients with a history of significant anal pathology, moderate to severe diverticulosis or a fixed sigmoid colon; for colonoscopies in young, non-sedated patients because of possible anal trauma; and when inflammatory bowel disease is suspected or active colitis is present. Endocuff Vision should be used with caution in patients aged over 85 years because of the higher risk of diverticular disease. The clinical experts also identified circumstances when using Endocuff Vision may be technically helpful: for example, as an insertion aid in patients with long and mobile colons, or when detecting and removing large polyps or those in difficult areas of the colon.
# Relevance to the NHS
## The evidence for Endocuff Vison in a screening population is broadly generalisable to the NHS
All 4 of the included studies were done at UK centres. The ADENOMA trial recruited patients across 7 NHS centres and involved a total of 48 colonoscopists with varying skill levels. Each site was allowed to have no more than 4 bowel cancer screening programme colonoscopists. The committee was aware of the role of JAG accreditation for colonoscopists in the bowel cancer screening programme. The bowel cancer screening programme establishes quality standards for screening colonoscopy, provides training resources for staff and records a national audit of the screening service. A representative from the screening programme confirmed that the use of Endocuff Vision is currently an option for screening colonoscopists. The committee recalled that the results of the single-centre studies were potentially biased by local expertise (see section 3.3) but it understood that the expertise of colonoscopists varied across the NHS. The committee concluded that overall the evidence was broadly generalisable to the NHS.
# NHS considerations
## It takes 20 to 30 procedures to become fully competent in using Endocuff Vision
Endocuff Vision is compatible with most colonoscopes and is available in 4 different sizes, depending on the diameter of the colonoscope used for the procedure. The clinical experts emphasised the importance of selecting the correct size and ensuring that Endocuff Vision is securely fitted to avoid detachment during the procedure. The clinical experts clarified that using Endocuff Vision is associated with a learning curve: in the ADENOMA trial, colonoscopists needed specific training and had to have done at least 20 procedures with Endocuff Vision before starting the study. The clinical experts considered that 20 to 30 procedures with Endocuff Vision would be sufficient to ensure competency. In its cost model, to represent the learning curve with Endocuff Vision, the company assumed that there would be no improvement in efficacy for the first 20 procedures with Endocuff Vision (for full details see section 4.2 of the assessment report).
## Endocuff Vision may be most beneficial when used by colonoscopists with low-to-moderate baseline adenoma detection rates
The committee recalled the EAC's conclusion that the level of improvement in the adenoma detection rate with Endocuff Vision was inversely related to the expertise of the colonoscopists involved; that is, more benefits were seen with Endocuff Vision when used by colonoscopists who had lower baseline adenoma detection rates (see section 3.3). The EAC identified a recent meta-analysis (Williet et al. 2018), which showed that Endocuff Vision (or its predecessor device Endocuff) improved adenoma detection rates in colonoscopists with low-to-moderate baseline rates (less than 35 %) but not in colonoscopists with high baseline rates (over 45 %). The clinical experts broadly agreed with this observation, but noted that statistically significant improvements were still seen in the ADENOMA trial even when baseline adenoma detection rates were above 45%.
# Service implications
## Endocuff Vision is unlikely to affect overall procedure time but may increase efficiency by helping with polyp removal
The results of the ADENOMA trial showed that the use of Endocuff Vision does not increase overall procedure time. The clinical experts also noted that in the trial, the withdrawal time for Endocuff Vision was comparable to that of standard colonoscopy despite more polyps being removed: this suggested that Endocuff Vision may increase efficiency. The clinical experts confirmed that this accurately reflected their own clinical experience; they added that Endocuff Vision may help with polyp removal by anchoring the scope and providing a degree of device stability. In the ADENOMA trial, inserting Endocuff Vision took 1 minute less than inserting a standard colonoscope. Although the clinical experts considered this to be a notable time saving, they understood that it would be unlikely to lead to an increase in patient throughput. However, they clarified that any improvements in procedure efficiency may lead to lower levels of colonoscopist fatigue and may be of particular value in complex cases.
# Cost modelling
## The EAC's revised model is more suitable for decision making
The committee considered the EAC's changes to the company's cost model (see section 3.5) and agreed that the updated parameters better reflected cost and resource use in a UK screening population. The committee acknowledged the unusually large number of assumptions in the cost modelling, but considered that this approach was necessary to fully capture Endocuff Vision's effect on adenoma detection rates and the likely incidence of interval cancers.
# Main cost drivers
## A 3% improvement in the adenoma detection rate is plausible with Endocuff Vision in a UK screening population
The EAC's sensitivity analyses showed that Endocuff Vision was cost saving when it improved the adenoma detection rate by over 3%. The clinical experts explained that this level of improvement was feasible in the context of a UK screening programme. Furthermore, the committee noted that the results of the ADENOMA trial implied that a 3% improvement is plausible even within a service delivered by colonoscopists with high baseline adenoma detection rates (and therefore high levels of expertise).
# Cost savings
## Endocuff Vision is cost saving for people having colonoscopies as part of bowel cancer screening
The EAC's revised cost model showed that over 10 years, the use of Endocuff Vision was associated with a cost saving of around £53 per patient if used by a colonoscopist with a baseline adenoma detection rate of 51%. An EAC scenario analysis showed that when initial screening is done using faecal immunochemical testing instead of faecal occult blood testing, the estimated cost saving per patient with Endocuff Vision increased to around £58. The committee noted that, although the clinical evidence for Endocuff Vision is in people with a positive faecal occult blood test result, the technology is also likely to benefit people who have a positive faecal immunochemical test result (because the test does not fundamentally change the colonoscopy procedure itself). The EAC also adapted the model to a non-screening population (see section 3.6), and results showed that using Endocuff Vision in this population is likely to incur additional costs. The committee concluded that using Endocuff Vision in people having colonoscopies as part of bowel cancer screening is likely to be associated with a small cost saving, largely through a reduced incidence of interval cancers and by allowing the diagnosis of cancers at an earlier stage. The committee concluded that on the basis of the evidence presented, the case for adopting Endocuff Vision in a screening population was supported.
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{'Recommendations': 'Evidence supports the case for adopting Endocuff Vision in the NHS because it improves the adenoma detection rate during colonoscopy, particularly for people having a colonoscopy as part of bowel cancer screening.\n\nEndocuff Vision should be considered as an option for people having a colonoscopy as part of bowel cancer screening following a positive stool test. There is limited evidence for the benefits of Endocuff Vision in a non-screening population.\n\nCost modelling shows that for people having a colonoscopy as part of bowel cancer screening, using Endocuff Vision is cost saving. Savings are related to the adenoma detection rate; for a colonoscopist with a baseline adenoma detection rate of 51%, using Endocuff Vision saves £53 per patient over 10\xa0years compared with standard colonoscopy.\n\nWhy the committee made these recommendations\n\nThe bowel cancer screening programme is an NHS service that offers tests (including colonoscopy) to people who are at risk of bowel cancer. Colonoscopy is used to detect bowel cancer but also to identify and remove adenomas that could develop into cancerous lesions if left untreated.\n\nEndocuff Vision is a disposable sleeve that fits over the end of most colonoscopes. It is designed to improve visualisation of the bowel during colonoscopy.\n\nClinical evidence shows that for people having a colonoscopy as part of bowel cancer screening, using Endocuff Vision improves the adenoma detection rate without increasing how long the procedure takes. Better detection of adenomas is likely to reduce the incidence of subsequent cancers. Cost analyses in this population also suggest that Endocuff Vision is cost saving if the adenoma detection rate is improved by more than 3%.\n\nThe clinical and cost effectiveness of Endocuff Vision in other populations (such as people having a colonoscopy unrelated to bowel screening) is less certain because of the limited evidence available.', 'The technology': 'Technology\n\nEndocuff Vision (Norgine Pharmaceuticals) is a single-use, disposable device which fits over the end of most conventional colonoscopes. It has a row of flexible arms, hinged at the base, which are retracted during insertion and spread out during withdrawal. These arms push out the mucosal folds of the colon, allowing more of the mucosal surface to be viewed. This helps with identifying colonic polyps, specifically adenomas and adenocarcinomas, and increases the likelihood of complete resection, as well as helping post-resection scar examination. Endocuff Vision received a CE mark in August 2016 as a class\xa0I sterile medical device.\n\nInnovative aspects\n\nThe row of flexible arms is designed to increase the diagnostic sensitivity of colonoscopy investigation by increasing the total surface area of the visual field. The company claims that using Endocuff Vision can also improve the stability of the colonoscope and control of the tip.\n\nIntended use\n\nEndocuff Vision is intended to be used as an add-on to a standard colonoscope for people having a colonoscopy:\n\nfor an unexplained change in bowel habit, iron deficiency or bleeding from the bowel (including those with positive faecal occult blood test or faecal immunochemical test result)\n\nto remove known polyps, which may be difficult to find, remove or ablate because of their size, position, or previous incomplete removal\n\nfor surveillance, after previous adenoma removal\n\nas part of bowel screening investigations following a positive faecal occult blood test.\n\nEndocuff Vision is not intended for deep ileal intubation. It should not be used in people with acute, severe colitis or if there is known colonic stricture. It should not be used for complex sub-mucosal dissection when a separate distal attachment is needed.\n\nCosts\n\nThe cost of an Endocuff Vision sleeve is £12.05 (excluding VAT) per unit. Endocuff Vision has been selected for the NHS Innovation and Technology (ITP) Payment 2018/19 scheme.\n\nFor more details, see the ITP product information for Endocuff Vision.', 'Evidence': "# Clinical evidence\n\n## Relevant evidence comes from 4 studies, 2 of which are randomised controlled trials\n\nOf the 4 studies that met the inclusion criteria in the scope, 2 were randomised controlled trials (ADENOMA and E‑Cap) and 2 were non-randomised prospective cohort studies (Rameshshanker et al. 2016 and Tsiamoulos et al. 2018).\n\n## A multicentre trial shows that Endocuff Vision increases adenoma detection rates\n\nADENOMA was a UK-based, multicentre, single-blind randomised controlled trial (n=1,772) that compared Endocuff Vision-assisted colonoscopy with standard colonoscopy (Ngu et al. 2018). The population comprised adults having a colonoscopy after presenting with clinical symptoms of bowel cancer, for post-polypectomy surveillance, or after a positive faecal occult blood test as part of bowel cancer screening. The results showed that for the whole study population, Endocuff Vision-assisted colonoscopy led to a significant increase in adenoma detection rates compared with standard colonoscopy (p=0.02). Subgroup analyses showed that this was mainly driven by a 10.8% improvement in the screening population, which comprised about 45% of the whole study population; there was no statistically significant improvement in adenoma detection rates in the other patient subgroups.\n\n## The 3 single-centre studies are potentially biased by local expertise and so may not be representative of UK practice\n\nThe other randomised controlled trial (E-Cap) was a single-blind, single-centre study (n=531) comparing Endocuff Vision-assisted colonoscopy with standard colonoscopy in adults who had a positive faecal occult blood test as part of bowel cancer screening. Tsiamoulos (2018) was a single-centre pilot service evaluation of Endocuff Vision, set up as a before-after study (n=410) in adults who had a positive faecal occult blood test as part of bowel cancer screening. Rameshshanker (2016) was a single-centre study (n=96) that prospectively compared Endocuff Vision-assisted colonoscopy with standard colonoscopy. These 3 single-centre studies showed various levels of improvement in adenoma detection rates with Endocuff Vision-assisted colonoscopies. The external assessment centre (EAC) noted that the level of improvement was inversely related to the expertise of the colonoscopists involved; that is, more benefits were seen with Endocuff Vision when used by colonoscopists with less expertise. Because of this, results of the single-centre studies are likely to be biased by local expertise and so may not be representative of NHS practice. For full details of the clinical evidence, see section\xa03 of the assessment report.\n\n# Cost evidence\n\n## The company's model shows that Endocuff Vision is cost saving in people having colonoscopies as part of bowel cancer screening\n\nThe company submitted a de novo cost model which compared Endocuff Vision-assisted colonoscopy with standard colonoscopy in patients having colonoscopies after a positive faecal occult blood test as part of bowel cancer screening. The model comprised a number of interlinked decision trees and Markov models based on an established model of colorectal cancer. The model results showed that over 10\xa0years, using Endocuff Vision in this patient population would save £12 per patient. Sensitivity analyses showed that the cost savings were driven by how much Endocuff Vision improved the adenoma detection rate, because a higher adenoma detection and resection rate is likely to result in a lower incidence of colorectal cancer (see section\xa04.5).\n\n## The EAC's revised model shows that Endocuff Vision is cost saving if it improves the adenoma detection rate by over 3%\n\nThe EAC considered the model structure, use of 1‑year cycles and a 10‑year time horizon to be appropriate. However, it revised the model to include more appropriate parameters based on data from the bowel cancer screening programme, including the stage distribution of screen-detected and symptomatic-detected colorectal cancer (Sagar et al. 2015) and the success rate for standard colonoscopy (Lee et al. 2012). The EAC's revised model showed that over 10\xa0years, using Endocuff Vision in a screening population would save around £53 per patient. Sensitivity analyses showed similar results to the company's analyses, with the cost savings mainly driven by how much Endocuff Vision improved the adenoma detection rate. Specifically, the EAC's revised model showed that Endocuff Vision was cost saving when it improved the adenoma detection rate by over\xa03%.\n\n## Endocuff Vision is unlikely to be cost saving for a non-screening population\n\nThe company did not submit an analysis of Endocuff Vision in people having treatment unrelated to bowel cancer screening. The EAC did additional analyses and concluded that Endocuff Vision was unlikely to be cost saving in this population because of the modest gain in adenoma detection rates seen with Endocuff Vision in the ADENOMA trial. For full details of the cost evidence, see section\xa04 of the assessment report.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Endocuff Vision improves the adenoma detection rate in people having colonoscopies as part of bowel cancer screening\n\nThe committee noted that 3 of the 4\xa0studies showed that Endocuff Vision improved the adenoma detection rate in people having colonoscopies as part of bowel cancer screening. The ADENOMA trial was the only study powered to detect a difference in adenoma detection rates and the results showed a statistically significant improvement with Endocuff Vision of almost\xa011%. The external assessment centre (EAC) concluded that ADENOMA was a high-quality study with a low risk of bias. The clinical experts confirmed that the trial accurately represented NHS clinical practice. The committee considered the E‑Cap study which was the only trial that showed no improvement in adenoma detection rates with Endocuff Vision. It understood that this study included only 4\xa0colonoscopists who already had baseline adenoma detection rates for standard colonoscopy that were much higher than the reported average of 46.5% (Lee et al. 2012). The committee noted that the benefits of Endocuff Vision may have been less apparent in this study because of the colonoscopists' relatively high level of expertise. Having considered all the clinical evidence, the committee concluded that using Endocuff Vision increases the adenoma detection rate in people having colonoscopies as part of bowel cancer screening and noted that the UK National Screening Committee is responsible for deciding if new technologies, such as Endocuff Vision, should be included in relevant screening pathway service specifications.\n\n## Using Endocuff Vision may increase the detection of cancers during bowel cancer screening\n\nThe committee noted that secondary outcomes from ADENOMA included a statistically significant increase in the number of detected cancers with Endocuff Vison. The study was not powered to detect differences in cancer detection rates, but the committee considered this secondary outcome to be promising. The committee concluded that more evidence on the detection of cancers during bowel cancer screening with Endocuff Vision would be helpful.\n\n## There is limited evidence for the benefits of Endocuff Vision in a non-screening population\n\nOnly 2 of the 4 studies (E-Cap and ADENOMA) included patients having colonoscopies unrelated to bowel cancer screening (n=1,135). E‑Cap also included patients who were under surveillance after having polyps removed, but ADENOMA was the only study that involved both symptomatic and surveillance populations. The clinical experts explained that the baseline adenoma detection rate was much lower in people having colonoscopies unrelated to bowel cancer screening, because this population is more heterogeneous in terms of patient age and presenting symptoms than the bowel cancer screening population. Results from the ADENOMA trial showed that use of Endocuff Vision in a non-screening population (n=975) was associated with a marginal (0.4%) improvement in adenoma detection rate from a baseline rate of 23.9% in the standard colonoscopy group. The committee therefore concluded that the benefits of Endocuff Vision are less certain in these patients.\n\n# Outcome measures\n\n## Adenoma detection rate is the best available surrogate quality indicator for diagnostic colonoscopy but it is influenced by a number of factors\n\nThe committee noted that adenoma detection rate is the most widely used quality indicator for diagnostic colonoscopy: it is used by the Joint Advisory Group on Gastrointestinal Endoscopy (JAG) and the NHS bowel cancer screening programme to monitor colonoscopy standards. The clinical experts, including a representative from the bowel cancer screening programme, explained that the minimum rate is 40% but that centres aspire to 50%. The clinical experts agreed that the average adenoma detection rate in a screening population was around 50%, and that anything above 65% would be considered exceptional. However, they noted that adenoma detection rates vary in both screening and non-screening populations. The clinical experts also explained that the adenoma detection rate is influenced by a number of factors, including how long the colonoscopist spends inspecting the walls of the bowel, how well the bowel is cleansed, levels of colonoscopist fatigue and the resolution of the colonoscope.\n\n## Increased adenoma detection with Endocuff Vision may lead to a reduced risk of interval cancers\n\nThe clinical experts explained that people having bowel cancer screening may develop subsequent cancers that are referred to as 'interval cancers' (that is, cancers that are diagnosed in the intervals between tests). The clinical experts noted that the incidence of interval cancers varies across the UK from 2% to 13%. Detecting and removing more adenomas may lead to a subsequent reduction in the risk of interval cancers (because some adenomas may progress to cancerous lesions). The EAC and clinical experts explained that increases in adenoma detection and resection rates are associated with a reduced risk of interval cancers. They referred to 2\xa0studies that evaluated this relationship:\n\nIn Kaminski et al. (2010), people who had colonoscopies done by colonoscopists with an adenoma detection rate of less than 20% were at a higher risk of developing interval cancers than people who had colonoscopies done by colonoscopists with an adenoma detection rate of over 20%.\n\nIn Corley et al. (2014), an increase in the adenoma detection rate of 1% resulted in a decrease in the risk of developing interval cancers of 3%.The clinical experts cautioned that a plateau effect is likely for the adenoma detection rate, above which there would be diminishing effects on interval cancer risk. Because these studies only evaluated baseline adenoma detection rates of up to 50%, it is uncertain if and at what level this plateau would become apparent. The clinical experts were uncertain as to what effect the increase in adenoma detection rate from 50% to 60% (as seen with Endocuff Vison in the ADENOMA trial) would have on interval cancer risk. However, they were not aware of any evidence to suggest that the increase would not be clinically useful. Consequently, the committee concluded that the adenoma detection rate could be considered a predictor of interval cancer risk, and so it is plausible that Endocuff Vision may reduce the incidence of interval cancers.\n\n# Side effects and adverse events\n\n## Adverse events are about as common with Endocuff Vision-assisted colonoscopy as with standard colonoscopy\n\nThe committee noted that some rare adverse events have been reported with the predecessor device, Endocuff, including colon perforation. The clinical experts explained that Endocuff Vision has been designed to avoid these problems. The committee noted that the incidence of adverse events with Endocuff Vision was comparable to that of standard colonoscopy.\n\n# Patient selection\n\n## Use of Endocuff Vision should be decided on a case-by-case basis\n\nThe clinical experts explained that the priority in colonoscopy is to achieve a complete procedure (with a high caecal intubation rate) with minimal discomfort to the patient. They noted that the use of Endocuff Vision may cause a small amount of pain and discomfort when inserting the colonoscope, but this is usually temporary and no additional sedation is needed. The clinical experts emphasised that the decision to use Endocuff Vision should be based on clinical judgement taking into consideration patients' comorbidities, physical presentation, symptoms and age.\n\n## Use of Endocuff Vision may not be suitable for some patient groups\n\nThe clinical experts described certain circumstances when Endocuff Vision is unlikely to provide benefits. These included: investigation in patients with a history of significant anal pathology, moderate to severe diverticulosis or a fixed sigmoid colon; for colonoscopies in young, non-sedated patients because of possible anal trauma; and when inflammatory bowel disease is suspected or active colitis is present. Endocuff Vision should be used with caution in patients aged over 85\xa0years because of the higher risk of diverticular disease. The clinical experts also identified circumstances when using Endocuff Vision may be technically helpful: for example, as an insertion aid in patients with long and mobile colons, or when detecting and removing large polyps or those in difficult areas of the colon.\n\n# Relevance to the NHS\n\n## The evidence for Endocuff Vison in a screening population is broadly generalisable to the NHS\n\nAll 4 of the included studies were done at UK centres. The ADENOMA trial recruited patients across 7\xa0NHS centres and involved a total of 48\xa0colonoscopists with varying skill levels. Each site was allowed to have no more than 4\xa0bowel cancer screening programme colonoscopists. The committee was aware of the role of JAG accreditation for colonoscopists in the bowel cancer screening programme. The bowel cancer screening programme establishes quality standards for screening colonoscopy, provides training resources for staff and records a national audit of the screening service. A representative from the screening programme confirmed that the use of Endocuff Vision is currently an option for screening colonoscopists. The committee recalled that the results of the single-centre studies were potentially biased by local expertise (see section 3.3) but it understood that the expertise of colonoscopists varied across the NHS. The committee concluded that overall the evidence was broadly generalisable to the NHS.\n\n# NHS considerations\n\n## It takes 20 to 30 procedures to become fully competent in using Endocuff Vision\n\nEndocuff Vision is compatible with most colonoscopes and is available in 4 different sizes, depending on the diameter of the colonoscope used for the procedure. The clinical experts emphasised the importance of selecting the correct size and ensuring that Endocuff Vision is securely fitted to avoid detachment during the procedure. The clinical experts clarified that using Endocuff Vision is associated with a learning curve: in the ADENOMA trial, colonoscopists needed specific training and had to have done at least 20\xa0procedures with Endocuff Vision before starting the study. The clinical experts considered that 20\xa0to 30\xa0procedures with Endocuff Vision would be sufficient to ensure competency. In its cost model, to represent the learning curve with Endocuff Vision, the company assumed that there would be no improvement in efficacy for the first 20\xa0procedures with Endocuff Vision (for full details see section\xa04.2 of the assessment report).\n\n## Endocuff Vision may be most beneficial when used by colonoscopists with low-to-moderate baseline adenoma detection rates\n\nThe committee recalled the EAC's conclusion that the level of improvement in the adenoma detection rate with Endocuff Vision was inversely related to the expertise of the colonoscopists involved; that is, more benefits were seen with Endocuff Vision when used by colonoscopists who had lower baseline adenoma detection rates (see section 3.3). The EAC identified a recent meta-analysis (Williet et al. 2018), which showed that Endocuff Vision (or its predecessor device Endocuff) improved adenoma detection rates in colonoscopists with low-to-moderate baseline rates (less than\xa035\u200a%) but not in colonoscopists with high baseline rates (over 45\u200a%). The clinical experts broadly agreed with this observation, but noted that statistically significant improvements were still seen in the ADENOMA trial even when baseline adenoma detection rates were above\xa045%.\n\n# Service implications\n\n## Endocuff Vision is unlikely to affect overall procedure time but may increase efficiency by helping with polyp removal\n\nThe results of the ADENOMA trial showed that the use of Endocuff Vision does not increase overall procedure time. The clinical experts also noted that in the trial, the withdrawal time for Endocuff Vision was comparable to that of standard colonoscopy despite more polyps being removed: this suggested that Endocuff Vision may increase efficiency. The clinical experts confirmed that this accurately reflected their own clinical experience; they added that Endocuff Vision may help with polyp removal by anchoring the scope and providing a degree of device stability. In the ADENOMA trial, inserting Endocuff Vision took 1\xa0minute less than inserting a standard colonoscope. Although the clinical experts considered this to be a notable time saving, they understood that it would be unlikely to lead to an increase in patient throughput. However, they clarified that any improvements in procedure efficiency may lead to lower levels of colonoscopist fatigue and may be of particular value in complex cases.\n\n# Cost modelling\n\n## The EAC's revised model is more suitable for decision making\n\nThe committee considered the EAC's changes to the company's cost model (see section 3.5) and agreed that the updated parameters better reflected cost and resource use in a UK screening population. The committee acknowledged the unusually large number of assumptions in the cost modelling, but considered that this approach was necessary to fully capture Endocuff Vision's effect on adenoma detection rates and the likely incidence of interval cancers.\n\n# Main cost drivers\n\n## A 3% improvement in the adenoma detection rate is plausible with Endocuff Vision in a UK screening population\n\nThe EAC's sensitivity analyses showed that Endocuff Vision was cost saving when it improved the adenoma detection rate by over\xa03%. The clinical experts explained that this level of improvement was feasible in the context of a UK screening programme. Furthermore, the committee noted that the results of the ADENOMA trial implied that a 3% improvement is plausible even within a service delivered by colonoscopists with high baseline adenoma detection rates (and therefore high levels of expertise).\n\n# Cost savings\n\n## Endocuff Vision is cost saving for people having colonoscopies as part of bowel cancer screening\n\nThe EAC's revised cost model showed that over 10\xa0years, the use of Endocuff Vision was associated with a cost saving of around £53 per patient if used by a colonoscopist with a baseline adenoma detection rate of\xa051%. An EAC scenario analysis showed that when initial screening is done using faecal immunochemical testing instead of faecal occult blood testing, the estimated cost saving per patient with Endocuff Vision increased to around £58. The committee noted that, although the clinical evidence for Endocuff Vision is in people with a positive faecal occult blood test result, the technology is also likely to benefit people who have a positive faecal immunochemical test result (because the test does not fundamentally change the colonoscopy procedure itself). The EAC also adapted the model to a non-screening population (see section 3.6), and results showed that using Endocuff Vision in this population is likely to incur additional costs. The committee concluded that using Endocuff Vision in people having colonoscopies as part of bowel cancer screening is likely to be associated with a small cost saving, largely through a reduced incidence of interval cancers and by allowing the diagnosis of cancers at an earlier stage. The committee concluded that on the basis of the evidence presented, the case for adopting Endocuff Vision in a screening population was supported."}
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https://www.nice.org.uk/guidance/mtg45
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Evidence-based recommendations on Endocuff Vision for assisting visualisation during colonoscopy.
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86f85d4ec1e88bb0170da02f7f130195f94070d2
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nice
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Atezolizumab in combination for treating metastatic non-squamous non-small-cell lung cancer
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Atezolizumab in combination for treating metastatic non-squamous non-small-cell lung cancer
Evidence-based recommendations on atezolizumab (Tecentriq) with bevacizumab (Avastin), carboplatin and paclitaxel for metastatic non-squamous non-small-cell lung cancer in adults.
# Recommendations
Atezolizumab plus bevacizumab, carboplatin and paclitaxel is recommended as an option for metastatic non-squamous non-small-cell lung cancer (NSCLC) in adults:
who have not had treatment for their metastatic NSCLC before and whose PD-L1 tumour proportion score is between 0% and 49% or
when targeted therapy for epidermal growth factor receptor (EGFR)‑positive or anaplastic lymphoma kinase (ALK)‑positive NSCLC has failed.It is recommended only if:
atezolizumab and bevacizumab are stopped at 2 years of uninterrupted treatment, or earlier if there is loss of clinical benefit (for atezolizumab) or if the disease progresses (for bevacizumab) and
the company provides atezolizumab and bevacizumab according to the commercial arrangements.
This recommendation is not intended to affect treatment with atezolizumab plus bevacizumab, carboplatin and paclitaxel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Pemetrexed plus carboplatin or cisplatin, with or without pemetrexed maintenance, is the current treatment for:
untreated metastatic non-squamous NSCLC (with no EGFR- or ALK‑positive mutations) with a PD‑L1 tumour proportion score between 0% and 49% and
metastatic non-squamous EGFR- or ALK-positive NSCLC when targeted therapy is either not an option or has failed.
Pembrolizumab monotherapy is the current treatment for untreated metastatic non-squamous NSCLC with a PD‑L1 tumour proportion score of at least 50%.
An indirect comparison of studies suggests that people having atezolizumab plus bevacizumab, carboplatin and paclitaxel live longer than those having pemetrexed plus carboplatin or cisplatin, with or without pemetrexed maintenance. This comparison also suggests that they live for longer before their condition worsens.
Atezolizumab plus bevacizumab, carboplatin and paclitaxel meets NICE's criteria to be considered a life-extending treatment at the end of life. There is uncertainty about the company's long-term survival estimates, especially for people with EGFR- or ALK‑positive NSCLC. But including the most plausible assumptions and the commercial arrangements, the cost-effectiveness estimates are within what NICE normally considers acceptable for an end-of-life treatment. Therefore, atezolizumab plus bevacizumab, carboplatin and paclitaxel is recommended for metastatic non-squamous NSCLC that is untreated (with no EGFR- or ALK‑positive mutations) and when the PD‑L1 tumour proportion score is between 0% and 49%, or that is EGFR- or ALK‑positive and for which targeted therapy has failed.
Atezolizumab and bevacizumab are stopped at 2 years of uninterrupted treatment, or earlier if there is loss of clinical benefit (for atezolizumab) or if the disease progresses (for bevacizumab). This is because the cost-effectiveness evidence was primarily based on 2 years of treatment and the best duration of treatment is unknown.
No recommendation can be made for atezolizumab plus bevacizumab, carboplatin and paclitaxel for treating untreated PD‑L1‑positive metastatic NSCLC in people whose PD‑L1 tumour proportion score is at least 50% because no cost-effectiveness analyses comparing atezolizumab plus bevacizumab, carboplatin and paclitaxel with pembrolizumab monotherapy were provided.# Information about atezolizumab plus bevacizumab, carboplatin and paclitaxel
Marketing authorisation indication
Atezolizumab (Tecentriq, Roche) plus bevacizumab (Avastin, Roche), paclitaxel and carboplatin, is indicated 'for the first-line treatment of adult patients with metastatic non-squamous non-small cell lung cancer (NSCLC). In patients with epidermal growth factor receptor (EGFR)-mutant or anaplastic lymphoma kinase (ALK)-positive NSCLC, Tecentriq, in combination with bevacizumab, paclitaxel and carboplatin, is indicated only after failure of appropriate targeted therapies'.
Atezolizumab plus bevacizumab, paclitaxel and carboplatin has been available in the UK for treating metastatic non-squamous EGFR- or ALK-positive NSCLC after failure of appropriate targeted therapies through the early access to medicines scheme.
Dosage in the marketing authorisation
In the induction phase, the recommended dose of atezolizumab is 1,200 mg administered by intravenous infusion, followed by bevacizumab (15 mg/kg), paclitaxel (200 mg/m2)*, and then carboplatin (area under the curve 6) every 3 weeks for 4 or 6 cycles. The induction phase is followed by a maintenance phase without chemotherapy in which 1,200 mg atezolizumab followed by bevacizumab (15 mg/kg) is administered by intravenous infusion every 3 weeks.
- In the pivotal clinical trial (IMpower150), the paclitaxel starting dose for patients of Asian family origin was 175 mg/m2 because of a higher overall level of haematological toxicities in these patients compared with those of non-Asian family origin.
It is recommended that patients have treatment with atezolizumab until loss of clinical benefit or unmanageable toxicity, and bevacizumab until disease progression or unacceptable toxicity, whichever occurs first. Dose reductions of atezolizumab are not recommended. Paclitaxel and carboplatin were administered in the IMpower150 trial until completion of 4 or 6 cycles, or progressive disease, or unacceptable toxicity, whichever occurs first.
Price
Atezolizumab: £3,807.69 per 1,200‑mg vial (excluding VAT; British national formulary online, accessed March 2019).
Bevacizumab: £242.66 per 100‑mg vial (excluding VAT; BNF online, accessed March 2019).
Costs of carboplatin and paclitaxel may vary in different settings because of negotiated procurement discounts.
The company has commercial arrangements. This makes atezolizumab and bevacizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need
## A new treatment option would benefit people with metastatic non-squamous NSCLC
People with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive metastatic non-squamous non-small-cell lung cancer (NSCLC) are offered pemetrexed plus carboplatin or cisplatin, with or without pemetrexed maintenance, after targeted therapy. After pemetrexed combination treatment, people may be offered immunotherapy if they are well enough. The clinical experts welcomed the option to use immunotherapy at an earlier point in the treatment pathway for EGFR- or ALK‑positive NSCLC because some people may not be well enough to go on to have further therapy. Immunotherapy is already an option for untreated metastatic non-squamous NSCLC in adults whose tumours have no EGFR- or ALK‑positive mutations. See NICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy, which is recommended for use in the Cancer Drugs Fund, and on pembrolizumab monotherapy for people whose tumours express PD‑L1 with at least a 50% tumour proportion score. Atezolizumab plus bevacizumab, carboplatin and paclitaxel would be a further immunotherapy option for the untreated group whose PD‑L1 tumour proportion score is between 0% and 49%. The company's submission did not include a comparison with pembrolizumab monotherapy for PD-L1 in people with a tumour proportion score of at least 50%. Therefore, the committee could not make a recommendation for this group. It agreed that more treatment options at an earlier point in the treatment pathway would benefit people with EGFR- or ALK‑positive NSCLC who have already had targeted therapy.
# Clinical management
## Pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance is the relevant comparator for this appraisal
The clinical experts explained that current standard care for people with untreated non-squamous NSCLC, and for people with EGFR- or ALK‑positive NSCLC who have had targeted therapy, is pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. They noted that not all people can have pemetrexed maintenance. The Cancer Drugs Fund clinical lead confirmed that pemetrexed plus carboplatin or cisplatin, with pemetrexed maintenance, was the relevant comparator for this appraisal. His statement included that other induction chemotherapies recommended in NICE's original guideline on lung cancer: diagnosis and management (April 2011; docetaxel, paclitaxel, gemcitabine, vinorelbine with carboplatin or cisplatin with or without pemetrexed maintenance) were not relevant comparators because these were rarely used to treat non-squamous metastatic NSCLC in clinical practice. The committee was aware that the company submission was not focusing on using atezolizumab plus bevacizumab, carboplatin and paclitaxel for people whose tumours express PD‑L1 with at least a 50% tumour proportion score. Therefore pembrolizumab monotherapy, which is recommended for this population, was not a relevant comparator. The committee concluded that pemetrexed plus carboplatin or cisplatin, with pemetrexed maintenance, was the relevant comparator for this appraisal.
## For EGFR- or ALK-positive NSCLC, atezolizumab plus bevacizumab, carboplatin and paclitaxel would be an option after all targeted therapies
The committee noted that for EGFR- or ALK-positive NSCLC, the marketing authorisation is for treating metastatic non-squamous NSCLC only after failure of appropriate targeted therapies. It understood that EGFR‑positive NSCLC is first treated with EGFR tyrosine kinase inhibitors, in line with NICE's technology appraisal guidance on afatinib, gefitinib or erlotinib. Osimertinib is recommended in the Cancer Drugs Fund as a treatment option for NSCLC with the T790M mutation after afatinib, gefitinib or erlotinib (see NICE's technology appraisal guidance on osimertinib). ALK‑positive NSCLC is first treated in line with NICE's technology appraisal guidance on alectinib, crizotinib or ceritinib. Ceritinib is also recommended as a treatment option after crizotinib (see NICE's technology appraisal guidance on ceritinib). The committee understood that the number of treatment options for NSCLC is increasing rapidly and that the treatment pathway is constantly changing. The company confirmed that the marketing authorisation permitted atezolizumab plus bevacizumab, carboplatin and paclitaxel to be used as a treatment option after all targeted therapies and not just those currently available. The committee concluded that atezolizumab plus bevacizumab, carboplatin and paclitaxel would be a treatment option after all targeted therapies.
## Atezolizumab plus bevacizumab, carboplatin and paclitaxel would only be a treatment option for people who are well enough
The patient expert highlighted the importance of careful selection of people who would be offered atezolizumab plus bevacizumab, carboplatin and paclitaxel in clinical practice. The Cancer Drugs Fund clinical lead confirmed that only people with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 would have atezolizumab plus bevacizumab, carboplatin and paclitaxel. This is because atezolizumab and bevacizumab are being added to chemotherapy and the dose of carboplatin would be higher (area under the curve 6) than usually used in clinical practice. The number of people with EGFR- or ALK‑positive disease who would be well enough (ECOG score of 0 or 1) to have atezolizumab plus bevacizumab, carboplatin and paclitaxel was considered to be small by the patient expert. The patient expert noted that side effects of treatment are an important consideration for patients. The Cancer Drugs Fund clinical lead explained that carboplatin plus paclitaxel results in hair loss, whereas pemetrexed plus carboplatin or cisplatin does not. The committee concluded that atezolizumab plus bevacizumab, carboplatin and paclitaxel would only be a treatment option for people who are well enough.
## Docetaxel would be offered as a subsequent therapy if people are well enough to have further therapy
The Cancer Drugs Fund clinical lead and the clinical experts confirmed that in NHS clinical practice, people who are well enough to have further therapy would take docetaxel after atezolizumab plus bevacizumab, carboplatin and paclitaxel. The committee concluded that docetaxel would be offered after atezolizumab plus bevacizumab, carboplatin and paclitaxel for people who are well enough to have further therapy.
## After pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance, people would have an immunotherapy if they are well enough
The Cancer Drugs Fund clinical lead and the clinical experts confirmed that after pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance, people would have an immunotherapy monotherapy if they are well enough for subsequent treatment. The committee was aware that the immunotherapy options that are available through routine commissioning are pembrolizumab for people with a PD‑L1 tumour proportion score of 1% to 100%, and atezolizumab for people with a PD‑L1 tumour proportion score of 0% to 100% (see NICE's technology appraisal guidance on pembrolizumab and atezolizumab). Nivolumab is also available through the Cancer Drugs Fund as an option for people with a PD‑L1 tumour proportion score of 1% to 100% (see NICE's technology appraisal guidance on nivolumab). The committee concluded that the next line of treatment after pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance is an immunotherapy monotherapy.
# Clinical evidence
## The main evidence for atezolizumab plus bevacizumab, carboplatin and paclitaxel is generalisable to UK clinical practice
The clinical-effectiveness evidence for atezolizumab plus bevacizumab, carboplatin and paclitaxel compared with bevacizumab plus carboplatin and paclitaxel came from IMpower150. This is an ongoing randomised, open-label, phase III study. IMpower150 included adults with untreated NSCLC (with tumours expressing no EGFR- or ALK-positive mutations) and adults with EGFR‑positive or ALK‑positive NSCLC who had already had a targeted therapy, and with an ECOG performance status of 0 or 1. The study included patients regardless of PD‑L1 status. IMpower150 did not include any UK study centres or comparators that are used in UK clinical practice. The committee was not made aware of any reason why the IMpower150 results for the atezolizumab plus bevacizumab, carboplatin and paclitaxel treatment arm were not generalisable to the UK. It accepted that the IMpower150 population broadly reflected people with non-squamous metastatic NSCLC in England. It acknowledged that, because there was no head-to-head evidence with the relevant comparator (pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance), an indirect treatment comparison would be the only way to judge the effectiveness of atezolizumab plus bevacizumab, carboplatin and paclitaxel compared with pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The committee concluded that IMpower150 provided evidence that was generalisable enough to clinical practice for decision making.
## Atezolizumab plus bevacizumab, carboplatin and paclitaxel improves overall and progression-free survival in the intention-to-treat population
At the most recent data cut (January 2018), median overall survival for atezolizumab plus bevacizumab, carboplatin and paclitaxel was reached in the intention-to-treat (ITT) population. The median follow‑up was around 20 months. The committee noted that the results show a statistically significant difference in overall and progression-free survival between the groups (see table 2). It concluded that atezolizumab plus bevacizumab, carboplatin and paclitaxel improved overall and progression-free survival compared with bevacizumab plus carboplatin and paclitaxel in the ITT population.
Atezolizumab plus bevacizumab, carboplatin and paclitaxel
Bevacizumab plus carboplatin and paclitaxel
Hazard ratio (95% confidence interval)
Number of people
Overall survival, median months (95% confidence interval)
(17.4 to 24.2)
(13.4 to 17.1)
(0.63 to 0.93); p=0.0060
Progression-free survival, median months (95% confidence interval)
(7.7 to 9.8)
(6.0 to 7.1)
(0.50 to 0.69); p<0.0001
## The EGFR- or ALK-positive subgroup in IMpower150 is small, with no biological reason for combining the groups, and survival data are immature
At the most recent data cut (January 2018), median overall survival for atezolizumab plus bevacizumab, carboplatin and paclitaxel was not reached for the EGFR- or ALK‑positive NSCLC subgroup. The median follow‑up was around 18 months. The ERG highlighted that caution was needed when interpreting the results for this subgroup because the study was not stratified by EGFR or ALK status. The clinical experts explained that there was no biological reason to group people with EGFR- and ALK-positive NSCLC together. The committee accepted this, and that this grouping was not part of the study design. At the time of the last data cut, only 13 events had been recorded in the atezolizumab plus bevacizumab, carboplatin and paclitaxel treatment arm (see table 3). The committee was aware that the final data from IMpower150 should help to reduce uncertainty in the overall survival estimates. But it noted that although more data are welcome, the number of events will still be low. The committee concluded that the EGFR- or ALK-positive NSCLC subgroup in IMpower150 was small, there was no biological reason for combining the groups and the survival data were immature. These factors substantially added to the uncertainty about survival. At consultation, the company agreed that the EGFR- or ALK-positive subgroup in IMpower150 was small but this reflects the mutation rates seen in NHS clinical practice. The company further justified grouping people with EGFR- and ALK-positive NSCLC together. The committee did not agree that this justification resolved the uncertainty about this combined subgroup.
Atezolizumab plus bevacizumab, carboplatin and paclitaxel
Bevacizumab plus carboplatin and paclitaxel
Hazard ratio (95% confidence interval)
Number of people
Overall survival: people with event, n (%)
Overall survival, median months (95% confidence interval)
Not estimated (17.0 to not estimated)
(10.4 to not estimated)
(0.29 to 1.03); p=0.0578
Progression-free survival: people with event, n (%)
Progression-free survival, median months (95% confidence interval)
(7.9 to 15.2)
(5.6 to 8.4)
(0.35 to 0.87); p=0.0101
## IMpower150 does not include any of the comparator treatments used in NHS clinical practice
The comparator in IMpower150 was bevacizumab plus carboplatin and paclitaxel (see section 3.7). The main overall and progression-free survival evidence for pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance came from 5 studies:
ERACLE
PRONOUNCE
KEYNOTE-021
KEYNOTE-189
PARAMOUNT.PARAMOUNT was the only study that reported results for pemetrexed plus carboplatin or cisplatin without pemetrexed maintenance. ERACLE and PRONOUNCE reported results for pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. KEYNOTE‑021 and KEYNOTE‑189 reported results for pembrolizumab with pemetrexed-based chemotherapy. The committee accepted that IMpower150 did not include any of the relevant comparator treatments used in NHS clinical practice. It concluded that data from other studies were needed for the comparator in this appraisal.
# Indirect treatment comparison
## An indirect comparison is appropriate because there are no head-to-head trials with the relevant comparators
Because there were no head-to-head trials comparing atezolizumab plus bevacizumab, carboplatin and paclitaxel with pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance, the company did a network meta-analysis. It estimated time-varying fractional polynomial hazards for overall and progression-free survival using a fixed effects Weibull model. To do subgroup analyses for the PD‑L1 tumour proportion score less than 50% and EGFR- or ALK‑positive populations, it was assumed that the level of PD‑L1 expression and presence of EGFR or ALK mutations were not effect modifiers. The ERG's clinical expert did not agree with this assumption. But the committee was aware that this limitation in the analysis was necessary for a connected network to be established and to be able to compare atezolizumab plus bevacizumab, carboplatin and paclitaxel with pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. The ERG noted that the company's approach to the indirect treatment comparison using a time-varying fractional polynomial model was appropriate given the different mechanisms and speeds of action for immunotherapies and chemotherapies and it agreed with the choice of the Weibull model. The committee concluded that the company's approach was appropriate.
## PARAMOUNT should not be included in the network meta-analysis
The company included PARAMOUNT in its network meta-analysis. PARAMOUNT was the only trial that had pemetrexed plus carboplatin or cisplatin without pemetrexed maintenance as a comparator. The ERG highlighted that including PARAMOUNT in the network meta-analysis greatly increased heterogeneity in the network because it had a different study design to the other included studies. The committee heard that the PARAMOUNT protocol included induction chemotherapy (pemetrexed-based), and this may have caused selection bias because only people whose disease responded to induction therapy would continue in the study. The committee understood that if PARAMOUNT was not included in the network then no comparison could be made with pemetrexed plus carboplatin or cisplatin without pemetrexed maintenance. But it recalled that the with-maintenance comparator was considered the relevant one for decision making (see section 3.2). The committee agreed that including PARAMOUNT in the network increased the heterogeneity in the network. At consultation, the company agreed that excluding PARAMOUNT from the network meta-analysis was reasonable and excluded it in an updated analysis. The committee agreed that the company's revised analysis was appropriate.
# The company's economic model
## The company's model structure is acceptable for decision making
The company presented a 3-state partitioned survival model to estimate the cost effectiveness of atezolizumab plus bevacizumab, carboplatin and paclitaxel compared with pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. People were able to move to different health states; from pre-progression to post-progression and death and from post-progression to death. The ERG agreed with the company's model structure. The company used the IMpower150 results to model overall and progression-free survival for people who had atezolizumab plus bevacizumab, carboplatin and paclitaxel. Specific survival curves were modelled for the ITT population and for the PD‑L1 tumour proportion score less than 50% subgroup and the EGFR- or ALK‑positive NSCLC subgroup. Hazard ratios from the indirect treatment comparison were then applied to the atezolizumab plus bevacizumab, carboplatin and paclitaxel data to estimate overall and progression-free survival for pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. The committee concluded that the model structure and approach to modelling survival for the atezolizumab plus bevacizumab, carboplatin and paclitaxel treatment arm was acceptable and appropriate for decision making.
# Clinical evidence in the economic model
## The results for the ITT network meta-analysis that excludes PARAMOUNT are appropriate to include in the model
The company used the hazard ratios from the network meta-analysis specific to the ITT population, the PD‑L1 tumour proportion score less than 50% subgroup and the EGFR- or ALK‑positive NSCLC subgroup to estimate relative effects for pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance in the economic model. The ERG preferred to use the hazard ratios from the ITT population for each subgroup, as well as for the overall ITT population. This was because IMpower150 did not show that PD‑L1, EGFR or ALK status modified the effect of the treatment so the ITT network meta-analysis results were considered more robust given the larger population. The committee recalled that including PARAMOUNT in the network increased heterogeneity (see section 3.12). At consultation, the company provided updated analyses (using the hazard ratios from the ITT network meta-analysis excluding PARAMOUNT for each subgroup, as well as for the overall ITT population) to estimate relative effects in the economic model for pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. The committee agreed that the company's revised analyses were more appropriate than analyses using the hazard ratios from the network meta-analysis specific to the ITT population, the PD‑L1 tumour proportion score less than 50% subgroup and the EGFR- or ALK‑positive NSCLC subgroup.
# Extrapolating overall survival data in the economic model
## The exponential and Weibull functions are both acceptable for extrapolating overall survival for the intervention and comparator
The company extrapolated overall survival in its model using the exponential function. The ERG's preferred choice was the Weibull function, based on it being a plausible alternative to the exponential function and giving long-term overall survival estimates for non-squamous NSCLC closer to those previously considered reasonable by the committee. The committee considered both functions to be suitable because they fitted the observed period of data well (based on statistical fit). The committee recalled its conclusion that a 5‑year survival rate of 5% to 11% for people with non-squamous NSCLC who had treatment with standard care chemotherapy was reasonable for decision making in NICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy. For the ITT population, the Weibull function gave 5‑year survival estimates at the top end of this range; 10% for atezolizumab plus bevacizumab, carboplatin and paclitaxel, and 9% for pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The exponential function gave values slightly above the 5% to 11% range, with 5‑year survival estimates of 13% for people who had atezolizumab plus bevacizumab, carboplatin and paclitaxel, and 12% for people who had pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. At consultation, the company submitted revised analyses using the Weibull function to extrapolate overall survival. The committee agreed that the exponential and Weibull functions were acceptable for extrapolating overall survival.
## The company's model gives 5-year overall survival estimates for the EGFR- or ALK-positive NSCLC subgroup that are not credible
For EGFR- or ALK-positive NSCLC, the company's model estimated that 27% (if the exponential function was used) or 26% (if the Weibull function was used) of people who had atezolizumab plus bevacizumab, carboplatin and paclitaxel would be alive after 5 years, and 18% of people who had pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance would be alive after 5 years. The committee discussed the much higher estimates of long-term overall survival for the EGFR- or ALK‑positive NSCLC subgroup compared with the ITT population (see section 3.15). The clinical experts confirmed that the estimate of 18% overall survival at 5 years for people who had pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance was too high. They estimated this to be between 5% and 10%, that is, more in line with the expected estimates for the ITT population. But they explained that the EGFR- or ALK‑positive NSCLC subgroup is distinct from the ITT population and that, for this group, it was biologically plausible that treatment with atezolizumab plus bevacizumab, carboplatin and paclitaxel would give 5‑year overall survival estimates that are substantially higher than treatment with pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance. This biological rationale was said to be particularly strong for EGFR‑positive NSCLC because of the vascular nature of these tumours and their response to vascular endothelial growth factor inhibitors such as bevacizumab. The committee accepted that the EGFR- or ALK‑positive NSCLC subgroup is distinct and acknowledged that the 5‑year overall survival estimates that had been accepted in previous appraisals in this disease area were likely not valid for this subgroup (see section 3.15). The committee was concerned that it had not heard a biological explanation why the long-term overall survival estimates were plausible for people with ALK‑positive NSCLC. It recalled that the EGFR- or ALK‑positive NSCLC subgroup in IMpower150 was small, there was no biological rationale for combining these groups and that median overall survival had not been reached at the last data cut, in January 2018 (see section 3.9). It was aware that there had only been 13 events in the atezolizumab plus bevacizumab, carboplatin and paclitaxel treatment arm of the study and this made extrapolation of long-term survival more uncertain. The committee agreed that the long-term overall survival estimates from the company's model were too high and not credible. But, a difference of around 8% to 10% between the long-term overall survival estimates for people who had atezolizumab with bevacizumab, carboplatin and paclitaxel and people who had pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance was plausible. At consultation, the company highlighted that the most conservative approach was taken when extrapolating the overall survival data for the EGFR- or ALK‑positive subgroup. It noted that the ERG's and NICE's preferred approach to use the relative effect from the ITT network meta-analysis to model long-term survival for the subgroups represented a more conservative way to model survival for the EGFR- or ALK-positive subgroup (see section 3.14). The ERG explained that the IMpower150 data for the EGFR- or ALK‑positive subgroup were limited by the small population and low number of events. The committee understood that the analysis of the ITT population (including the EGFR- or ALK‑positive subgroup) was more robust for decision making. The committee accepted that there were limitations with the overall survival data for the EGFR- or ALK‑positive subgroup and concluded that the ITT population was more appropriate for decision making.
# Stopping rule
## Including a 2-year stopping rule is acceptable
The company included a 2-year treatment stopping rule for atezolizumab and bevacizumab in the model. The committee was aware that in IMpower150, people had treatment until loss of clinical benefit for atezolizumab and until disease progression for bevacizumab, or unacceptable toxicity. It noted that a 2‑year stopping rule had been implemented in other technology appraisal guidance on NSCLC (see the NICE Pathway on lung cancer). The patient expert explained that stopping treatment is a worry for people with NSCLC, but they generally understood that treatment would be stopped at some point. The Cancer Drugs Fund clinical lead's statement included that a 2‑year stopping rule would be implemented in clinical practice. The committee agreed that the best treatment duration with atezolizumab plus bevacizumab, carboplatin and paclitaxel was unknown but accepted that a 2‑year stopping rule would be used in clinical practice. It therefore concluded that it was appropriate for the company to include a 2‑year treatment stopping rule in its economic model.
# Duration of treatment benefit after progression
## A long-term treatment effect of atezolizumab and bevacizumab after stopping treatment is plausible
The company's base case included a 3-year treatment effect after stopping treatment with atezolizumab and bevacizumab. The committee was aware that the duration of treatment effect is an area of uncertainty for new immunotherapies. In previous technology appraisals in this disease area, scenarios of a treatment effect lasting between 3 and 5 years have been considered. The committee was also aware that there was no evidence to inform the long-term treatment effect of atezolizumab and bevacizumab from IMpower150 or any other sources. It agreed that, although it was biologically plausible for the treatment effect to continue after stopping atezolizumab and bevacizumab, its duration was uncertain. It concluded that the 3‑year treatment effect from when treatment was stopped in the company's and the ERG's base case was appropriate for decision making.
# Subsequent therapy
## The assumption that everyone has subsequent therapy is not appropriate
In their base cases, the company and ERG assumed that 100% of people would have subsequent therapy after atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. The clinical experts explained that no more than 60% of people would be well enough to have subsequent therapy. However, the Cancer Drugs Fund clinical lead estimated this to be no more than 50%. The committee was aware that in previous technology appraisals for ALK‑positive NSCLC, clinical experts estimated that 50% of people whose disease had progressed while taking alectinib would have subsequent therapy. The committee heard that some people with non-squamous NSCLC can have poor performance status and their disease can progress quickly. People with brain metastases would not have any further treatment with a cytotoxic chemotherapy or immunotherapy. The clinical experts noted that fewer people would have subsequent therapy after atezolizumab plus bevacizumab, carboplatin and paclitaxel than after pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance given that there would be fewer therapeutic options available. They estimated that 30% to 40% of people would have subsequent therapy after atezolizumab plus bevacizumab, carboplatin and paclitaxel in larger centres but noted this estimate would be much lower in smaller centres. At consultation, the company submitted updated analyses including 2 scenarios for people having subsequent therapy. The proportions were equal after treatment with atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance:
Scenario 1: 46.6% of people had subsequent therapy (based on the proportion having subsequent therapy in the standard care arm in the KEYNOTE-189 trial).
Scenario 2: 60% of people had subsequent therapy (based on the upper estimate given in the appraisal consultation document).The Cancer Drugs Fund clinical lead reminded the committee that his estimate was that no more than 50% of people would have subsequent therapy in clinical practice. He noted that an estimate of between 40% and 50% was reasonable. The committee agreed that the company's revised analysis including 46.6% of people having subsequent therapy after treatment with atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance was appropriate for decision making.
## The distribution of subsequent therapies in the company's model after pemetrexed combination treatment is not appropriate for decision making
The subsequent therapies offered in IMpower150 did not reflect the treatment options available in NHS clinical practice in England. The company included docetaxel, nivolumab, pembrolizumab and atezolizumab as subsequent treatment options in its economic model and estimated the distributions from UK market share data. The committee heard that because nivolumab is recommended in the Cancer Drugs Fund and not routinely commissioned in the NHS in England, it should not be considered in decision making. The Cancer Drugs Fund clinical lead and the clinical experts explained that after pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance, people would have an immunotherapy (see section 3.6). Therefore, nivolumab and docetaxel were not considered to be appropriate subsequent therapies to be included in the analysis. At consultation, the company provided updated analyses that included only atezolizumab and pembrolizumab as subsequent therapies after pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The committee agreed that the company's revised analyses were more appropriate than analyses including treatment options that are not immunotherapies or not routinely commissioned in the NHS in England.
# Health-related quality of life
## It is reasonable to include a disutility for treatment-related adverse events
The company included utility values using the proximity to death approach. The utility values were the same for atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. It did not include a disutility for adverse events. The ERG included a disutility for treatment-related adverse events that were grade 3 or higher in IMpower150. Disutility values were sourced from Nafees et al. (2008). The clinical experts explained that atezolizumab plus bevacizumab, carboplatin and paclitaxel has similar toxicity to pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance. The main toxicity concern is hypertension with atezolizumab plus bevacizumab, carboplatin and paclitaxel. At consultation, the company provided updated analyses that included a disutility for treatment-related adverse events that were grade 3 or higher in IMpower150. The committee agreed that the company's revised analyses were more appropriate for decision making.
# Cost-effectiveness results
## The company's base case is appropriate for decision making
The company revised its base-case cost-effectiveness analysis at consultation. In line with the ERG's preferred assumptions, it:
corrected discrepancies in the company model
used a Weibull distribution to extrapolate overall survival
used the hazard ratios from the meta-analysis that excluded PARAMOUNT from the network
used the hazard ratios from the ITT network meta-analysis for overall and progression-free survival for the PD‑L1 tumour proportion score less than 50% subgroup and the EGFR- or ALK‑positive NSCLC subgroup
included a disutility for treatment-related adverse events of grade 3 or higher.The company also included a new discount to the price of bevacizumab and included only immunotherapies as subsequent therapies after pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The committee considered the incremental cost-effectiveness ratios (ICERs) from the company's revised base case for the ITT population. The revised base case included 46.6% of people having subsequent therapy and the discounts from the commercial access agreements and patient access schemes for atezolizumab, bevacizumab, pemetrexed maintenance and pembrolizumab (which are confidential so the ICERs cannot be reported here). The company's base-case ICER comparing atezolizumab plus bevacizumab, carboplatin and paclitaxel with pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance was below £50,000 per quality-adjusted life year (QALY) gained for the ITT population. The committee concluded that the company's base case was appropriate for decision making.
## The committee's most plausible ICER is less than £50,000 per QALY gained
The committee agreed with the company's revised base case in which 46.6% of people had subsequent therapy after atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance. Although it was aware of the uncertainties about overall survival benefit for the EGFR- or ALK‑positive subgroup, the committee concluded that the most plausible ICER for atezolizumab plus bevacizumab, carboplatin and paclitaxel compared with pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance in people with metastatic non-squamous NSCLC was below £50,000 per QALY gained.
# End of life
## Life expectancy for people with metastatic non-squamous NSCLC is considered to be less than 24 months
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company's model predicted a mean overall survival for people with metastatic non-squamous NSCLC of more than 24 months after pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance (26 months for the ITT population, 27 months for the PD‑L1 tumour proportion score less than 50% subgroup and 38 months for the EGFR- or ALK‑positive NSCLC subgroup). The ERG's model predicted a mean overall survival of 21 months for the ITT population. At consultation, the company updated its base-case cost-effectiveness analysis in line with the ERG's preferred assumptions (see section 3.22). The company's updated model predicted mean overall survival of less than 24 months after pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The committee concluded that the life expectancy of people with metastatic non-squamous NSCLC was less than 24 months.
## Atezolizumab plus bevacizumab, carboplatin and paclitaxel extends life by at least 3 months
The company estimated a mean life extension of 5 months for the ITT population, 3.5 months for the PD‑L1 tumour proportion score less than 50% subgroup and 24 months for the EGFR- or ALK‑positive NSCLC subgroup with atezolizumab plus bevacizumab, carboplatin and paclitaxel, compared with pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance. These estimates met the second criterion for an end-of-life treatment. The committee acknowledged that the data used to estimate the extension to life in the EGFR- or ALK‑positive NSCLC subgroup were not robust, but extension to life in the ITT population and all subgroups was likely to be at least 3 months. The committee concluded that atezolizumab plus bevacizumab, carboplatin and paclitaxel for metastatic non-squamous NSCLC would extend life by at least 3 months.
## Atezolizumab plus bevacizumab, carboplatin and paclitaxel meets the criteria for end-of-life treatments
The committee concluded that it was satisfied that atezolizumab plus bevacizumab, carboplatin and paclitaxel met the criteria for end-of-life treatments.
# Innovation
## The benefits of atezolizumab plus bevacizumab, carboplatin and paclitaxel are captured in the measurement of the QALY
The company stated that atezolizumab plus bevacizumab, carboplatin and paclitaxel was innovative because it was the first checkpoint inhibitor with a phase III combination study showing a statistically significant and clinically meaningful overall and progression-free survival benefit. The company highlighted in its submission that atezolizumab plus bevacizumab, carboplatin and paclitaxel improved survival in all key subgroups including people with EGFR- or ALK‑positive NSCLC and people with liver metastases. The committee was aware that the Medicines and Healthcare products Regulatory Agency had granted atezolizumab plus bevacizumab, carboplatin and paclitaxel early access to medicines scheme status for treating metastatic non-squamous EGFR‑positive or ALK-positive NSCLC after failure of appropriate targeted therapies. However, the committee concluded that there were no relevant additional benefits that had not been captured in the QALY calculations.
# Other factors
No equality or social value judgement issues were identified.
# Conclusion
## Atezolizumab plus bevacizumab, carboplatin and paclitaxel is recommended for people with metastatic non-squamous NSCLC
The committee agreed that atezolizumab plus bevacizumab, carboplatin and paclitaxel, with the discounts agreed in the commercial arrangements, is a cost-effective use of NHS resources, and can be recommended as an option for metastatic non-squamous NSCLC in adults:
who have not had treatment for their metastatic NSCLC before and whose PD‑L1 tumour proportion score is between 0% and 49% or
when targeted therapy for EGFR‑positive or ALK‑positive NSCLC has failed
-nly if atezolizumab and bevacizumab are stopped at 2 years of uninterrupted treatment, or earlier if there is loss of clinical benefit (for atezolizumab) or if the disease progresses (for bevacizumab).
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{'Recommendations': "Atezolizumab plus bevacizumab, carboplatin and paclitaxel is recommended as an option for metastatic non-squamous non-small-cell lung cancer (NSCLC) in adults:\n\nwho have not had treatment for their metastatic NSCLC before and whose PD-L1 tumour proportion score is between 0% and 49% or\n\nwhen targeted therapy for epidermal growth factor receptor (EGFR)‑positive or anaplastic lymphoma kinase (ALK)‑positive NSCLC has failed.It is recommended only if:\n\natezolizumab and bevacizumab are stopped at 2\xa0years of uninterrupted treatment, or earlier if there is loss of clinical benefit (for atezolizumab) or if the disease progresses (for bevacizumab) and\n\nthe company provides atezolizumab and bevacizumab according to the commercial arrangements.\n\nThis recommendation is not intended to affect treatment with atezolizumab plus bevacizumab, carboplatin and paclitaxel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPemetrexed plus carboplatin or cisplatin, with or without pemetrexed maintenance, is the current treatment for:\n\nuntreated metastatic non-squamous NSCLC (with no EGFR- or ALK‑positive mutations) with a PD‑L1 tumour proportion score between 0% and 49% and\n\nmetastatic non-squamous EGFR- or ALK-positive NSCLC when targeted therapy is either not an option or has failed.\n\nPembrolizumab monotherapy is the current treatment for untreated metastatic non-squamous NSCLC with a PD‑L1 tumour proportion score of at least 50%.\n\nAn indirect comparison of studies suggests that people having atezolizumab plus bevacizumab, carboplatin and paclitaxel live longer than those having pemetrexed plus carboplatin or cisplatin, with or without pemetrexed maintenance. This comparison also suggests that they live for longer before their condition worsens.\n\nAtezolizumab plus bevacizumab, carboplatin and paclitaxel meets NICE's criteria to be considered a life-extending treatment at the end of life. There is uncertainty about the company's long-term survival estimates, especially for people with EGFR- or ALK‑positive NSCLC. But including the most plausible assumptions and the commercial arrangements, the cost-effectiveness estimates are within what NICE normally considers acceptable for an end-of-life treatment. Therefore, atezolizumab plus bevacizumab, carboplatin and paclitaxel is recommended for metastatic non-squamous NSCLC that is untreated (with no EGFR- or ALK‑positive mutations) and when the PD‑L1 tumour proportion score is between 0% and 49%, or that is EGFR- or ALK‑positive and for which targeted therapy has failed.\n\nAtezolizumab and bevacizumab are stopped at 2\xa0years of uninterrupted treatment, or earlier if there is loss of clinical benefit (for atezolizumab) or if the disease progresses (for bevacizumab). This is because the cost-effectiveness evidence was primarily based on 2\xa0years of treatment and the best duration of treatment is unknown.\n\nNo recommendation can be made for atezolizumab plus bevacizumab, carboplatin and paclitaxel for treating untreated PD‑L1‑positive metastatic NSCLC in people whose PD‑L1 tumour proportion score is at least 50% because no cost-effectiveness analyses comparing atezolizumab plus bevacizumab, carboplatin and paclitaxel with pembrolizumab monotherapy were provided.", 'Information about atezolizumab plus bevacizumab, carboplatin and paclitaxel': "Marketing authorisation indication\n\nAtezolizumab (Tecentriq, Roche) plus bevacizumab (Avastin, Roche), paclitaxel and carboplatin, is indicated 'for the first-line treatment of adult patients with metastatic non-squamous non-small cell lung cancer (NSCLC). In patients with epidermal growth factor receptor (EGFR)-mutant or anaplastic lymphoma kinase (ALK)-positive NSCLC, Tecentriq, in combination with bevacizumab, paclitaxel and carboplatin, is indicated only after failure of appropriate targeted therapies'.\n\nAtezolizumab plus bevacizumab, paclitaxel and carboplatin has been available in the UK for treating metastatic non-squamous EGFR- or ALK-positive NSCLC after failure of appropriate targeted therapies through the early access to medicines scheme.\n\nDosage in the marketing authorisation\n\nIn the induction phase, the recommended dose of atezolizumab is 1,200\xa0mg administered by intravenous infusion, followed by bevacizumab (15\xa0mg/kg), paclitaxel (200\xa0mg/m2)*, and then carboplatin (area under the curve\xa06) every 3\xa0weeks for 4 or 6\xa0cycles. The induction phase is followed by a maintenance phase without chemotherapy in which 1,200\xa0mg atezolizumab followed by bevacizumab (15\xa0mg/kg) is administered by intravenous infusion every 3\xa0weeks.\n\n* In the pivotal clinical trial (IMpower150), the paclitaxel starting dose for patients of Asian family origin was 175\xa0mg/m2 because of a higher overall level of haematological toxicities in these patients compared with those of non-Asian family origin.\n\nIt is recommended that patients have treatment with atezolizumab until loss of clinical benefit or unmanageable toxicity, and bevacizumab until disease progression or unacceptable toxicity, whichever occurs first. Dose reductions of atezolizumab are not recommended. Paclitaxel and carboplatin were administered in the IMpower150 trial until completion of 4 or 6\xa0cycles, or progressive disease, or unacceptable toxicity, whichever occurs first.\n\nPrice\n\nAtezolizumab: £3,807.69 per 1,200‑mg vial (excluding VAT; British national formulary [BNF] online, accessed March 2019).\n\nBevacizumab: £242.66 per 100‑mg vial (excluding VAT; BNF online, accessed March 2019).\n\nCosts of carboplatin and paclitaxel may vary in different settings because of negotiated procurement discounts.\n\nThe company has commercial arrangements. This makes atezolizumab and bevacizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## A new treatment option would benefit people with metastatic non-squamous NSCLC\n\nPeople with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive metastatic non-squamous non-small-cell lung cancer (NSCLC) are offered pemetrexed plus carboplatin or cisplatin, with or without pemetrexed maintenance, after targeted therapy. After pemetrexed combination treatment, people may be offered immunotherapy if they are well enough. The clinical experts welcomed the option to use immunotherapy at an earlier point in the treatment pathway for EGFR- or ALK‑positive NSCLC because some people may not be well enough to go on to have further therapy. Immunotherapy is already an option for untreated metastatic non-squamous NSCLC in adults whose tumours have no EGFR- or ALK‑positive mutations. See NICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy, which is recommended for use in the Cancer Drugs Fund, and on pembrolizumab monotherapy for people whose tumours express PD‑L1 with at least a 50% tumour proportion score. Atezolizumab plus bevacizumab, carboplatin and paclitaxel would be a further immunotherapy option for the untreated group whose PD‑L1 tumour proportion score is between 0% and 49%. The company's submission did not include a comparison with pembrolizumab monotherapy for PD-L1 in people with a tumour proportion score of at least 50%. Therefore, the committee could not make a recommendation for this group. It agreed that more treatment options at an earlier point in the treatment pathway would benefit people with EGFR- or ALK‑positive NSCLC who have already had targeted therapy.\n\n# Clinical management\n\n## Pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance is the relevant comparator for this appraisal\n\nThe clinical experts explained that current standard care for people with untreated non-squamous NSCLC, and for people with EGFR- or ALK‑positive NSCLC who have had targeted therapy, is pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. They noted that not all people can have pemetrexed maintenance. The Cancer Drugs Fund clinical lead confirmed that pemetrexed plus carboplatin or cisplatin, with pemetrexed maintenance, was the relevant comparator for this appraisal. His statement included that other induction chemotherapies recommended in NICE's original guideline on lung cancer: diagnosis and management (April 2011; docetaxel, paclitaxel, gemcitabine, vinorelbine with carboplatin or cisplatin with or without pemetrexed maintenance) were not relevant comparators because these were rarely used to treat non-squamous metastatic NSCLC in clinical practice. The committee was aware that the company submission was not focusing on using atezolizumab plus bevacizumab, carboplatin and paclitaxel for people whose tumours express PD‑L1 with at least a 50% tumour proportion score. Therefore pembrolizumab monotherapy, which is recommended for this population, was not a relevant comparator. The committee concluded that pemetrexed plus carboplatin or cisplatin, with pemetrexed maintenance, was the relevant comparator for this appraisal.\n\n## For EGFR- or ALK-positive NSCLC, atezolizumab plus bevacizumab, carboplatin and paclitaxel would be an option after all targeted therapies\n\nThe committee noted that for EGFR- or ALK-positive NSCLC, the marketing authorisation is for treating metastatic non-squamous NSCLC only after failure of appropriate targeted therapies. It understood that EGFR‑positive NSCLC is first treated with EGFR tyrosine kinase inhibitors, in line with NICE's technology appraisal guidance on afatinib, gefitinib or erlotinib. Osimertinib is recommended in the Cancer Drugs Fund as a treatment option for NSCLC with the T790M mutation after afatinib, gefitinib or erlotinib (see NICE's technology appraisal guidance on osimertinib). ALK‑positive NSCLC is first treated in line with NICE's technology appraisal guidance on alectinib, crizotinib or ceritinib. Ceritinib is also recommended as a treatment option after crizotinib (see NICE's technology appraisal guidance on ceritinib). The committee understood that the number of treatment options for NSCLC is increasing rapidly and that the treatment pathway is constantly changing. The company confirmed that the marketing authorisation permitted atezolizumab plus bevacizumab, carboplatin and paclitaxel to be used as a treatment option after all targeted therapies and not just those currently available. The committee concluded that atezolizumab plus bevacizumab, carboplatin and paclitaxel would be a treatment option after all targeted therapies.\n\n## Atezolizumab plus bevacizumab, carboplatin and paclitaxel would only be a treatment option for people who are well enough\n\nThe patient expert highlighted the importance of careful selection of people who would be offered atezolizumab plus bevacizumab, carboplatin and paclitaxel in clinical practice. The Cancer Drugs Fund clinical lead confirmed that only people with an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01 would have atezolizumab plus bevacizumab, carboplatin and paclitaxel. This is because atezolizumab and bevacizumab are being added to chemotherapy and the dose of carboplatin would be higher (area under the curve\xa06) than usually used in clinical practice. The number of people with EGFR- or ALK‑positive disease who would be well enough (ECOG score of 0\xa0or\xa01) to have atezolizumab plus bevacizumab, carboplatin and paclitaxel was considered to be small by the patient expert. The patient expert noted that side effects of treatment are an important consideration for patients. The Cancer Drugs Fund clinical lead explained that carboplatin plus paclitaxel results in hair loss, whereas pemetrexed plus carboplatin or cisplatin does not. The committee concluded that atezolizumab plus bevacizumab, carboplatin and paclitaxel would only be a treatment option for people who are well enough.\n\n## Docetaxel would be offered as a subsequent therapy if people are well enough to have further therapy\n\nThe Cancer Drugs Fund clinical lead and the clinical experts confirmed that in NHS clinical practice, people who are well enough to have further therapy would take docetaxel after atezolizumab plus bevacizumab, carboplatin and paclitaxel. The committee concluded that docetaxel would be offered after atezolizumab plus bevacizumab, carboplatin and paclitaxel for people who are well enough to have further therapy.\n\n## After pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance, people would have an immunotherapy if they are well enough\n\nThe Cancer Drugs Fund clinical lead and the clinical experts confirmed that after pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance, people would have an immunotherapy monotherapy if they are well enough for subsequent treatment. The committee was aware that the immunotherapy options that are available through routine commissioning are pembrolizumab for people with a PD‑L1 tumour proportion score of 1% to 100%, and atezolizumab for people with a PD‑L1 tumour proportion score of 0% to 100% (see NICE's technology appraisal guidance on pembrolizumab and atezolizumab). Nivolumab is also available through the Cancer Drugs Fund as an option for people with a PD‑L1 tumour proportion score of 1% to 100% (see NICE's technology appraisal guidance on nivolumab). The committee concluded that the next line of treatment after pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance is an immunotherapy monotherapy.\n\n# Clinical evidence\n\n## The main evidence for atezolizumab plus bevacizumab, carboplatin and paclitaxel is generalisable to UK clinical practice\n\nThe clinical-effectiveness evidence for atezolizumab plus bevacizumab, carboplatin and paclitaxel compared with bevacizumab plus carboplatin and paclitaxel came from IMpower150. This is an ongoing randomised, open-label, phase\xa0III study. IMpower150 included adults with untreated NSCLC (with tumours expressing no EGFR- or ALK-positive mutations) and adults with EGFR‑positive or ALK‑positive NSCLC who had already had a targeted therapy, and with an ECOG performance status of 0\xa0or\xa01. The study included patients regardless of PD‑L1 status. IMpower150 did not include any UK study centres or comparators that are used in UK clinical practice. The committee was not made aware of any reason why the IMpower150 results for the atezolizumab plus bevacizumab, carboplatin and paclitaxel treatment arm were not generalisable to the UK. It accepted that the IMpower150 population broadly reflected people with non-squamous metastatic NSCLC in England. It acknowledged that, because there was no head-to-head evidence with the relevant comparator (pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance), an indirect treatment comparison would be the only way to judge the effectiveness of atezolizumab plus bevacizumab, carboplatin and paclitaxel compared with pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The committee concluded that IMpower150 provided evidence that was generalisable enough to clinical practice for decision making.\n\n## Atezolizumab plus bevacizumab, carboplatin and paclitaxel improves overall and progression-free survival in the intention-to-treat population\n\nAt the most recent data cut (January 2018), median overall survival for atezolizumab plus bevacizumab, carboplatin and paclitaxel was reached in the intention-to-treat (ITT) population. The median follow‑up was around 20\xa0months. The committee noted that the results show a statistically significant difference in overall and progression-free survival between the groups (see table\xa02). It concluded that atezolizumab plus bevacizumab, carboplatin and paclitaxel improved overall and progression-free survival compared with bevacizumab plus carboplatin and paclitaxel in the ITT population.\n\n\n\n-\n\nAtezolizumab plus bevacizumab, carboplatin and paclitaxel\n\nBevacizumab plus carboplatin and paclitaxel\n\nHazard ratio (95% confidence interval)\n\nNumber of people\n\n\n\n\n\n-\n\nOverall survival, median months (95% confidence interval)\n\n(17.4 to 24.2)\n\n(13.4 to 17.1)\n\n(0.63 to 0.93); p=0.0060\n\nProgression-free survival, median months (95% confidence interval)\n\n(7.7 to 9.8)\n\n(6.0 to 7.1)\n\n(0.50 to 0.69); p<0.0001\n\n## The EGFR- or ALK-positive subgroup in IMpower150 is small, with no biological reason for combining the groups, and survival data are immature\n\nAt the most recent data cut (January 2018), median overall survival for atezolizumab plus bevacizumab, carboplatin and paclitaxel was not reached for the EGFR- or ALK‑positive NSCLC subgroup. The median follow‑up was around 18\xa0months. The ERG highlighted that caution was needed when interpreting the results for this subgroup because the study was not stratified by EGFR or ALK status. The clinical experts explained that there was no biological reason to group people with EGFR- and ALK-positive NSCLC together. The committee accepted this, and that this grouping was not part of the study design. At the time of the last data cut, only 13\xa0events had been recorded in the atezolizumab plus bevacizumab, carboplatin and paclitaxel treatment arm (see table\xa03). The committee was aware that the final data from IMpower150 should help to reduce uncertainty in the overall survival estimates. But it noted that although more data are welcome, the number of events will still be low. The committee concluded that the EGFR- or ALK-positive NSCLC subgroup in IMpower150 was small, there was no biological reason for combining the groups and the survival data were immature. These factors substantially added to the uncertainty about survival. At consultation, the company agreed that the EGFR- or ALK-positive subgroup in IMpower150 was small but this reflects the mutation rates seen in NHS clinical practice. The company further justified grouping people with EGFR- and ALK-positive NSCLC together. The committee did not agree that this justification resolved the uncertainty about this combined subgroup.\n\n-\n\nAtezolizumab plus bevacizumab, carboplatin and paclitaxel\n\nBevacizumab plus carboplatin and paclitaxel\n\nHazard ratio (95% confidence interval)\n\nNumber of people\n\n\n\n\n\n-\n\nOverall survival: people with event, n (%)\n\n(31.7)\n\n(52.4)\n\n-\n\nOverall survival, median months (95% confidence interval)\n\nNot estimated (17.0 to not estimated)\n\n(10.4 to not estimated)\n\n(0.29 to 1.03); p=0.0578\n\nProgression-free survival: people with event, n (%)\n\n(68.3)\n\n(90.5)\n\n-\n\nProgression-free survival, median months (95% confidence interval)\n\n(7.9 to 15.2)\n\n(5.6 to 8.4)\n\n(0.35 to 0.87); p=0.0101\n\n## IMpower150 does not include any of the comparator treatments used in NHS clinical practice\n\nThe comparator in IMpower150 was bevacizumab plus carboplatin and paclitaxel (see section\xa03.7). The main overall and progression-free survival evidence for pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance came from 5\xa0studies:\n\nERACLE\n\nPRONOUNCE\n\nKEYNOTE-021\n\nKEYNOTE-189\n\nPARAMOUNT.PARAMOUNT was the only study that reported results for pemetrexed plus carboplatin or cisplatin without pemetrexed maintenance. ERACLE and PRONOUNCE reported results for pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. KEYNOTE‑021 and KEYNOTE‑189 reported results for pembrolizumab with pemetrexed-based chemotherapy. The committee accepted that IMpower150 did not include any of the relevant comparator treatments used in NHS clinical practice. It concluded that data from other studies were needed for the comparator in this appraisal.\n\n# Indirect treatment comparison\n\n## An indirect comparison is appropriate because there are no head-to-head trials with the relevant comparators\n\nBecause there were no head-to-head trials comparing atezolizumab plus bevacizumab, carboplatin and paclitaxel with pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance, the company did a network meta-analysis. It estimated time-varying fractional polynomial hazards for overall and progression-free survival using a fixed effects Weibull model. To do subgroup analyses for the PD‑L1 tumour proportion score less than 50% and EGFR- or ALK‑positive populations, it was assumed that the level of PD‑L1 expression and presence of EGFR or ALK mutations were not effect modifiers. The ERG's clinical expert did not agree with this assumption. But the committee was aware that this limitation in the analysis was necessary for a connected network to be established and to be able to compare atezolizumab plus bevacizumab, carboplatin and paclitaxel with pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. The ERG noted that the company's approach to the indirect treatment comparison using a time-varying fractional polynomial model was appropriate given the different mechanisms and speeds of action for immunotherapies and chemotherapies and it agreed with the choice of the Weibull model. The committee concluded that the company's approach was appropriate.\n\n## PARAMOUNT should not be included in the network meta-analysis\n\nThe company included PARAMOUNT in its network meta-analysis. PARAMOUNT was the only trial that had pemetrexed plus carboplatin or cisplatin without pemetrexed maintenance as a comparator. The ERG highlighted that including PARAMOUNT in the network meta-analysis greatly increased heterogeneity in the network because it had a different study design to the other included studies. The committee heard that the PARAMOUNT protocol included induction chemotherapy (pemetrexed-based), and this may have caused selection bias because only people whose disease responded to induction therapy would continue in the study. The committee understood that if PARAMOUNT was not included in the network then no comparison could be made with pemetrexed plus carboplatin or cisplatin without pemetrexed maintenance. But it recalled that the with-maintenance comparator was considered the relevant one for decision making (see section\xa03.2). The committee agreed that including PARAMOUNT in the network increased the heterogeneity in the network. At consultation, the company agreed that excluding PARAMOUNT from the network meta-analysis was reasonable and excluded it in an updated analysis. The committee agreed that the company's revised analysis was appropriate.\n\n# The company's economic model\n\n## The company's model structure is acceptable for decision making\n\nThe company presented a 3-state partitioned survival model to estimate the cost effectiveness of atezolizumab plus bevacizumab, carboplatin and paclitaxel compared with pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. People were able to move to different health states; from pre-progression to post-progression and death and from post-progression to death. The ERG agreed with the company's model structure. The company used the IMpower150 results to model overall and progression-free survival for people who had atezolizumab plus bevacizumab, carboplatin and paclitaxel. Specific survival curves were modelled for the ITT population and for the PD‑L1 tumour proportion score less than\xa050% subgroup and the EGFR- or ALK‑positive NSCLC subgroup. Hazard ratios from the indirect treatment comparison were then applied to the atezolizumab plus bevacizumab, carboplatin and paclitaxel data to estimate overall and progression-free survival for pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. The committee concluded that the model structure and approach to modelling survival for the atezolizumab plus bevacizumab, carboplatin and paclitaxel treatment arm was acceptable and appropriate for decision making.\n\n# Clinical evidence in the economic model\n\n## The results for the ITT network meta-analysis that excludes PARAMOUNT are appropriate to include in the model\n\nThe company used the hazard ratios from the network meta-analysis specific to the ITT population, the PD‑L1 tumour proportion score less than 50% subgroup and the EGFR- or ALK‑positive NSCLC subgroup to estimate relative effects for pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance in the economic model. The ERG preferred to use the hazard ratios from the ITT population for each subgroup, as well as for the overall ITT population. This was because IMpower150 did not show that PD‑L1, EGFR or ALK status modified the effect of the treatment so the ITT network meta-analysis results were considered more robust given the larger population. The committee recalled that including PARAMOUNT in the network increased heterogeneity (see section\xa03.12). At consultation, the company provided updated analyses (using the hazard ratios from the ITT network meta-analysis excluding PARAMOUNT for each subgroup, as well as for the overall ITT population) to estimate relative effects in the economic model for pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. The committee agreed that the company's revised analyses were more appropriate than analyses using the hazard ratios from the network meta-analysis specific to the ITT population, the PD‑L1 tumour proportion score less than 50% subgroup and the EGFR- or ALK‑positive NSCLC subgroup.\n\n# Extrapolating overall survival data in the economic model\n\n## The exponential and Weibull functions are both acceptable for extrapolating overall survival for the intervention and comparator\n\nThe company extrapolated overall survival in its model using the exponential function. The ERG's preferred choice was the Weibull function, based on it being a plausible alternative to the exponential function and giving long-term overall survival estimates for non-squamous NSCLC closer to those previously considered reasonable by the committee. The committee considered both functions to be suitable because they fitted the observed period of data well (based on statistical fit). The committee recalled its conclusion that a 5‑year survival rate of 5% to 11% for people with non-squamous NSCLC who had treatment with standard care chemotherapy was reasonable for decision making in NICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy. For the ITT population, the Weibull function gave 5‑year survival estimates at the top end of this range; 10% for atezolizumab plus bevacizumab, carboplatin and paclitaxel, and 9% for pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The exponential function gave values slightly above the 5% to 11% range, with 5‑year survival estimates of 13% for people who had atezolizumab plus bevacizumab, carboplatin and paclitaxel, and 12% for people who had pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. At consultation, the company submitted revised analyses using the Weibull function to extrapolate overall survival. The committee agreed that the exponential and Weibull functions were acceptable for extrapolating overall survival.\n\n## The company's model gives 5-year overall survival estimates for the EGFR- or ALK-positive NSCLC subgroup that are not credible\n\nFor EGFR- or ALK-positive NSCLC, the company's model estimated that 27% (if the exponential function was used) or 26% (if the Weibull function was used) of people who had atezolizumab plus bevacizumab, carboplatin and paclitaxel would be alive after 5\xa0years, and 18% of people who had pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance would be alive after 5\xa0years. The committee discussed the much higher estimates of long-term overall survival for the EGFR- or ALK‑positive NSCLC subgroup compared with the ITT population (see section\xa03.15). The clinical experts confirmed that the estimate of 18% overall survival at 5\xa0years for people who had pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance was too high. They estimated this to be between 5% and 10%, that is, more in line with the expected estimates for the ITT population. But they explained that the EGFR- or ALK‑positive NSCLC subgroup is distinct from the ITT population and that, for this group, it was biologically plausible that treatment with atezolizumab plus bevacizumab, carboplatin and paclitaxel would give 5‑year overall survival estimates that are substantially higher than treatment with pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance. This biological rationale was said to be particularly strong for EGFR‑positive NSCLC because of the vascular nature of these tumours and their response to vascular endothelial growth factor inhibitors such as bevacizumab. The committee accepted that the EGFR- or ALK‑positive NSCLC subgroup is distinct and acknowledged that the 5‑year overall survival estimates that had been accepted in previous appraisals in this disease area were likely not valid for this subgroup (see section\xa03.15). The committee was concerned that it had not heard a biological explanation why the long-term overall survival estimates were plausible for people with ALK‑positive NSCLC. It recalled that the EGFR- or ALK‑positive NSCLC subgroup in IMpower150 was small, there was no biological rationale for combining these groups and that median overall survival had not been reached at the last data cut, in January 2018 (see section\xa03.9). It was aware that there had only been 13\xa0events in the atezolizumab plus bevacizumab, carboplatin and paclitaxel treatment arm of the study and this made extrapolation of long-term survival more uncertain. The committee agreed that the long-term overall survival estimates from the company's model were too high and not credible. But, a difference of around 8% to 10% between the long-term overall survival estimates for people who had atezolizumab with bevacizumab, carboplatin and paclitaxel and people who had pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance was plausible. At consultation, the company highlighted that the most conservative approach was taken when extrapolating the overall survival data for the EGFR- or ALK‑positive subgroup. It noted that the ERG's and NICE's preferred approach to use the relative effect from the ITT network meta-analysis to model long-term survival for the subgroups represented a more conservative way to model survival for the EGFR- or ALK-positive subgroup (see section\xa03.14). The ERG explained that the IMpower150 data for the EGFR- or ALK‑positive subgroup were limited by the small population and low number of events. The committee understood that the analysis of the ITT population (including the EGFR- or ALK‑positive subgroup) was more robust for decision making. The committee accepted that there were limitations with the overall survival data for the EGFR- or ALK‑positive subgroup and concluded that the ITT population was more appropriate for decision making.\n\n# Stopping rule\n\n## Including a 2-year stopping rule is acceptable\n\nThe company included a 2-year treatment stopping rule for atezolizumab and bevacizumab in the model. The committee was aware that in IMpower150, people had treatment until loss of clinical benefit for atezolizumab and until disease progression for bevacizumab, or unacceptable toxicity. It noted that a 2‑year stopping rule had been implemented in other technology appraisal guidance on NSCLC (see the NICE Pathway on lung cancer). The patient expert explained that stopping treatment is a worry for people with NSCLC, but they generally understood that treatment would be stopped at some point. The Cancer Drugs Fund clinical lead's statement included that a 2‑year stopping rule would be implemented in clinical practice. The committee agreed that the best treatment duration with atezolizumab plus bevacizumab, carboplatin and paclitaxel was unknown but accepted that a 2‑year stopping rule would be used in clinical practice. It therefore concluded that it was appropriate for the company to include a 2‑year treatment stopping rule in its economic model.\n\n# Duration of treatment benefit after progression\n\n## A long-term treatment effect of atezolizumab and bevacizumab after stopping treatment is plausible\n\nThe company's base case included a 3-year treatment effect after stopping treatment with atezolizumab and bevacizumab. The committee was aware that the duration of treatment effect is an area of uncertainty for new immunotherapies. In previous technology appraisals in this disease area, scenarios of a treatment effect lasting between 3\xa0and 5\xa0years have been considered. The committee was also aware that there was no evidence to inform the long-term treatment effect of atezolizumab and bevacizumab from IMpower150 or any other sources. It agreed that, although it was biologically plausible for the treatment effect to continue after stopping atezolizumab and bevacizumab, its duration was uncertain. It concluded that the 3‑year treatment effect from when treatment was stopped in the company's and the ERG's base case was appropriate for decision making.\n\n# Subsequent therapy\n\n## The assumption that everyone has subsequent therapy is not appropriate\n\nIn their base cases, the company and ERG assumed that 100% of people would have subsequent therapy after atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. The clinical experts explained that no more than 60% of people would be well enough to have subsequent therapy. However, the Cancer Drugs Fund clinical lead estimated this to be no more than 50%. The committee was aware that in previous technology appraisals for ALK‑positive NSCLC, clinical experts estimated that 50% of people whose disease had progressed while taking alectinib would have subsequent therapy. The committee heard that some people with non-squamous NSCLC can have poor performance status and their disease can progress quickly. People with brain metastases would not have any further treatment with a cytotoxic chemotherapy or immunotherapy. The clinical experts noted that fewer people would have subsequent therapy after atezolizumab plus bevacizumab, carboplatin and paclitaxel than after pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance given that there would be fewer therapeutic options available. They estimated that 30% to 40% of people would have subsequent therapy after atezolizumab plus bevacizumab, carboplatin and paclitaxel in larger centres but noted this estimate would be much lower in smaller centres. At consultation, the company submitted updated analyses including 2\xa0scenarios for people having subsequent therapy. The proportions were equal after treatment with atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance:\n\nScenario 1: 46.6% of people had subsequent therapy (based on the proportion having subsequent therapy in the standard care arm in the KEYNOTE-189 trial).\n\nScenario 2: 60% of people had subsequent therapy (based on the upper estimate given in the appraisal consultation document).The Cancer Drugs Fund clinical lead reminded the committee that his estimate was that no more than 50% of people would have subsequent therapy in clinical practice. He noted that an estimate of between 40% and 50% was reasonable. The committee agreed that the company's revised analysis including 46.6% of people having subsequent therapy after treatment with atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance was appropriate for decision making.\n\n## The distribution of subsequent therapies in the company's model after pemetrexed combination treatment is not appropriate for decision making\n\nThe subsequent therapies offered in IMpower150 did not reflect the treatment options available in NHS clinical practice in England. The company included docetaxel, nivolumab, pembrolizumab and atezolizumab as subsequent treatment options in its economic model and estimated the distributions from UK market share data. The committee heard that because nivolumab is recommended in the Cancer Drugs Fund and not routinely commissioned in the NHS in England, it should not be considered in decision making. The Cancer Drugs Fund clinical lead and the clinical experts explained that after pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance, people would have an immunotherapy (see section\xa03.6). Therefore, nivolumab and docetaxel were not considered to be appropriate subsequent therapies to be included in the analysis. At consultation, the company provided updated analyses that included only atezolizumab and pembrolizumab as subsequent therapies after pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The committee agreed that the company's revised analyses were more appropriate than analyses including treatment options that are not immunotherapies or not routinely commissioned in the NHS in England.\n\n# Health-related quality of life\n\n## It is reasonable to include a disutility for treatment-related adverse events\n\nThe company included utility values using the proximity to death approach. The utility values were the same for atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin with or without pemetrexed maintenance. It did not include a disutility for adverse events. The ERG included a disutility for treatment-related adverse events that were grade\xa03 or higher in IMpower150. Disutility values were sourced from Nafees et al. (2008). The clinical experts explained that atezolizumab plus bevacizumab, carboplatin and paclitaxel has similar toxicity to pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance. The main toxicity concern is hypertension with atezolizumab plus bevacizumab, carboplatin and paclitaxel. At consultation, the company provided updated analyses that included a disutility for treatment-related adverse events that were grade\xa03 or higher in IMpower150. The committee agreed that the company's revised analyses were more appropriate for decision making.\n\n# Cost-effectiveness results\n\n## The company's base case is appropriate for decision making\n\nThe company revised its base-case cost-effectiveness analysis at consultation. In line with the ERG's preferred assumptions, it:\n\ncorrected discrepancies in the company model\n\nused a Weibull distribution to extrapolate overall survival\n\nused the hazard ratios from the meta-analysis that excluded PARAMOUNT from the network\n\nused the hazard ratios from the ITT network meta-analysis for overall and progression-free survival for the PD‑L1 tumour proportion score less than 50% subgroup and the EGFR- or ALK‑positive NSCLC subgroup\n\nincluded a disutility for treatment-related adverse events of grade\xa03 or higher.The company also included a new discount to the price of bevacizumab and included only immunotherapies as subsequent therapies after pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The committee considered the incremental cost-effectiveness ratios (ICERs) from the company's revised base case for the ITT population. The revised base case included 46.6% of people having subsequent therapy and the discounts from the commercial access agreements and patient access schemes for atezolizumab, bevacizumab, pemetrexed maintenance and pembrolizumab (which are confidential so the ICERs cannot be reported here). The company's base-case ICER comparing atezolizumab plus bevacizumab, carboplatin and paclitaxel with pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance was below £50,000 per quality-adjusted life year (QALY) gained for the ITT population. The committee concluded that the company's base case was appropriate for decision making.\n\n## The committee's most plausible ICER is less than £50,000 per QALY gained\n\nThe committee agreed with the company's revised base case in which 46.6% of people had subsequent therapy after atezolizumab plus bevacizumab, carboplatin and paclitaxel and pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance. Although it was aware of the uncertainties about overall survival benefit for the EGFR- or ALK‑positive subgroup, the committee concluded that the most plausible ICER for atezolizumab plus bevacizumab, carboplatin and paclitaxel compared with pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance in people with metastatic non-squamous NSCLC was below £50,000 per QALY gained.\n\n# End of life\n\n## Life expectancy for people with metastatic non-squamous NSCLC is considered to be less than 24\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company's model predicted a mean overall survival for people with metastatic non-squamous NSCLC of more than 24\xa0months after pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance (26\xa0months for the ITT population, 27\xa0months for the PD‑L1 tumour proportion score less than 50% subgroup and 38\xa0months for the EGFR- or ALK‑positive NSCLC subgroup). The ERG's model predicted a mean overall survival of 21\xa0months for the ITT population. At consultation, the company updated its base-case cost-effectiveness analysis in line with the ERG's preferred assumptions (see section\xa03.22). The company's updated model predicted mean overall survival of less than 24\xa0months after pemetrexed plus carboplatin or cisplatin with pemetrexed maintenance. The committee concluded that the life expectancy of people with metastatic non-squamous NSCLC was less than 24\xa0months.\n\n## Atezolizumab plus bevacizumab, carboplatin and paclitaxel extends life by at least 3\xa0months\n\nThe company estimated a mean life extension of 5\xa0months for the ITT population, 3.5\xa0months for the PD‑L1 tumour proportion score less than 50% subgroup and 24\xa0months for the EGFR- or ALK‑positive NSCLC subgroup with atezolizumab plus bevacizumab, carboplatin and paclitaxel, compared with pemetrexed plus carboplatin or cisplatin and pemetrexed maintenance. These estimates met the second criterion for an end-of-life treatment. The committee acknowledged that the data used to estimate the extension to life in the EGFR- or ALK‑positive NSCLC subgroup were not robust, but extension to life in the ITT population and all subgroups was likely to be at least 3\xa0months. The committee concluded that atezolizumab plus bevacizumab, carboplatin and paclitaxel for metastatic non-squamous NSCLC would extend life by at least 3\xa0months.\n\n## Atezolizumab plus bevacizumab, carboplatin and paclitaxel meets the criteria for end-of-life treatments\n\nThe committee concluded that it was satisfied that atezolizumab plus bevacizumab, carboplatin and paclitaxel met the criteria for end-of-life treatments.\n\n# Innovation\n\n## The benefits of atezolizumab plus bevacizumab, carboplatin and paclitaxel are captured in the measurement of the QALY\n\nThe company stated that atezolizumab plus bevacizumab, carboplatin and paclitaxel was innovative because it was the first checkpoint inhibitor with a phase\xa0III combination study showing a statistically significant and clinically meaningful overall and progression-free survival benefit. The company highlighted in its submission that atezolizumab plus bevacizumab, carboplatin and paclitaxel improved survival in all key subgroups including people with EGFR- or ALK‑positive NSCLC and people with liver metastases. The committee was aware that the Medicines and Healthcare products Regulatory Agency had granted atezolizumab plus bevacizumab, carboplatin and paclitaxel early access to medicines scheme status for treating metastatic non-squamous EGFR‑positive or ALK-positive NSCLC after failure of appropriate targeted therapies. However, the committee concluded that there were no relevant additional benefits that had not been captured in the QALY calculations.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Atezolizumab plus bevacizumab, carboplatin and paclitaxel is recommended for people with metastatic non-squamous NSCLC\n\nThe committee agreed that atezolizumab plus bevacizumab, carboplatin and paclitaxel, with the discounts agreed in the commercial arrangements, is a cost-effective use of NHS resources, and can be recommended as an option for metastatic non-squamous NSCLC in adults:\n\nwho have not had treatment for their metastatic NSCLC before and whose PD‑L1 tumour proportion score is between 0% and 49% or\n\nwhen targeted therapy for EGFR‑positive or ALK‑positive NSCLC has failed\n\nonly if atezolizumab and bevacizumab are stopped at 2\xa0years of uninterrupted treatment, or earlier if there is loss of clinical benefit (for atezolizumab) or if the disease progresses (for bevacizumab)."}
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https://www.nice.org.uk/guidance/ta584
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Evidence-based recommendations on atezolizumab (Tecentriq) with bevacizumab (Avastin), carboplatin and paclitaxel for metastatic non-squamous non-small-cell lung cancer in adults.
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ec58c5a9bda330692513c6f72264f43c0d261c74
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nice
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Ertugliflozin with metformin and a dipeptidyl peptidase-4 inhibitor for treating type 2 diabetes
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Ertugliflozin with metformin and a dipeptidyl peptidase-4 inhibitor for treating type 2 diabetes
Evidence-based recommendations on ertugliflozin (Steglatro) with metformin and a dipeptidyl peptidase‑4 inhibitor for treating type 2 diabetes in adults.
# Recommendations
Ertugliflozin with metformin and a dipeptidyl peptidase‑4 (DPP‑4) inhibitor is recommended as an option for treating type 2 diabetes in adults when diet and exercise alone do not provide adequate glycaemic control, only if:
the disease is uncontrolled with metformin and a DPP‑4 inhibitor, and
a sulfonylurea or pioglitazone is not appropriate.
If patients and their clinicians consider ertugliflozin to be 1 of a range of suitable treatments, including canagliflozin, dapagliflozin and empagliflozin, the least expensive should be chosen.
These recommendations are not intended to affect treatment with ertugliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Ertugliflozin is a sodium-glucose cotransporter 2 (SGLT‑2) inhibitor. Other SGLT‑2 inhibitors are already used with metformin and a DPP‑4 inhibitor for treating type 2 diabetes. Ertugliflozin appears to have similar health benefits to other SGLT‑2 inhibitors when taken with metformin and a DPP‑4 inhibitor, and it has a lower acquisition cost. But it has only been compared with other SGLT‑2 inhibitors, not with other third-line treatments for type 2 diabetes (sulfonylureas or pioglitazone). Ertugliflozin is therefore recommended as an option for treating type 2 diabetes that is uncontrolled with metformin and a DPP‑4 inhibitor, only if a sulfonylurea or pioglitazone is not appropriate.# Information about ertugliflozin
Marketing authorisation indication
Ertugliflozin (Steglatro, Merck Sharp & Dohme) is indicated 'in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
as monotherapy in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications
in addition to other medicinal products for the treatment of diabetes.'
Dosage in the marketing authorisation
The recommended dosage for monotherapy is 5 mg once daily, increasing to 15 mg once daily if additional glycaemic control is needed. In combination therapy, dosage should be individualised using the recommended daily dose of 5 mg or 15 mg.
Price
The list price for 28 tablets of ertugliflozin 5 mg or 15 mg is £29.40 per pack (company submission). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need and current management
## Ertugliflozin would offer an additional option alongside other sodium-glucose cotransporter 2 inhibitors (SGLT‑2 inhibitors) available in the NHS
Ertugliflozin is a SGLT‑2 inhibitor, a class of drugs that is already used in the NHS for treating type 2 diabetes. NICE has produced technology appraisal guidance on canagliflozin, dapagliflozin and empagliflozin, 3 other SGLT‑2 inhibitors in triple therapy regimens for treating type 2 diabetes. These treatments are recommended with metformin and a sulfonylurea (dapagliflozin), and with metformin and a thiazolidinedione (canagliflozin and empagliflozin). The clinical experts explained that, in addition to lowering haemoglobin A1c (HbA1c), which is a measure of blood glucose levels over the previous 2 to 3 months, SGLT‑2 inhibitors help to reduce blood pressure and body weight. Weight loss is a particularly important outcome for people with type 2 diabetes because there is a strong association with excess body weight, and some treatments such as sulfonylureas, insulin and pioglitazone can result in weight gain. The clinical experts also explained that new evidence suggests that SGLT‑2 inhibitors provide cardiovascular protection and, although there are no data on cardiovascular outcomes for ertugliflozin yet, this appears to be a class effect. The new data also suggest that SGLT‑2 inhibitors have a protective effect on kidney function. The committee concluded that ertugliflozin offers similar benefits to the other SGLT‑2 inhibitors.
## SGLT‑2 inhibitors are already used with metformin and a DPP‑4 inhibitor for treating type 2 diabetes in the NHS
The company compared ertugliflozin with metformin and DPP‑4 inhibitor against other SGLT‑2 inhibitors. The NICE scope specified other comparators (sulfonylureas, pioglitazone, glucagon-like peptide-1 mimetics and insulin) that were not included in the company's submission. The company justified its approach on the basis that the combination of an SGLT‑2 inhibitor with metformin and DPP‑4 inhibitor is sufficiently used in clinical practice for it to be regarded as standard therapy, and therefore the main comparison is with other SGLT‑2 inhibitors. It presented data from a panel of 150 general practices (800 GPs) in the UK, showing that 11.4% of people taking triple therapy in 2017 were on this combination. The data showed that SGLT‑2 inhibitors are also used with metformin and a sulfonylurea (by 15% of people on triple therapy). However, the company and the clinical experts explained that taking an SGLT‑2 inhibitor with a sulfonylurea may increase the risk of hypoglycaemia and lead to weight gain, because sulfonylureas have an opposite effect on weight to SGLT‑2 inhibitors. The company supplied additional prescribing data showing that prescriptions for an SGLT‑2 inhibitor with metformin and a DPP‑4 inhibitor increased from less than 10% in January 2017 to almost 15% in December 2018. Data from the Clinical Practice Research Datalink showed a similar pattern of increased use. The committee noted that the combination is recommended in the European Association for the Study of Diabetes and American Diabetes Association 2018 consensus guidelines when there is a compelling need to minimise hypoglycaemic events, and it is recommended in some NHS local guidelines. The company presented extracts from clinical experts about the use of the combination in clinical practice. The committee heard that advantages include different and complementary modes of action, favourable effect on weight reduction, low risk of hypoglycaemia, reduced heart failure risk and positive effects on blood pressure and cardiovascular outcomes, and that it is particularly used in patients at risk of hypoglycaemia or weight gain. The committee noted that NICE has not previously appraised the combination of metformin, a DPP‑4 inhibitor and a SGLT‑2 inhibitor. However, it accepted that the combination is used in the NHS, particularly in patients at risk of hypoglycaemia or weight gain when sulfonylureas and pioglitazone would be considered less suitable.
## Other SGLT‑2 inhibitors are appropriate comparators for ertugliflozin, but sulfonylureas and pioglitazone may also be relevant
The committee considered that the company's exclusion of some comparators in the NICE scope (GLP‑1 mimetics and insulin) is appropriate because these are injectable agents usually used later in the course of diabetes. The committee noted the company's opinion that sulfonylureas are not relevant comparators. This is because it intends to position ertugliflozin for use when sulfonylureas are not appropriate because of the risk of hypoglycaemia and weight gain. The committee accepted that there is an increased risk of hypoglycaemia with sulfonylureas, and that ertugliflozin would be an alternative treatment when sulfonylureas are not appropriate. It also noted that the company excluded pioglitazone as a comparator because of clinical expert opinion expressed in previous NICE technology appraisal guidance for SGLT‑2 inhibitors. This stated that the use of pioglitazone is decreasing annually and is low in triple‑therapy combinations because of concerns about adverse effects (such as risk of heart failure, oedema and weight gain). The committee noted the ERG's opinion that pioglitazone is less costly than ertugliflozin, and that prescription data suggest it is still widely used in the NHS and is a valid comparator. However, it accepted that pioglitazone use is decreasing in triple therapy and that it is unsuitable for some patients because of adverse effects. The committee concluded that other SGLT‑2 inhibitors are appropriate comparators for ertugliflozin (see section 3.2). However, it also concluded that sulfonylureas and pioglitazone are also relevant options for use in a triple therapy regimen with metformin and a DPP‑4 inhibitors when they are not ruled out by concerns about their adverse effects.
# Clinical evidence
## Ertugliflozin with metformin and a DPP‑4 inhibitor is clinically effective compared with placebo
The clinical evidence came from VERTIS‑SITA 2, which was a double-blind randomised placebo-controlled trial. It assessed the clinical effectiveness of ertugliflozin at the licensed doses (5 mg and 15 mg) in 462 adults with type 2 diabetes who were also taking metformin and sitagliptin (a DPP‑4 inhibitor) and had inadequate glycaemic control on the dual therapy. The ERG noted that although VERTIS‑SITA 2 did not include any patients from the UK, it was generally well conducted and representative of patients with type 2 diabetes in the NHS. The primary outcome was change in HbA1c (measured as change in least-squared means from baseline to week 26). Both doses of ertugliflozin showed a statistically significant improvement compared with placebo in the full analysis set, which included all randomised patients who took at least 1 dose of study medication and had at least 1 measurement of the outcome variable. There was also a statistically significant improvement with ertugliflozin in patients with an HbA1c less than 7% (less than 53 mmol/mol) at week 26, and for changes in body weight and systolic blood pressure from baseline to week 26. The committee concluded that ertugliflozin added to treatment with metformin and a DPP‑4 inhibitor in people with inadequate glycaemic control on the dual therapy is clinically effective compared with placebo.
## Ertugliflozin has similar clinical effectiveness to other SGLT‑2 inhibitors when added to metformin and a DPP‑4 inhibitor
The company presented a network meta-analysis comparing the clinical effectiveness of ertugliflozin against canagliflozin, dapagliflozin and empagliflozin, all taken with metformin and a DPP‑4 inhibitor. The network meta-analysis included data from VERTIS‑SITA 2 and 4 other trials, and all outcomes were assessed at 24 to 26 weeks. The results showed that ertugliflozin, canagliflozin, dapagliflozin and empagliflozin have similar efficacy and safety. The ERG considered that the included trials are of good quality and broadly similar but noted that a simpler comparison of clinical effectiveness could have been carried out against 1 of the SGLT‑2 inhibitors already recommended as an option by NICE. The ERG compared the data for ertugliflozin from VERTIS‑SITA 2 against another well-matched study (a dapagliflozin trial by Mathieu et al. 2015). It concluded that this comparison provides reasonable evidence that ertugliflozin is at least as effective as dapagliflozin. The committee also acknowledged the clinical experts' opinions that the clinical effectiveness of ertugliflozin is likely to be similar to other SGLT‑2 inhibitors. The committee concluded that ertugliflozin has similar clinical effectiveness to canagliflozin, dapagliflozin and empagliflozin when added to metformin and a DPP‑4 inhibitor.
## Ertugliflozin has an acceptable adverse-event profile that is likely to be similar to that of other SGLT‑2 inhibitors
The company's network meta-analysis showed no statistically significant differences in adverse-event rates between ertugliflozin and the other SGLT‑2 inhibitors (canagliflozin, dapagliflozin and empagliflozin). The committee noted that ertugliflozin was well-tolerated in VERTIS‑SITA 2. The overall frequency of adverse events, serious adverse events and treatment-related adverse events leading to stopping treatment were similar in the ertugliflozin and placebo arms of the trial. The clinical experts explained that the main adverse effects of treatment are genital mycotic infections, which are unpleasant but are usually easy to treat. They also explained that the adverse-effects profile of ertugliflozin is likely to be similar to that of other SGLT‑2 inhibitors. The committee heard that diabetic ketoacidosis is an extremely rare adverse effect of SGLT‑2 inhibitors but was not reported in VERTIS‑SITA 2. It was also aware that a warning about Fournier's gangrene (an infection of the perineum and genital region) has been added to the product information for all SGLT‑2 inhibitors, after post-marketing reports that this was possibly related to using SGLT‑2 inhibitors. The committee noted that this is a potentially life-threatening but very rare condition. It concluded that ertugliflozin has an acceptable adverse-event profile that is likely to be similar to that of other SGLT‑2 inhibitors recommended by NICE.
# Company's economic analysis
## The company's cost-minimisation approach is appropriate for the population who cannot take pioglitazone and sulfonylureas
The company considered cost minimisation to be the most appropriate form of economic evaluation because it believed that the relevant comparators were other SGLT‑2 inhibitors with metformin and DPP‑4 inhibitor (see section 3.2 and section 3.3). It also considered that the results of the network meta-analysis suggested that ertugliflozin and other SGLT‑2 inhibitors with metformin and a DPP‑4 inhibitor all have similar health benefits (see section 3.5). The committee heard that differences in cost between the SGLT‑2 inhibitors relate to drug acquisition costs only because there are no differences in testing, initiation, administration or monitoring costs. The company therefore presented a cost-comparison analysis for 1 year of treatment comparing the drug acquisition costs of ertugliflozin against canagliflozin, dapagliflozin and empagliflozin, all with metformin and DPP‑4 inhibitor. The committee concluded that the company's cost-minimisation approach is appropriate for comparing ertugliflozin with other SGLT‑2 inhibitors. However, having concluded that sulfonylureas and pioglitazone are relevant comparators for ertugliflozin used with metformin and a DPP‑4 inhibitor (see section 3.3), it could not conclude that ertugliflozin is cost effective relative to these comparators, which are relatively inexpensive, without having seen a full cost-effectiveness analysis. Therefore, the committee concluded that it could only make a recommendation for ertugliflozin, with metformin and DPP‑4 inhibitor, for people in whom sulfonylureas and pioglitazone are not appropriate.
## Ertugliflozin with metformin and a DPP‑4 inhibitor is cost effective compared with other SGLT‑2 inhibitors with metformin and a DPP‑4 inhibitor
The committee noted that the overall health benefits of ertugliflozin are similar to other SGLT‑2 inhibitors recommended as an option by NICE and the acquisition costs are lower. It therefore agreed that ertugliflozin with metformin and a DPP‑4 inhibitor is cost effective compared with other SGLT‑2 inhibitors. However, the committee noted that the cost effectiveness of ertugliflozin had not been compared with sulfonylureas or pioglitazone (see section 3.3 and section 3.7). Therefore, the committee concluded that ertugliflozin with metformin and a DPP‑4 inhibitor could be recommended as an option for type 2 diabetes in adults when it is uncontrolled with metformin and a DPP‑4 inhibitor, but only when sulfonylureas and pioglitazone are not appropriate.
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{'Recommendations': 'Ertugliflozin with metformin and a dipeptidyl peptidase‑4 (DPP‑4) inhibitor is recommended as an option for treating type\xa02 diabetes in adults when diet and exercise alone do not provide adequate glycaemic control, only if:\n\nthe disease is uncontrolled with metformin and a DPP‑4 inhibitor, and\n\na sulfonylurea or pioglitazone is not appropriate.\n\nIf patients and their clinicians consider ertugliflozin to be 1\xa0of a range of suitable treatments, including canagliflozin, dapagliflozin and empagliflozin, the least expensive should be chosen.\n\nThese recommendations are not intended to affect treatment with ertugliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nErtugliflozin is a sodium-glucose cotransporter\xa02 (SGLT‑2) inhibitor. Other SGLT‑2 inhibitors are already used with metformin and a DPP‑4 inhibitor for treating type\xa02 diabetes. Ertugliflozin appears to have similar health benefits to other SGLT‑2 inhibitors when taken with metformin and a DPP‑4 inhibitor, and it has a lower acquisition cost. But it has only been compared with other SGLT‑2 inhibitors, not with other third-line treatments for type\xa02 diabetes (sulfonylureas or pioglitazone). Ertugliflozin is therefore recommended as an option for treating type\xa02 diabetes that is uncontrolled with metformin and a DPP‑4 inhibitor, only if a sulfonylurea or pioglitazone is not appropriate.', 'Information about ertugliflozin': "Marketing authorisation indication\n\nErtugliflozin (Steglatro, Merck Sharp & Dohme) is indicated 'in adults aged 18\xa0years and older with type\xa02 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:\n\nas monotherapy in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications\n\nin addition to other medicinal products for the treatment of diabetes.'\n\nDosage in the marketing authorisation\n\nThe recommended dosage for monotherapy is 5\xa0mg once daily, increasing to 15\xa0mg once daily if additional glycaemic control is needed. In combination therapy, dosage should be individualised using the recommended daily dose of 5\xa0mg or 15\xa0mg.\n\nPrice\n\nThe list price for 28\xa0tablets of ertugliflozin 5\xa0mg or 15\xa0mg is £29.40 per pack (company submission). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need and current management\n\n## Ertugliflozin would offer an additional option alongside other sodium-glucose cotransporter\xa02 inhibitors (SGLT‑2 inhibitors) available in the NHS\n\nErtugliflozin is a SGLT‑2 inhibitor, a class of drugs that is already used in the NHS for treating type\xa02 diabetes. NICE has produced technology appraisal guidance on canagliflozin, dapagliflozin and empagliflozin, 3\xa0other SGLT‑2 inhibitors in triple therapy regimens for treating type\xa02 diabetes. These treatments are recommended with metformin and a sulfonylurea (dapagliflozin), and with metformin and a thiazolidinedione (canagliflozin and empagliflozin). The clinical experts explained that, in addition to lowering haemoglobin\xa0A1c (HbA1c), which is a measure of blood glucose levels over the previous 2\xa0to 3\xa0months, SGLT‑2 inhibitors help to reduce blood pressure and body weight. Weight loss is a particularly important outcome for people with type\xa02 diabetes because there is a strong association with excess body weight, and some treatments such as sulfonylureas, insulin and pioglitazone can result in weight gain. The clinical experts also explained that new evidence suggests that SGLT‑2 inhibitors provide cardiovascular protection and, although there are no data on cardiovascular outcomes for ertugliflozin yet, this appears to be a class effect. The new data also suggest that SGLT‑2 inhibitors have a protective effect on kidney function. The committee concluded that ertugliflozin offers similar benefits to the other SGLT‑2 inhibitors.\n\n## SGLT‑2 inhibitors are already used with metformin and a DPP‑4 inhibitor for treating type\xa02 diabetes in the NHS\n\nThe company compared ertugliflozin with metformin and DPP‑4 inhibitor against other SGLT‑2 inhibitors. The NICE scope specified other comparators (sulfonylureas, pioglitazone, glucagon-like peptide-1 [GLP‑1] mimetics and insulin) that were not included in the company's submission. The company justified its approach on the basis that the combination of an SGLT‑2 inhibitor with metformin and DPP‑4 inhibitor is sufficiently used in clinical practice for it to be regarded as standard therapy, and therefore the main comparison is with other SGLT‑2 inhibitors. It presented data from a panel of 150\xa0general practices (800\xa0GPs) in the UK, showing that 11.4% of people taking triple therapy in 2017 were on this combination. The data showed that SGLT‑2 inhibitors are also used with metformin and a sulfonylurea (by 15% of people on triple therapy). However, the company and the clinical experts explained that taking an SGLT‑2 inhibitor with a sulfonylurea may increase the risk of hypoglycaemia and lead to weight gain, because sulfonylureas have an opposite effect on weight to SGLT‑2 inhibitors. The company supplied additional prescribing data showing that prescriptions for an SGLT‑2 inhibitor with metformin and a DPP‑4 inhibitor increased from less than 10% in January 2017 to almost 15% in December 2018. Data from the Clinical Practice Research Datalink showed a similar pattern of increased use. The committee noted that the combination is recommended in the European Association for the Study of Diabetes and American Diabetes Association 2018 consensus guidelines when there is a compelling need to minimise hypoglycaemic events, and it is recommended in some NHS local guidelines. The company presented extracts from clinical experts about the use of the combination in clinical practice. The committee heard that advantages include different and complementary modes of action, favourable effect on weight reduction, low risk of hypoglycaemia, reduced heart failure risk and positive effects on blood pressure and cardiovascular outcomes, and that it is particularly used in patients at risk of hypoglycaemia or weight gain. The committee noted that NICE has not previously appraised the combination of metformin, a DPP‑4 inhibitor and a SGLT‑2 inhibitor. However, it accepted that the combination is used in the NHS, particularly in patients at risk of hypoglycaemia or weight gain when sulfonylureas and pioglitazone would be considered less suitable.\n\n## Other SGLT‑2 inhibitors are appropriate comparators for ertugliflozin, but sulfonylureas and pioglitazone may also be relevant\n\nThe committee considered that the company's exclusion of some comparators in the NICE scope (GLP‑1 mimetics and insulin) is appropriate because these are injectable agents usually used later in the course of diabetes. The committee noted the company's opinion that sulfonylureas are not relevant comparators. This is because it intends to position ertugliflozin for use when sulfonylureas are not appropriate because of the risk of hypoglycaemia and weight gain. The committee accepted that there is an increased risk of hypoglycaemia with sulfonylureas, and that ertugliflozin would be an alternative treatment when sulfonylureas are not appropriate. It also noted that the company excluded pioglitazone as a comparator because of clinical expert opinion expressed in previous NICE technology appraisal guidance for SGLT‑2 inhibitors. This stated that the use of pioglitazone is decreasing annually and is low in triple‑therapy combinations because of concerns about adverse effects (such as risk of heart failure, oedema and weight gain). The committee noted the ERG's opinion that pioglitazone is less costly than ertugliflozin, and that prescription data suggest it is still widely used in the NHS and is a valid comparator. However, it accepted that pioglitazone use is decreasing in triple therapy and that it is unsuitable for some patients because of adverse effects. The committee concluded that other SGLT‑2 inhibitors are appropriate comparators for ertugliflozin (see section\xa03.2). However, it also concluded that sulfonylureas and pioglitazone are also relevant options for use in a triple therapy regimen with metformin and a DPP‑4 inhibitors when they are not ruled out by concerns about their adverse effects.\n\n# Clinical evidence\n\n## Ertugliflozin with metformin and a DPP‑4 inhibitor is clinically effective compared with placebo\n\nThe clinical evidence came from VERTIS‑SITA\xa02, which was a double-blind randomised placebo-controlled trial. It assessed the clinical effectiveness of ertugliflozin at the licensed doses (5\xa0mg and 15\xa0mg) in 462\xa0adults with type\xa02 diabetes who were also taking metformin and sitagliptin (a DPP‑4 inhibitor) and had inadequate glycaemic control on the dual therapy. The ERG noted that although VERTIS‑SITA\xa02 did not include any patients from the UK, it was generally well conducted and representative of patients with type\xa02 diabetes in the NHS. The primary outcome was change in HbA1c (measured as change in least-squared means from baseline to week\xa026). Both doses of ertugliflozin showed a statistically significant improvement compared with placebo in the full analysis set, which included all randomised patients who took at least 1\xa0dose of study medication and had at least 1\xa0measurement of the outcome variable. There was also a statistically significant improvement with ertugliflozin in patients with an HbA1c less than 7% (less than 53\xa0mmol/mol) at week\xa026, and for changes in body weight and systolic blood pressure from baseline to week\xa026. The committee concluded that ertugliflozin added to treatment with metformin and a DPP‑4 inhibitor in people with inadequate glycaemic control on the dual therapy is clinically effective compared with placebo.\n\n## Ertugliflozin has similar clinical effectiveness to other SGLT‑2 inhibitors when added to metformin and a DPP‑4 inhibitor\n\nThe company presented a network meta-analysis comparing the clinical effectiveness of ertugliflozin against canagliflozin, dapagliflozin and empagliflozin, all taken with metformin and a DPP‑4 inhibitor. The network meta-analysis included data from VERTIS‑SITA\xa02 and 4\xa0other trials, and all outcomes were assessed at 24\xa0to 26\xa0weeks. The results showed that ertugliflozin, canagliflozin, dapagliflozin and empagliflozin have similar efficacy and safety. The ERG considered that the included trials are of good quality and broadly similar but noted that a simpler comparison of clinical effectiveness could have been carried out against 1\xa0of the SGLT‑2 inhibitors already recommended as an option by NICE. The ERG compared the data for ertugliflozin from VERTIS‑SITA\xa02 against another well-matched study (a dapagliflozin trial by Mathieu et al. 2015). It concluded that this comparison provides reasonable evidence that ertugliflozin is at least as effective as dapagliflozin. The committee also acknowledged the clinical experts' opinions that the clinical effectiveness of ertugliflozin is likely to be similar to other SGLT‑2 inhibitors. The committee concluded that ertugliflozin has similar clinical effectiveness to canagliflozin, dapagliflozin and empagliflozin when added to metformin and a DPP‑4 inhibitor.\n\n## Ertugliflozin has an acceptable adverse-event profile that is likely to be similar to that of other SGLT‑2 inhibitors\n\nThe company's network meta-analysis showed no statistically significant differences in adverse-event rates between ertugliflozin and the other SGLT‑2 inhibitors (canagliflozin, dapagliflozin and empagliflozin). The committee noted that ertugliflozin was well-tolerated in VERTIS‑SITA\xa02. The overall frequency of adverse events, serious adverse events and treatment-related adverse events leading to stopping treatment were similar in the ertugliflozin and placebo arms of the trial. The clinical experts explained that the main adverse effects of treatment are genital mycotic infections, which are unpleasant but are usually easy to treat. They also explained that the adverse-effects profile of ertugliflozin is likely to be similar to that of other SGLT‑2 inhibitors. The committee heard that diabetic ketoacidosis is an extremely rare adverse effect of SGLT‑2 inhibitors but was not reported in VERTIS‑SITA\xa02. It was also aware that a warning about Fournier's gangrene (an infection of the perineum and genital region) has been added to the product information for all SGLT‑2 inhibitors, after post-marketing\xa0reports that this was possibly related to using SGLT‑2\xa0inhibitors. The committee noted that this is a potentially life-threatening but very rare condition. It concluded that ertugliflozin has an acceptable adverse-event profile that is likely to be similar to that of other SGLT‑2 inhibitors recommended by NICE.\n\n# Company's economic analysis\n\n## The company's cost-minimisation approach is appropriate for the population who cannot take pioglitazone and sulfonylureas\n\nThe company considered cost minimisation to be the most appropriate form of economic evaluation because it believed that the relevant comparators were other SGLT‑2 inhibitors with metformin and DPP‑4 inhibitor (see section\xa03.2 and section\xa03.3). It also considered that the results of the network meta-analysis suggested that ertugliflozin and other SGLT‑2 inhibitors with metformin and a DPP‑4 inhibitor all have similar health benefits (see section\xa03.5). The committee heard that differences in cost between the SGLT‑2 inhibitors relate to drug acquisition costs only because there are no differences in testing, initiation, administration or monitoring costs. The company therefore presented a cost-comparison analysis for 1 year of treatment comparing the drug acquisition costs of ertugliflozin against canagliflozin, dapagliflozin and empagliflozin, all with metformin and DPP‑4 inhibitor. The committee concluded that the company's cost-minimisation approach is appropriate for comparing ertugliflozin with other SGLT‑2 inhibitors. However, having concluded that sulfonylureas and pioglitazone are relevant comparators for ertugliflozin used with metformin and a DPP‑4 inhibitor (see section\xa03.3), it could not conclude that ertugliflozin is cost effective relative to these comparators, which are relatively inexpensive, without having seen a full cost-effectiveness analysis. Therefore, the committee concluded that it could only make a recommendation for ertugliflozin, with metformin and DPP‑4 inhibitor, for people in whom sulfonylureas and pioglitazone are not appropriate.\n\n## Ertugliflozin with metformin and a DPP‑4 inhibitor is cost effective compared with other SGLT‑2 inhibitors with metformin and a DPP‑4 inhibitor\n\nThe committee noted that the overall health benefits of ertugliflozin are similar to other SGLT‑2 inhibitors recommended as an option by NICE and the acquisition costs are lower. It therefore agreed that ertugliflozin with metformin and a DPP‑4 inhibitor is cost effective compared with other SGLT‑2 inhibitors. However, the committee noted that the cost effectiveness of ertugliflozin had not been compared with sulfonylureas or pioglitazone (see section\xa03.3 and section\xa03.7). Therefore, the committee concluded that ertugliflozin with metformin and a DPP‑4 inhibitor could be recommended as an option for type\xa02 diabetes in adults when it is uncontrolled with metformin and a DPP‑4 inhibitor, but only when sulfonylureas and pioglitazone are not appropriate."}
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https://www.nice.org.uk/guidance/ta583
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Evidence-based recommendations on ertugliflozin (Steglatro) with metformin and a dipeptidyl peptidase‑4 inhibitor for treating type 2 diabetes in adults.
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b6e6c937029119833fc4f1f1987a755469d58785
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nice
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The Sherlock 3CG Tip Confirmation System for placement of peripherally inserted central catheters
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The Sherlock 3CG Tip Confirmation System for placement of peripherally inserted central catheters
Evidence-based recommendations on The Sherlock 3CG Tip Confirmation System for placement of peripherally inserted central catheters.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by companies. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.
The case for adopting the Sherlock 3CG Tip Confirmation System for placement of peripherally inserted central catheters is supported by the evidence. The technology usually avoids the need for a confirmatory chest X‑ray in patients who would otherwise have blind insertion, minimising the delay before the catheter can be used for infusion. Using the technology increases staff confidence during catheter insertion.
The Sherlock 3CG Tip Confirmation System should be considered as an option for placement of peripherally inserted central catheters in adults. For patients whose electrocardiogram does not show a P wave (for example, patients with atrial fibrillation), a chest X‑ray will still be needed to confirm tip location of the peripherally inserted central catheter.
The cost of using the Sherlock 3CG Tip Confirmation System (TCS) is similar to that of blind insertion and subsequent chest X‑ray in adults who need a peripherally inserted central catheter in a non‑intensive care setting. When the Sherlock 3CG TCS is used instead of fluoroscopy, the estimated cost saving is £109 per patient. In an intensive care setting, where the rate of misplacement with blind insertion is generally higher, there is an estimated cost saving of £54 per patient per use of the Sherlock 3CG TCS and a confirmatory chest X‑ray compared with using blind insertion and chest X‑ray. All these cost savings are subject to some uncertainty and need to be considered in the context of the clinical benefits. # The technology
# Description of the technology
The Sherlock 3CG Tip Confirmation System (TCS; BD) is designed to confirm the correct tip placement of a peripherally inserted central catheter (PICC; that is, a catheter inserted through a large vein in or near the arm rather than the neck or chest). Sherlock 3CG is also available within the Site Rite ultrasound device (version 8). By using magnetic and electrocardiographic (ECG) real‑time tracking of the PICC tip, Sherlock 3CG is intended to allow the person placing the PICC to detect and correct any error in tip positioning. The tip location sensor is only compatible with a Bard PowerPICC SOLO catheter. The Sherlock 3CG TCS is designed to remove the need for a chest X‑ray which is used to confirm tip location after insertion of a PICC in most patients.
The Sherlock 3CG TCS comprises: a system console, including a control processor with display interface; a tip location sensor; a PowerPICC SOLO catheter with the Sherlock 3CG tip positioning stylet; a remote control; and an optional miniature wireless printer to create a paper record of the ECG. The sensor is positioned on the patient's sternum with 2 leads placed to pick up external ECG waveforms. The catheter is then inserted into a suitable vein in the upper arm with the stylet. During insertion, magnets in the stylet generate a field that is detected by the sensor. This enables clinicians to track the PICC on the display interface in real time, allowing them to see if the PICC is taking the correct path towards the cavoatrial junction. The stylet is removed once the catheter has been appropriately positioned. The display interface also shows real‑time ECG waveforms received from the patient's skin (baseline) and from the tip of the catheter (intravascular, measured by a column of saline which the placer injects into the PICC). The P wave changes on the ECG as the PICC tip moves towards the right atrium and right ventricle. By observing the P wave, a clinician can determine the PICC tip location relative to the chambers of the heart and the superior vena cava.
The Sherlock 3CG TCS is intended for use in any indication in adults where therapy means accessing a vein through a PICC. PICCs have a wide range of applications and are commonly used for intravenous access for drugs and fluids (infusion of irritant drugs, such as in chemotherapy; total parenteral nutrition; or long‑term administration of drugs such as antibiotics) and monitoring or interventions (such as central venous pressure, repeated blood sampling, or when there is poor peripheral access). The instructions for use state that the device should be used with caution in patients with altered cardiac rhythms, specifically those in whom a P wave is not easily detectable, for example patients with atrial fibrillation, rapid tachycardia, or pacemaker‑driven rhythm. Although the Sherlock 3CG TCS can be used in these patients, the company recommends a chest X‑ray to confirm PICC tip location.
The cost of the Sherlock 3CG TCS – comprising the system console, tip location sensor, remote control, stand and printer – is stated in the company's submission as £10,653.97 (excluding VAT). The cost of consumables associated with each insertion is £215.05, comprising primarily the cost of the PICC (including the stylet), sterile barrier and ECG leads. Maintenance costs associated with the technology are £840 per year per system console.
The claimed benefits of the Sherlock 3CG TCS in the case for adoption presented by the company were as follows:
Better accuracy of PICC placement (reducing the need for repositioning after insertion).
Removed need for a chest X‑ray or fluoroscopy to confirm tip location after PICC insertion.
Intraprocedural verification of the PICC tip position allows the PICC to be used immediately after insertion. This reduces treatment delays, which may be up to 48 hours after PICC insertion.
A safe method for PICC tip placement with no associated adverse events or complications.
PICC placement and tip confirmation happen during the same clinical procedure.
Increased patient confidence in whoever is placing the PICC, because the rate of malpositioning and repositioning is reduced.
A reduced and more efficient care pathway because no confirmation X‑ray is needed.
Lower staff requirements (radiologists, radiology nurses, radiographers, radiology healthcare support workers) because the need for an X‑ray to confirm PICC placement is reduced or eliminated. All staff who are freed by the use of the Sherlock 3CG can be redirected to other areas of need.
Potential reduction of bed occupancy due to reductions in treatment delays post‑PICC insertion and delays caused by repositioning. This may lead to earlier discharge of hospital patients having intravenous therapy, enabling management in the community.
Reduced costs of consequences of incorrect PICC placement.
Reduced costs of using resource‑intensive departments such as radiology.
# Current management
In current NHS clinical practice, there is substantial variation between sites in the ways in which PICCs are inserted. Catheters are typically inserted by nurse‑led or consultant‑led vascular access teams, although PICCs may be inserted by a range of healthcare professionals, including nurse specialists, intensive care consultants, anaesthetists, general physicians, radiologists and radiographers. Clinical settings where PICCs are inserted include operating theatres, emergency rooms, oncology, orthopaedic and other wards, radiology departments, intensive care units, high dependency units and outpatient clinics. Sterility is a major concern, and can best be achieved using a maximum barrier sterile field at the bedside.
Ultrasound is used to identify a suitable vein in the upper arm. The PICC is then inserted using a modified Seldinger technique, which involves inserting a small gauge needle into the vein followed by a wire. A sheath and dilator are used for the catheter to gain access to the vein before the wire is removed. The PICC is advanced to a suitable point using a measurement of the distance between the insertion site and a suitable anatomical landmark indicating the target site for the tip of the PICC (for example, the third right intercostal space below the right clavicular head). This technique is referred to as blind bedside insertion or blind insertion. The position of the PICC is confirmed by chest X‑ray, which typically requires the patient to go to the X‑ray department; the X‑ray then needs to be checked by whoever inserted the PICC, or by a radiologist. Alternatively, fluoroscopy can be used to position the PICC, especially when this is difficult, such as in patients with narrow vessels.# Clinical evidence
# Summary of clinical evidence
Full details of all clinical outcomes considered by the Committee are available in the assessment report overview.
The key clinical outcomes for the Sherlock 3CG Tip Confirmation System (TCS) presented in the decision problem were:
accuracy of catheter tip placement
incidence of catheter malposition
need for catheter repositioning
impact of malposition‑related complications such as infection or thrombosis
treatment delay following catheter placement
reduced staff time
reduced hospital stay
need for confirmatory chest X‑ray
need for fluoroscopy to place the peripherally inserted central catheter (PICC) tip correctly
time taken to insert PICC
PICC failure and reinsertion rates
patient experience measures
quality of life
device‑related adverse events.
The External Assessment Centre considered that 5 of the 14 outcomes in the decision problem were reported in the published evidence. These were: accuracy of catheter tip placement; incidence of catheter malposition; treatment delay following catheter placement; change in staff time, and need for confirmatory chest X‑ray. The External Assessment Centre considered that some additional outcomes had also been partially addressed. Outcomes for which no evidence was presented included reduced hospital stay and treatment delay following catheter placement. The company stated that it was unable to report on device‑related adverse events because of a lack of reported evidence.
The company identified 13 studies from its literature search but it excluded 9 and presented 4 published abstracts (Adams et al. 2013; Barton, 2014; Parikh, 2012; Stewart, 2013). It also presented responses from a questionnaire sent to 6 NHS hospitals, as supporting clinical evidence. The External Assessment Centre considered that the studies presented by the company were in keeping with the scope and were appropriate for inclusion. It also identified 1 study published after the company submission and that it considered suitable for assessment (Johnston et al. 2014). To ensure that all relevant evidence was identified, the External Assessment Centre carried out a further literature search with a wider scope which included any previous model of the device that had both magnetic tracking and electrocardiogram (ECG) tip confirmation components. One additional presentation was identified (Symington et al. 2013).
Johnston et al. (2014) reported a retrospective case‑series review of the first 250 patients to have PICCs inserted using the Sherlock 3CG TCS following its introduction to a UK NHS hospital. The population comprised patients in the intensive care unit (ICU). The vascular access team placed PICCs at the bedside, and used a portable chest X‑ray to confirm the tip location. Two independent reviewers examined the X‑rays. From the first 250 patients, 11 were excluded because of: failed insertion (n=2); no chest X‑ray being taken after the procedure (n=2); a failure to identify the tip position on the chest X‑ray (n=2); a failure to interpret the ECG criteria (n=4); and the catheter being too short (n=1). Tip location was reported for the 239 PICC placements where ECG was used for tip confirmation. Although there was no direct comparator for the intervention in this study, the same authors published a retrospective service evaluation a year before the Sherlock 3CG TCS was introduced, reviewing records for both ICU patients (n=246) and non‑ICU patients (n=233, Johnston 2013). The External Assessment Centre used this as a form of comparator to assess the impact of the Sherlock 3CG TCS on malposition rates. Both Johnston studies reported results using 2 different definitions of malposition, 1 from the USA and the other from Europe. The definition of appropriate placement typically used in US guidelines is the low superior vena cava or cavoatrial junction (National Association of Vascular Access Networks 1998, Infusion Nurses Society 2006, Funaki 2002). A European guideline uses a broader definition, stating that appropriate placement is in the mid or lower superior vena cava, cavoatrial junction, or high right atrium (Pittiruti 2009). Using the definition as per US guidelines, 56.1% (95% confidence interval 50% to 62%, n=134) of ICU patients had a malpositioned PICC using the Sherlock 3CG TCS compared with 76% (n=187) who had blind bedside insertion. Using the definition as per European guidelines, 20.5% (95% CI 16% to 26%, n=49) of ICU patients had a malpositioned PICC using the Sherlock 3CG TCS compared with 50.8% (n=125) who had blind bedside insertion. The malposition rate using the Sherlock 3CG TCS was significantly lower than blind placement using both sets of criteria (p<0.0001). However, it was also substantially higher than that reported in other studies. The authors suggest several reasons for this. They noted that it may be difficult to determine the exact point of a maximum or biphasic P wave for patients in intensive care, who may have ECG artefacts due to comorbidities. The authors also noted that tip position is not static, and that the catheter tip may move (due to, for example, arm movement, because the PICC is placed with the arm drawn away from the body and the chest X‑ray is taken with the arm drawn towards the body). The authors concluded that, if the European guideline definition of an adequate tip position is considered to be acceptable, the Sherlock 3CG TCS can be used for tip confirmation without chest X‑ray. If a more precise tip position of low superior vena cava or cavoatrial junction is used, as in the US guidelines, a chest X‑ray may be necessary.
Adams et al. (2013) presented a poster reporting on the introduction of the Sherlock 3CG TCS to a healthcare centre in the US. Over a 9‑month period, 333 patients had PICC insertion using the Sherlock 3CG TCS, which was subsequently verified using chest X‑ray and confirmed by 2 radiologists. Accurate placement was defined as the catheter tip being in the distal superior vena cava or at the cavoatrial junction. The Sherlock 3CG TCS was used to confirm tip position in 83.5% of patients (278/333). In the remaining 16.5% (55/333), the ECG system could not be used either because of an abnormal P wave (12.9%) or because of technical factors such as loose connections and poor electrode placement (3.6%). When the Sherlock 3CG TCS was used to confirm tip position, 1 radiologist reported that 96.4% (268/278) of PICCs were placed accurately, and that 3.6% (10/278) were malpositioned; the other radiologist reported that 98.2% (273/278) of PICCs were placed accurately and 1.8% (5/278) were malpositioned. In 2011, the malposition rate using the predecessor device, the Sherlock Tip Location System (magnetic tracking only) was reported to be 14% based on a subsequent chest X‑ray. Adams et al. also reported that the PICC was ready for infusion 61.0 minutes earlier using the Sherlock 3CG TCS (39.5 minutes) than using a chest X‑ray and a radiologist report for tip position confirmation (101.0 minutes), although no information was reported on how this was measured. The researchers confirmed that chest X‑rays are no longer mandatory for PICCs placed using the Sherlock 3CG TCS at this centre.
The abstract by Barton (2014) described the introduction of the Sherlock 3CG TCS to a nurse‑led PICC service at a UK NHS hospital. In an initial trial, clinicians used the Sherlock 3CG TCS for PICC placement in 65 adults with no atrial fibrillation. They used chest X‑rays, reviewed by an independent physician, to confirm tip location. Following the initial trial, an application was made to amend local protocol and remove the need for a mandatory chest X‑ray following PICC placement. During the application process, clinicians placed another 160 PICCs using the Sherlock 3CG TCS, with position confirmed using a chest X‑ray. In total, data were reported on 225 patients. The definition of acceptable tip position was the lower third of the superior vena cava or the cavoatrial junction, as used in US guidelines. Chest X‑rays confirmed that tip position was acceptable in 100% of cases reported. Only success rates of tip positioning in patients for whom magnetic tip position and ECG tip confirmation could be used were reported. Cases where the Sherlock 3CG TCS was not suitable or where there was a failure of the ECG system were not included. The authors reported to the External Assessment Centre that, during the trial period, 2 patients were not suitable for the Sherlock 3CG TCS and had PICCs placed with fluoroscopy. Since the introduction of the Sherlock 3CG TCS, 11 patients needed chest X‑rays due to the failure of the ECG system to provide tip confirmation. Five of these cases were because of atrial fibrillation, and 6 because of a failure of the electrode connections. The hospital has since removed the need for chest X‑ray after PICC placement using the Sherlock 3CG TCS.
Parikh (2012) presented a poster reporting a prospective case series from October 2011 to April 2012 of 247 PICCs placed in 221 patients (mean age 62 years, range 15–100) in a US hospital. The Sherlock 3CG TCS was used for tip placement and confirmation, except in patients with atrial fibrillation, atrial flutter or no discernible P wave (15.4%, 38/247). Tip position was confirmed by chest X‑ray and evaluated by 2 independent observers. Successful tip placement was defined as the superior vena cava or cavoatrial junction, as in the US guidelines. The study was divided into 2 phases. Phase 1 was a voluntary training phase. Nurses who wished to be trained in the use of the Sherlock 3CG TCS (4 of 7 nurses) had training, which consisted of a PICC refresher course, an online course, a 1‑hour taught course and 1‑to‑1 training with a nurse trainer provided by the company. The nurses then placed 62 PICCs using the Sherlock 3CG TCS. As per the exclusion criteria, 3 patients were excluded. Successful tip placement was 83% (n=62) for those using the Sherlock 3CG TCS. For phase 2, the 3 other nurses who had not had training in the Sherlock 3CG TCS had phase 1 training. All 7 nurses then inserted 5 PICCs while being observed by a nurse trainer. All staff completed phase 2 training. Staff placed 147 PICCs using the Sherlock 3CG TCS, excluding 35 patients as per the criteria. Successful tip placement was 96% (n=147) for those using the Sherlock 3CG TCS. From November 2012 to May 2013, staff placed a further 567 PICCs, 437 using the Sherlock 3CG TCS. Of these, 24.9% (109/437) still needed a chest X‑ray for confirmation, for reasons that included unclear baseline rhythm, and complicated or uncertain PICC placement. It is unknown if the PICCs which did not use the Sherlock 3CG TCS needed a chest X‑ray to confirm, but this is probable.
An abstract and poster by Stewart (2013) presented a study in an Australian hospital which recruited over 65 patients between November 2012 and March 2013. The exact number of patients and methodology were not reported. Clinicians placed PICCs using the Sherlock 3CG TCS and confirmed the tip position using a chest X‑ray. No information was given on what tip positions were considered to be acceptable or who reported on the chest X‑ray. The abstract reported that 100% of malpositions were corrected at time of placement. Of PICC placements using the Sherlock 3CG TCS, 96% were within the cavoatrial junction. The other 4% were reported in the right atrium. Discrepancies were noted between locations reported by ECG and X‑ray, which were resolved with clinical experience and collaboration. A time saving of 1 hour and 51 minutes was reported, being the average wait time between PICC insertion and X‑ray results. No information was given on how time savings were measured or if there was any resulting change in treatment time or outcomes.
Symington et al. (2011) was a conference presentation on a US centre using the Sapiens TCS in conjunction with the Sherlock TLS II. These devices are the predecessor devices to, and when used together have the same mode of action as, the Sherlock 3CG TCS. The author reported on a consecutive case series during April 2011 (n=63). No information was given on the patient population. The company provided training. Tip placement was verified with a chest X‑ray, reviewed by the author. The author reported a 5% technical failure rate, including difficulties with cannulation of the vein, advancement of the catheter and occluded veins. It was reported that technical failures were 'thrown out', although this was not explained in greater detail. The authors reported that 62 of 63 tip placements were appropriately positioned, although no specific criteria for appropriate placement were reported. They reported that, by July 2011, there had been 604 PICC placements using the Sapiens TCS in conjunction with the Sherlock TLS II. The lead author reported that he was formally requesting that his hospital remove the need for mandatory chest X‑ray from its procedural guidelines. He was also a paid presenter for Bard Access Systems (a division of CR Bard), which was clearly stated.
The company contacted 7 UK NHS hospitals currently using the Sherlock 3CG TCS and collected questionnaire responses from them. The initial clinical evidence submission did not include these data, but they were later provided to the External Assessment Centre. The External Assessment Centre judged that the structuring of the questions and format of the answers did not allow for the assessment of relevant evidence on outcomes as defined in the decision problem. The External Assessment Centre noted the variation in reported clinical practice for issues such as hospital policy for confirmation, typical levels of malposition, dealing with malpositions and PICC reinsertions. In general, all respondents reported fewer malpositions using the Sherlock 3CG TCS than before its introduction. The External Assessment Centre noted that there was a risk of bias because not all hospitals using the Sherlock 3CG TCS were asked to provide data to the company. To explore this, the External Assessment Centre contacted 7 of the other 8 hospitals (not included in the company's survey) currently using the device, and 1 hospital that had not responded to the company's initial questionnaire. The External Assessment Centre concluded that the hospital questionnaires provided no assessable data relevant to the scope.
The company did not identify any adverse events from the published literature, or from a search of the Medicines and Healthcare Products Regulatory Agency's website. The company retrieved 51 records from the US Food and Drug Administration's MAUDE database, but stated that they were not necessarily device‑related adverse events. The External Assessment Centre retrieved 100 records from the same database, using a wider search strategy. Adverse events submitted to MAUDE are not verified. No searches were carried out for adverse event reports from PICC insertion using comparator technologies (blind PICC insertion with chest X‑ray, or fluoroscopy). Reported adverse events included: broken or damaged wire tip or stylet (n=29); adverse patient reactions (such as shortness of breath; n=23); catheter malfunction (such as leaks or splits; n=18) and tip malposition (n=14). The External Assessment Centre sought clinical expert opinion, but could not rule out the possibility that the adverse events reported with the Sherlock 3CG TCS were common to all PICC insertion techniques.
## Committee considerations
The Committee noted that the overall quality and quantity of the clinical evidence was low, consisting largely of abstracts and posters reporting on case series. The only comparative data available were from a historical comparison by the External Assessment Centre, based on the outcomes reported by Johnston et al. (2013, 2014) before and after the introduction of the Sherlock 3CG TCS. Nevertheless, the Committee judged that the available evidence all pointed towards the use of the Sherlock 3CG TCS providing more reliable tip placement than blind insertion.
The Committee noted in particular that a number of hospitals had stopped using chest X‑rays for confirmation of PICC tip position after their clinicians had become experienced at using the Sherlock 3CG TCS and they had audited success rates. It was mindful of the benefits to patients of avoiding confirmatory chest X‑rays, including avoidance of radiation exposure and travel to the X‑ray department, and the possibility of having treatments through their PICCs without delay.
The Committee considered that the variation between definitions of correct PICC placement was less important than whether a PICC is so misplaced that a further procedure is needed to correct its position. Although the definitions provide a means of assessing the accuracy of different methods of PICC placement, experts told the Committee that minor discrepancies in catheter tip position identified by a chest X‑ray after blind insertion would be unlikely to have serious clinical consequences. They also stated that the need for catheter repositioning as a result of malpositioning is uncommon. The External Assessment Centre told the Committee that no published evidence was available about further procedures to reposition misplaced PICCs following placement with the Sherlock 3CG TCS. The Committee was also advised that the PICCs may change position after insertion.# NHS considerations
# System impact
The company claimed that the Sherlock 3CG Tip Confirmation System (TCS) increases efficiency in the care pathway by eliminating the need for a confirmatory chest X‑ray following the insertion of a peripherally inserted central catheter (PICC). The costs and time involved in transporting patients to an X‑ray department for a confirmatory X‑ray would be eliminated in most cases. This would reduce staff requirements, particularly in nursing and radiology, and allow these staff to be directed to other areas of need.
Experts also advised the Committee about potential system benefits associated with the reduced need for fluoroscopy and reduced number of X‑rays, including cost savings and an increased throughput of patients, meaning that patient access to radiology departments would be quicker and more efficient. One expert also advised that earlier access to infusion treatment may result in earlier discharge of patients from hospital.
The Sherlock 3CG TCS was launched in the UK in April 2013. The company reported that it was being used in 14 NHS hospitals in England and 2 in Northern Ireland. The company also stated that 9 of the English hospitals have discontinued routine chest X‑ray confirmation following PICC placement. The External Assessment Centre was able to confirm this for 6 of the 9 hospitals.
## Committee considerations
The Committee recognised that avoiding the need for routine confirmatory chest X‑rays by using the Sherlock 3CG TCS for PICC placement would release resources in X‑ray departments. It would also mean that nurses and porters would not be needed to help transfer patients between X‑ray departments and other parts of the hospital.
The Committee noted that using the Sherlock 3CG TCS could increase staff and patient confidence compared with using blind insertion. An expert adviser from a hospital which has discontinued X‑ray confirmation advised the Committee that procedures performed without the Sherlock 3CG TCS now feel more uncertain and less secure.
The Committee considered the need for training in the use of the Sherlock 3CG TCS. It recognised that there is a learning curve associated with the technology and that confirmatory chest X‑rays may be useful during this phase. It was also advised that clinical experience and judgement are needed to use the system reliably. An expert adviser described to the Committee some incidents of the ECG component of the Sherlock 3CG TCS showing that the PICC had reached the cavoatrial junction before this was actually the case. This could have led to a malpositioned PICC without sufficient understanding of the procedure and the application of appropriate clinical judgement.
The Committee was advised that the Sherlock 3CG TCS may also be useful for patients for whom it is difficult to identify a P wave (patients with atrial fibrillation, tachycardia, or paced rhythm). In such cases, the magnetic tracking component functions normally and can help to guide insertion, although a confirmatory chest X‑ray is still needed in these patients.# Cost considerations
# Cost evidence
The company identified 2 health economic studies in its submission (Adams 2013; Stewart 2013). Both studies were cost‑comparison studies from outside the UK healthcare system. The company noted that these studies were of low quality and limited relevance. The External Assessment Centre agreed with the company's assessment of the studies, and did not identify any additional relevant studies.
The company submitted a de novo cost analysis comparing the cost consequences of using the Sherlock 3CG Tip Confirmation System (TCS), both with and without confirmatory chest X‑ray, for both blind bedside insertion with confirmatory chest X‑ray of a peripherally inserted central catheter (PICC) and insertion using fluoroscopy. Costs were modelled from an NHS and Personal Social Services perspective. The population included in the model was adult patients needing a PICC, for whom the Sherlock 3CG TCS was suitable (that is, adult patients needing PICC insertion who had an identifiable P wave). Patients for whom it was difficult to identify a P wave (see section 2.3) were not included in the model. The model used a decision tree structure, presenting all clinical pathways of patients having PICC insertion. All patients exited the model with an accurate insertion. The model was cost‑based and did not include any health states. The time horizon was limited to the time taken to successful insertion.
The company used parameters derived from Parikh et al. (2012) and Adams (2013) and resource‑use figures presented in Walker et al. (2013) to inform its model. The model used different accuracy rates for the Sherlock 3CG TCS (96%), blind bedside insertion (93%) and fluoroscopy (100%). In cases where initial insertion was unsuccessful, all reinsertions were performed under fluoroscopy. The Sherlock 3CG TCS was considered to be suitable for 83.5% of the patient population. The company's model only considered patients for whom the technology was suitable, and not the estimated 16.5% of patients with an altered cardiac rhythm for whom the ECG component may be unreliable.
The price of the technology (£9990 excluding VAT) was calculated to be £6.39 per PICC inserted, based on the assumed patient population of 468 potential uses per year, spread over a 4‑year lifespan. The company also reported the cost of consumables (£189.91), maintenance (£1.52) and training (£1.42), and other costs for each insertion using the Sherlock 3CG TCS. The overall cost of each insertion using the Sherlock 3CG TCS with X‑ray was estimated to be £310.15, and without X‑ray to be £272.30. The company calculated the cost of blind bedside insertion to be £274.33, and insertion under fluoroscopy to be £814.93.
The results of the company's base case suggested that the Sherlock 3CG TCS without X‑ray confirmation was associated with a cost of £304.90 per patient, assuming that 96% of all placements were successful and that reinsertions were done under fluoroscopy. Based on this result, the technology was associated with a cost saving of £25.66 compared with blind PICC insertion with X‑ray confirmation and a cost saving of £510.03 compared with PICC insertion with fluoroscopy.
The company carried out extensive sensitivity analyses to test the structural assumptions underlying its base‑case model, and to identify the key drivers. The company acknowledged the limitations of the available evidence base, but considered that the extensive sensitivity analyses mitigated this somewhat. The cost of a PICC insertion and the success of placement at initial insertion were identified by the company as the key drivers of the cost model. The company's threshold analysis reported that the Sherlock 3CG TCS became cost‑incurring with less than 93% successful placement, but also became cost‑incurring if blind placement had a success rate greater than 96%. When considering the Sherlock 3CG TCS compared with insertion using fluoroscopy, the company found the Sherlock 3CG TCS to be always cost saving across the parameters considered. The company carried out scenario analyses, testing parameters such as the proportion of failed insertions, the proportion of successful reinsertions after an initial misplacement, and a variety of changes to the costs presented in the base case. The Sherlock 3CG TCS without confirmatory X‑ray remained cost saving in all scenarios identified by the company, except when the costs associated with the Sherlock 3CG TCS itself were increased by 25% (incurring an additional cost of £50.20).
The External Assessment Centre did not report any major concerns with either the structure of the company's model or its parameters, although it reported that the lack of evidence made it difficult to be confident about the cost‑model results, both from the company's analysis and its own revised analysis.
The External Assessment Centre considered that some of the clinical parameters and inputs into the company's model needed revisions to ensure their accuracy and completeness. The model did not include the setup costs of a bedside insertion service for hospitals currently using a fluoroscopy service. The External Assessment Centre noted that the scope of the company's economic submission contained a deviation from that specified by NICE and from the clinical evidence submitted. It specified that the patient population was only those for whom the Sherlock 3CG TCS is suitable, which overlooked the proportion of the population needing PICC insertion for whom the Sherlock 3CG TCS is not suitable. The External Assessment Centre also reported that a significant factor in the company's cost analysis was the time taken by a nurse to perform a bedside PICC insertion. The company's base‑case model assumed that a blind bedside insertion took the same time as a bedside insertion using the Sherlock 3CG TCS plus confirmatory X‑ray (62.49 minutes, based on Walker et al. ). Bedside insertion using the Sherlock 3CG TCS without a confirmatory X‑ray was assumed to take 39.5 minutes (Adams et al. 2013). The External Assessment Centre considered the use of 2 different data sources to inform the same procedure in different arms of the model to be irrational. In its own analysis, nurse time was adjusted to ensure parity across both treatment groups (62.49 minutes; Walker et al. 2013).
The External Assessment Centre updated the parameters in the company's model to reflect alternative assumptions made:
It incorporated the additional costs of patients needing PICC insertion who are not suitable for the Sherlock 3CG TCS (16.5% of patients). These patients had not been accounted for in the original economic model, despite being specified in the scope.
The amount of nurse time need for PICC insertion was set to be equal for both insertion using the Sherlock 3CG TCS and blind bedside insertion. The External Assessment Centre noted that results of the model for bedside procedures were strongly driven by nurse time.
It set the standard reinsertion option for unsuccessful insertions to be reinsertion using the original method, instead of fluoroscopy, to reflect the clinical experts' advice. For example, a PICC that was misplaced using the Sherlock 3CG TCS would be reinserted using the Sherlock 3CG TCS.
The malposition rate for the Sherlock 3CG TCS with no X‑ray confirmation was set to 0% instead of 4%, on the basis that there was no way to confirm a malpositioned PICC in the time horizon of the model.
Theatre costs for fluoroscopy were reset from £507.18 to £101.00.
Results of the base case in the company's model when run with the External Assessment Centre's revised parameters suggested that the Sherlock 3CG TCS without X‑ray confirmation was associated with a cost of £302.63 per patient. At this cost, it became cost incurring by £9.37 compared with blind bedside insertion. It was still associated with a cost saving compared with PICC insertion under fluoroscopy (£106.12), although this was lower than in the company's base case.
The External Assessment Centre carried out sensitivity analyses to test the impact on the costs of the technology of the accuracy of placement using both the Sherlock 3CG TCS and blind PICC placement, because there had been considerable uncertainty surrounding the clinically realistic accuracy rates of both. The External Assessment Centre also carried out a 1‑way sensitivity analysis to test the impact of varying the nurse time associated with insertion, because this had been noted to be a key driver in the model.
The results of the sensitivity analysis surrounding accuracy rates showed that, if use of the Sherlock 3CG TCS was accurate in 100% of patients (confirmed using chest X‑ray), then it would become cost incurring if blind PICC placement was accurate in just over 87% of patients. If the Sherlock 3CG without X‑ray confirmation had a 100% accuracy rate, it was cost saving if blind bedside insertion was less than 89% accurate.
The sensitivity analysis surrounding nurse times explored the impact of varying the nurse time needed for insertion of the Sherlock 3CG TCS by ±20 minutes when the nurse time needed for blind PICC insertion was 30 minutes and 80 minutes. The results showed that the factor which made the most impact was the difference in nurse times between the 2 technologies, rather than the actual length of time allocated to the procedure, and that a 10 minute difference between nurse times could make the Sherlock 3CG TCS cost saving or incurring. The External Assessment Centre reported that there was no evidence available to state with certainty that the nurse times used as inputs in the model were definitive. Expert advice reported a wide variation in nurse time depending on clinical setting and patient population.
The External Assessment Centre also carried out a separate analysis based on the results for intensive care patients presented in the studies by Johnston et al. (2013, 2014). In this analysis, the Sherlock 3CG TCS with X‑ray confirmation was compared with blind PICC placement with X‑ray confirmation to reflect the available data. PICC reinsertion was done with the original method in all cases. The External Assessment Centre used effectiveness rates based on results that met European guideline requirements as reported in Johnston et al. (2013, 2014): specifically, 79.5% for the Sherlock 3CG TCS with X‑ray, and 49.2% for blind PICC placement with X‑ray. This analysis showed that use of the Sherlock 3CG TCS with confirmatory X‑ray compared with blind insertion with X‑ray was associated with a cost saving of £41.35 per patient. The External Assessment Centre considered that intensive care patients may be a subgroup for whom the Sherlock 3CG TCS holds particular benefit, given the higher rates of malposition associated with this patient population. However, it noted that the evidence may not be generalisable, because the data were historical and from a single centre, and the actual number of repositionings was not reported.
The External Assessment Centre reported that there were numerous uncertainties in the model structure and inputs due to the lack of data available. The model was limited by the lack of available evidence, which was exacerbated by large variations in clinical practice, and different patient groups and settings. No evidence was available to the company on the impact of identified malpositions, and it was therefore unknown if PICCs were repositioned or reinserted as a result. No comparative evidence was available on the rate of complications or adverse events. The External Assessment Centre presented an alternative set of assumptions in its analysis, but stated that the lack of information did not allow for absolute certainty over which were correct. The External Assessment Centre reported that, given currently available information, use of the Sherlock 3CG TCS compared with blind PICC insertion using a chest X‑ray appeared overall to be close to cost neutral.
Following discussions at the Committee meeting, the External Assessment Centre carried out additional analysis to assess more fully the impact of an increasingly streamlined care pathway, in particular as a result of the reduced need for X‑ray confirmation. It considered potential cost savings in areas associated with this, such as portering and X‑ray interpretation. The External Assessment Centre considered a scenario in which nurse time was slightly reduced, because there was no need for interpretation of an X‑ray, and where the radiologist and portering time associated with a typical X‑ray did not need to be included. Using these parameters, use of the Sherlock 3CG TCS without X‑ray compared with blind bedside insertion was associated with a cost saving of £1.16 per patient.
## Committee considerations
The Committee recognised that the uncertainties in the economic evidence and cost modelling assumptions were substantial. It was told by the External Assessment Centre that the company had carried out substantive and appropriate sensitivity analyses to address the problem of the poor evidence base.
The Committee considered that use of the Sherlock 3CG TCS was likely to be cost saving compared with fluoroscopy‑guided PICC insertion, based on the results in both the company's base case and the results of the External Assessment Centre's revised model parameters. The Committee considered the costs presented by the External Assessment Centre to be more realistic, and accepted its estimated cost savings of £106.12 per patient to be reasonable within certain clinical settings. The External Assessment Centre noted at consultation stage that the cost savings presented may be an overestimate in a clinical setting that only uses fluoroscopy‑guided PICC insertion, because of the additional service redesign costs and the need to train staff in bedside insertion. As a result of the substantial variation in clinical settings, and the different training costs which may apply depending on the setting, the exact effect of these changes on the estimated cost saving is unknown.
The Committee considered the estimated proportion of the patient population for whom ECG tip confirmation was not used, namely those patients in whom it is difficult to identify a P wave. The External Assessment Centre presented the Committee with the full range of unsuccessful tip confirmation rates reported in the clinical evidence, ranging from 4.4% to 29.9%, and noted that varying the figure of 16.5% did not have a substantial impact on the cost modelling. The Committee noted this summary of tip confirmation failure rates, and accepted the value used by the External Assessment Centre (16.5%, Adams et al. 2013) in the cost modelling as reasonable (see section 3.6).
The Committee considered the evidence presented on the use of the Sherlock 3CG TCS in an intensive care population. It noted input from clinical experts, who confirmed that accurate PICC insertion is more difficult in intensive care patients due to problems with positioning and comorbidities. The External Assessment Centre advised the Committee that the primary driver of cost savings is the relative difference in the accuracy rates between the Sherlock 3CG TCS and bedside insertion. The Committee accepted the estimated cost saving of £41.35 obtained in a scenario analysis using the revised model with parameters from the Johnston et al. (2013, 2014) studies.
With regard to the use of the Sherlock 3CG TCS compared with blind insertion with confirmatory X‑rays, the Committee considered that the outputs of the company's model using the External Assessment Centre's updated parameters were appropriate. It was advised that the removal of X‑rays from the care pathway led to increased efficiency of service and an improved patient experience. Depending on the exact clinical context and whether or not it is used with X‑ray, the use of the Sherlock 3CG TCS in adults who need a PICC in a non‑intensive care setting ranged from slightly cost incurring (£24) to slightly cost saving (£26) compared with blind insertion with confirmatory chest X‑ray. These results led the Committee to conclude that the technology was likely to be more or less cost neutral.
For the guidance review, the External Assessment Centre revised the model to reflect 2019 costs (costs in original guidance given in brackets). The main parameter change was the cost of the Sherlock 3CG system: £10,654 (£9,990). Results for the 2019 revised base case showed that the cost saving associated with Sherlock 3CG was £109 (£106) when compared with fluoroscopy. In the ICU, use of the Sherlock 3CG system compared with blind PICC placement with confirmatory X-ray was cost saving at £54 (£41) per patient. The External Assessment Centre considered the impact of purchasing Sherlock 3CG technology incorporated within the Site Rite v8 ultrasound device instead of a separate Sherlock 3CG and Site Rite v5. The cost model result was a cost saving of £0.55 per patient. No changes in the clinical pathway are needed to use Site Rite v8. Further details of the 2017 revised model are in the costing review report. # Conclusions
The Committee concluded that the available clinical evidence, together with expert clinical advice, showed that the Sherlock 3CG Tip Confirmation System (TCS) is an effective method of placement for peripherally inserted central catheters (PICCs). The Committee concluded that the main benefit of the technology for patients who would otherwise have blind insertion is avoidance of a confirmatory chest X‑ray. Patients for whom the Sherlock 3CG TCS was used would not need to make journeys to an X‑ray department, would not be exposed to radiation and their PICC could be used without the associated delay. The Committee was advised by a clinical expert that avoidance of chest X‑rays also saves staff time (porters, nurses and sometimes radiologists). The Committee further concluded that use of the technology increases the confidence of both staff and patients during PICC insertion.
The Committee accepted modelling using revised parameters and sensitivity analyses and concluded that use of the Sherlock 3CG TCS could generate cost savings of about £106 per patient compared with using fluoroscopy as a guide to PICC insertion. The Committee also accepted the estimate of a cost saving of £41 per patient in an intensive care setting when the Sherlock 3CG TCS and confirmatory chest X‑ray are used in place of blind insertion and confirmatory chest X‑ray. The Committee concluded that in other settings, the cost of using the Sherlock 3CG TCS is similar to that of blind PICC insertion with a subsequent chest X‑ray.Andrew DillonChief ExecutiveDecember 2014
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{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified to NICE by companies. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.\n\nThe case for adopting the Sherlock\xa03CG Tip Confirmation System for placement of peripherally inserted central catheters is supported by the evidence. The technology usually avoids the need for a confirmatory chest X‑ray in patients who would otherwise have blind insertion, minimising the delay before the catheter can be used for infusion. Using the technology increases staff confidence during catheter insertion.\n\nThe Sherlock\xa03CG Tip Confirmation System should be considered as an option for placement of peripherally inserted central catheters in adults. For patients whose electrocardiogram does not show a P wave (for example, patients with atrial fibrillation), a chest X‑ray will still be needed to confirm tip location of the peripherally inserted central catheter.\n\nThe cost of using the Sherlock\xa03CG\xa0Tip Confirmation System (TCS) is similar to that of blind insertion and subsequent chest X‑ray in adults who need a peripherally inserted central catheter in a non‑intensive care setting. When the Sherlock\xa03CG\xa0TCS is used instead of fluoroscopy, the estimated cost saving is £109 per patient. In an intensive care setting, where the rate of misplacement with blind insertion is generally higher, there is an estimated cost saving of £54 per patient per use of the Sherlock\xa03CG\xa0TCS and a confirmatory chest X‑ray compared with using blind insertion and chest X‑ray. All these cost savings are subject to some uncertainty and need to be considered in the context of the clinical benefits. ", 'The technology': "# Description of the technology\n\nThe Sherlock\xa03CG Tip Confirmation System (TCS; BD) is designed to confirm the correct tip placement of a peripherally inserted central catheter (PICC; that is, a catheter inserted through a large vein in or near the arm rather than the neck or chest). Sherlock\xa03CG is also available within the Site Rite ultrasound device (version\xa08). By using magnetic and electrocardiographic (ECG) real‑time tracking of the PICC tip, Sherlock\xa03CG is intended to allow the person placing the PICC to detect and correct any error in tip positioning. The tip location sensor is only compatible with a Bard PowerPICC SOLO catheter. The Sherlock\xa03CG\xa0TCS is designed to remove the need for a chest X‑ray which is used to confirm tip location after insertion of a PICC in most patients. \n\nThe Sherlock\xa03CG\xa0TCS comprises: a system console, including a control processor with display interface; a tip location sensor; a PowerPICC SOLO catheter with the Sherlock\xa03CG tip positioning stylet; a remote control; and an optional miniature wireless printer to create a paper record of the ECG. The sensor is positioned on the patient's sternum with 2\xa0leads placed to pick up external ECG waveforms. The catheter is then inserted into a suitable vein in the upper arm with the stylet. During insertion, magnets in the stylet generate a field that is detected by the sensor. This enables clinicians to track the PICC on the display interface in real time, allowing them to see if the PICC is taking the correct path towards the cavoatrial junction. The stylet is removed once the catheter has been appropriately positioned. The display interface also shows real‑time ECG waveforms received from the patient's skin (baseline) and from the tip of the catheter (intravascular, measured by a column of saline which the placer injects into the PICC). The P wave changes on the ECG as the PICC tip moves towards the right atrium and right ventricle. By observing the P wave, a clinician can determine the PICC tip location relative to the chambers of the heart and the superior vena cava.\n\nThe Sherlock\xa03CG\xa0TCS is intended for use in any indication in adults where therapy means accessing a vein through a PICC. PICCs have a wide range of applications and are commonly used for intravenous access for drugs and fluids (infusion of irritant drugs, such as in chemotherapy; total parenteral nutrition; or long‑term administration of drugs such as antibiotics) and monitoring or interventions (such as central venous pressure, repeated blood sampling, or when there is poor peripheral access). The instructions for use state that the device should be used with caution in patients with altered cardiac rhythms, specifically those in whom a P wave is not easily detectable, for example patients with atrial fibrillation, rapid tachycardia, or pacemaker‑driven rhythm. Although the Sherlock\xa03CG\xa0TCS can be used in these patients, the company recommends a chest X‑ray to confirm PICC tip location.\n\nThe cost of the Sherlock\xa03CG\xa0TCS – comprising the system console, tip location sensor, remote control, stand and printer – is stated in the company's submission as £10,653.97 (excluding VAT). The cost of consumables associated with each insertion is £215.05, comprising primarily the cost of the PICC (including the stylet), sterile barrier and ECG leads. Maintenance costs associated with the technology are £840 per\xa0year per system console. \n\nThe claimed benefits of the Sherlock\xa03CG\xa0TCS in the case for adoption presented by the company were as follows:\n\nBetter accuracy of PICC placement (reducing the need for repositioning after insertion).\n\nRemoved need for a chest X‑ray or fluoroscopy to confirm tip location after PICC insertion.\n\nIntraprocedural verification of the PICC tip position allows the PICC to be used immediately after insertion. This reduces treatment delays, which may be up to 48\xa0hours after PICC insertion.\n\nA safe method for PICC tip placement with no associated adverse events or complications.\n\nPICC placement and tip confirmation happen during the same clinical procedure.\n\nIncreased patient confidence in whoever is placing the PICC, because the rate of malpositioning and repositioning is reduced.\n\nA reduced and more efficient care pathway because no confirmation X‑ray is needed.\n\nLower staff requirements (radiologists, radiology nurses, radiographers, radiology healthcare support workers) because the need for an X‑ray to confirm PICC placement is reduced or eliminated. All staff who are freed by the use of the Sherlock\xa03CG can be redirected to other areas of need.\n\nPotential reduction of bed occupancy due to reductions in treatment delays post‑PICC insertion and delays caused by repositioning. This may lead to earlier discharge of hospital patients having intravenous therapy, enabling management in the community.\n\nReduced costs of consequences of incorrect PICC placement.\n\nReduced costs of using resource‑intensive departments such as radiology.\n\n# Current management\n\nIn current NHS clinical practice, there is substantial variation between sites in the ways in which PICCs are inserted. Catheters are typically inserted by nurse‑led or consultant‑led vascular access teams, although PICCs may be inserted by a range of healthcare professionals, including nurse specialists, intensive care consultants, anaesthetists, general physicians, radiologists and radiographers. Clinical settings where PICCs are inserted include operating theatres, emergency rooms, oncology, orthopaedic and other wards, radiology departments, intensive care units, high dependency units and outpatient clinics. Sterility is a major concern, and can best be achieved using a maximum barrier sterile field at the bedside.\n\nUltrasound is used to identify a suitable vein in the upper arm. The PICC is then inserted using a modified Seldinger technique, which involves inserting a small gauge needle into the vein followed by a wire. A sheath and dilator are used for the catheter to gain access to the vein before the wire is removed. The PICC is advanced to a suitable point using a measurement of the distance between the insertion site and a suitable anatomical landmark indicating the target site for the tip of the PICC (for example, the third right intercostal space below the right clavicular head). This technique is referred to as blind bedside insertion or blind insertion. The position of the PICC is confirmed by chest X‑ray, which typically requires the patient to go to the X‑ray department; the X‑ray then needs to be checked by whoever inserted the PICC, or by a radiologist. Alternatively, fluoroscopy can be used to position the PICC, especially when this is difficult, such as in patients with narrow vessels.", 'Clinical evidence': "# Summary of clinical evidence\n\nFull details of all clinical outcomes considered by the Committee are available in the assessment report overview.\n\nThe key clinical outcomes for the Sherlock\xa03CG Tip Confirmation System (TCS) presented in the decision problem were:\n\naccuracy of catheter tip placement\n\nincidence of catheter malposition\n\nneed for catheter repositioning\n\nimpact of malposition‑related complications such as infection or thrombosis\n\ntreatment delay following catheter placement\n\nreduced staff time\n\nreduced hospital stay\n\nneed for confirmatory chest X‑ray\n\nneed for fluoroscopy to place the peripherally inserted central catheter (PICC) tip correctly\n\ntime taken to insert PICC\n\nPICC failure and reinsertion rates\n\npatient experience measures\n\nquality of life\n\ndevice‑related adverse events.\n\nThe External Assessment Centre considered that 5 of the 14 outcomes in the decision problem were reported in the published evidence. These were: accuracy of catheter tip placement; incidence of catheter malposition; treatment delay following catheter placement; change in staff time, and need for confirmatory chest X‑ray. The External Assessment Centre considered that some additional outcomes had also been partially addressed. Outcomes for which no evidence was presented included reduced hospital stay and treatment delay following catheter placement. The company stated that it was unable to report on device‑related adverse events because of a lack of reported evidence.\n\nThe company identified 13\xa0studies from its literature search but it excluded 9 and presented 4\xa0published abstracts (Adams et\xa0al. 2013; Barton, 2014; Parikh, 2012; Stewart, 2013). It also presented responses from a questionnaire sent to 6\xa0NHS hospitals, as supporting clinical evidence. The External Assessment Centre considered that the studies presented by the company were in keeping with the scope and were appropriate for inclusion. It also identified 1\xa0study published after the company submission and that it considered suitable for assessment (Johnston et\xa0al. 2014). To ensure that all relevant evidence was identified, the External Assessment Centre carried out a further literature search with a wider scope which included any previous model of the device that had both magnetic tracking and electrocardiogram (ECG) tip confirmation components. One additional presentation was identified (Symington et\xa0al. 2013).\n\nJohnston et al. (2014) reported a retrospective case‑series review of the first 250\xa0patients to have PICCs inserted using the Sherlock\xa03CG\xa0TCS following its introduction to a UK NHS hospital. The population comprised patients in the intensive care unit (ICU). The vascular access team placed PICCs at the bedside, and used a portable chest X‑ray to confirm the tip location. Two independent reviewers examined the X‑rays. From the first 250\xa0patients, 11\xa0were excluded because of: failed insertion (n=2); no chest X‑ray being taken after the procedure (n=2); a failure to identify the tip position on the chest X‑ray (n=2); a failure to interpret the ECG criteria (n=4); and the catheter being too short (n=1). Tip location was reported for the 239\xa0PICC placements where ECG was used for tip confirmation. Although there was no direct comparator for the intervention in this study, the same authors published a retrospective service evaluation a\xa0year before the Sherlock\xa03CG\xa0TCS was introduced, reviewing records for both ICU patients (n=246) and non‑ICU patients (n=233, Johnston 2013). The External Assessment Centre used this as a form of comparator to assess the impact of the Sherlock\xa03CG\xa0TCS on malposition rates. Both Johnston studies reported results using 2\xa0different definitions of malposition, 1\xa0from the USA and the other from Europe. The definition of appropriate placement typically used in US guidelines is the low superior vena cava or cavoatrial junction (National Association of Vascular Access Networks 1998, Infusion Nurses Society 2006, Funaki 2002). A European guideline uses a broader definition, stating that appropriate placement is in the mid or lower superior vena cava, cavoatrial junction, or high right atrium (Pittiruti 2009). Using the definition as per US guidelines, 56.1% (95%\xa0confidence interval [CI] 50%\xa0to\xa062%, n=134) of ICU patients had a malpositioned PICC using the Sherlock\xa03CG\xa0TCS compared with 76% (n=187) who had blind bedside insertion. Using the definition as per European guidelines, 20.5% (95%\xa0CI 16%\xa0to\xa026%, n=49) of ICU patients had a malpositioned PICC using the Sherlock\xa03CG\xa0TCS compared with 50.8% (n=125) who had blind bedside insertion. The malposition rate using the Sherlock\xa03CG\xa0TCS was significantly lower than blind placement using both sets of criteria (p<0.0001). However, it was also substantially higher than that reported in other studies. The authors suggest several reasons for this. They noted that it may be difficult to determine the exact point of a maximum or biphasic P wave for patients in intensive care, who may have ECG artefacts due to comorbidities. The authors also noted that tip position is not static, and that the catheter tip may move (due to, for example, arm movement, because the PICC is placed with the arm drawn away from the body and the chest X‑ray is taken with the arm drawn towards the body). The authors concluded that, if the European guideline definition of an adequate tip position is considered to be acceptable, the Sherlock\xa03CG\xa0TCS can be used for tip confirmation without chest X‑ray. If a more precise tip position of low superior vena cava or cavoatrial junction is used, as in the US guidelines, a chest X‑ray may be necessary.\n\nAdams et al. (2013) presented a poster reporting on the introduction of the Sherlock\xa03CG\xa0TCS to a healthcare centre in the US. Over a 9‑month period, 333\xa0patients had PICC insertion using the Sherlock\xa03CG\xa0TCS, which was subsequently verified using chest X‑ray and confirmed by 2\xa0radiologists. Accurate placement was defined as the catheter tip being in the distal superior vena cava or at the cavoatrial junction. The Sherlock\xa03CG\xa0TCS was used to confirm tip position in 83.5% of patients (278/333). In the remaining 16.5% (55/333), the ECG system could not be used either because of an abnormal P\xa0wave (12.9%) or because of technical factors such as loose connections and poor electrode placement (3.6%). When the Sherlock\xa03CG\xa0TCS was used to confirm tip position, 1\xa0radiologist reported that 96.4% (268/278) of PICCs were placed accurately, and that 3.6% (10/278) were malpositioned; the other radiologist reported that 98.2% (273/278) of PICCs were placed accurately and 1.8% (5/278) were malpositioned. In 2011, the malposition rate using the predecessor device, the Sherlock Tip Location System (magnetic tracking only) was reported to be 14% based on a subsequent chest X‑ray. Adams et al. also reported that the PICC was ready for infusion 61.0\xa0minutes earlier using the Sherlock\xa03CG\xa0TCS (39.5\xa0minutes) than using a chest X‑ray and a radiologist report for tip position confirmation (101.0\xa0minutes), although no information was reported on how this was measured. The researchers confirmed that chest X‑rays are no longer mandatory for PICCs placed using the Sherlock\xa03CG\xa0TCS at this centre.\n\nThe abstract by Barton (2014) described the introduction of the Sherlock\xa03CG\xa0TCS to a nurse‑led PICC service at a UK NHS hospital. In an initial trial, clinicians used the Sherlock\xa03CG\xa0TCS for PICC placement in 65\xa0adults with no atrial fibrillation. They used chest X‑rays, reviewed by an independent physician, to confirm tip location. Following the initial trial, an application was made to amend local protocol and remove the need for a mandatory chest X‑ray following PICC placement. During the application process, clinicians placed another 160\xa0PICCs using the Sherlock\xa03CG\xa0TCS, with position confirmed using a chest X‑ray. In total, data were reported on 225\xa0patients. The definition of acceptable tip position was the lower third of the superior vena cava or the cavoatrial junction, as used in US guidelines. Chest X‑rays confirmed that tip position was acceptable in 100% of cases reported. Only success rates of tip positioning in patients for whom magnetic tip position and ECG tip confirmation could be used were reported. Cases where the Sherlock\xa03CG\xa0TCS was not suitable or where there was a failure of the ECG system were not included. The authors reported to the External Assessment Centre that, during the trial period, 2\xa0patients were not suitable for the Sherlock\xa03CG\xa0TCS and had PICCs placed with fluoroscopy. Since the introduction of the Sherlock\xa03CG\xa0TCS, 11\xa0patients needed chest X‑rays due to the failure of the ECG system to provide tip confirmation. Five of these cases were because of atrial fibrillation, and 6 because of a failure of the electrode connections. The hospital has since removed the need for chest X‑ray after PICC placement using the Sherlock\xa03CG TCS.\n\nParikh (2012) presented a poster reporting a prospective case series from October 2011 to April 2012 of 247\xa0PICCs placed in 221\xa0patients (mean age 62\xa0years, range 15–100) in a US hospital. The Sherlock\xa03CG\xa0TCS was used for tip placement and confirmation, except in patients with atrial fibrillation, atrial flutter or no discernible P wave (15.4%,\xa038/247). Tip position was confirmed by chest X‑ray and evaluated by 2\xa0independent observers. Successful tip placement was defined as the superior vena cava or cavoatrial junction, as in the US guidelines. The study was divided into 2\xa0phases. Phase\xa01 was a voluntary training phase. Nurses who wished to be trained in the use of the Sherlock\xa03CG\xa0TCS (4\xa0of\xa07\xa0nurses) had training, which consisted of a PICC refresher course, an online course, a 1‑hour taught course and 1‑to‑1 training with a nurse trainer provided by the company. The nurses then placed 62\xa0PICCs using the Sherlock\xa03CG\xa0TCS. As per the exclusion criteria, 3\xa0patients were excluded. Successful tip placement was 83% (n=62) for those using the Sherlock\xa03CG\xa0TCS. For phase\xa02, the 3\xa0other nurses who had not had training in the Sherlock\xa03CG\xa0TCS had phase\xa01 training. All 7\xa0nurses then inserted 5\xa0PICCs while being observed by a nurse trainer. All staff completed phase\xa02 training. Staff placed 147\xa0PICCs using the Sherlock\xa03CG\xa0TCS, excluding 35\xa0patients as per the criteria. Successful tip placement was 96% (n=147) for those using the Sherlock\xa03CG\xa0TCS. From November\xa02012 to May\xa02013, staff placed a further 567\xa0PICCs, 437\xa0using the Sherlock\xa03CG\xa0TCS. Of these, 24.9% (109/437) still needed a chest X‑ray for confirmation, for reasons that included unclear baseline rhythm, and complicated or uncertain PICC placement. It is unknown if the PICCs which did not use the Sherlock\xa03CG\xa0TCS needed a chest X‑ray to confirm, but this is probable.\n\nAn abstract and poster by Stewart (2013) presented a study in an Australian hospital which recruited over 65\xa0patients between November\xa02012 and March\xa02013. The exact number of patients and methodology were not reported. Clinicians placed PICCs using the Sherlock\xa03CG\xa0TCS and confirmed the tip position using a chest X‑ray. No information was given on what tip positions were considered to be acceptable or who reported on the chest X‑ray. The abstract reported that 100% of malpositions were corrected at time of placement. Of PICC placements using the Sherlock\xa03CG\xa0TCS, 96% were within the cavoatrial junction. The other 4% were reported in the right atrium. Discrepancies were noted between locations reported by ECG and X‑ray, which were resolved with clinical experience and collaboration. A time saving of 1\xa0hour and 51\xa0minutes was reported, being the average wait time between PICC insertion and X‑ray results. No information was given on how time savings were measured or if there was any resulting change in treatment time or outcomes.\n\nSymington et al. (2011) was a conference presentation on a US centre using the Sapiens\xa0TCS in conjunction with the Sherlock\xa0TLS\xa0II. These devices are the predecessor devices to, and when used together have the same mode of action as, the Sherlock\xa03CG\xa0TCS. The author reported on a consecutive case series during April\xa02011 (n=63). No information was given on the patient population. The company provided training. Tip placement was verified with a chest X‑ray, reviewed by the author. The author reported a 5% technical failure rate, including difficulties with cannulation of the vein, advancement of the catheter and occluded veins. It was reported that technical failures were 'thrown out', although this was not explained in greater detail. The authors reported that 62\xa0of 63\xa0tip placements were appropriately positioned, although no specific criteria for appropriate placement were reported. They reported that, by July\xa02011, there had been 604\xa0PICC placements using the Sapiens\xa0TCS in conjunction with the Sherlock\xa0TLS\xa0II. The lead author reported that he was formally requesting that his hospital remove the need for mandatory chest X‑ray from its procedural guidelines. He was also a paid presenter for Bard Access Systems (a division of CR Bard), which was clearly stated.\n\nThe company contacted 7\xa0UK NHS hospitals currently using the Sherlock\xa03CG\xa0TCS and collected questionnaire responses from them. The initial clinical evidence submission did not include these data, but they were later provided to the External Assessment Centre. The External Assessment Centre judged that the structuring of the questions and format of the answers did not allow for the assessment of relevant evidence on outcomes as defined in the decision problem. The External Assessment Centre noted the variation in reported clinical practice for issues such as hospital policy for confirmation, typical levels of malposition, dealing with malpositions and PICC reinsertions. In general, all respondents reported fewer malpositions using the Sherlock\xa03CG\xa0TCS than before its introduction. The External Assessment Centre noted that there was a risk of bias because not all hospitals using the Sherlock\xa03CG\xa0TCS were asked to provide data to the company. To explore this, the External Assessment Centre contacted 7\xa0of the other 8\xa0hospitals (not included in the company's survey) currently using the device, and 1\xa0hospital that had not responded to the company's initial questionnaire. The External Assessment Centre concluded that the hospital questionnaires provided no assessable data relevant to the scope.\n\nThe company did not identify any adverse events from the published literature, or from a search of the Medicines and Healthcare Products Regulatory Agency's website. The company retrieved 51\xa0records from the US Food and Drug Administration's MAUDE database, but stated that they were not necessarily device‑related adverse events. The External Assessment Centre retrieved 100\xa0records from the same database, using a wider search strategy. Adverse events submitted to MAUDE are not verified. No searches were carried out for adverse event reports from PICC insertion using comparator technologies (blind PICC insertion with chest X‑ray, or fluoroscopy). Reported adverse events included: broken or damaged wire tip or stylet (n=29); adverse patient reactions (such as shortness of breath; n=23); catheter malfunction (such as leaks or splits; n=18) and tip malposition (n=14). The External Assessment Centre sought clinical expert opinion, but could not rule out the possibility that the adverse events reported with the Sherlock\xa03CG\xa0TCS were common to all PICC insertion techniques.\n\n## Committee considerations\n\nThe Committee noted that the overall quality and quantity of the clinical evidence was low, consisting largely of abstracts and posters reporting on case series. The only comparative data available were from a historical comparison by the External Assessment Centre, based on the outcomes reported by Johnston et\xa0al. (2013, 2014) before and after the introduction of the Sherlock\xa03CG\xa0TCS. Nevertheless, the Committee judged that the available evidence all pointed towards the use of the Sherlock\xa03CG\xa0TCS providing more reliable tip placement than blind insertion.\n\nThe Committee noted in particular that a number of hospitals had stopped using chest X‑rays for confirmation of PICC tip position after their clinicians had become experienced at using the Sherlock\xa03CG\xa0TCS and they had audited success rates. It was mindful of the benefits to patients of avoiding confirmatory chest X‑rays, including avoidance of radiation exposure and travel to the X‑ray department, and the possibility of having treatments through their PICCs without delay.\n\nThe Committee considered that the variation between definitions of correct PICC placement was less important than whether a PICC is so misplaced that a further procedure is needed to correct its position. Although the definitions provide a means of assessing the accuracy of different methods of PICC placement, experts told the Committee that minor discrepancies in catheter tip position identified by a chest X‑ray after blind insertion would be unlikely to have serious clinical consequences. They also stated that the need for catheter repositioning as a result of malpositioning is uncommon. The External Assessment Centre told the Committee that no published evidence was available about further procedures to reposition misplaced PICCs following placement with the Sherlock\xa03CG\xa0TCS. The Committee was also advised that the PICCs may change position after insertion.", 'NHS considerations': '# System impact\n\nThe company claimed that the Sherlock\xa03CG Tip Confirmation System (TCS) increases efficiency in the care pathway by eliminating the need for a confirmatory chest X‑ray following the insertion of a peripherally inserted central catheter (PICC). The costs and time involved in transporting patients to an X‑ray department for a confirmatory X‑ray would be eliminated in most cases. This would reduce staff requirements, particularly in nursing and radiology, and allow these staff to be directed to other areas of need.\n\nExperts also advised the Committee about potential system benefits associated with the reduced need for fluoroscopy and reduced number of X‑rays, including cost savings and an increased throughput of patients, meaning that patient access to radiology departments would be quicker and more efficient. One expert also advised that earlier access to infusion treatment may result in earlier discharge of patients from hospital.\n\nThe Sherlock\xa03CG\xa0TCS was launched in the UK in April\xa02013. The company reported that it was being used in 14\xa0NHS hospitals in England and 2\xa0in Northern Ireland. The company also stated that 9\xa0of the English hospitals have discontinued routine chest X‑ray confirmation following PICC placement. The External Assessment Centre was able to confirm this for 6\xa0of the 9\xa0hospitals.\n\n## Committee considerations\n\nThe Committee recognised that avoiding the need for routine confirmatory chest X‑rays by using the Sherlock\xa03CG\xa0TCS for PICC placement would release resources in X‑ray departments. It would also mean that nurses and porters would not be needed to help transfer patients between X‑ray departments and other parts of the hospital.\n\nThe Committee noted that using the Sherlock\xa03CG\xa0TCS could increase staff and patient confidence compared with using blind insertion. An expert adviser from a hospital which has discontinued X‑ray confirmation advised the Committee that procedures performed without the Sherlock\xa03CG\xa0TCS now feel more uncertain and less secure.\n\nThe Committee considered the need for training in the use of the Sherlock\xa03CG\xa0TCS. It recognised that there is a learning curve associated with the technology and that confirmatory chest X‑rays may be useful during this phase. It was also advised that clinical experience and judgement are needed to use the system reliably. An expert adviser described to the Committee some incidents of the ECG component of the Sherlock\xa03CG\xa0TCS showing that the PICC had reached the cavoatrial junction before this was actually the case. This could have led to a malpositioned PICC without sufficient understanding of the procedure and the application of appropriate clinical judgement.\n\nThe Committee was advised that the Sherlock\xa03CG\xa0TCS may also be useful for patients for whom it is difficult to identify a P wave (patients with atrial fibrillation, tachycardia, or paced rhythm). In such cases, the magnetic tracking component functions normally and can help to guide insertion, although a confirmatory chest X‑ray is still needed in these patients.', 'Cost considerations': "# Cost evidence\n\nThe company identified 2\xa0health economic studies in its submission (Adams 2013; Stewart 2013). Both studies were cost‑comparison studies from outside the UK healthcare system. The company noted that these studies were of low quality and limited relevance. The External Assessment Centre agreed with the company's assessment of the studies, and did not identify any additional relevant studies.\n\nThe company submitted a de novo cost analysis comparing the cost consequences of using the Sherlock\xa03CG Tip Confirmation System (TCS), both with and without confirmatory chest X‑ray, for both blind bedside insertion with confirmatory chest X‑ray of a peripherally inserted central catheter (PICC) and insertion using fluoroscopy. Costs were modelled from an NHS and Personal Social Services perspective. The population included in the model was adult patients needing a PICC, for whom the Sherlock\xa03CG\xa0TCS was suitable (that is, adult patients needing PICC insertion who had an identifiable P wave). Patients for whom it was difficult to identify a P wave (see section\xa02.3) were not included in the model. The model used a decision tree structure, presenting all clinical pathways of patients having PICC insertion. All patients exited the model with an accurate insertion. The model was cost‑based and did not include any health states. The time horizon was limited to the time taken to successful insertion.\n\nThe company used parameters derived from Parikh et\xa0al. (2012) and Adams (2013) and resource‑use figures presented in Walker et al. (2013) to inform its model. The model used different accuracy rates for the Sherlock\xa03CG\xa0TCS (96%), blind bedside insertion (93%) and fluoroscopy (100%). In cases where initial insertion was unsuccessful, all reinsertions were performed under fluoroscopy. The Sherlock\xa03CG\xa0TCS was considered to be suitable for 83.5% of the patient population. The company's model only considered patients for whom the technology was suitable, and not the estimated 16.5% of patients with an altered cardiac rhythm for whom the ECG component may be unreliable.\n\nThe price of the technology (£9990 excluding VAT) was calculated to be £6.39 per PICC inserted, based on the assumed patient population of 468 potential uses per\xa0year, spread over a 4‑year lifespan. The company also reported the cost of consumables (£189.91), maintenance (£1.52) and training (£1.42), and other costs for each insertion using the Sherlock\xa03CG\xa0TCS. The overall cost of each insertion using the Sherlock\xa03CG\xa0TCS with X‑ray was estimated to be £310.15, and without X‑ray to be £272.30. The company calculated the cost of blind bedside insertion to be £274.33, and insertion under fluoroscopy to be £814.93.\n\nThe results of the company's base case suggested that the Sherlock\xa03CG\xa0TCS without X‑ray confirmation was associated with a cost of £304.90 per patient, assuming that 96% of all placements were successful and that reinsertions were done under fluoroscopy. Based on this result, the technology was associated with a cost saving of £25.66 compared with blind PICC insertion with X‑ray confirmation and a cost saving of £510.03 compared with PICC insertion with fluoroscopy.\n\nThe company carried out extensive sensitivity analyses to test the structural assumptions underlying its base‑case model, and to identify the key drivers. The company acknowledged the limitations of the available evidence base, but considered that the extensive sensitivity analyses mitigated this somewhat. The cost of a PICC insertion and the success of placement at initial insertion were identified by the company as the key drivers of the cost model. The company's threshold analysis reported that the Sherlock\xa03CG\xa0TCS became cost‑incurring with less than 93% successful placement, but also became cost‑incurring if blind placement had a success rate greater than 96%. When considering the Sherlock\xa03CG\xa0TCS compared with insertion using fluoroscopy, the company found the Sherlock\xa03CG\xa0TCS to be always cost saving across the parameters considered. The company carried out scenario analyses, testing parameters such as the proportion of failed insertions, the proportion of successful reinsertions after an initial misplacement, and a variety of changes to the costs presented in the base case. The Sherlock\xa03CG\xa0TCS without confirmatory X‑ray remained cost saving in all scenarios identified by the company, except when the costs associated with the Sherlock\xa03CG\xa0TCS itself were increased by 25% (incurring an additional cost of £50.20).\n\nThe External Assessment Centre did not report any major concerns with either the structure of the company's model or its parameters, although it reported that the lack of evidence made it difficult to be confident about the cost‑model results, both from the company's analysis and its own revised analysis.\n\nThe External Assessment Centre considered that some of the clinical parameters and inputs into the company's model needed revisions to ensure their accuracy and completeness. The model did not include the setup costs of a bedside insertion service for hospitals currently using a fluoroscopy service. The External Assessment Centre noted that the scope of the company's economic submission contained a deviation from that specified by NICE and from the clinical evidence submitted. It specified that the patient population was only those for whom the Sherlock\xa03CG\xa0TCS is suitable, which overlooked the proportion of the population needing PICC insertion for whom the Sherlock\xa03CG\xa0TCS is not suitable. The External Assessment Centre also reported that a significant factor in the company's cost analysis was the time taken by a nurse to perform a bedside PICC insertion. The company's base‑case model assumed that a blind bedside insertion took the same time as a bedside insertion using the Sherlock\xa03CG\xa0TCS plus confirmatory X‑ray (62.49\xa0minutes, based on Walker et\xa0al. ). Bedside insertion using the Sherlock\xa03CG\xa0TCS without a confirmatory X‑ray was assumed to take 39.5\xa0minutes (Adams et\xa0al. 2013). The External Assessment Centre considered the use of 2\xa0different data sources to inform the same procedure in different arms of the model to be irrational. In its own analysis, nurse time was adjusted to ensure parity across both treatment groups (62.49\xa0minutes; Walker et\xa0al. 2013).\n\nThe External Assessment Centre updated the parameters in the company's model to reflect alternative assumptions made:\n\nIt incorporated the additional costs of patients needing PICC insertion who are not suitable for the Sherlock\xa03CG\xa0TCS (16.5% of patients). These patients had not been accounted for in the original economic model, despite being specified in the scope.\n\nThe amount of nurse time need for PICC insertion was set to be equal for both insertion using the Sherlock\xa03CG\xa0TCS and blind bedside insertion. The External Assessment Centre noted that results of the model for bedside procedures were strongly driven by nurse time.\n\nIt set the standard reinsertion option for unsuccessful insertions to be reinsertion using the original method, instead of fluoroscopy, to reflect the clinical experts' advice. For example, a PICC that was misplaced using the Sherlock\xa03CG\xa0TCS would be reinserted using the Sherlock\xa03CG\xa0TCS.\n\nThe malposition rate for the Sherlock\xa03CG\xa0TCS with no X‑ray confirmation was set to 0% instead of 4%, on the basis that there was no way to confirm a malpositioned PICC in the time horizon of the model.\n\nTheatre costs for fluoroscopy were reset from £507.18 to £101.00.\n\nResults of the base case in the company's model when run with the External Assessment Centre's revised parameters suggested that the Sherlock\xa03CG\xa0TCS without X‑ray confirmation was associated with a cost of £302.63 per patient. At this cost, it became cost incurring by £9.37 compared with blind bedside insertion. It was still associated with a cost saving compared with PICC insertion under fluoroscopy (£106.12), although this was lower than in the company's base case.\n\nThe External Assessment Centre carried out sensitivity analyses to test the impact on the costs of the technology of the accuracy of placement using both the Sherlock\xa03CG\xa0TCS and blind PICC placement, because there had been considerable uncertainty surrounding the clinically realistic accuracy rates of both. The External Assessment Centre also carried out a 1‑way sensitivity analysis to test the impact of varying the nurse time associated with insertion, because this had been noted to be a key driver in the model.\n\nThe results of the sensitivity analysis surrounding accuracy rates showed that, if use of the Sherlock\xa03CG\xa0TCS was accurate in 100% of patients (confirmed using chest X‑ray), then it would become cost incurring if blind PICC placement was accurate in just over 87% of patients. If the Sherlock\xa03CG without X‑ray confirmation had a 100% accuracy rate, it was cost saving if blind bedside insertion was less than 89% accurate.\n\nThe sensitivity analysis surrounding nurse times explored the impact of varying the nurse time needed for insertion of the Sherlock\xa03CG\xa0TCS by ±20\xa0minutes when the nurse time needed for blind PICC insertion was 30\xa0minutes and 80\xa0minutes. The results showed that the factor which made the most impact was the difference in nurse times between the 2\xa0technologies, rather than the actual length of time allocated to the procedure, and that a 10\xa0minute difference between nurse times could make the Sherlock\xa03CG\xa0TCS cost saving or incurring. The External Assessment Centre reported that there was no evidence available to state with certainty that the nurse times used as inputs in the model were definitive. Expert advice reported a wide variation in nurse time depending on clinical setting and patient population.\n\nThe External Assessment Centre also carried out a separate analysis based on the results for intensive care patients presented in the studies by Johnston et al. (2013, 2014). In this analysis, the Sherlock\xa03CG\xa0TCS with X‑ray confirmation was compared with blind PICC placement with X‑ray confirmation to reflect the available data. PICC reinsertion was done with the original method in all cases. The External Assessment Centre used effectiveness rates based on results that met European guideline requirements as reported in Johnston et al. (2013, 2014): specifically, 79.5% for the Sherlock\xa03CG\xa0TCS with X‑ray, and 49.2% for blind PICC placement with X‑ray. This analysis showed that use of the Sherlock\xa03CG\xa0TCS with confirmatory X‑ray compared with blind insertion with X‑ray was associated with a cost saving of £41.35 per patient. The External Assessment Centre considered that intensive care patients may be a subgroup for whom the Sherlock\xa03CG\xa0TCS holds particular benefit, given the higher rates of malposition associated with this patient population. However, it noted that the evidence may not be generalisable, because the data were historical and from a single centre, and the actual number of repositionings was not reported.\n\nThe External Assessment Centre reported that there were numerous uncertainties in the model structure and inputs due to the lack of data available. The model was limited by the lack of available evidence, which was exacerbated by large variations in clinical practice, and different patient groups and settings. No evidence was available to the company on the impact of identified malpositions, and it was therefore unknown if PICCs were repositioned or reinserted as a result. No comparative evidence was available on the rate of complications or adverse events. The External Assessment Centre presented an alternative set of assumptions in its analysis, but stated that the lack of information did not allow for absolute certainty over which were correct. The External Assessment Centre reported that, given currently available information, use of the Sherlock\xa03CG\xa0TCS compared with blind PICC insertion using a chest X‑ray appeared overall to be close to cost neutral.\n\nFollowing discussions at the Committee meeting, the External Assessment Centre carried out additional analysis to assess more fully the impact of an increasingly streamlined care pathway, in particular as a result of the reduced need for X‑ray confirmation. It considered potential cost savings in areas associated with this, such as portering and X‑ray interpretation. The External Assessment Centre considered a scenario in which nurse time was slightly reduced, because there was no need for interpretation of an X‑ray, and where the radiologist and portering time associated with a typical X‑ray did not need to be included. Using these parameters, use of the Sherlock\xa03CG\xa0TCS without X‑ray compared with blind bedside insertion was associated with a cost saving of £1.16 per patient.\n\n## Committee considerations\n\nThe Committee recognised that the uncertainties in the economic evidence and cost modelling assumptions were substantial. It was told by the External Assessment Centre that the company had carried out substantive and appropriate sensitivity analyses to address the problem of the poor evidence base.\n\nThe Committee considered that use of the Sherlock\xa03CG\xa0TCS was likely to be cost saving compared with fluoroscopy‑guided PICC insertion, based on the results in both the company's base case and the results of the External Assessment Centre's revised model parameters. The Committee considered the costs presented by the External Assessment Centre to be more realistic, and accepted its estimated cost savings of £106.12 per patient to be reasonable within certain clinical settings. The External Assessment Centre noted at consultation stage that the cost savings presented may be an overestimate in a clinical setting that only uses fluoroscopy‑guided PICC insertion, because of the additional service redesign costs and the need to train staff in bedside insertion. As a result of the substantial variation in clinical settings, and the different training costs which may apply depending on the setting, the exact effect of these changes on the estimated cost saving is unknown.\n\nThe Committee considered the estimated proportion of the patient population for whom ECG tip confirmation was not used, namely those patients in whom it is difficult to identify a P wave. The External Assessment Centre presented the Committee with the full range of unsuccessful tip confirmation rates reported in the clinical evidence, ranging from 4.4% to 29.9%, and noted that varying the figure of 16.5% did not have a substantial impact on the cost modelling. The Committee noted this summary of tip confirmation failure rates, and accepted the value used by the External Assessment Centre (16.5%, Adams et\xa0al. 2013) in the cost modelling as reasonable (see section\xa03.6).\n\nThe Committee considered the evidence presented on the use of the Sherlock\xa03CG\xa0TCS in an intensive care population. It noted input from clinical experts, who confirmed that accurate PICC insertion is more difficult in intensive care patients due to problems with positioning and comorbidities. The External Assessment Centre advised the Committee that the primary driver of cost savings is the relative difference in the accuracy rates between the Sherlock\xa03CG\xa0TCS and bedside insertion. The Committee accepted the estimated cost saving of £41.35 obtained in a scenario analysis using the revised model with parameters from the Johnston et\xa0al. (2013, 2014) studies.\n\nWith regard to the use of the Sherlock\xa03CG\xa0TCS compared with blind insertion with confirmatory X‑rays, the Committee considered that the outputs of the company's model using the External Assessment Centre's updated parameters were appropriate. It was advised that the removal of X‑rays from the care pathway led to increased efficiency of service and an improved patient experience. Depending on the exact clinical context and whether or not it is used with X‑ray, the use of the Sherlock\xa03CG\xa0TCS in adults who need a PICC in a non‑intensive care setting ranged from slightly cost incurring (£24) to slightly cost saving (£26) compared with blind insertion with confirmatory chest X‑ray. These results led the Committee to conclude that the technology was likely to be more or less cost neutral.\n\nFor the guidance review, the External Assessment Centre revised the model to reflect 2019 costs (costs in original guidance given in brackets). The main parameter change was the cost of the Sherlock\xa03CG system: £10,654 (£9,990). Results for the 2019 revised base case showed that the cost saving associated with Sherlock\xa03CG was £109 (£106) when compared with fluoroscopy. In the ICU, use of the Sherlock\xa03CG system compared with blind PICC placement with confirmatory X-ray was cost saving at £54 (£41) per patient. The External Assessment Centre considered the impact of purchasing Sherlock\xa03CG technology incorporated within the Site Rite v8 ultrasound device instead of a separate Sherlock\xa03CG and Site Rite v5. The cost model result was a cost saving of £0.55 per patient. No changes in the clinical pathway are needed to use Site Rite v8. Further details of the 2017 revised model are in the costing review report. ", 'Conclusions': 'The Committee concluded that the available clinical evidence, together with expert clinical advice, showed that the Sherlock\xa03CG Tip Confirmation System (TCS) is an effective method of placement for peripherally inserted central catheters (PICCs). The Committee concluded that the main benefit of the technology for patients who would otherwise have blind insertion is avoidance of a confirmatory chest X‑ray. Patients for whom the Sherlock\xa03CG\xa0TCS was used would not need to make journeys to an X‑ray department, would not be exposed to radiation and their PICC could be used without the associated delay. The Committee was advised by a clinical expert that avoidance of chest X‑rays also saves staff time (porters, nurses and sometimes radiologists). The Committee further concluded that use of the technology increases the confidence of both staff and patients during PICC insertion.\n\nThe Committee accepted modelling using revised parameters and sensitivity analyses and concluded that use of the Sherlock\xa03CG\xa0TCS could generate cost savings of about £106 per patient compared with using fluoroscopy as a guide to PICC insertion. The Committee also accepted the estimate of a cost saving of £41 per patient in an intensive care setting when the Sherlock\xa03CG\xa0TCS and confirmatory chest X‑ray are used in place of blind insertion and confirmatory chest X‑ray. The Committee concluded that in other settings, the cost of using the Sherlock\xa03CG\xa0TCS is similar to that of blind PICC insertion with a subsequent chest X‑ray.Andrew DillonChief ExecutiveDecember 2014'}
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https://www.nice.org.uk/guidance/mtg24
|
Evidence-based recommendations on The Sherlock 3CG Tip Confirmation System for placement of peripherally inserted central catheters.
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74e057c38a44a424366c659f5a5e229a14f39602
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nice
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Therapeutic hypothermia for acute ischaemic stroke
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Therapeutic hypothermia for acute ischaemic stroke
Evidence-based recommendations on therapeutic hypothermia for acute ischaemic stroke in adults. This involves using a cooling device to reduce the body’s temperature after a stroke.
# Recommendations
Current evidence on the safety of therapeutic hypothermia for acute ischaemic stroke shows that there are serious complications. Evidence on efficacy does not show any meaningful improvement in outcomes. Therefore, this procedure should not be used. Find out why NICE recommends not to use some procedures on the NICE interventional procedures guidance page.# The condition, current treatments and procedure
# The condition
Acute ischaemic stroke is characterised by the sudden loss of blood circulation to an area of the brain and a corresponding loss of neurological function. This may lead to symptoms such as numbness or weakness of the face, arm or leg on 1 side of the body, and often problems with speech and swallowing. Stroke severity can be measured using scales such as the National Institutes of Health Stroke scale and the Modified Rankin scale. Broadly, strokes are classified as either haemorrhagic or ischaemic. Acute ischaemic stroke refers to a stroke caused by an arterial thrombosis or embolism. It is more common than haemorrhagic stroke.
# Current treatments
Patients suspected to be having an acute ischaemic stroke should have rapid assessment and early intervention with specialist care according to NICE's guideline on stroke and transient ischaemic attack in over 16s. Recanalisation strategies, such as thrombolysis, attempt to re-establish blood flow so that cells starved of oxygen can be rescued before they are irreversibly damaged. Effective stroke care also includes specialised supportive care and rehabilitation when appropriate.
# The procedure
The timing, duration and degree of therapeutic hypothermia in trials has varied. Typically, however, cooling has been attempted as close to stroke onset as possible (usually within 6 hours) and continued for at least 12 to 24 hours, with body temperature maintained at 33°C to 36°C. This guidance only refers to the use of therapeutic hypothermia and not to other targeted temperature management approaches that treat or prevent pyrexia.
Before the procedure, the patient's temperature is measured and further temperature monitoring is done continuously with an internal (intravesical, rectal or oesophageal) probe connected to the cooling device. Cooling devices can be surface (ice-cold saline, surface cooling, cooling helmets and nasal cooling) or endovascular systems. After cooling, the body is slowly rewarmed, at a rate of 0.25°C to 0.5°C every hour. Rewarming takes about 8 hours. During cooling, patients need close cardiovascular monitoring in an intensive care environment, and may also need intubation and sedation. Drugs, including neuromuscular blockers, may be used to manage shivering.
The procedure may be used with thrombolysis (intravenous alteplase), mechanical thrombectomy or other vascular reperfusion techniques.
The aim of the procedure is to reduce the risk of secondary brain damage.
|
{'Recommendations': 'Current evidence on the safety of therapeutic hypothermia for acute ischaemic stroke shows that there are serious complications. Evidence on efficacy does not show any meaningful improvement in outcomes. Therefore, this procedure should not be used. Find out why NICE recommends not to use some procedures on the NICE interventional procedures guidance page.', 'The condition, current treatments and procedure': "# The condition\n\nAcute ischaemic stroke is characterised by the sudden loss of blood circulation to an area of the brain and a corresponding loss of neurological function. This may lead to symptoms such as numbness or weakness of the face, arm or leg on 1\xa0side of the body, and often problems with speech and swallowing. Stroke severity can be measured using scales such as the National Institutes of Health Stroke scale and the Modified Rankin scale. Broadly, strokes are classified as either haemorrhagic or ischaemic. Acute ischaemic stroke refers to a stroke caused by an arterial thrombosis or embolism. It is more common than haemorrhagic stroke.\n\n# Current treatments\n\nPatients suspected to be having an acute ischaemic stroke should have rapid assessment and early intervention with specialist care according to NICE's guideline on stroke and transient ischaemic attack in over 16s. Recanalisation strategies, such as thrombolysis, attempt to re-establish blood flow so that cells starved of oxygen can be rescued before they are irreversibly damaged. Effective stroke care also includes specialised supportive care and rehabilitation when appropriate.\n\n# The procedure\n\nThe timing, duration and degree of therapeutic hypothermia in trials has varied. Typically, however, cooling has been attempted as close to stroke onset as possible (usually within 6\xa0hours) and continued for at least 12\xa0to 24\xa0hours, with body temperature maintained at 33°C to 36°C. This guidance only refers to the use of therapeutic hypothermia and not to other targeted temperature management approaches that treat or prevent pyrexia.\n\nBefore the procedure, the patient's temperature is measured and further temperature monitoring is done continuously with an internal (intravesical, rectal or oesophageal) probe connected to the cooling device. Cooling devices can be surface (ice-cold saline, surface cooling, cooling helmets and nasal cooling) or endovascular systems. After cooling, the body is slowly rewarmed, at a rate of 0.25°C to 0.5°C every hour. Rewarming takes about 8\xa0hours. During cooling, patients need close cardiovascular monitoring in an intensive care environment, and may also need intubation and sedation. Drugs, including neuromuscular blockers, may be used to manage shivering.\n\nThe procedure may be used with thrombolysis (intravenous alteplase), mechanical thrombectomy or other vascular reperfusion techniques.\n\nThe aim of the procedure is to reduce the risk of secondary brain damage."}
|
https://www.nice.org.uk/guidance/ipg647
|
Evidence-based recommendations on therapeutic hypothermia for acute ischaemic stroke in adults. This involves using a cooling device to reduce the body’s temperature after a stroke.
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8a020e24d3f65043d3254f631ca16cd908b70eea
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nice
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Collagen paste for closing an anal fistula
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Collagen paste for closing an anal fistula
Evidence-based recommendations on collagen paste for closing an anal fistula in adults. This involves using the paste to fill the fistula to seal it. The aim is to encourage healing.
# Recommendations
Current evidence on the safety and efficacy of collagen paste for closing an anal fistula is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should report details of patient selection, the type of fistula treated, how the internal fistula opening was closed, and long-term outcomes including recurrence and the need for reoperation.# The condition, current treatments and procedure
# The condition
An anal fistula is an abnormal tract between the anal canal and the skin around the anus. It usually results from previous anal abscesses (cryptoglandular) and can be associated with other conditions such as inflammatory bowel disease and cancer. It may cause symptoms such as pain or discomfort in the anal area, and leakage of blood or pus. Anal fistulas can be classified according to their relationship with the external sphincter. Intersphincteric fistulas are the most common type and cross only the internal sphincter. Trans-sphincteric fistulas pass through the internal and external sphincter.
# Current treatments
Treatment of anal fistulas usually involves surgery. The type of surgery depends on the location and complexity of the fistula. For intersphincteric and low trans-sphincteric anal fistulas, the most common procedure is a fistulotomy or laying open of the fistula tract. For deeper fistulas that involve more muscle, and for recurrent fistulas, a seton (a piece of suture material or rubber sling) may be used, either alone or with fistulotomy. Setons can be loose (designed to drain the sepsis but not for cure) or snug or tight (designed to cut through the muscles in a slow controlled fashion). Fistulas that cross the external sphincter at a high level are sometimes treated with a mucosal advancement flap or other procedures to close the internal opening. Another option for treating an anal fistula is to fill the tract with a plug or glue.
# The procedure
The use of collagen paste for closing an anal fistula is done using general anaesthesia and with the patient in the lithotomy position. The fistula tract is de-epithelised and granulation tissue is removed, then it is cleaned with dilute hydrogen peroxide followed by saline. A guiding catheter is connected to a syringe containing the paste and the other end is inserted into the external opening of the fistula. The paste is injected into the fistula until it is visible at the internal opening, and then the guiding catheter is slowly withdrawn. The internal opening of the fistula is closed using resorbable stitches. The external opening is partially closed, using resorbable stitches if needed, to allow any inflammatory fluid to drain out without allowing the collagen paste to escape.
The paste fills the exact shape of the tract, which is intended to reduce the risk of it being expelled from the body when defaecating.
It is a less invasive procedure than traditional surgery and the aim is to allow the fistula to heal while preserving sphincter function.
|
{'Recommendations': 'Current evidence on the safety and efficacy of collagen paste for closing an anal fistula is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should report details of patient selection, the type of fistula treated, how the internal fistula opening was closed, and long-term outcomes including recurrence and the need for reoperation.', 'The condition, current treatments and procedure': '# The condition\n\nAn anal fistula is an abnormal tract between the anal canal and the skin around the anus. It usually results from previous anal abscesses (cryptoglandular) and can be associated with other conditions such as inflammatory bowel disease and cancer. It may cause symptoms such as pain or discomfort in the anal area, and leakage of blood or pus. Anal fistulas can be classified according to their relationship with the external sphincter. Intersphincteric fistulas are the most common type and cross only the internal sphincter. Trans-sphincteric fistulas pass through the internal and external sphincter.\n\n# Current treatments\n\nTreatment of anal fistulas usually involves surgery. The type of surgery depends on the location and complexity of the fistula. For intersphincteric and low trans-sphincteric anal fistulas, the most common procedure is a fistulotomy or laying open of the fistula tract. For deeper fistulas that involve more muscle, and for recurrent fistulas, a seton (a piece of suture material or rubber sling) may be used, either alone or with fistulotomy. Setons can be loose (designed to drain the sepsis but not for cure) or snug or tight (designed to cut through the muscles in a slow controlled fashion). Fistulas that cross the external sphincter at a high level are sometimes treated with a mucosal advancement flap or other procedures to close the internal opening. Another option for treating an anal fistula is to fill the tract with a plug or glue.\n\n# The procedure\n\nThe use of collagen paste for closing an anal fistula is done using general anaesthesia and with the patient in the lithotomy position. The fistula tract is de-epithelised and granulation tissue is removed, then it is cleaned with dilute hydrogen peroxide followed by saline. A guiding catheter is connected to a syringe containing the paste and the other end is inserted into the external opening of the fistula. The paste is injected into the fistula until it is visible at the internal opening, and then the guiding catheter is slowly withdrawn. The internal opening of the fistula is closed using resorbable stitches. The external opening is partially closed, using resorbable stitches if needed, to allow any inflammatory fluid to drain out without allowing the collagen paste to escape.\n\nThe paste fills the exact shape of the tract, which is intended to reduce the risk of it being expelled from the body when defaecating.\n\nIt is a less invasive procedure than traditional surgery and the aim is to allow the fistula to heal while preserving sphincter function.'}
|
https://www.nice.org.uk/guidance/ipg648
|
Evidence-based recommendations on collagen paste for closing an anal fistula in adults. This involves using the paste to fill the fistula to seal it. The aim is to encourage healing.
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3b092accd55a0d4f393a3273d0ee5c525a41117d
|
nice
|
Percutaneous mitral valve leaflet repair for mitral regurgitation
|
Percutaneous mitral valve leaflet repair for mitral regurgitation
Evidence-based recommendations on percutaneous mitral valve leaflet repair for mitral regurgitation in adults. This involves attaching a clip to the leaflets of the mitral valve.
# Recommendations
Current evidence on the safety and efficacy of percutaneous mitral valve leaflet repair for mitral regurgitation is adequate to support the use of this procedure, in patients for whom open surgery is contraindicated following risk assessment, provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Patient selection should be done by a multidisciplinary structural heart team, typically including an interventional cardiologist, an expert in transoesophageal echocardiography, an expert in heart failure, a cardiac anaesthetist, a cardiac surgeon and a specialist nurse.
Percutaneous mitral valve leaflet repair for mitral regurgitation should only be done in specialised centres with access to both cardiac surgical and vascular surgical support in case emergency treatment of complications is needed.
This procedure should only be done by clinicians with specialist training and supervision by an experienced mentor for at least the first 20 procedures.
Clinicians should enter details about all patients having percutaneous mitral valve leaflet repair for mitral regurgitation onto the National Institute for Cardiovascular Outcomes Research database.# The condition, current treatments and procedure
# The condition
The mitral valve allows blood to flow from the left atrium to the left ventricle. Mitral valve regurgitation (MR) happens when the valve doesn't close properly, allowing blood to flow back into the atrium from the ventricle during systole. The heart has to work harder, resulting in an enlarged left ventricle. If not treated, this can lead to problems including heart failure.
MR can be degenerative (primary or structural) or functional (secondary). Degenerative MR is caused by 'wear and tear' to the chords and leaflets in the valve. In functional MR the chords and leaflets are structurally normal but there is geometrical distortion of the subvalvular apparatus caused by idiopathic cardiomyopathy, or weakening of the cardiac walls caused by coronary artery disease (ischaemic MR).
# Current treatments
Degenerative MR is treated by surgery to repair or replace the mitral valve. Functional MR can be conservatively managed using drugs for treating heart failure but this is not curative, and surgical options such as undersized annuloplasty may be an option. However, people with MR of either cause are usually older (typically over 70 years) and frail, with multiple comorbidities. This increases the perioperative risks of morbidity and mortality for open heart surgery. For these patients, percutaneous mitral valve leaflet repair (PMVR) may be an appropriate management option.
# The procedure
PMVR is a treatment option for MR if the mitral valve meets the anatomical eligibility criteria for coaption length, coaption depth, flail gap and flail width. The procedure is done using general anaesthesia and transoesophageal echocardiography guidance, with the optional use of fluoroscopy. Access is provided through the femoral vein and an atrial trans-septal puncture is done to reach the mitral valve.
The device is lowered through the mitral valve into the left ventricle. The arms of the device grip the leaflets, bringing them closer together, and the device is released from the delivery system. Adequate reduction of MR is assessed using echocardiography. Sometimes, more than 1 device is needed. After the procedure, patients usually have anti-platelet therapy for 6 months.
|
{'Recommendations': 'Current evidence on the safety and efficacy of percutaneous mitral valve leaflet repair for mitral regurgitation is adequate to support the use of this procedure, in patients for whom open surgery is contraindicated following risk assessment, provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a multidisciplinary structural heart team, typically including an interventional cardiologist, an expert in transoesophageal echocardiography, an expert in heart failure, a cardiac anaesthetist, a cardiac surgeon and a specialist nurse.\n\nPercutaneous mitral valve leaflet repair for mitral regurgitation should only be done in specialised centres with access to both cardiac surgical and vascular surgical support in case emergency treatment of complications is needed.\n\nThis procedure should only be done by clinicians with specialist training and supervision by an experienced mentor for at least the first 20\xa0procedures.\n\nClinicians should enter details about all patients having percutaneous mitral valve leaflet repair for mitral regurgitation onto the National Institute for Cardiovascular Outcomes Research database.', 'The condition, current treatments and procedure': "# The condition\n\nThe mitral valve allows blood to flow from the left atrium to the left ventricle. Mitral valve regurgitation (MR) happens when the valve doesn't close properly, allowing blood to flow back into the atrium from the ventricle during systole. The heart has to work harder, resulting in an enlarged left ventricle. If not treated, this can lead to problems including heart failure.\n\nMR can be degenerative (primary or structural) or functional (secondary). Degenerative MR is caused by 'wear and tear' to the chords and leaflets in the valve. In functional MR the chords and leaflets are structurally normal but there is geometrical distortion of the subvalvular apparatus caused by idiopathic cardiomyopathy, or weakening of the cardiac walls caused by coronary artery disease (ischaemic MR).\n\n# Current treatments\n\nDegenerative MR is treated by surgery to repair or replace the mitral valve. Functional MR can be conservatively managed using drugs for treating heart failure but this is not curative, and surgical options such as undersized annuloplasty may be an option. However, people with MR of either cause are usually older (typically over 70\xa0years) and frail, with multiple comorbidities. This increases the perioperative risks of morbidity and mortality for open heart surgery. For these patients, percutaneous mitral valve leaflet repair (PMVR) may be an appropriate management option.\n\n# The procedure\n\nPMVR is a treatment option for MR if the mitral valve meets the anatomical eligibility criteria for coaption length, coaption depth, flail gap and flail width. The procedure is done using general anaesthesia and transoesophageal echocardiography guidance, with the optional use of fluoroscopy. Access is provided through the femoral vein and an atrial trans-septal puncture is done to reach the mitral valve.\n\nThe device is lowered through the mitral valve into the left ventricle. The arms of the device grip the leaflets, bringing them closer together, and the device is released from the delivery system. Adequate reduction of MR is assessed using echocardiography. Sometimes, more than 1\xa0device is needed. After the procedure, patients usually have anti-platelet therapy for 6\xa0months."}
|
https://www.nice.org.uk/guidance/ipg649
|
Evidence-based recommendations on percutaneous mitral valve leaflet repair for mitral regurgitation in adults. This involves attaching a clip to the leaflets of the mitral valve.
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b2cfba774a3f7cce068980ae26c424a5e334c993
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nice
|
Hyperparathyroidism (primary): diagnosis, assessment and initial management
|
Hyperparathyroidism (primary): diagnosis, assessment and initial management
This guideline covers diagnosing, assessing and managing primary hyperparathyroidism. It aims to improve recognition and treatment of this condition, reducing long‑term complications and improving quality of life.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.
# Diagnostic testing in primary care
## Measuring albumin-adjusted serum calcium
Measure albumin-adjusted serum calcium for people with any of the following features, which might indicate primary hyperparathyroidism:
symptoms of hypercalcaemia, such as thirst, frequent or excessive urination, or constipation
-steoporosis or a previous fragility fracture (for recommendations on assessing the risk of fragility fracture in people with osteoporosis, see the NICE guideline on osteoporosis)
a renal stone (for recommendations on assessing and managing renal stones, see the NICE guideline on renal and ureteric stones)
an incidental finding of elevated albumin-adjusted serum calcium (2.6 mmol/litre or above).
Consider measuring albumin-adjusted serum calcium for people with chronic non-differentiated symptoms.
Do not measure ionised calcium when testing for primary hyperparathyroidism.
Repeat the albumin-adjusted serum calcium measurement at least once if the first measurement is either:
mmol/litre or above or
mmol/litre or above and features of primary hyperparathyroidism are present.Base the decision to carry out further repeat measurements on the level of albumin-adjusted serum calcium and the person's symptoms.
## Measuring parathyroid hormone
Measure parathyroid hormone (PTH) for people whose albumin-adjusted serum calcium level is either:
mmol/litre or above on at least 2 separate occasions or
mmol/litre or above on at least 2 separate occasions and primary hyperparathyroidism is suspected.
When measuring PTH, use a random sample and do a concurrent measurement of the albumin-adjusted serum calcium level.
Do not routinely repeat PTH measurement in primary care.
Seek advice from a specialist with expertise in primary hyperparathyroidism if the person's PTH measurement is either:
above the midpoint of the reference range and primary hyperparathyroidism is suspected or
below the midpoint of the reference range with a concurrent albumin-adjusted serum calcium level of 2.6 mmol/litre or above.
Do not offer further investigations for primary hyperparathyroidism if:
the person's PTH is within the reference range but below the midpoint of the reference range and
their concurrent albumin-adjusted serum calcium level is below 2.6 mmol/litre.
Look for alternative diagnoses, including malignancy, if the person's PTH is below the lower limit of the reference range.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on diagnostic testing in primary care .
Full details of the evidence and the committee's discussion are in evidence review A: indications for diagnostic testing and evidence review B: diagnostic tests.
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# Testing and assessment in secondary care
## Measuring vitamin D
For people with a probable diagnosis of primary hyperparathyroidism, measure vitamin D and offer vitamin D supplements if needed.
## Excluding familial hypocalciuric hypercalcaemia
To differentiate primary hyperparathyroidism from familial hypocalciuric hypercalcaemia, measure urine calcium excretion using any one of the following tests:
-hour urinary calcium excretion
random renal calcium:creatinine excretion ratio
random calcium:creatinine clearance ratio.
## Assessment after diagnosis
For people with a confirmed diagnosis of primary hyperparathyroidism:
assess symptoms and comorbidities
measure eGFR (estimated glomerular filtration rate) or serum creatinine
do a DXA (dual-energy X‑ray absorptiometry) scan of the lumbar spine, distal radius and hip
do an ultrasound scan of the renal tract.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on testing and assessment in secondary care .
Full details of the evidence and the committee's discussion are in evidence review A: indications for diagnostic testing and evidence review B: diagnostic tests.
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# Referral for surgery
Refer people with a confirmed diagnosis of primary hyperparathyroidism to a surgeon with expertise in parathyroid surgery if they have:
symptoms of hypercalcaemia such as thirst, frequent or excessive urination, or constipation or
end-organ disease (renal stones, fragility fractures or osteoporosis) or
an albumin-adjusted serum calcium level of 2.85 mmol/litre or above.
Consider referral to a surgeon with expertise in parathyroid surgery for people with a confirmed diagnosis of primary hyperparathyroidism even if they do not have the features listed in recommendation 1.3.1.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on referral for surgery .
Full details of the evidence and the committee's discussion are in evidence review C: indications for surgery.
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# Surgical management
## Preoperative imaging
Offer preoperative imaging (usually ultrasound) to people having surgery for primary hyperparathyroidism if it will inform the surgical approach.
Consider a second preoperative imaging modality (usually a sestamibi scan) if it will further guide the surgical approach.
Do not offer more preoperative imaging if the first-modality (usually ultrasound) and second-modality scans (usually a sestamibi scan) do not identify an adenoma or are discordant.
Proceed with surgery, performed by a surgeon with expertise in 4‑gland exploration, even if preoperative imaging has not identified an adenoma.
If preoperative imaging shows an ectopic adenoma, refer the person to a centre with the relevant expertise.
## Type of surgery
Offer a choice of either 4‑gland exploration or focused parathyroidectomy to people whose preoperative imaging shows a single adenoma in the neck. Discuss the choice of surgery with the person, and explain:
what happens during each type of surgery
how well each type of surgery works
what types of anaesthesia are used
how long each type of surgery is likely to take
how large the resulting scars are likely to be
the risks of each type of surgery.
Offer 4‑gland exploration to people who have had preoperative imaging that does not identify a single adenoma.
Consider 4‑gland exploration for people having surgery for primary hyperparathyroidism whose first-modality and second-modality scans are discordant.
## Intraoperative PTH monitoring
Do not use intraoperative PTH monitoring in first-time parathyroid surgery.
## Follow-up after surgery
Measure albumin-adjusted serum calcium and PTH before discharge after surgery for primary hyperparathyroidism to provide baseline information for later follow‑up.
Measure albumin-adjusted serum calcium 3 to 6 months after surgery for primary hyperparathyroidism to confirm whether surgery has been successful.
If albumin-adjusted serum calcium is within the reference range 3 to 6 months after surgery for primary hyperparathyroidism, regard the surgery as successful. Monitor albumin-adjusted serum calcium once a year. See the section on monitoring.
For people who have had unsuccessful surgery for primary hyperparathyroidism:
conduct a multidisciplinary team (MDT) review at a specialist centre that includes:
initial findings from surgery
previous imaging and histology
the clinical and biochemical indications for repeat surgery
-ffer monitoring as set out in the section on monitoring.
If repeat surgery is performed for primary hyperparathyroidism, it should be done at a centre with expertise in reoperative parathyroid surgery.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on surgical management .
Full details of the evidence and the committee's discussion are in evidence review D: surgical localisation (for the recommendations on preoperative imaging)
evidence review E: surgical interventions (for the recommendations on type of surgery)
evidence review F: management options in failed primary surgery (for the recommendations on unsuccessful surgery)
evidence review I: monitoring (for the recommendations on follow‑up after surgery).
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# Non-surgical management
## Calcimimetics
In May 2019, the use of cinacalcet after unsuccessful surgery for primary hyperparathyroidism was off label. See NICE's information on prescribing medicines.
Consider cinacalcet for people with primary hyperparathyroidism if surgery has been unsuccessful, is unsuitable or has been declined, and if their albumin-adjusted serum calcium level is either:
mmol/litre or above with symptoms of hypercalcaemia or
mmol/litre or above with or without symptoms of hypercalcaemia.
For people whose initial albumin-adjusted serum calcium level is 2.85 mmol/litre or above with symptoms of hypercalcaemia, base decisions on whether to continue treatment with cinacalcet on how well it reduces symptoms.
For people whose initial albumin-adjusted serum calcium level is 3.0 mmol/litre or above, base decisions on whether to continue treatment with cinacalcet on how well it reduces either symptoms or albumin-adjusted serum calcium level.
## Bisphosphonates
Consider a bisphosphonate to reduce fracture risk for people with primary hyperparathyroidism and increased fracture risk.
Do not offer bisphosphonates for chronic hypercalcaemia of primary hyperparathyroidism.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on non-surgical management .
Full details of the evidence and the committee's discussion are in:
evidence review F: management options in failed primary surgery
evidence review G: calcimimetics
evidence review H: bisphosphonates.
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# Monitoring
Offer monitoring to all people diagnosed with primary hyperparathyroidism, as set out in table 1.
People who have had successful parathyroid surgery
People who have not had parathyroid surgery, or whose surgery has not been successful
Measure albumin-adjusted serum calcium once a year.
Measure albumin-adjusted serum calcium and estimated glomerular filtration rate or serum creatinine once a year, unless the person is taking cinacalcet. (In May 2019, cinacalcet was off label for use after unsuccessful surgery for primary hyperparathyroidism. See NICE's information on prescribing medicines.)
If the person is taking cinacalcet, offer monitoring as set out in the summary of product characteristics.
If the results of monitoring raise concerns, follow the recommendation on repeating the measurement in the section on measuring albumin-adjusted serum calcium.
If the person has osteoporosis, seek specialist opinion according to local pathways on monitoring.
Consider a dual-energy X-ray absorptiometry scan at diagnosis and every 2 to 3 years.
If the results of monitoring raise concerns, follow the recommendation on referring people with features listed in the section on referral for surgery.
If the person has renal stones, seek specialist opinion according to local pathways on monitoring.
Offer ultrasound of the renal tract at diagnosis, when presenting and if a renal stone is suspected (for recommendations on assessing and managing renal stones, see the NICE guideline on renal and ureteric stones).
If the results of monitoring raise concerns, follow the recommendation on referring people with features listed in the section on referral for surgery.
For people who have had parathyroid surgery for multigland disease, or have disease that recurs after successful surgery, seek specialist endocrine opinion on monitoring.
For women who are pregnant, see the section on pregnancy.
For all people with primary hyperparathyroidism, assess cardiovascular risk and fracture risk in line with the NICE guidelines on cardiovascular disease and osteoporosis.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on monitoring .
Full details of the evidence and the committee's discussion are in evidence review F: management options in failed primary surgery and evidence review I: monitoring.
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# Pregnancy
## Care before pregnancy
Offer parathyroid surgery to women who have primary hyperparathyroidism and are considering pregnancy.
## Care during pregnancy
Discuss the management of primary hyperparathyroidism for pregnant women with a MDT in a specialist centre, and refer the woman for specialist care if needed. The MDT should include:
an obstetrician
a physician with expertise in primary hyperparathyroidism
a surgeon
a midwife
an anaesthetist.
Do not offer cinacalcet to pregnant women with primary hyperparathyroidism.
Do not offer a bisphosphonate to pregnant women with primary hyperparathyroidism.
Be aware that women with primary hyperparathyroidism are at increased risk of hypertensive disease in pregnancy. For recommendations on diagnosing and managing hypertension in pregnant women, see the NICE guideline on hypertension in pregnancy.
Consult a specialist centre MDT for advice on monitoring for pregnant women with primary hyperparathyroidism.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on pregnancy .
Full details of the evidence and the committee's discussion are in evidence review J: pregnancy.
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# Information and support
Follow the recommendations on enabling people to actively participate in their care in the NICE guideline on patient experience in adult NHS services.
Give people with primary hyperparathyroidism information about the condition, including:
what primary hyperparathyroidism is
what the parathyroid glands do
causes of primary hyperparathyroidism
symptoms
diagnosis, including diagnosis if calcium or PTH levels are normal
prognosis
possible effects on daily life
possible long-term effects.
Give people information about treatments for primary hyperparathyroidism that includes:
the surgical and non-surgical treatments that are available
how well the treatments are likely to work
the advantages and disadvantages of each treatment, including possible complications and side effects
why these particular treatments are being offered
why other treatments are not advised.
Give advice on how to reduce the symptoms of primary hyperparathyroidism and prepare for surgery or other treatment, including:
exercise
diet
hydration
pain relief
what to expect after treatment, recovery time and return to daily activities, including return to work.
Discuss ongoing care and monitoring for primary hyperparathyroidism, explaining the type and frequency of monitoring that will be offered and the purpose of each. See the section on monitoring.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information and support .
Full details of the evidence and the committee's discussion are in evidence review K: patient information.
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# Terms used in this guideline
## Advice from a specialist
This may be a referral or a telephone call to a specialist.
## Chronic non-differentiated symptoms
Long-term symptoms that could have a number of different causes. Some of these symptoms are experienced by people with primary hyperparathyroidism, but they can also be symptoms of other conditions. Examples include fatigue, mild confusion, bone, muscle or joint pain, anxiety, depression, irritability, low mood, apathy, insomnia, frequent urination, increased thirst and digestive problems.
## Hypercalcaemia
A high level of calcium in the blood, defined as an albumin-adjusted serum calcium level of 2.6 mmol/litre or above. Although hypercalcaemia often causes few or no symptoms, some people feel unusually thirsty, need to urinate frequently or become constipated.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Bone turnover markers
What is the clinical utility of bone turnover markers in the diagnosis and management of primary hyperparathyroidism?
For a short explanation of why the committee made the recommendation for research, see the rationale on assessment after diagnosis .
Full details of the evidence and the committee's discussion are in evidence review B: diagnostic tests.
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# Management after unsuccessful first surgery
What is the best and most cost-effective management strategy for people whose first surgery for primary hyperparathyroidism is not successful?
For a short explanation of why the committee made the recommendation for research, see the rationale on unsuccessful surgery .
Full details of the evidence and the committee's discussion are in evidence review F: management options in failed primary surgery.
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# Long-term outcomes of different management strategies
What are the long-term outcomes of different management strategies for primary hyperparathyroidism? Which strategies are most cost effective?
For a short explanation of why the committee made the recommendation for research, see the rationale on all people with primary hyperparathyroidism .
Full details of the evidence and the committee's discussion are in evidence review I: monitoring.
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# Managing primary hyperparathyroidism during pregnancy
What are the optimal management strategies for primary hyperparathyroidism during pregnancy?
For a short explanation of why the committee made the recommendation for research, see the rationale on care during pregnancy .
Full details of the evidence and the committee's discussion are in evidence review J: pregnancy.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Diagnostic testing in primary care
Recommendations 1.1.1 to 1.1.10
## Why the committee made the recommendations
Although no evidence was available, the committee are confident, based on their knowledge and experience, that albumin-adjusted serum calcium measurement produces an accurate indication of the amount of calcium that is active in the body. Calcium that is bound to albumin is not active and does not have clinical effects. Adjusting for albumin compensates for this, and allows better identification of the active calcium that may be causing symptoms or signs.
Limited evidence, and the committee's experience, suggest that hypercalcaemia in primary hyperparathyroidism is associated with particular symptoms, notably thirst, frequent or excessive urination, or constipation, and with conditions such as osteoporosis, fragility fractures or renal stones. Diagnostic testing is therefore indicated for people with these symptoms or conditions. However, the committee noted that hypercalcaemia is often asymptomatic and agreed that an incidental finding of elevated albumin-adjusted serum calcium in a person without symptoms should also trigger diagnostic testing.
Noting that people with primary hyperparathyroidism sometimes have chronic non-differentiated symptoms, the committee agreed that diagnostic testing could be considered for people with these symptoms. Examples include fatigue, depression, mild confusion, anxiety, irritability, insomnia or digestive problems. The committee acknowledged that there could be multiple causes for these symptoms and that their association with primary hyperparathyroidism is uncertain.
The committee agreed that ionised calcium should not be measured because point-of-care testing is not subject to the stringency of laboratory testing and the sample has to be handled very quickly, making ionised calcium measurement unreliable.
Because serum calcium levels can vary with changes in blood pH or serum albumin, and the cost of measurement is relatively low, the committee agreed that albumin-adjusted serum calcium should be measured at least twice before moving on to more expensive measurement of parathyroid hormone (PTH).
No evidence was available on measurement of PTH in the diagnosis or assessment of primary hyperparathyroidism. The committee based their recommendations on the normal reference range for albumin-adjusted serum calcium as defined by the Association of Clinical Biochemistry, which is 2.2 to 2.6 mmol/litre, and their own experience.
The committee noted that most people with primary hyperparathyroidism have an albumin-adjusted serum calcium level above 2.6 mmol/litre. However, they also discussed a type of primary hyperparathyroidism that affects a smaller number of people, in which the albumin-adjusted serum calcium level is within the normal range. This is known as 'normocalcaemic primary hyperparathyroidism' and it often goes unrecognised. To address this, the committee added a lower criterion of 2.5 mmol/litre (with clinical suspicion of primary hyperparathyroidism) for PTH measurement.
The committee were in agreement that PTH measurement can be done at any time of day. Although there is a marginal diurnal difference, it is not enough to need adjusting for. They agreed that the PTH measurement needs to be interpreted in the context of a concurrent albumin-adjusted serum calcium measurement. They also agreed that there is no benefit in repeating the PTH measurement in primary care.
The committee noted that PTH levels can vary widely from one individual to another, and that there is uncertainty about the level of PTH at which primary hyperparathyroidism can be ruled out. The reference range for PTH differs between laboratories so the committee were unable to specify numerical PTH thresholds.
The committee agreed, based on their experience, that advice from a specialist with expertise in primary hyperparathyroidism should be sought if:
PTH is above the midpoint of the reference range and primary hyperparathyroidism is suspected, because these features indicate that primary hyperparathyroidism is likely
PTH is below the midpoint of the reference range but albumin-adjusted serum calcium is raised, because this indicates that primary hyperparathyroidism cannot be ruled out.
If PTH is below the midpoint of the reference range and albumin-adjusted serum calcium is not raised, the committee agreed that primary hyperparathyroidism is unlikely.
## How the recommendations might affect practice
The committee expects that these recommendations could lead to a change in practice for some providers. There may be an increased demand for primary care services (such as appointments or blood tests) as a result of increased awareness of symptoms such as thirst, frequent or excessive urination, or constipation. Repeating albumin-adjusted serum calcium measurements will increase the number of such tests but can be expected to reduce the number of PTH tests.
Implementing a standardised sequence of diagnostic tests should lead to more rapid diagnosis, and reduce the need to manage complications of undiagnosed primary hyperparathyroidism such as fractures, renal stones and chronic long-term symptoms.
Return to recommendations
# Testing and assessment in secondary care
Recommendations 1.2.1 to 1.2.3
## Why the committee made the recommendations
No evidence was available on measuring vitamin D to assess primary hyperparathyroidism, so the recommendation is based on the committee's knowledge and experience.
The committee noted that vitamin D deficiency can lead to a rise in PTH level, exacerbate bone disease and increase postoperative risk. It is therefore important to assess and correct vitamin D for people with primary hyperparathyroidism. However, the committee were aware that vitamin D testing is not available to all primary care providers, and that waiting for vitamin D to be measured, and corrected if necessary, before seeking specialist advice could delay diagnosis. They therefore concluded that vitamin D measurement and correction are best carried out in secondary care.
The committee agreed that it is important to exclude familial hypocalciuric hypercalcaemia (FHH) because it needs no operative treatment. Evidence showed that the 3 tests recommended are equally accurate in the diagnosis of FHH. The committee were not able to recommend thresholds for these measurements because the evidence is inconsistent.
The committee agreed that baseline assessment will help to determine optimal management in secondary care. They did not recommend phosphate measurement because improvements in PTH assays have reduced its usefulness.
The committee acknowledged the potential of bone turnover markers to enable earlier and more accurate diagnosis of primary hyperparathyroidism but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation on bone turnover markers.
## How the recommendations might affect practice
Measuring vitamin D in secondary care is expected to be a change in practice for some services. Current practice varies, partly because of the varying availability of vitamin D measurement in primary care. In primary care services where vitamin D measurement is available, vitamin D is being measured and deficiencies corrected before PTH is measured. By standardising practice and reducing delays in diagnostic testing, the committee expects improvements in the diagnosis of primary hyperparathyroidism and more prompt treatment for people with the condition.
Measuring urine calcium excretion in secondary care is current practice.
Return to recommendations
# Referral for surgery
Recommendations 1.3.1 and 1.3.2
## Why the committee made the recommendations
There was no evidence available on surgery compared with non-surgical treatment for people with a confirmed diagnosis of primary hyperparathyroidism and symptoms or other indications for surgery. However, the committee reasoned that the lack of evidence is likely to reflect the broad consensus that surgery is beneficial for these people. The committee also agreed that surgery is cost effective because, although the initial cost is high, it can be expected to result in a cure and eliminate the need for further treatment. It relieves symptoms of hypercalcaemia such as thirst, polyuria and constipation, and can prevent future adverse events such as renal stones and fragility fractures. Non-surgical treatment, such as calcimimetics, is an ongoing cost with no curative benefit.
For people with a confirmed diagnosis of primary hyperparathyroidism but no symptoms or indications for surgery, the committee based their recommendation on limited evidence together with their clinical experience. They noted that surgery has shown benefits for this group. Although specific symptoms of primary hyperparathyroidism are absent, people in this group can experience non-specific symptoms such as fatigue, depression or muscle weakness that affect their quality of life. Furthermore, future decrements in quality of life and events associated with end‑organ damage may occur. Therefore surgery can be considered as a means of resolving non-specific symptoms and avoiding further deterioration in health.
The committee acknowledged the potential of bone turnover markers to help identify people who could benefit from surgery but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation on bone turnover markers.
## How the recommendations might affect practice
The recommendations are broadly in line with current practice. It is uncertain how many additional surgeries will be performed as a result of the recommendation to consider surgery for people without symptoms or signs, but the committee do not anticipate a significant increase in the number of referrals for surgery.
Return to recommendations
# Surgical management
Recommendations 1.4.1 to 1.4.14
## Why the committee made the recommendations
There was limited evidence on preoperative imaging so the committee also used their clinical knowledge and experience to make the recommendations. They agreed that the purpose of preoperative imaging is to help guide the surgical approach. It is not essential in all circumstances (for example, if a decision has already been made to perform 4‑gland exploration).
Evidence suggested that ultrasound scanning is accurate in identifying abnormal parathyroid tissue. Ultrasound scanning is widely available, safe and does not involve any exposure to radiation. However, the committee noted that the accuracy of ultrasound depends on the expertise of the person performing it. They therefore recommended sestamibi as an alternative.
Although dual scanning using 2 different imaging modalities has the advantage of providing both anatomical and functional information, the committee agreed that a second imaging modality is only needed if it will further inform the surgical approach. Evidence suggests that sestamibi scanning is accurate in detecting single-gland disease. The committee did not make a recommendation on 4D CT scanning because there was no evidence available.
The committee agreed that if dual scanning fails to identify an adenoma or is discordant, further imaging will not add useful information and will expose the person to unnecessary radiation. They acknowledged that preoperative imaging does not detect all adenomas, so 4‑gland exploration should be offered if preoperative imaging does not identify an adenoma.
The committee agreed that, based on their experience, people whose preoperative imaging does not identify a single adenoma will more frequently have multigland disease and will benefit from 4‑gland exploration. If the first-modality and second-modality scans are discordant, 4‑gland exploration can be considered because the specific anatomical location of the adenoma cannot be assured.
For people with a single adenoma, a small amount of evidence shows that both focused parathyroidectomy and 4‑gland exploration are safe and effective. The committee agreed that focused parathyroidectomy offers the potential advantages of lower temporary hypocalcaemia, a shorter surgery time and minor cosmetic benefit. However, it also carries a marginally (around 5%) higher chance of recurrence or persistent disease. They therefore agreed that people with a single adenoma should be offered a choice of focused parathyroidectomy or 4‑gland exploration, and that the possible benefits and risks of each type of surgery should be discussed with them.
There was limited evidence on intraoperative PTH (IOPTH) monitoring. The committee noted that in their experience, there is a marginal benefit with the use of IOPTH, but this could be partially attributed to surgical expertise.
IOPTH monitoring is costly and its effectiveness in improving surgical outcomes is uncertain. The committee agreed that their experience together with the limited evidence did not support IOPTH monitoring as part of standard practice.
Based on their knowledge and experience, the committee agreed that people who have had parathyroid surgery can be considered biochemically cured if their albumin-adjusted serum calcium and PTH levels are within the reference range before discharge after surgery and their albumin-adjusted serum calcium level is within the reference range 3 to 6 months after surgery.
The committee acknowledged the potential of bone turnover markers to check bone health after surgery for primary hyperparathyroidism but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation on bone turnover markers.
There was no evidence on further surgical management for people who have had unsuccessful first surgery, and very limited evidence on drug therapy with cinacalcet compared with placebo. The committee agreed that input from a multidisciplinary team at a specialist centre should be sought, noting that repeat parathyroid surgery is relatively uncommon, failure rates are higher than in first surgery and it carries a higher risk. They also made a research recommendation on management after unsuccessful first surgery.
## How the recommendations might affect practice
The recommendations for preoperative imaging largely reflect current practice. However, there is variation in the number and type of preoperative tests carried out and the resulting course of action. The committee thought that the recommendations will necessitate changes in practice for some providers. They noted that using a maximum of 2 imaging modalities before surgery would change practice in centres that currently use more than 2 imaging modalities.
Although not widely used, IOPTH testing is most likely to be found in larger centres that are undertaking parathyroidectomies most frequently. The recommendation is expected to lead to changes in practice in these centres.
The recommendations on type of surgery are considered to generally reflect current practice. However, in some centres, current practice is not to offer surgery to people if no adenoma is identified on imaging. These recommendations will therefore necessitate changes in practice for some providers.
The recommendations on follow‑up after surgery reflect current practice in most NHS centres, so the committee thought that there would be little change in practice.
The recommendations on unsuccessful surgery are current practice in many areas.
Return to recommendations
# Non-surgical management
Recommendations 1.5.1 to 1.5.5
## Why the committee made the recommendations
Cinacalcet is the only calcimimetic for which evidence was available. The committee noted that cinacalcet does not directly stop kidney problems or bone loss caused by primary hyperparathyroidism, and that surgery is the only definitive treatment for primary hyperparathyroidism.
Based on the evidence and their experience, the committee agreed that treatment with cinacalcet could be considered for the purpose of reducing symptoms and lowering the risk of a hypercalcaemic crisis for people who have not had surgery and those for whom surgery has not been successful. The committee agreed that, in their experience, cinacalcet can improve quality of life for people with symptoms of hypercalcaemia and an albumin-adjusted serum calcium level of 2.85 mmol/litre or above. For people with an albumin-adjusted serum calcium level of 3.0 mmol/litre or above, who are more at risk of hypercalcaemic crises, cinacalcet can both improve quality of life and help to prevent hypercalcaemic crises.
The committee agreed that treatment-related changes in serum calcium should be managed by basing initiation and continuation of treatment on albumin-adjusted serum calcium level and symptoms. They also agreed that treatment with cinacalcet should be continued if it produces a decrease in albumin-adjusted serum calcium or an improvement in symptoms, because discontinuation is likely to reverse these improvements. The committee noted that there is no evidence for and little likelihood of benefit from cinacalcet for people with normal calcium levels and no symptoms.
There was evidence showing that bisphosphonate treatment improves lumbar spine bone mineral density for people with primary hyperparathyroidism. The committee based the recommendation on the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.
Based on the evidence and their clinical experience, the committee agreed that bisphosphonates should not be offered to reduce hypercalcaemia in the long term.
## How the recommendations might affect practice
These recommendations are considered to be current practice in many areas, and are not expected to lead to major changes in practice.
Return to recommendations
# Monitoring
Recommendation 1.6.1
## Why the committee made the recommendations
Based on their knowledge and experience, the committee agreed that the risk of recurrent disease after successful parathyroid surgery is very low and therefore it is sufficient to monitor albumin-adjusted serum calcium levels once a year.
For people who have osteoporosis, although bone density improves after surgery, skeletal recovery can take some time and needs specialist monitoring. The risk of renal stones decreases after successful surgery, but the residual risk persists and the committee agreed that specialist opinion on monitoring should be sought.
Based on their clinical experience, the committee agreed that monitoring for people who have had unsuccessful surgery should be the same as for people who have had no previous surgery. Monitoring bridges the gap between first surgery and multidisciplinary review and reassessment in a specialist centre.
The committee noted the increased risk of renal stones and fractures in people who have had unsuccessful or no parathyroid surgery. Evidence suggests that around one‑third of people who do not have symptoms or indications for surgery will go on to develop these. The committee agreed that monitoring will ensure that surgery, including repeat surgery, can be offered when needed.
The committee agreed that people with multigland disease, or disease that has recurred after successful surgery, have a slightly increased risk of future recurrence and will benefit from specialist endocrine opinion on monitoring.
For all people with primary hyperparathyroidism, the committee agreed that there was no evidence to suggest that surgery modifies cardiovascular disease risk or fracture risk, so these should be assessed in line with NICE guidance.
The committee noted the limited evidence on long-term outcomes and made a research recommendation on long-term outcomes of different management strategies.
## How the recommendations might affect practice
The recommendations reflect current practice in most NHS centres, so the committee expects little change in practice.
Return to recommendations
# Pregnancy
Recommendations 1.7.1 to 1.7.6
## Why the committee made the recommendations
The committee noted that having surgery for primary hyperparathyroidism before becoming pregnant allows women to start their pregnancy with a normal serum calcium level, which reduces their risk of pregnancy-associated complications of primary hyperparathyroidism. They noted that the risk of stillbirth and neonatal tetany increases with a serum calcium level above 2.85 mmol/litre.
Based on their experience, the committee agreed that management of primary hyperparathyroidism during pregnancy should be discussed with a multidisciplinary team (MDT) because of the high risk of maternal and neonatal complications.
The safety and efficacy of cinacalcet for pregnant women is largely unknown, so the committee agreed that cinacalcet should not be offered during pregnancy. They also agreed that bisphosphonates are potentially harmful for the mother and the fetus.
There was no evidence on monitoring for pregnant women. The committee agreed that monitoring should be guided by a specialist centre MDT because of the risk of maternal or fetal complications. They also highlighted primary hyperparathyroidism as a risk factor for pre‑eclampsia and hypertension.
There was little overall evidence so the committee made a research recommendation on managing primary hyperparathyroidism during pregnancy.
## How the recommendations might affect practice
The recommendations made for women who are pregnant or considering pregnancy might change practice in some areas. However, this is a small population so they are not expected to have a substantial impact on practice.
Return to recommendations
# Information and support
Recommendations 1.8.1 to 1.8.5
## Why the committee made the recommendations
No evidence was found so the committee based the recommendations on their knowledge and experience. The committee agreed that primary hyperparathyroidism is an under-recognised condition among both the general population and healthcare professionals. They emphasised the importance of accurate, balanced and up-to-date information so that people with the condition can understand it and make informed choices, particularly with regard to surgery.
## How the recommendations might affect practice
The recommendations broadly reflect current practice. They focus on the information and support that should be given rather than on specific interventions and therefore are not expected to change practice.
Return to recommendations# Context
Primary hyperparathyroidism is a disorder of one or more of the parathyroid glands. The parathyroid gland becomes overactive and secretes excess amounts of parathyroid hormone, causing hypercalcaemia, hypophosphataemia and hypercalciuria. The most common cause of primary hyperparathyroidism is a non-cancerous tumour (an adenoma) in one of the parathyroid glands.
Primary hyperparathyroidism is one of the leading causes of hypercalcaemia and one of the most common endocrine disorders. About 1 to 4 people per 1,000 are known to have the condition. Women are twice as likely to develop primary hyperparathyroidism as men. It can develop at any age, but in women in the UK, it is most often diagnosed between the ages of 50 and 60.
The signs and symptoms of primary hyperparathyroidism are predominantly brought about by hypercalcaemia and include thirst and increased urine output, gastrointestinal symptoms such as constipation, and effects on the central nervous system such as fatigue and memory impairment. Long-term effects include kidney stones, bone-related complications such as osteoporosis and fractures, and cardiovascular disease.
This guideline provides recommendations on recognition, diagnosis and management of primary hyperparathyroidism. It offers advice for primary care professionals on initial diagnostic testing. It also provides guidance for secondary care professionals on indications for surgery, preoperative imaging, types of surgery and follow‑up care after surgery.# Finding more information and resources
You can see everything NICE says on primary hyperparathyroidism in the NICE Pathway on primary hyperparathyroidism.
To find out what NICE has said on topics related to this guideline, see NICE's webpage on thyroid disorders.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.
ISBN: 978-1-4731-3415-7
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.\n\n# Diagnostic testing in primary care\n\n## Measuring albumin-adjusted serum calcium\n\nMeasure albumin-adjusted serum calcium for people with any of the following features, which might indicate primary hyperparathyroidism:\n\nsymptoms of hypercalcaemia, such as thirst, frequent or excessive urination, or constipation\n\nosteoporosis or a previous fragility fracture (for recommendations on assessing the risk of fragility fracture in people with osteoporosis, see the NICE guideline on osteoporosis)\n\na renal stone (for recommendations on assessing and managing renal stones, see the NICE guideline on renal and ureteric stones)\n\nan incidental finding of elevated albumin-adjusted serum calcium (2.6\xa0mmol/litre or above).\n\nConsider measuring albumin-adjusted serum calcium for people with chronic non-differentiated symptoms.\n\nDo not measure ionised calcium when testing for primary hyperparathyroidism.\n\nRepeat the albumin-adjusted serum calcium measurement at least once if the first measurement is either:\n\nmmol/litre or above or\n\nmmol/litre or above and features of primary hyperparathyroidism are present.Base the decision to carry out further repeat measurements on the level of albumin-adjusted serum calcium and the person's symptoms.\n\n## Measuring parathyroid hormone\n\nMeasure parathyroid hormone (PTH) for people whose albumin-adjusted serum calcium level is either:\n\nmmol/litre or above on at least 2\xa0separate occasions or\n\nmmol/litre or above on at least 2\xa0separate occasions and primary hyperparathyroidism is suspected.\n\nWhen measuring PTH, use a random sample and do a concurrent measurement of the albumin-adjusted serum calcium level.\n\nDo not routinely repeat PTH measurement in primary care.\n\nSeek advice from a specialist with expertise in primary hyperparathyroidism if the person's PTH measurement is either:\n\nabove the midpoint of the reference range and primary hyperparathyroidism is suspected or\n\nbelow the midpoint of the reference range with a concurrent albumin-adjusted serum calcium level of 2.6\xa0mmol/litre or above.\n\nDo not offer further investigations for primary hyperparathyroidism if:\n\nthe person's PTH is within the reference range but below the midpoint of the reference range and\n\ntheir concurrent albumin-adjusted serum calcium level is below 2.6\xa0mmol/litre.\n\nLook for alternative diagnoses, including malignancy, if the person's PTH is below the lower limit of the reference range.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on diagnostic testing in primary care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: indications for diagnostic testing and evidence review\xa0B: diagnostic tests.\n\nLoading. Please wait.\n\n# Testing and assessment in secondary care\n\n## Measuring vitamin\xa0D\n\nFor people with a probable diagnosis of primary hyperparathyroidism, measure vitamin\xa0D and offer vitamin\xa0D supplements if needed.\n\n## Excluding familial hypocalciuric hypercalcaemia\n\nTo differentiate primary hyperparathyroidism from familial hypocalciuric hypercalcaemia, measure urine calcium excretion using any one of the following tests:\n\n-hour urinary calcium excretion\n\nrandom renal calcium:creatinine excretion ratio\n\nrandom calcium:creatinine clearance ratio.\n\n## Assessment after diagnosis\n\nFor people with a confirmed diagnosis of primary hyperparathyroidism:\n\nassess symptoms and comorbidities\n\nmeasure eGFR (estimated glomerular filtration rate) or serum creatinine\n\ndo a DXA (dual-energy X‑ray absorptiometry) scan of the lumbar spine, distal radius and hip\n\ndo an ultrasound scan of the renal tract.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on testing and assessment in secondary care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: indications for diagnostic testing and evidence review\xa0B: diagnostic tests.\n\nLoading. Please wait.\n\n# Referral for surgery\n\nRefer people with a confirmed diagnosis of primary hyperparathyroidism to a surgeon with expertise in parathyroid surgery if they have:\n\nsymptoms of hypercalcaemia such as thirst, frequent or excessive urination, or constipation or\n\nend-organ disease (renal stones, fragility fractures or osteoporosis) or\n\nan albumin-adjusted serum calcium level of 2.85\xa0mmol/litre or above.\n\nConsider referral to a surgeon with expertise in parathyroid surgery for people with a confirmed diagnosis of primary hyperparathyroidism even if they do not have the features listed in recommendation\xa01.3.1.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on referral for surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: indications for surgery.\n\nLoading. Please wait.\n\n# Surgical management\n\n## Preoperative imaging\n\nOffer preoperative imaging (usually ultrasound) to people having surgery for primary hyperparathyroidism if it will inform the surgical approach.\n\nConsider a second preoperative imaging modality (usually a sestamibi scan) if it will further guide the surgical approach.\n\nDo not offer more preoperative imaging if the first-modality (usually ultrasound) and second-modality scans (usually a sestamibi scan) do not identify an adenoma or are discordant.\n\nProceed with surgery, performed by a surgeon with expertise in 4‑gland exploration, even if preoperative imaging has not identified an adenoma.\n\nIf preoperative imaging shows an ectopic adenoma, refer the person to a centre with the relevant expertise.\n\n## Type of surgery\n\nOffer a choice of either 4‑gland exploration or focused parathyroidectomy to people whose preoperative imaging shows a single adenoma in the neck. Discuss the choice of surgery with the person, and explain:\n\nwhat happens during each type of surgery\n\nhow well each type of surgery works\n\nwhat types of anaesthesia are used\n\nhow long each type of surgery is likely to take\n\nhow large the resulting scars are likely to be\n\nthe risks of each type of surgery.\n\nOffer 4‑gland exploration to people who have had preoperative imaging that does not identify a single adenoma.\n\nConsider 4‑gland exploration for people having surgery for primary hyperparathyroidism whose first-modality and second-modality scans are discordant.\n\n## Intraoperative PTH monitoring\n\nDo not use intraoperative PTH monitoring in first-time parathyroid surgery.\n\n## Follow-up after surgery\n\nMeasure albumin-adjusted serum calcium and PTH before discharge after surgery for primary hyperparathyroidism to provide baseline information for later follow‑up.\n\nMeasure albumin-adjusted serum calcium 3\xa0to 6\xa0months after surgery for primary hyperparathyroidism to confirm whether surgery has been successful.\n\nIf albumin-adjusted serum calcium is within the reference range 3\xa0to 6\xa0months after surgery for primary hyperparathyroidism, regard the surgery as successful. Monitor albumin-adjusted serum calcium once a year. See the section on monitoring.\n\nFor people who have had unsuccessful surgery for primary hyperparathyroidism:\n\nconduct a multidisciplinary team (MDT) review at a specialist centre that includes:\n\n\n\ninitial findings from surgery\n\nprevious imaging and histology\n\nthe clinical and biochemical indications for repeat surgery\n\n\n\noffer monitoring as set out in the section on monitoring.\n\nIf repeat surgery is performed for primary hyperparathyroidism, it should be done at a centre with expertise in reoperative parathyroid surgery.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on surgical management\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: surgical localisation (for the recommendations on preoperative imaging)\n\nevidence review\xa0E: surgical interventions (for the recommendations on type of surgery)\n\nevidence review\xa0F: management options in failed primary surgery (for the recommendations on unsuccessful surgery)\n\nevidence review\xa0I: monitoring (for the recommendations on follow‑up after surgery).\n\nLoading. Please wait.\n\n# Non-surgical management\n\n## Calcimimetics\n\nIn May 2019, the use of cinacalcet after unsuccessful surgery for primary hyperparathyroidism was off label. See NICE's information on prescribing medicines.\n\nConsider cinacalcet for people with primary hyperparathyroidism if surgery has been unsuccessful, is unsuitable or has been declined, and if their albumin-adjusted serum calcium level is either:\n\nmmol/litre or above with symptoms of hypercalcaemia or\n\nmmol/litre or above with or without symptoms of hypercalcaemia.\n\nFor people whose initial albumin-adjusted serum calcium level is 2.85\xa0mmol/litre or above with symptoms of hypercalcaemia, base decisions on whether to continue treatment with cinacalcet on how well it reduces symptoms.\n\nFor people whose initial albumin-adjusted serum calcium level is 3.0\xa0mmol/litre or above, base decisions on whether to continue treatment with cinacalcet on how well it reduces either symptoms or albumin-adjusted serum calcium level.\n\n## Bisphosphonates\n\nConsider a bisphosphonate to reduce fracture risk for people with primary hyperparathyroidism and increased fracture risk.\n\nDo not offer bisphosphonates for chronic hypercalcaemia of primary hyperparathyroidism.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on non-surgical management\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0F: management options in failed primary surgery\n\nevidence review\xa0G: calcimimetics\n\nevidence review\xa0H: bisphosphonates.\n\nLoading. Please wait.\n\n# Monitoring\n\nOffer monitoring to all people diagnosed with primary hyperparathyroidism, as set out in table\xa01.\n\nPeople who have had successful parathyroid surgery\n\nPeople who have not had parathyroid surgery, or whose surgery has not been successful\n\nMeasure albumin-adjusted serum calcium once a year.\n\nMeasure albumin-adjusted serum calcium and estimated glomerular filtration rate or serum creatinine once a year, unless the person is taking cinacalcet. (In May 2019, cinacalcet was off label for use after unsuccessful surgery for primary hyperparathyroidism. See NICE's information on prescribing medicines.)\n\n\n\nIf the person is taking cinacalcet, offer monitoring as set out in the summary of product characteristics.\n\nIf the results of monitoring raise concerns, follow the recommendation on repeating the measurement in the section on measuring albumin-adjusted serum calcium.\n\nIf the person has osteoporosis, seek specialist opinion according to local pathways on monitoring.\n\nConsider a dual-energy X-ray absorptiometry scan at diagnosis and every 2\xa0to 3\xa0years.\n\nIf the results of monitoring raise concerns, follow the recommendation on referring people with features listed in the section on referral for surgery.\n\nIf the person has renal stones, seek specialist opinion according to local pathways on monitoring.\n\nOffer ultrasound of the renal tract at diagnosis, when presenting and if a renal stone is suspected (for recommendations on assessing and managing renal stones, see the NICE guideline on renal and ureteric stones).\n\nIf the results of monitoring raise concerns, follow the recommendation on referring people with features listed in the section on referral for surgery.\n\nFor people who have had parathyroid surgery for multigland disease, or have disease that recurs after successful surgery, seek specialist endocrine opinion on monitoring.\n\nFor women who are pregnant, see the section on pregnancy.\n\nFor all people with primary hyperparathyroidism, assess cardiovascular risk and fracture risk in line with the NICE guidelines on cardiovascular disease and osteoporosis.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: management options in failed primary surgery and evidence review\xa0I: monitoring.\n\nLoading. Please wait.\n\n# Pregnancy\n\n## Care before pregnancy\n\nOffer parathyroid surgery to women who have primary hyperparathyroidism and are considering pregnancy.\n\n## Care during pregnancy\n\nDiscuss the management of primary hyperparathyroidism for pregnant women with a MDT in a specialist centre, and refer the woman for specialist care if needed. The MDT should include:\n\nan obstetrician\n\na physician with expertise in primary hyperparathyroidism\n\na surgeon\n\na midwife\n\nan anaesthetist.\n\nDo not offer cinacalcet to pregnant women with primary hyperparathyroidism.\n\nDo not offer a bisphosphonate to pregnant women with primary hyperparathyroidism.\n\nBe aware that women with primary hyperparathyroidism are at increased risk of hypertensive disease in pregnancy. For recommendations on diagnosing and managing hypertension in pregnant women, see the NICE guideline on hypertension in pregnancy.\n\nConsult a specialist centre MDT for advice on monitoring for pregnant women with primary hyperparathyroidism.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: pregnancy.\n\nLoading. Please wait.\n\n# Information and support\n\nFollow the recommendations on enabling people to actively participate in their care in the NICE guideline on patient experience in adult NHS services.\n\nGive people with primary hyperparathyroidism information about the condition, including:\n\nwhat primary hyperparathyroidism is\n\nwhat the parathyroid glands do\n\ncauses of primary hyperparathyroidism\n\nsymptoms\n\ndiagnosis, including diagnosis if calcium or PTH levels are normal\n\nprognosis\n\npossible effects on daily life\n\npossible long-term effects.\n\nGive people information about treatments for primary hyperparathyroidism that includes:\n\nthe surgical and non-surgical treatments that are available\n\nhow well the treatments are likely to work\n\nthe advantages and disadvantages of each treatment, including possible complications and side effects\n\nwhy these particular treatments are being offered\n\nwhy other treatments are not advised.\n\nGive advice on how to reduce the symptoms of primary hyperparathyroidism and prepare for surgery or other treatment, including:\n\nexercise\n\ndiet\n\nhydration\n\npain relief\n\nwhat to expect after treatment, recovery time and return to daily activities, including return to work.\n\nDiscuss ongoing care and monitoring for primary hyperparathyroidism, explaining the type and frequency of monitoring that will be offered and the purpose of each. See the section on monitoring.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: patient information.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Advice from a specialist\n\nThis may be a referral or a telephone call to a specialist.\n\n## Chronic non-differentiated symptoms\n\nLong-term symptoms that could have a number of different causes. Some of these symptoms are experienced by people with primary hyperparathyroidism, but they can also be symptoms of other conditions. Examples include fatigue, mild confusion, bone, muscle or joint pain, anxiety, depression, irritability, low mood, apathy, insomnia, frequent urination, increased thirst and digestive problems.\n\n## Hypercalcaemia\n\nA high level of calcium in the blood, defined as an albumin-adjusted serum calcium level of 2.6\xa0mmol/litre or above. Although hypercalcaemia often causes few or no symptoms, some people feel unusually thirsty, need to urinate frequently or become constipated.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Bone turnover markers\n\nWhat is the clinical utility of bone turnover markers in the diagnosis and management of primary hyperparathyroidism?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on assessment after diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: diagnostic tests.\n\nLoading. Please wait.\n\n# Management after unsuccessful first surgery\n\nWhat is the best and most cost-effective management strategy for people whose first surgery for primary hyperparathyroidism is not successful?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on unsuccessful surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: management options in failed primary surgery.\n\nLoading. Please wait.\n\n# Long-term outcomes of different management strategies\n\nWhat are the long-term outcomes of different management strategies for primary hyperparathyroidism? Which strategies are most cost effective?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on all people with primary hyperparathyroidism\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: monitoring.\n\nLoading. Please wait.\n\n# Managing primary hyperparathyroidism during pregnancy\n\nWhat are the optimal management strategies for primary hyperparathyroidism during pregnancy?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on care during pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: pregnancy.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Diagnostic testing in primary care\n\nRecommendations 1.1.1 to 1.1.10\n\n## Why the committee made the recommendations\n\nAlthough no evidence was available, the committee are confident, based on their knowledge and experience, that albumin-adjusted serum calcium measurement produces an accurate indication of the amount of calcium that is active in the body. Calcium that is bound to albumin is not active and does not have clinical effects. Adjusting for albumin compensates for this, and allows better identification of the active calcium that may be causing symptoms or signs.\n\nLimited evidence, and the committee's experience, suggest that hypercalcaemia in primary hyperparathyroidism is associated with particular symptoms, notably thirst, frequent or excessive urination, or constipation, and with conditions such as osteoporosis, fragility fractures or renal stones. Diagnostic testing is therefore indicated for people with these symptoms or conditions. However, the committee noted that hypercalcaemia is often asymptomatic and agreed that an incidental finding of elevated albumin-adjusted serum calcium in a person without symptoms should also trigger diagnostic testing.\n\nNoting that people with primary hyperparathyroidism sometimes have chronic non-differentiated symptoms, the committee agreed that diagnostic testing could be considered for people with these symptoms. Examples include fatigue, depression, mild confusion, anxiety, irritability, insomnia or digestive problems. The committee acknowledged that there could be multiple causes for these symptoms and that their association with primary hyperparathyroidism is uncertain.\n\nThe committee agreed that ionised calcium should not be measured because point-of-care testing is not subject to the stringency of laboratory testing and the sample has to be handled very quickly, making ionised calcium measurement unreliable.\n\nBecause serum calcium levels can vary with changes in blood pH or serum albumin, and the cost of measurement is relatively low, the committee agreed that albumin-adjusted serum calcium should be measured at least twice before moving on to more expensive measurement of parathyroid hormone (PTH).\n\nNo evidence was available on measurement of PTH in the diagnosis or assessment of primary hyperparathyroidism. The committee based their recommendations on the normal reference range for albumin-adjusted serum calcium as defined by the Association of Clinical Biochemistry, which is 2.2\xa0to 2.6\xa0mmol/litre, and their own experience.\n\nThe committee noted that most people with primary hyperparathyroidism have an albumin-adjusted serum calcium level above 2.6\xa0mmol/litre. However, they also discussed a type of primary hyperparathyroidism that affects a smaller number of people, in which the albumin-adjusted serum calcium level is within the normal range. This is known as 'normocalcaemic primary hyperparathyroidism' and it often goes unrecognised. To address this, the committee added a lower criterion of 2.5\xa0mmol/litre (with clinical suspicion of primary hyperparathyroidism) for PTH measurement.\n\nThe committee were in agreement that PTH measurement can be done at any time of day. Although there is a marginal diurnal difference, it is not enough to need adjusting for. They agreed that the PTH measurement needs to be interpreted in the context of a concurrent albumin-adjusted serum calcium measurement. They also agreed that there is no benefit in repeating the PTH measurement in primary care.\n\nThe committee noted that PTH levels can vary widely from one individual to another, and that there is uncertainty about the level of PTH at which primary hyperparathyroidism can be ruled out. The reference range for PTH differs between laboratories so the committee were unable to specify numerical PTH thresholds.\n\nThe committee agreed, based on their experience, that advice from a specialist with expertise in primary hyperparathyroidism should be sought if:\n\nPTH is above the midpoint of the reference range and primary hyperparathyroidism is suspected, because these features indicate that primary hyperparathyroidism is likely\n\nPTH is below the midpoint of the reference range but albumin-adjusted serum calcium is raised, because this indicates that primary hyperparathyroidism cannot be ruled out.\n\nIf PTH is below the midpoint of the reference range and albumin-adjusted serum calcium is not raised, the committee agreed that primary hyperparathyroidism is unlikely.\n\n## How the recommendations might affect practice\n\nThe committee expects that these recommendations could lead to a change in practice for some providers. There may be an increased demand for primary care services (such as appointments or blood tests) as a result of increased awareness of symptoms such as thirst, frequent or excessive urination, or constipation. Repeating albumin-adjusted serum calcium measurements will increase the number of such tests but can be expected to reduce the number of PTH tests.\n\nImplementing a standardised sequence of diagnostic tests should lead to more rapid diagnosis, and reduce the need to manage complications of undiagnosed primary hyperparathyroidism such as fractures, renal stones and chronic long-term symptoms.\n\nReturn to recommendations\n\n# Testing and assessment in secondary care\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nNo evidence was available on measuring vitamin\xa0D to assess primary hyperparathyroidism, so the recommendation is based on the committee's knowledge and experience.\n\nThe committee noted that vitamin\xa0D deficiency can lead to a rise in PTH level, exacerbate bone disease and increase postoperative risk. It is therefore important to assess and correct vitamin\xa0D for people with primary hyperparathyroidism. However, the committee were aware that vitamin\xa0D testing is not available to all primary care providers, and that waiting for vitamin\xa0D to be measured, and corrected if necessary, before seeking specialist advice could delay diagnosis. They therefore concluded that vitamin\xa0D measurement and correction are best carried out in secondary care.\n\nThe committee agreed that it is important to exclude familial hypocalciuric hypercalcaemia (FHH) because it needs no operative treatment. Evidence showed that the 3\xa0tests recommended are equally accurate in the diagnosis of FHH. The committee were not able to recommend thresholds for these measurements because the evidence is inconsistent.\n\nThe committee agreed that baseline assessment will help to determine optimal management in secondary care. They did not recommend phosphate measurement because improvements in PTH assays have reduced its usefulness.\n\nThe committee acknowledged the potential of bone turnover markers to enable earlier and more accurate diagnosis of primary hyperparathyroidism but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation on bone turnover markers.\n\n## How the recommendations might affect practice\n\nMeasuring vitamin\xa0D in secondary care is expected to be a change in practice for some services. Current practice varies, partly because of the varying availability of vitamin\xa0D measurement in primary care. In primary care services where vitamin\xa0D measurement is available, vitamin\xa0D is being measured and deficiencies corrected before PTH is measured. By standardising practice and reducing delays in diagnostic testing, the committee expects improvements in the diagnosis of primary hyperparathyroidism and more prompt treatment for people with the condition.\n\nMeasuring urine calcium excretion in secondary care is current practice.\n\nReturn to recommendations\n\n# Referral for surgery\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nThere was no evidence available on surgery compared with non-surgical treatment for people with a confirmed diagnosis of primary hyperparathyroidism and symptoms or other indications for surgery. However, the committee reasoned that the lack of evidence is likely to reflect the broad consensus that surgery is beneficial for these people. The committee also agreed that surgery is cost effective because, although the initial cost is high, it can be expected to result in a cure and eliminate the need for further treatment. It relieves symptoms of hypercalcaemia such as thirst, polyuria and constipation, and can prevent future adverse events such as renal stones and fragility fractures. Non-surgical treatment, such as calcimimetics, is an ongoing cost with no curative benefit.\n\nFor people with a confirmed diagnosis of primary hyperparathyroidism but no symptoms or indications for surgery, the committee based their recommendation on limited evidence together with their clinical experience. They noted that surgery has shown benefits for this group. Although specific symptoms of primary hyperparathyroidism are absent, people in this group can experience non-specific symptoms such as fatigue, depression or muscle weakness that affect their quality of life. Furthermore, future decrements in quality of life and events associated with end‑organ damage may occur. Therefore surgery can be considered as a means of resolving non-specific symptoms and avoiding further deterioration in health.\n\nThe committee acknowledged the potential of bone turnover markers to help identify people who could benefit from surgery but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation on bone turnover markers.\n\n## How the recommendations might affect practice\n\nThe recommendations are broadly in line with current practice. It is uncertain how many additional surgeries will be performed as a result of the recommendation to consider surgery for people without symptoms or signs, but the committee do not anticipate a significant increase in the number of referrals for surgery.\n\nReturn to recommendations\n\n# Surgical management\n\nRecommendations 1.4.1 to 1.4.14\n\n## Why the committee made the recommendations\n\nThere was limited evidence on preoperative imaging so the committee also used their clinical knowledge and experience to make the recommendations. They agreed that the purpose of preoperative imaging is to help guide the surgical approach. It is not essential in all circumstances (for example, if a decision has already been made to perform 4‑gland exploration).\n\nEvidence suggested that ultrasound scanning is accurate in identifying abnormal parathyroid tissue. Ultrasound scanning is widely available, safe and does not involve any exposure to radiation. However, the committee noted that the accuracy of ultrasound depends on the expertise of the person performing it. They therefore recommended sestamibi as an alternative.\n\nAlthough dual scanning using 2\xa0different imaging modalities has the advantage of providing both anatomical and functional information, the committee agreed that a second imaging modality is only needed if it will further inform the surgical approach. Evidence suggests that sestamibi scanning is accurate in detecting single-gland disease. The committee did not make a recommendation on 4D\xa0CT scanning because there was no evidence available.\n\nThe committee agreed that if dual scanning fails to identify an adenoma or is discordant, further imaging will not add useful information and will expose the person to unnecessary radiation. They acknowledged that preoperative imaging does not detect all adenomas, so 4‑gland exploration should be offered if preoperative imaging does not identify an adenoma.\n\nThe committee agreed that, based on their experience, people whose preoperative imaging does not identify a single adenoma will more frequently have multigland disease and will benefit from 4‑gland exploration. If the first-modality and second-modality scans are discordant, 4‑gland exploration can be considered because the specific anatomical location of the adenoma cannot be assured.\n\nFor people with a single adenoma, a small amount of evidence shows that both focused parathyroidectomy and 4‑gland exploration are safe and effective. The committee agreed that focused parathyroidectomy offers the potential advantages of lower temporary hypocalcaemia, a shorter surgery time and minor cosmetic benefit. However, it also carries a marginally (around 5%) higher chance of recurrence or persistent disease. They therefore agreed that people with a single adenoma should be offered a choice of focused parathyroidectomy or 4‑gland exploration, and that the possible benefits and risks of each type of surgery should be discussed with them.\n\nThere was limited evidence on intraoperative PTH (IOPTH) monitoring. The committee noted that in their experience, there is a marginal benefit with the use of IOPTH, but this could be partially attributed to surgical expertise.\n\nIOPTH monitoring is costly and its effectiveness in improving surgical outcomes is uncertain. The committee agreed that their experience together with the limited evidence did not support IOPTH monitoring as part of standard practice.\n\nBased on their knowledge and experience, the committee agreed that people who have had parathyroid surgery can be considered biochemically cured if their albumin-adjusted serum calcium and PTH levels are within the reference range before discharge after surgery and their albumin-adjusted serum calcium level is within the reference range 3\xa0to 6\xa0months after surgery.\n\nThe committee acknowledged the potential of bone turnover markers to check bone health after surgery for primary hyperparathyroidism but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation on bone turnover markers.\n\nThere was no evidence on further surgical management for people who have had unsuccessful first surgery, and very limited evidence on drug therapy with cinacalcet compared with placebo. The committee agreed that input from a multidisciplinary team at a specialist centre should be sought, noting that repeat parathyroid surgery is relatively uncommon, failure rates are higher than in first surgery and it carries a higher risk. They also made a research recommendation on management after unsuccessful first surgery.\n\n## How the recommendations might affect practice\n\nThe recommendations for preoperative imaging largely reflect current practice. However, there is variation in the number and type of preoperative tests carried out and the resulting course of action. The committee thought that the recommendations will necessitate changes in practice for some providers. They noted that using a maximum of 2\xa0imaging modalities before surgery would change practice in centres that currently use more than 2\xa0imaging modalities.\n\nAlthough not widely used, IOPTH testing is most likely to be found in larger centres that are undertaking parathyroidectomies most frequently. The recommendation is expected to lead to changes in practice in these centres.\n\nThe recommendations on type of surgery are considered to generally reflect current practice. However, in some centres, current practice is not to offer surgery to people if no adenoma is identified on imaging. These recommendations will therefore necessitate changes in practice for some providers.\n\nThe recommendations on follow‑up after surgery reflect current practice in most NHS centres, so the committee thought that there would be little change in practice.\n\nThe recommendations on unsuccessful surgery are current practice in many areas.\n\nReturn to recommendations\n\n# Non-surgical management\n\nRecommendations 1.5.1 to 1.5.5\n\n## Why the committee made the recommendations\n\nCinacalcet is the only calcimimetic for which evidence was available. The committee noted that cinacalcet does not directly stop kidney problems or bone loss caused by primary hyperparathyroidism, and that surgery is the only definitive treatment for primary hyperparathyroidism.\n\nBased on the evidence and their experience, the committee agreed that treatment with cinacalcet could be considered for the purpose of reducing symptoms and lowering the risk of a hypercalcaemic crisis for people who have not had surgery and those for whom surgery has not been successful. The committee agreed that, in their experience, cinacalcet can improve quality of life for people with symptoms of hypercalcaemia and an albumin-adjusted serum calcium level of 2.85\xa0mmol/litre or above. For people with an albumin-adjusted serum calcium level of 3.0\xa0mmol/litre or above, who are more at risk of hypercalcaemic crises, cinacalcet can both improve quality of life and help to prevent hypercalcaemic crises.\n\nThe committee agreed that treatment-related changes in serum calcium should be managed by basing initiation and continuation of treatment on albumin-adjusted serum calcium level and symptoms. They also agreed that treatment with cinacalcet should be continued if it produces a decrease in albumin-adjusted serum calcium or an improvement in symptoms, because discontinuation is likely to reverse these improvements. The committee noted that there is no evidence for and little likelihood of benefit from cinacalcet for people with normal calcium levels and no symptoms.\n\nThere was evidence showing that bisphosphonate treatment improves lumbar spine bone mineral density for people with primary hyperparathyroidism. The committee based the recommendation on the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.\n\nBased on the evidence and their clinical experience, the committee agreed that bisphosphonates should not be offered to reduce hypercalcaemia in the long term.\n\n## How the recommendations might affect practice\n\nThese recommendations are considered to be current practice in many areas, and are not expected to lead to major changes in practice.\n\nReturn to recommendations\n\n# Monitoring\n\nRecommendation 1.6.1\n\n## Why the committee made the recommendations\n\nBased on their knowledge and experience, the committee agreed that the risk of recurrent disease after successful parathyroid surgery is very low and therefore it is sufficient to monitor albumin-adjusted serum calcium levels once a year.\n\nFor people who have osteoporosis, although bone density improves after surgery, skeletal recovery can take some time and needs specialist monitoring. The risk of renal stones decreases after successful surgery, but the residual risk persists and the committee agreed that specialist opinion on monitoring should be sought.\n\nBased on their clinical experience, the committee agreed that monitoring for people who have had unsuccessful surgery should be the same as for people who have had no previous surgery. Monitoring bridges the gap between first surgery and multidisciplinary review and reassessment in a specialist centre.\n\nThe committee noted the increased risk of renal stones and fractures in people who have had unsuccessful or no parathyroid surgery. Evidence suggests that around one‑third of people who do not have symptoms or indications for surgery will go on to develop these. The committee agreed that monitoring will ensure that surgery, including repeat surgery, can be offered when needed.\n\nThe committee agreed that people with multigland disease, or disease that has recurred after successful surgery, have a slightly increased risk of future recurrence and will benefit from specialist endocrine opinion on monitoring.\n\nFor all people with primary hyperparathyroidism, the committee agreed that there was no evidence to suggest that surgery modifies cardiovascular disease risk or fracture risk, so these should be assessed in line with NICE guidance.\n\nThe committee noted the limited evidence on long-term outcomes and made a research recommendation on long-term outcomes of different management strategies.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice in most NHS centres, so the committee expects little change in practice.\n\nReturn to recommendations\n\n# Pregnancy\n\nRecommendations 1.7.1 to 1.7.6\n\n## Why the committee made the recommendations\n\nThe committee noted that having surgery for primary hyperparathyroidism before becoming pregnant allows women to start their pregnancy with a normal serum calcium level, which reduces their risk of pregnancy-associated complications of primary hyperparathyroidism. They noted that the risk of stillbirth and neonatal tetany increases with a serum calcium level above 2.85\xa0mmol/litre.\n\nBased on their experience, the committee agreed that management of primary hyperparathyroidism during pregnancy should be discussed with a multidisciplinary team (MDT) because of the high risk of maternal and neonatal complications.\n\nThe safety and efficacy of cinacalcet for pregnant women is largely unknown, so the committee agreed that cinacalcet should not be offered during pregnancy. They also agreed that bisphosphonates are potentially harmful for the mother and the fetus.\n\nThere was no evidence on monitoring for pregnant women. The committee agreed that monitoring should be guided by a specialist centre MDT because of the risk of maternal or fetal complications. They also highlighted primary hyperparathyroidism as a risk factor for pre‑eclampsia and hypertension.\n\nThere was little overall evidence so the committee made a research recommendation on managing primary hyperparathyroidism during pregnancy.\n\n## How the recommendations might affect practice\n\nThe recommendations made for women who are pregnant or considering pregnancy might change practice in some areas. However, this is a small population so they are not expected to have a substantial impact on practice.\n\nReturn to recommendations\n\n# Information and support\n\nRecommendations 1.8.1 to 1.8.5\n\n## Why the committee made the recommendations\n\nNo evidence was found so the committee based the recommendations on their knowledge and experience. The committee agreed that primary hyperparathyroidism is an under-recognised condition among both the general population and healthcare professionals. They emphasised the importance of accurate, balanced and up-to-date information so that people with the condition can understand it and make informed choices, particularly with regard to surgery.\n\n## How the recommendations might affect practice\n\nThe recommendations broadly reflect current practice. They focus on the information and support that should be given rather than on specific interventions and therefore are not expected to change practice.\n\nReturn to recommendations", 'Context': 'Primary hyperparathyroidism is a disorder of one or more of the parathyroid glands. The parathyroid gland becomes overactive and secretes excess amounts of parathyroid hormone, causing hypercalcaemia, hypophosphataemia and hypercalciuria. The most common cause of primary hyperparathyroidism is a non-cancerous tumour (an adenoma) in one of the parathyroid glands.\n\nPrimary hyperparathyroidism is one of the leading causes of hypercalcaemia and one of the most common endocrine disorders. About 1\xa0to\xa04\xa0people per\xa01,000 are known to have the condition. Women are twice as likely to develop primary hyperparathyroidism as men. It can develop at any age, but in women in the UK, it is most often diagnosed between the ages of\xa050 and\xa060.\n\nThe signs and symptoms of primary hyperparathyroidism are predominantly brought about by hypercalcaemia and include thirst and increased urine output, gastrointestinal symptoms such as constipation, and effects on the central nervous system such as fatigue and memory impairment. Long-term effects include kidney stones, bone-related complications such as osteoporosis and fractures, and cardiovascular disease.\n\nThis guideline provides recommendations on recognition, diagnosis and management of primary hyperparathyroidism. It offers advice for primary care professionals on initial diagnostic testing. It also provides guidance for secondary care professionals on indications for surgery, preoperative imaging, types of surgery and follow‑up care after surgery.', 'Finding more information and resources': "You can see everything NICE says on primary hyperparathyroidism in the NICE Pathway on primary hyperparathyroidism.\n\nTo find out what NICE has said on topics related to this guideline, see NICE's webpage on thyroid disorders.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.\n\nISBN: 978-1-4731-3415-7"}
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https://www.nice.org.uk/guidance/ng132
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This guideline covers diagnosing, assessing and managing primary hyperparathyroidism. It aims to improve recognition and treatment of this condition, reducing long‑term complications and improving quality of life.
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7f571b407d13d594acc38d3dcc6637314506701a
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nice
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Enzalutamide for hormone-relapsed non-metastatic prostate cancer
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Enzalutamide for hormone-relapsed non-metastatic prostate cancer
Evidence-based recommendations on enzalutamide (Xtandi) for treating high-risk hormone-relapsed non-metastatic prostate cancer in adults.
# Recommendations
Enzalutamide is not recommended, within its marketing authorisation, for treating high-risk hormone-relapsed non-metastatic prostate cancer in adults.
This recommendation is not intended to affect treatment with enzalutamide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Currently, when prostate cancer no longer responds to hormone treatment (androgen deprivation therapy), but has not yet spread beyond the prostate, the only option is to continue hormone treatment. The company proposes using enzalutamide in this setting.
Clinical trial evidence shows that adding in enzalutamide extends the time until the cancer starts spreading to other parts of the body. But there is no evidence that it increases how long people live.
Cost-effectiveness estimates comparing enzalutamide plus androgen deprivation therapy with androgen deprivation therapy alone are uncertain. This is because:
it is not possible to estimate accurately how long people who take enzalutamide live
the costs and benefits of treatments used after enzalutamide in the economic analysis do not reflect NHS practice.
The estimates are not within the range that NICE usually considers a cost-effective use of NHS resources. Therefore, enzalutamide is not recommended in the NHS for treating hormone-relapsed non-metastatic prostate cancer.# Information about enzalutamide
Marketing authorisation indication
Enzalutamide (Xtandi, Astellas) has a marketing authorisation 'for the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer'.
Dosage in the marketing authorisation
Enzalutamide is administered orally at a dose of 160 mg (4×40 mg soft capsules) daily.
Price
£2,734.67 per 112 capsules (excluding VAT; British national formulary online, accessed December 2018) The daily dose comprises 4 capsules and costs £97.67.
The company has a commercial arrangement which would apply if the technology had been recommended.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Astellas and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Treatment pathway
## The company places enzalutamide earlier in the treatment pathway than existing indications
The committee noted that there are different clinical circumstances in which people with prostate cancer may have treatment. These are broadly defined by whether the cancer is hormone sensitive or hormone relapsed, and whether it has spread (metastasised) or not. This appraisal focuses on enzalutamide for hormone-relapsed non-metastatic prostate cancer. The clinical experts noted that this group is small and becoming smaller. This is because improved, more sensitive, radiographic imaging means that there are fewer people with undetected metastases who would otherwise be labelled as having non-metastatic disease. NICE's technology appraisal guidance on enzalutamide before chemotherapy and on enzalutamide after a docetaxel‑containing regimen already recommend enzalutamide for hormone-relapsed metastatic prostate cancer before and after treatment with docetaxel. This appraisal relates to using enzalutamide at an earlier point in the treatment pathway. The committee noted that NHS England's policy stipulates that either enzalutamide or abiraterone (another antiandrogen) is to be offered only once in the treatment of prostate cancer. Therefore, using enzalutamide at this earlier position in the treatment pathway would mean that neither it nor abiraterone would be an option later (either before or after chemotherapy) once the cancer has metastasised.
# Experience of people with prostate cancer
## Prostate cancer causes few symptoms until metastases occur
Patient experts commented that most people with hormone-relapsed non-metastatic prostate cancer have no or few symptoms. Those who have symptoms experience mainly urinary difficulties. Symptoms increase when metastases develop. For example, bone and visceral metastases may cause pain and visceral metastases may cause site-specific symptoms. The committee noted that patients consider there to be an unmet need for treatments that delay metastasis.
# Clinical management
## Androgen deprivation therapy is the relevant comparator in this appraisal
Androgen deprivation therapy (ADT) has long been the standard of care for treating prostate cancer. The clinical experts explained that ADT is continued throughout the treatment pathway, even when the cancer becomes hormone relapsed. This is because stopping treatment may speed up metastasis. The clinical experts commented that bicalutamide and dexamethasone are sometimes used for hormone-relapsed non-metastatic disease, but that the evidence for their effectiveness is limited. The committee considered ADT to be the standard of care in patients with hormone-relapsed prostate cancer, and the relevant comparator in this appraisal.
## The company's definition of high risk does not closely match what is considered high risk in clinical practice
The company's decision problem focused on the subset of people with hormone-relapsed non-metastatic prostate cancer whose disease is at 'high risk' of metastasis, defined as:
an absolute prostate-specific antigen (PSA) level of 2 ng/millilitre or more
a PSA doubling time of 10 months or less.This definition reflects the inclusion criteria in the key trial for enzalutamide (see section 3.5) and the marketing authorisation. NICE's guideline on prostate cancer: diagnosis and management recommends starting ADT if the PSA doubling time is less than 3 months in the hormone-sensitive setting. The clinical experts commented that, when assessing risk, clinicians take into account PSA doubling time but also other factors such as the age and fitness of patients. They advised that a clinically meaningful PSA doubling time in this setting would be less than 6 months. The committee concluded that clinicians' definition of people with high-risk disease in clinical practice does not closely match the patients the company defined as having high-risk disease. Although this was a source of uncertainty, the committee did not expect it to affect the generalisability of clinical results from 1 group to the other.
# Clinical evidence
## The PROSPER trial provides the main clinical evidence for enzalutamide
The main evidence for enzalutamide came from PROSPER, a double-blind randomised placebo-controlled trial. It included 1,401 patients with high-risk hormone-relapsed non-metastatic cancer, allocated to either enzalutamide plus ADT (n=933) or placebo plus ADT (n=468). The primary outcome was metastasis-free survival, defined as the time to radiographic evidence of metastasis or death, whichever occurred first. Scans were done every 16 weeks, or sooner if metastatic disease was suspected. Secondary outcomes included overall survival, quality of life, time to stopping treatment and safety.
## The population in PROSPER has lower-risk disease but is otherwise similar to patients in the NHS who may have enzalutamide
The clinical experts advised that, apart from the criterion for PSA doubling time (see section 3.4), patients in PROSPER were generally like people who would be offered enzalutamide in the hormone-relapsed non-metastatic setting in clinical practice. The committee noted that some patients had a PSA doubling time greater than 10 months (which the study protocol did not allow), or a serum PSA higher than would be expected in the non-metastatic setting. The ERG commented that few patients did not meet the selection criteria and so were unlikely to have biased the results. The committee concluded that the population in PROSPER was sufficiently generalisable to NHS clinical practice.
## Enzalutamide increases metastasis-free survival
The median metastasis-free survival with enzalutamide was 36.6 months compared with 14.7 months for placebo (hazard ratio 0.29, 95% confidence interval 0.24 to 0.35; p<0.0001) based on the final analysis. The committee agreed that enzalutamide was more effective than placebo at delaying metastasis.
## The overall survival data are immature
The company presented 2 of 3 planned interim analyses of overall survival: the first after 135 deaths (coinciding with the final analysis for metastasis-free survival; see section 3.7), and the second after 285 deaths (about 1 year later). The company stated that it intends to do another interim analysis and a final analysis. The committee appreciated that, in its amended statistical plan, the company planned the final analysis for when 596 deaths had occurred. It agreed that the overall survival data from PROSPER presented by the company were immature and provided too few deaths to detect a statistically significant difference between treatment arms. For example, at the second interim analysis, the median overall survival had not been reached and the hazard ratio between the 2 treatment arms was not statistically significant as predefined (HR 0.83, 95% CI 0.65 to 1.06; p=0.134). In response to consultation, the company agreed that the overall survival data were immature because the study was statistically powered to detect a benefit in metastasis-free survival rather than overall survival. The committee noted this comment but agreed that overall survival was clinically important and key to populating the economic model.
## Enzalutamide has not been shown to prolong life in patients with high-risk hormone-relapsed non-metastatic prostate cancer relative to placebo
The committee noted that the data did not show that enzalutamide plus ADT confers a survival benefit relative to ADT, acknowledging that the hazard ratio should be interpreted with caution because the data violate the proportional hazard assumption. The committee queried whether the lack of survival benefit could be explained by patients in the placebo arm being offered active therapies such as enzalutamide after metastasis and then 'catching up' with those randomised to enzalutamide earlier who had also progressed. The clinical experts stated that there was not enough evidence to comment on this. The committee also queried whether the effect of enzalutamide plus ADT relative to ADT alone decreased towards the end of the trial follow up, having observed that patients initially randomised to enzalutamide were more likely to stop life-extending subsequent therapies. The clinical experts suggested that this was unlikely. The committee concluded that the latest evidence available did not show a survival benefit with enzalutamide relative to placebo for hormone-relapsed non-metastatic prostate cancer. In response to consultation, the company suggested that it was difficult to show a statistically significant benefit in this population because, over time, people may die from causes other than prostate cancer. However, the committee agreed that, in a randomised trial, mortality from causes other than prostate cancer would be similar in both treatment arms. In the absence of new evidence, the committee did not change its conclusions about enzalutamide's survival benefit compared with placebo.
## Enzalutamide may be less effective in terms of overall survival, both absolutely and relatively, when used earlier in the treatment pathway
The committee discussed whether the relative effectiveness of enzalutamide at later points in the treatment pathway could provide insight into its survival benefit in the hormone-relapsed non-metastatic setting. In this setting (see section 3.8), the hazard ratio for overall survival was 0.83 (95% CI 0.65 to 1.06). This compared with hazard ratios later in the treatment pathway (that is, for hormone-relapsed metastatic disease) of 0.76 (95% CI 0.66 to 0.88) in the pre-chemotherapy setting and 0.62 (95% CI 0.52 to 0.73) in the post-chemotherapy setting. Assuming that the hazard ratio of 0.83 was a valid estimate (see section 3.9), the committee queried the differences in absolute benefit with enzalutamide along the treatment pathway. The clinical experts explained that, for hormone-sensitive prostate cancer, there was some evidence that abiraterone and docetaxel may provide greater benefit if used earlier in the pathway, but there was no such evidence for enzalutamide. For hormone-relapsed disease, they highlighted the unclear relationship between the timing of enzalutamide treatment and overall survival. However, they agreed that the absolute benefit with enzalutamide was larger after chemotherapy than before. The committee acknowledged concerns with the validity of the hazard ratio for overall survival (see section 3.8). It agreed that, if enzalutamide does prolong life, the evidence to date suggests that the benefit is lower when offered earlier than later in therapy. The committee concluded that enzalutamide may be less effective with respect to overall survival when used earlier in the treatment pathway, both absolutely and relatively.
## Subsequent treatments in PROSPER confound overall survival
The company presented information on the treatments used after metastasis for each treatment arm in PROSPER. The committee noted that:
Some patients in the enzalutamide plus ADT arm had further treatment with abiraterone and enzalutamide, which would not be available in NHS clinical practice and for which there may be a survival benefit.
Some patients in both arms had treatments not used in the NHS, which may be associated with a survival benefit (for example, sipuleucel-T).
The distribution of subsequent therapies differed between treatment arms after metastasis, with a larger proportion of patients in the enzalutamide arm having no active therapies, and a larger proportion in the placebo arm having enzalutamide, abiraterone and docetaxel.The committee agreed that the subsequent therapies used in PROSPER meant that the relative effectiveness of enzalutamide in clinical practice is unlikely to reflect the reported effect in PROSPER. The committee concluded that the company should have adjusted for the effect of both life-extending subsequent treatments not available in the NHS and of life-extending subsequent treatments available in the NHS but which were used more frequently in PROSPER. In response to consultation, the company maintained that it did not need to adjust for the sequential use of enzalutamide and abiraterone because there was no evidence of a survival benefit. Although the committee accepted this possibility, it remained concerned that the proportion of patients randomised to placebo with ADT who had subsequent therapies differed from the NHS. The committee acknowledged that there is no straightforward method to adjust for this and recognised that it would remain an area of uncertainty, which the company could explore in scenario analyses by varying its assumptions about long-term treatment effects.
# Quality of life
## The relationship between enzalutamide and quality of life is not appropriately modelled
The patient experts explained that they had no problems with any aspect of their quality of life while having enzalutamide over several years. The company presented health-related quality-of-life data from PROSPER measured after 22 months of follow up using various quality-of-life instruments. These included the Brief Pain Inventory, the European Organisation for Research and Treatment of Cancer prostate cancer module (EORTC), Functional Assessment of Cancer Therapy – Prostate (FACT‑P) and the EQ‑5D. The only statistically significant (p<0.05) differences between treatments were detected using the EORTC in hormonal-treatment related symptoms and the FACT‑P social wellbeing instruments. The committee concluded that there was not enough evidence from PROSPER to show that enzalutamide improved quality of life compared with placebo. In response to consultation, the company stated that enzalutamide increased the time until deterioration of quality of life compared with placebo rather than improving quality of life. The committee noted that data from PROSPER supported this, but that the company did not reflect this benefit in its economic model.
# Company's economic model
## The model has a semi-Markov partitioned survival structure
The company developed a semi-Markov partitioned survival model to assess the cost effectiveness of enzalutamide plus ADT compared with ADT alone. The model contained 3 states: hormone-relapsed non-metastatic, hormone-relapsed metastatic and death. The company used a partitioned survival model, informed by data from PROSPER, to model the transition of patients from the non-metastatic to the metastatic state, and from the non-metastatic or metastatic state to death. Within the metastatic state, the company used a Markov model with 3 sub-states (progressed-disease states 1 to 3) to capture disease progression beyond metastasis, and associated treatment options, costs and utilities. To model the transitions of patients within this state, the company used data from other trials, namely PREVAIL (enzalutamide compared with placebo in the pre-chemotherapy metastatic setting) and TAX‑327 (docetaxel compared with mitoxantrone in the metastatic setting).
## The company's model structure introduces additional uncertainty by splitting overall survival
The company chose a model structure in which overall survival needed breaking down into death before or after metastasis to align the data with the model states. However, this increased uncertainty in the model. The company stated that it chose this model structure to reflect clinical practice. The committee considered that the company did not sufficiently justify using a model structure that increased uncertainty. The company provided a scenario analysis using a single overall survival curve; however, this did not use the latest data available on overall survival. The scenario analysis was a useful approximation of the standard 3‑state partitioned survival model. However, the committee considered that the company should have at least validated the output of its model against the 3‑state partitioned survival model commonly used in oncology, and on which NICE's Decision Support Unit provides guidance. The committee concluded that the model structure chosen by the company unnecessarily introduced additional uncertainty to the model's outputs.
## There is no evidence to support that enzalutamide prolongs life before disease metastasises
To model death rates before disease metastasis, the company extrapolated pre-progression survival from PROSPER beyond the follow-up period of the trial. This was based on a few patients who died before metastasis, and the diverging curves translated to a large absolute benefit for enzalutamide compared with ADT. The clinical experts explained that the death rate pre-metastasis was likely to reflect the mortality of the general population because people are unlikely to die from non-metastatic prostate cancer. The committee agreed that the company's modelling of pre-progression survival lacked face validity and was likely to bias results in favour of enzalutamide.
## Post-progression survival is biased
The committee noted that the company's extrapolation of post-metastasis survival did not preserve randomisation in PROSPER because most patients in the ADT arm, but only half of those in the enzalutamide arm, developed metastasis. This introduced selection bias because the extrapolation of the enzalutamide arm was based only on patients whose disease metastasised early (relative to the median time to metastasis), whereas the extrapolation of the ADT was based on almost all patients whose disease metastasised. It also meant that the extrapolation was based on disproportionate numbers at risk between the 2 arms. The committee agreed that this approach divided immature data in inappropriate ways and introduced bias.
## Survival in each progressed-disease state is likely to differ
The company used PROSPER to model the transition from the metastatic state to death. This was constant over time and so the company implicitly assumed that all modelled patients with metastatic disease had the same rate of death before, during and after docetaxel treatment for metastatic disease. The clinical experts advised that this was implausible because they would expect to see a lower death rate in early metastatic disease than after chemotherapy. The company's assumption of equal instead of lower death rates in the early metastatic sub-state disproportionately affected the survival rates of patients having ADT, who moved to the metastatic state faster than those having enzalutamide. The committee concluded that the company's model structure and assumptions biased survival in favour of enzalutamide.
## It is better to use data for overall survival from the second rather than the first interim analysis
The company used results for time to death (overall survival) in its base case from the first of 4 planned analyses to coincide with the final analysis of metastasis-free survival. However, the committee preferred using overall survival from the second interim analysis (see section 3.8) because the data, although immature, were more mature than from the first interim analysis.
## The lack of data on time to metastasis at the time of the second interim analysis of overall survival is a limitation of the modelling
To estimate the time patients spent before their disease metastasised and the time they spent before they died, the company presented 2 scenarios. The first (company's base case) used metastasis-free survival from the final analysis of metastasis-free survival, and overall survival from the first interim analysis of overall survival (which coincided with the final analysis of metastasis-free survival). The second scenario used time to stopping treatment (as a proxy for metastasis-free survival) and overall survival, both from the time of the second interim analysis for overall survival. The ERG commented that it was uncertain how long people stayed on treatment after metastasis. It preferred time to metastasis (only available from the time of the first interim analysis of overall survival) over time to stopping treatment to model the time patients spend before their disease metastasises. The committee agreed with this, also noting that metastasis-free survival was the protocol-defined primary outcome of the trial and reflected the health state in the model. It also recalled that it preferred overall survival from the second interim analysis (see section 3.18). However, the company, in response to consultation, noted that using time to metastasis (from the 1 analysis that analysed it) and overall survival from the second interim analysis meant that time to stopping treatment had to be used to spilt overall survival. This was because it split overall survival into pre- and post-progression survival and because PROSPER did not report time to metastasis at the time of the second interim analysis of overall survival. The committee agreed that this introduced methodological issues. It also meant the timings of the data-cuts constrained the company to forever modelling events from the time of the first interim analysis of overall survival despite ongoing data collection. The committee considered this to be irrational. It maintained its preferences for time to metastasis to model the time patients spent before their disease metastasises, and for the most mature overall survival data to model the time people spend alive. However, it appreciated the limitations of its preferences. These arose from the lack of time to metastasis data from the time of the second interim analysis of overall survival, and from having to use time to stopping treatment to split overall survival into pre- and post-progression survival.
## The company's modelled output does not match what occurred in PROSPER
The company used the survival data from the first interim analysis to generate a model, which showed that the rate of death in the ADT arm differed from, and increased more quickly than, that in the enzalutamide arm. This meant that the relative effectiveness of the treatments in the enzalutamide arm on overall survival continued to improve over time (the hazard ratio decreased). This modelled survival did not correspond with the latest data for overall survival seen in PROSPER, which showed no survival benefit (see section 3.8). The ERG used data for overall survival from the second interim analysis. This resulted in the relative effectiveness for survival of the treatments in the enzalutamide arm improving for up to 8.7 years (hazard ratio decreasing), then waning over the following 8.0 years (hazard ratio increasing to 1) and then reversing (hazard ratio greater than 1). The committee appreciated that, although this was a more reasonable assumption than the company's, it still did not reflect the observed data. It concluded that there was a disconnect between observed and modelled overall survival in both the company's and ERG's models.
# Treatment sequence in the economic model
## The economic model should include cabazitaxel and radium‑223
The company modelled a treatment sequence based on what the company's clinical expert expected in NHS clinical practice, and applied costs to these treatments. This assumed that everyone starting on enzalutamide had ADT after developing metastases (progressed-disease state 1, see section 3.12) and vice versa. In progressed-disease state 2, 40% of people in both arms of the model had docetaxel and 60% had ADT alone. In progressed-disease state 3, everyone in both arms had best supportive care (which included ADT). The committee discussed the sequence of treatments that best reflected NHS practice, appreciating that:
enzalutamide would be continued for longer in clinical practice than it was in PROSPER because radiographic progression to determine metastasis is not measured as frequently in clinical practice as it was in PROSPER, and because clinicians may offer treatment beyond metastasis in certain clinical circumstances
abiraterone and enzalutamide are used in approximately equal proportions in the pre-docetaxel setting (corresponding to the modelled progressed-disease state 1)
clinical experts consider that more than 40% of patients will be fit enough to have docetaxel when symptoms appear
about 20% of patients who have treatment in the post-docetaxel setting have cabazitaxel
radium‑223 is considered for patients with bone metastatic disease and is used only with ADT.The committee agreed that enzalutamide is likely to be continued for longer in practice than in the trial, which would increase the cost of treatment. However, it considered that it was inappropriate to include the cost of enzalutamide based on a longer treatment. This was because longer treatment might also be associated with higher effectiveness, which would be difficult to model. In general, the committee concluded that an appropriate treatment sequence should have included cabazitaxel and radium‑223.
## The modelled sequence of treatments does not match the observed sequence of treatments in PROSPER
The committee appreciated that the company modelled the costs of treatments for patients with metastatic disease. However, the therapies for metastatic disease as modelled do not reflect what happened in PROSPER. For example, only 11% of patients with progressed disease in placebo arm of PROSPER had enzalutamide at follow up, compared with 100% in the economic model. The committee concluded that dissociating costs and effectiveness in the economic model biased the estimates of cost effectiveness in favour of enzalutamide.
# Treatment duration in the economic model
## For people having enzalutamide, the time spent in the first progressed-disease state is unlikely to be as long as that modelled by the company
In its base case, the company assumed that patients whose cancer metastasised having had enzalutamide would remain in the first progressed-disease state (pre-chemotherapy) for 7.3 months, based on the PREVAIL trial (enzalutamide compared with placebo in the pre-chemotherapy metastatic setting). The ERG was concerned that the population of PREVAIL was not generalisable to the population of PROSPER because PROSPER included only patients with a high risk of progression to metastasis at baseline. The clinical experts agreed that 7.3 months was an implausibly long amount of time to have ADT alone in the metastatic state. The ERG proposed a scenario using the time between metastasis and first use of active treatment seen in the enzalutamide arm of PROSPER, which led to a shorter time. The committee agreed with the ERG's approach.
# Utility values in the economic model
## The utility value for the first metastatic progressed-disease state should come from PROSPER
The company used EQ‑5D data collected in PROSPER to inform the utility value in the economic model for the first progressed-disease state. The ERG considered the company's choice of utility value for this state to be lower than expected, considering people have few symptoms. It considered the baseline utility from PREVAIL, which measured utility in the metastatic pre-chemotherapy setting, to be more representative of people at this stage of the disease. The committee acknowledged the uncertainty around the utility estimate for the first metastatic progressed-disease state. However, it considered the utility value derived from PROSPER to be more appropriate because the model then used the same source for both utility and clinical data.
# Costs in the economic model
## The costs of monitoring disease would be the same whether people have enzalutamide plus ADT or ADT alone
The company presented higher monitoring costs for people having ADT alone compared with people on enzalutamide plus ADT within the model. The clinical experts said that the frequency of monitoring would not differ, a conclusion shared by the ERG's clinical expert. The ERG presented a scenario that equalised the monitoring frequencies and costs between both arms. The committee concluded that the ERG's scenario was appropriate.
## The costs of major adverse events are not included appropriately
The committee was concerned that the company's model did not fully reflect the costs of major adverse events. Significant adverse events that occurred substantially more often with enzalutamide than with placebo in the trials included hypertension, memory impairment and major adverse cardiovascular events. The clinical experts also noted that fatigue and osteoporosis are common adverse effects with enzalutamide. The ERG noted that the company did not model costs for memory impairment or explore costs associated with osteoporosis. It was also concerned that the costs of major adverse cardiovascular events were not included appropriately considering the higher incidence of these events in patients having enzalutamide. The company used the costs of non-elective short stays for all major adverse cardiovascular events, but most events were coded as long stays. The company confirmed that it did not include the costs associated with rehabilitation from strokes. The ERG presented a scenario that included the costs of the total distribution of lengths of inpatient stays, which substantially increased the costs of major adverse cardiovascular events. The company agreed with this. The committee concluded that the scenario with increased costs was appropriate.
# Cost-effectiveness estimates
## Enzalutamide plus ADT is not cost effective compared with ADT alone
The committee considered whether enzalutamide would be a cost-effective use of NHS resources for non-metastatic hormone resistant prostate cancer, taking into account the patient access scheme (discount) associated with enzalutamide. The company presented a base-case deterministic incremental cost-effectiveness ratio (ICER) of £28,853 per quality-adjusted life year (QALY) gained. However, this value was uncertain and included several assumptions that the committee considered inappropriate, notably, that enzalutamide prolongs survival when used in non-metastatic disease. The ERG presented a base-case ICER of £56,168 per QALY gained, which included:
using data on overall survival from the second interim analysis (see section 3.17)
modelling less time spent in the first progressed-disease state for patients in the enzalutamide arm (see section 3.22) than modelled by the company
increasing baseline utility in the first progressed-disease state (see section 3.23) compared with the company's value
correcting the company's costs (see section 3.24 and section 3.25).The committee concluded that most of the ERG's changes to the company's model were appropriate. It noted that the ERG's ICERs may even have been low because they did not include the costs of radium‑223 and cabazitaxel. Also, the ERG's model did not reflect the absence of an overall survival benefit for enzalutamide in the trial (see section 3.8). The committee noted that the ERG provided a scenario that included the costs of cabazitaxel and radium‑223, both associated with confidential discounts, which increased the ICERs. The committee reiterated that both the company's and ERG's ICERs were associated with substantial uncertainty. This mainly arose from: the immaturity of the overall survival data; the lack of evidence of a survival benefit or quality-of-life improvement by delaying metastasis; and the disconnect between the costs and benefits of subsequent treatments in the model. Furthermore, splitting survival into before and after metastasis in the model introduced an additional layer of uncertainty. It concluded that enzalutamide could not be recommended as a cost-effective use of NHS resources for hormone-relapsed non-metastatic prostate cancer.
# Other factors
## The health benefits associated with enzalutamide are captured
The company noted that this is the first indication for a drug within the high-risk non-metastatic prostate cancer population. However, the committee agreed that this was not associated with additional gains in health-related quality of life over those already included in the QALY calculations.
|
{'Recommendations': 'Enzalutamide is not recommended, within its marketing authorisation, for treating high-risk hormone-relapsed non-metastatic prostate cancer in adults.\n\nThis recommendation is not intended to affect treatment with enzalutamide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrently, when prostate cancer no longer responds to hormone treatment (androgen deprivation therapy), but has not yet spread beyond the prostate, the only option is to continue hormone treatment. The company proposes using enzalutamide in this setting.\n\nClinical trial evidence shows that adding in enzalutamide extends the time until the cancer starts spreading to other parts of the body. But there is no evidence that it increases how long people live.\n\nCost-effectiveness estimates comparing enzalutamide plus androgen deprivation therapy with androgen deprivation therapy alone are uncertain. This is because:\n\nit is not possible to estimate accurately how long people who take enzalutamide live\n\nthe costs and benefits of treatments used after enzalutamide in the economic analysis do not reflect NHS practice.\n\nThe estimates are not within the range that NICE usually considers a cost-effective use of NHS resources. Therefore, enzalutamide is not recommended in the NHS for treating hormone-relapsed non-metastatic prostate cancer.', 'Information about enzalutamide': "Marketing authorisation indication\n\nEnzalutamide (Xtandi, Astellas) has a marketing authorisation 'for the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer'.\n\nDosage in the marketing authorisation\n\nEnzalutamide is administered orally at a dose of 160\xa0mg (4×40\xa0mg soft capsules) daily.\n\nPrice\n\n£2,734.67 per 112\xa0capsules (excluding VAT; British national formulary online, accessed December 2018) The daily dose comprises 4\xa0capsules and costs £97.67.\n\nThe company has a commercial arrangement which would apply if the technology had been recommended.", 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by Astellas and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## The company places enzalutamide earlier in the treatment pathway than existing indications\n\nThe committee noted that there are different clinical circumstances in which people with prostate cancer may have treatment. These are broadly defined by whether the cancer is hormone sensitive or hormone relapsed, and whether it has spread (metastasised) or not. This appraisal focuses on enzalutamide for hormone-relapsed non-metastatic prostate cancer. The clinical experts noted that this group is small and becoming smaller. This is because improved, more sensitive, radiographic imaging means that there are fewer people with undetected metastases who would otherwise be labelled as having non-metastatic disease. NICE's technology appraisal guidance on enzalutamide before chemotherapy and on enzalutamide after a docetaxel‑containing regimen already recommend enzalutamide for hormone-relapsed metastatic prostate cancer before and after treatment with docetaxel. This appraisal relates to using enzalutamide at an earlier point in the treatment pathway. The committee noted that NHS England's policy stipulates that either enzalutamide or abiraterone (another antiandrogen) is to be offered only once in the treatment of prostate cancer. Therefore, using enzalutamide at this earlier position in the treatment pathway would mean that neither it nor abiraterone would be an option later (either before or after chemotherapy) once the cancer has metastasised.\n\n# Experience of people with prostate cancer\n\n## Prostate cancer causes few symptoms until metastases occur\n\nPatient experts commented that most people with hormone-relapsed non-metastatic prostate cancer have no or few symptoms. Those who have symptoms experience mainly urinary difficulties. Symptoms increase when metastases develop. For example, bone and visceral metastases may cause pain and visceral metastases may cause site-specific symptoms. The committee noted that patients consider there to be an unmet need for treatments that delay metastasis.\n\n# Clinical management\n\n## Androgen deprivation therapy is the relevant comparator in this appraisal\n\nAndrogen deprivation therapy (ADT) has long been the standard of care for treating prostate cancer. The clinical experts explained that ADT is continued throughout the treatment pathway, even when the cancer becomes hormone relapsed. This is because stopping treatment may speed up metastasis. The clinical experts commented that bicalutamide and dexamethasone are sometimes used for hormone-relapsed non-metastatic disease, but that the evidence for their effectiveness is limited. The committee considered ADT to be the standard of care in patients with hormone-relapsed prostate cancer, and the relevant comparator in this appraisal.\n\n## The company's definition of high risk does not closely match what is considered high risk in clinical practice\n\nThe company's decision problem focused on the subset of people with hormone-relapsed non-metastatic prostate cancer whose disease is at 'high risk' of metastasis, defined as:\n\nan absolute prostate-specific antigen (PSA) level of 2\xa0ng/millilitre or more\n\na PSA doubling time of 10\xa0months or less.This definition reflects the inclusion criteria in the key trial for enzalutamide (see section\xa03.5) and the marketing authorisation. NICE's guideline on prostate cancer: diagnosis and management recommends starting ADT if the PSA doubling time is less than 3\xa0months in the hormone-sensitive setting. The clinical experts commented that, when assessing risk, clinicians take into account PSA doubling time but also other factors such as the age and fitness of patients. They advised that a clinically meaningful PSA doubling time in this setting would be less than 6\xa0months. The committee concluded that clinicians' definition of people with high-risk disease in clinical practice does not closely match the patients the company defined as having high-risk disease. Although this was a source of uncertainty, the committee did not expect it to affect the generalisability of clinical results from 1\xa0group to the other.\n\n# Clinical evidence\n\n## The PROSPER trial provides the main clinical evidence for enzalutamide\n\nThe main evidence for enzalutamide came from PROSPER, a double-blind randomised placebo-controlled trial. It included 1,401\xa0patients with high-risk hormone-relapsed non-metastatic cancer, allocated to either enzalutamide plus ADT (n=933) or placebo plus ADT (n=468). The primary outcome was metastasis-free survival, defined as the time to radiographic evidence of metastasis or death, whichever occurred first. Scans were done every 16\xa0weeks, or sooner if metastatic disease was suspected. Secondary outcomes included overall survival, quality of life, time to stopping treatment and safety.\n\n## The population in PROSPER has lower-risk disease but is otherwise similar to patients in the NHS who may have enzalutamide\n\nThe clinical experts advised that, apart from the criterion for PSA doubling time (see section\xa03.4), patients in PROSPER were generally like people who would be offered enzalutamide in the hormone-relapsed non-metastatic setting in clinical practice. The committee noted that some patients had a PSA doubling time greater than 10\xa0months (which the study protocol did not allow), or a serum PSA higher than would be expected in the non-metastatic setting. The ERG commented that few patients did not meet the selection criteria and so were unlikely to have biased the results. The committee concluded that the population in PROSPER was sufficiently generalisable to NHS clinical practice.\n\n## Enzalutamide increases metastasis-free survival\n\nThe median metastasis-free survival with enzalutamide was 36.6\xa0months compared with 14.7\xa0months for placebo (hazard ratio [HR]\xa00.29, 95% confidence interval [CI] 0.24 to 0.35; p<0.0001) based on the final analysis. The committee agreed that enzalutamide was more effective than placebo at delaying metastasis.\n\n## The overall survival data are immature\n\nThe company presented 2\xa0of 3\xa0planned interim analyses of overall survival: the first after 135\xa0deaths (coinciding with the final analysis for metastasis-free survival; see section\xa03.7), and the second after 285\xa0deaths (about 1\xa0year later). The company stated that it intends to do another interim analysis and a final analysis. The committee appreciated that, in its amended statistical plan, the company planned the final analysis for when 596\xa0deaths had occurred. It agreed that the overall survival data from PROSPER presented by the company were immature and provided too few deaths to detect a statistically significant difference between treatment arms. For example, at the second interim analysis, the median overall survival had not been reached and the hazard ratio between the 2\xa0treatment arms was not statistically significant as predefined (HR\xa00.83, 95%\xa0CI 0.65\xa0to\xa01.06; p=0.134). In response to consultation, the company agreed that the overall survival data were immature because the study was statistically powered to detect a benefit in metastasis-free survival rather than overall survival. The committee noted this comment but agreed that overall survival was clinically important and key to populating the economic model.\n\n## Enzalutamide has not been shown to prolong life in patients with high-risk hormone-relapsed non-metastatic prostate cancer relative to placebo\n\nThe committee noted that the data did not show that enzalutamide plus ADT confers a survival benefit relative to ADT, acknowledging that the hazard ratio should be interpreted with caution because the data violate the proportional hazard assumption. The committee queried whether the lack of survival benefit could be explained by patients in the placebo arm being offered active therapies such as enzalutamide after metastasis and then 'catching up' with those randomised to enzalutamide earlier who had also progressed. The clinical experts stated that there was not enough evidence to comment on this. The committee also queried whether the effect of enzalutamide plus ADT relative to ADT alone decreased towards the end of the trial follow up, having observed that patients initially randomised to enzalutamide were more likely to stop life-extending subsequent therapies. The clinical experts suggested that this was unlikely. The committee concluded that the latest evidence available did not show a survival benefit with enzalutamide relative to placebo for hormone-relapsed non-metastatic prostate cancer. In response to consultation, the company suggested that it was difficult to show a statistically significant benefit in this population because, over time, people may die from causes other than prostate cancer. However, the committee agreed that, in a randomised trial, mortality from causes other than prostate cancer would be similar in both treatment arms. In the absence of new evidence, the committee did not change its conclusions about enzalutamide's survival benefit compared with placebo.\n\n## Enzalutamide may be less effective in terms of overall survival, both absolutely and relatively, when used earlier in the treatment pathway\n\nThe committee discussed whether the relative effectiveness of enzalutamide at later points in the treatment pathway could provide insight into its survival benefit in the hormone-relapsed non-metastatic setting. In this setting (see section\xa03.8), the hazard ratio for overall survival was 0.83 (95%\xa0CI 0.65\xa0to\xa01.06). This compared with hazard ratios later in the treatment pathway (that is, for hormone-relapsed metastatic disease) of 0.76 (95%\xa0CI 0.66\xa0to\xa00.88) in the pre-chemotherapy setting and\xa00.62 (95%\xa0CI 0.52\xa0to\xa00.73) in the post-chemotherapy setting. Assuming that the hazard ratio of 0.83 was a valid estimate (see section\xa03.9), the committee queried the differences in absolute benefit with enzalutamide along the treatment pathway. The clinical experts explained that, for hormone-sensitive prostate cancer, there was some evidence that abiraterone and docetaxel may provide greater benefit if used earlier in the pathway, but there was no such evidence for enzalutamide. For hormone-relapsed disease, they highlighted the unclear relationship between the timing of enzalutamide treatment and overall survival. However, they agreed that the absolute benefit with enzalutamide was larger after chemotherapy than before. The committee acknowledged concerns with the validity of the hazard ratio for overall survival (see section\xa03.8). It agreed that, if enzalutamide does prolong life, the evidence to date suggests that the benefit is lower when offered earlier than later in therapy. The committee concluded that enzalutamide may be less effective with respect to overall survival when used earlier in the treatment pathway, both absolutely and relatively.\n\n## Subsequent treatments in PROSPER confound overall survival\n\nThe company presented information on the treatments used after metastasis for each treatment arm in PROSPER. The committee noted that:\n\nSome patients in the enzalutamide plus ADT arm had further treatment with abiraterone and enzalutamide, which would not be available in NHS clinical practice and for which there may be a survival benefit.\n\nSome patients in both arms had treatments not used in the NHS, which may be associated with a survival benefit (for example, sipuleucel-T).\n\nThe distribution of subsequent therapies differed between treatment arms after metastasis, with a larger proportion of patients in the enzalutamide arm having no active therapies, and a larger proportion in the placebo arm having enzalutamide, abiraterone and docetaxel.The committee agreed that the subsequent therapies used in PROSPER meant that the relative effectiveness of enzalutamide in clinical practice is unlikely to reflect the reported effect in PROSPER. The committee concluded that the company should have adjusted for the effect of both life-extending subsequent treatments not available in the NHS and of life-extending subsequent treatments available in the NHS but which were used more frequently in PROSPER. In response to consultation, the company maintained that it did not need to adjust for the sequential use of enzalutamide and abiraterone because there was no evidence of a survival benefit. Although the committee accepted this possibility, it remained concerned that the proportion of patients randomised to placebo with ADT who had subsequent therapies differed from the NHS. The committee acknowledged that there is no straightforward method to adjust for this and recognised that it would remain an area of uncertainty, which the company could explore in scenario analyses by varying its assumptions about long-term treatment effects.\n\n# Quality of life\n\n## The relationship between enzalutamide and quality of life is not appropriately modelled\n\nThe patient experts explained that they had no problems with any aspect of their quality of life while having enzalutamide over several years. The company presented health-related quality-of-life data from PROSPER measured after 22\xa0months of follow up using various quality-of-life instruments. These included the Brief Pain Inventory, the European Organisation for Research and Treatment of Cancer prostate cancer module (EORTC), Functional Assessment of Cancer Therapy – Prostate (FACT‑P) and the EQ‑5D. The only statistically significant (p<0.05) differences between treatments were detected using the EORTC in hormonal-treatment related symptoms and the FACT‑P social wellbeing instruments. The committee concluded that there was not enough evidence from PROSPER to show that enzalutamide improved quality of life compared with placebo. In response to consultation, the company stated that enzalutamide increased the time until deterioration of quality of life compared with placebo rather than improving quality of life. The committee noted that data from PROSPER supported this, but that the company did not reflect this benefit in its economic model.\n\n# Company's economic model\n\n## The model has a semi-Markov partitioned survival structure\n\nThe company developed a semi-Markov partitioned survival model to assess the cost effectiveness of enzalutamide plus ADT compared with ADT alone. The model contained 3\xa0states: hormone-relapsed non-metastatic, hormone-relapsed metastatic and death. The company used a partitioned survival model, informed by data from PROSPER, to model the transition of patients from the non-metastatic to the metastatic state, and from the non-metastatic or metastatic state to death. Within the metastatic state, the company used a Markov model with 3\xa0sub-states (progressed-disease states 1\xa0to\xa03) to capture disease progression beyond metastasis, and associated treatment options, costs and utilities. To model the transitions of patients within this state, the company used data from other trials, namely PREVAIL (enzalutamide compared with placebo in the pre-chemotherapy metastatic setting) and TAX‑327 (docetaxel compared with mitoxantrone in the metastatic setting).\n\n## The company's model structure introduces additional uncertainty by splitting overall survival\n\nThe company chose a model structure in which overall survival needed breaking down into death before or after metastasis to align the data with the model states. However, this increased uncertainty in the model. The company stated that it chose this model structure to reflect clinical practice. The committee considered that the company did not sufficiently justify using a model structure that increased uncertainty. The company provided a scenario analysis using a single overall survival curve; however, this did not use the latest data available on overall survival. The scenario analysis was a useful approximation of the standard 3‑state partitioned survival model. However, the committee considered that the company should have at least validated the output of its model against the 3‑state partitioned survival model commonly used in oncology, and on which NICE's Decision Support Unit provides guidance. The committee concluded that the model structure chosen by the company unnecessarily introduced additional uncertainty to the model's outputs.\n\n## There is no evidence to support that enzalutamide prolongs life before disease metastasises\n\nTo model death rates before disease metastasis, the company extrapolated pre-progression survival from PROSPER beyond the follow-up period of the trial. This was based on a few patients who died before metastasis, and the diverging curves translated to a large absolute benefit for enzalutamide compared with ADT. The clinical experts explained that the death rate pre-metastasis was likely to reflect the mortality of the general population because people are unlikely to die from non-metastatic prostate cancer. The committee agreed that the company's modelling of pre-progression survival lacked face validity and was likely to bias results in favour of enzalutamide.\n\n## Post-progression survival is biased\n\nThe committee noted that the company's extrapolation of post-metastasis survival did not preserve randomisation in PROSPER because most patients in the ADT arm, but only half of those in the enzalutamide arm, developed metastasis. This introduced selection bias because the extrapolation of the enzalutamide arm was based only on patients whose disease metastasised early (relative to the median time to metastasis), whereas the extrapolation of the ADT was based on almost all patients whose disease metastasised. It also meant that the extrapolation was based on disproportionate numbers at risk between the 2\xa0arms. The committee agreed that this approach divided immature data in inappropriate ways and introduced bias.\n\n## Survival in each progressed-disease state is likely to differ\n\nThe company used PROSPER to model the transition from the metastatic state to death. This was constant over time and so the company implicitly assumed that all modelled patients with metastatic disease had the same rate of death before, during and after docetaxel treatment for metastatic disease. The clinical experts advised that this was implausible because they would expect to see a lower death rate in early metastatic disease than after chemotherapy. The company's assumption of equal instead of lower death rates in the early metastatic sub-state disproportionately affected the survival rates of patients having ADT, who moved to the metastatic state faster than those having enzalutamide. The committee concluded that the company's model structure and assumptions biased survival in favour of enzalutamide.\n\n## It is better to use data for overall survival from the second rather than the first interim analysis\n\nThe company used results for time to death (overall survival) in its base case from the first of 4\xa0planned analyses to coincide with the final analysis of metastasis-free survival. However, the committee preferred using overall survival from the second interim analysis (see section\xa03.8) because the data, although immature, were more mature than from the first interim analysis.\n\n## The lack of data on time to metastasis at the time of the second interim analysis of overall survival is a limitation of the modelling\n\nTo estimate the time patients spent before their disease metastasised and the time they spent before they died, the company presented 2\xa0scenarios. The first (company's base case) used metastasis-free survival from the final analysis of metastasis-free survival, and overall survival from the first interim analysis of overall survival (which coincided with the final analysis of metastasis-free survival). The second scenario used time to stopping treatment (as a proxy for metastasis-free survival) and overall survival, both from the time of the second interim analysis for overall survival. The ERG commented that it was uncertain how long people stayed on treatment after metastasis. It preferred time to metastasis (only available from the time of the first interim analysis of overall survival) over time to stopping treatment to model the time patients spend before their disease metastasises. The committee agreed with this, also noting that metastasis-free survival was the protocol-defined primary outcome of the trial and reflected the health state in the model. It also recalled that it preferred overall survival from the second interim analysis (see section\xa03.18). However, the company, in response to consultation, noted that using time to metastasis (from the 1\xa0analysis that analysed it) and overall survival from the second interim analysis meant that time to stopping treatment had to be used to spilt overall survival. This was because it split overall survival into pre- and post-progression survival and because PROSPER did not report time to metastasis at the time of the second interim analysis of overall survival. The committee agreed that this introduced methodological issues. It also meant the timings of the data-cuts constrained the company to forever modelling events from the time of the first interim analysis of overall survival despite ongoing data collection. The committee considered this to be irrational. It maintained its preferences for time to metastasis to model the time patients spent before their disease metastasises, and for the most mature overall survival data to model the time people spend alive. However, it appreciated the limitations of its preferences. These arose from the lack of time to metastasis data from the time of the second interim analysis of overall survival, and from having to use time to stopping treatment to split overall survival into pre- and post-progression survival.\n\n## The company's modelled output does not match what occurred in PROSPER\n\nThe company used the survival data from the first interim analysis to generate a model, which showed that the rate of death in the ADT arm differed from, and increased more quickly than, that in the enzalutamide arm. This meant that the relative effectiveness of the treatments in the enzalutamide arm on overall survival continued to improve over time (the hazard ratio decreased). This modelled survival did not correspond with the latest data for overall survival seen in PROSPER, which showed no survival benefit (see section\xa03.8). The ERG used data for overall survival from the second interim analysis. This resulted in the relative effectiveness for survival of the treatments in the enzalutamide arm improving for up to 8.7\xa0years (hazard ratio decreasing), then waning over the following 8.0\xa0years (hazard ratio increasing to\xa01) and then reversing (hazard ratio greater than\xa01). The committee appreciated that, although this was a more reasonable assumption than the company's, it still did not reflect the observed data. It concluded that there was a disconnect between observed and modelled overall survival in both the company's and ERG's models.\n\n# Treatment sequence in the economic model\n\n## The economic model should include cabazitaxel and radium‑223\n\nThe company modelled a treatment sequence based on what the company's clinical expert expected in NHS clinical practice, and applied costs to these treatments. This assumed that everyone starting on enzalutamide had ADT after developing metastases (progressed-disease state\xa01, see section\xa03.12) and vice versa. In progressed-disease state\xa02, 40% of people in both arms of the model had docetaxel and 60% had ADT alone. In progressed-disease state\xa03, everyone in both arms had best supportive care (which included ADT). The committee discussed the sequence of treatments that best reflected NHS practice, appreciating that:\n\nenzalutamide would be continued for longer in clinical practice than it was in PROSPER because radiographic progression to determine metastasis is not measured as frequently in clinical practice as it was in PROSPER, and because clinicians may offer treatment beyond metastasis in certain clinical circumstances\n\nabiraterone and enzalutamide are used in approximately equal proportions in the pre-docetaxel setting (corresponding to the modelled progressed-disease state\xa01)\n\nclinical experts consider that more than 40% of patients will be fit enough to have docetaxel when symptoms appear\n\nabout 20% of patients who have treatment in the post-docetaxel setting have cabazitaxel\n\nradium‑223 is considered for patients with bone metastatic disease and is used only with ADT.The committee agreed that enzalutamide is likely to be continued for longer in practice than in the trial, which would increase the cost of treatment. However, it considered that it was inappropriate to include the cost of enzalutamide based on a longer treatment. This was because longer treatment might also be associated with higher effectiveness, which would be difficult to model. In general, the committee concluded that an appropriate treatment sequence should have included cabazitaxel and radium‑223.\n\n## The modelled sequence of treatments does not match the observed sequence of treatments in PROSPER\n\nThe committee appreciated that the company modelled the costs of treatments for patients with metastatic disease. However, the therapies for metastatic disease as modelled do not reflect what happened in PROSPER. For example, only 11% of patients with progressed disease in placebo arm of PROSPER had enzalutamide at follow up, compared with 100% in the economic model. The committee concluded that dissociating costs and effectiveness in the economic model biased the estimates of cost effectiveness in favour of enzalutamide.\n\n# Treatment duration in the economic model\n\n## For people having enzalutamide, the time spent in the first progressed-disease state is unlikely to be as long as that modelled by the company\n\nIn its base case, the company assumed that patients whose cancer metastasised having had enzalutamide would remain in the first progressed-disease state (pre-chemotherapy) for 7.3\xa0months, based on the PREVAIL trial (enzalutamide compared with placebo in the pre-chemotherapy metastatic setting). The ERG was concerned that the population of PREVAIL was not generalisable to the population of PROSPER because PROSPER included only patients with a high risk of progression to metastasis at baseline. The clinical experts agreed that 7.3\xa0months was an implausibly long amount of time to have ADT alone in the metastatic state. The ERG proposed a scenario using the time between metastasis and first use of active treatment seen in the enzalutamide arm of PROSPER, which led to a shorter time. The committee agreed with the ERG's approach.\n\n# Utility values in the economic model\n\n## The utility value for the first metastatic progressed-disease state should come from PROSPER\n\nThe company used EQ‑5D data collected in PROSPER to inform the utility value in the economic model for the first progressed-disease state. The ERG considered the company's choice of utility value for this state to be lower than expected, considering people have few symptoms. It considered the baseline utility from PREVAIL, which measured utility in the metastatic pre-chemotherapy setting, to be more representative of people at this stage of the disease. The committee acknowledged the uncertainty around the utility estimate for the first metastatic progressed-disease state. However, it considered the utility value derived from PROSPER to be more appropriate because the model then used the same source for both utility and clinical data.\n\n# Costs in the economic model\n\n## The costs of monitoring disease would be the same whether people have enzalutamide plus ADT or ADT alone\n\nThe company presented higher monitoring costs for people having ADT alone compared with people on enzalutamide plus ADT within the model. The clinical experts said that the frequency of monitoring would not differ, a conclusion shared by the ERG's clinical expert. The ERG presented a scenario that equalised the monitoring frequencies and costs between both arms. The committee concluded that the ERG's scenario was appropriate.\n\n## The costs of major adverse events are not included appropriately\n\nThe committee was concerned that the company's model did not fully reflect the costs of major adverse events. Significant adverse events that occurred substantially more often with enzalutamide than with placebo in the trials included hypertension, memory impairment and major adverse cardiovascular events. The clinical experts also noted that fatigue and osteoporosis are common adverse effects with enzalutamide. The ERG noted that the company did not model costs for memory impairment or explore costs associated with osteoporosis. It was also concerned that the costs of major adverse cardiovascular events were not included appropriately considering the higher incidence of these events in patients having enzalutamide. The company used the costs of non-elective short stays for all major adverse cardiovascular events, but most events were coded as long stays. The company confirmed that it did not include the costs associated with rehabilitation from strokes. The ERG presented a scenario that included the costs of the total distribution of lengths of inpatient stays, which substantially increased the costs of major adverse cardiovascular events. The company agreed with this. The committee concluded that the scenario with increased costs was appropriate.\n\n# Cost-effectiveness estimates\n\n## Enzalutamide plus ADT is not cost effective compared with ADT alone\n\nThe committee considered whether enzalutamide would be a cost-effective use of NHS resources for non-metastatic hormone resistant prostate cancer, taking into account the patient access scheme (discount) associated with enzalutamide. The company presented a base-case deterministic incremental cost-effectiveness ratio (ICER) of £28,853 per quality-adjusted life year (QALY) gained. However, this value was uncertain and included several assumptions that the committee considered inappropriate, notably, that enzalutamide prolongs survival when used in non-metastatic disease. The ERG presented a base-case ICER of £56,168 per QALY gained, which included:\n\nusing data on overall survival from the second interim analysis (see section\xa03.17)\n\nmodelling less time spent in the first progressed-disease state for patients in the enzalutamide arm (see section\xa03.22) than modelled by the company\n\nincreasing baseline utility in the first progressed-disease state (see section\xa03.23) compared with the company's value\n\ncorrecting the company's costs (see section\xa03.24 and\xa0section 3.25).The committee concluded that most of the ERG's changes to the company's model were appropriate. It noted that the ERG's ICERs may even have been low because they did not include the costs of radium‑223 and cabazitaxel. Also, the ERG's model did not reflect the absence of an overall survival benefit for enzalutamide in the trial (see section\xa03.8). The committee noted that the ERG provided a scenario that included the costs of cabazitaxel and radium‑223, both associated with confidential discounts, which increased the ICERs. The committee reiterated that both the company's and ERG's ICERs were associated with substantial uncertainty. This mainly arose from: the immaturity of the overall survival data; the lack of evidence of a survival benefit or quality-of-life improvement by delaying metastasis; and the disconnect between the costs and benefits of subsequent treatments in the model. Furthermore, splitting survival into before and after metastasis in the model introduced an additional layer of uncertainty. It concluded that enzalutamide could not be recommended as a cost-effective use of NHS resources for hormone-relapsed non-metastatic prostate cancer.\n\n# Other factors\n\n## The health benefits associated with enzalutamide are captured\n\nThe company noted that this is the first indication for a drug within the high-risk non-metastatic prostate cancer population. However, the committee agreed that this was not associated with additional gains in health-related quality of life over those already included in the QALY calculations."}
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https://www.nice.org.uk/guidance/ta580
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Evidence-based recommendations on enzalutamide (Xtandi) for treating high-risk hormone-relapsed non-metastatic prostate cancer in adults.
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6c68ab39aa4a2eef88c2f31cdbdb365bac318423
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nice
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Curos for preventing infections when using needleless connectors
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Curos for preventing infections when using needleless connectors
Evidence-based recommendations on Curos for preventing infections when using needleless connectors.
# Recommendations
Curos disinfecting cap shows promise for preventing infections when using needleless connectors, but there is currently insufficient evidence to support the case for routine adoption in the NHS.
Research is therefore recommended to address uncertainties about the clinical benefits of using Curos. This research should:
determine if Curos adds value to the standard bundle of care for preventing infections when using needleless connectors
explore the use of Curos in people at high risk of infection, including those whose condition is managed in the community
clearly define the patient groups included and use consistent outcomes.NICE will facilitate this research, in collaboration with the company, clinical and academic partners, and will update this guidance if or when substantive new evidence becomes available.
Why the committee made these recommendations
Curos is a disinfecting cap which, when placed on the needleless connector at the end of a vascular access line, is intended to reduce the risk of infection. Curos can stay in place for up to 7 days but must be replaced each time the line is used.
Evidence for the clinical effectiveness of Curos is limited. The studies include a wide range of people in different clinical situations and use different definitions of bloodstream infection. It is not clear if Curos would provide any additional benefit to the standard bundle of care for preventing infections. There is also no evidence for its effectiveness in community settings and any cost benefits are uncertain.
Despite these uncertainties, Curos shows promise for preventing infections when using needleless connectors, especially in people at high risk of infection. Because of this, further research on Curos is recommended.# The technology
Technology
The Curos disinfecting cap (3M) is a single-use device which is placed over the needleless connector of vascular access lines. It contains a foam that is impregnated with 70% isopropyl alcohol, which acts as an antiseptic.
The cap can stay in place for up to 7 days, but must be replaced with a new cap if it is removed.
Curos is supplied individually or in strips of 10. It received a class IIa CE mark in September 2016.
Innovative aspects
Curos avoids the need to manually disinfect needleless connectors. The company claims that it differs from technologies with a similar purpose because:
it has a wide spectrum of antimicrobial action
it is easy and convenient to use
its design makes it easier to attach and harder to dislodge
its distinctive green colour avoids confusion with other covers.
Intended use
Curos is twisted onto the end of a needleless connector and should be left in place for at least 1 minute. The company claims that, after 1 minute, the antiseptic will kill 6 microorganisms commonly associated with bloodstream infections.
Curos would be used as part of a bundle of care for preventing infections when using vascular access lines. It is intended to replace the use of alcohol wipes or solution.
The company provides online training videos for staff using Curos, and further training if needed.
Costs
The unit cost of a Curos cap in the company's submission is £0.32 (including VAT).
For more details, see the website for Curos disinfecting caps.# Evidence
# Clinical evidence
## The evidence for Curos is limited in quantity and quality and may not be generalisable to NHS practice
The clinical evidence for Curos comprises 6 uncontrolled before-and-after studies and 9 unpublished abstracts. Overall, the before-and-after studies reported a reduction in bloodstream infections but were of low quality and have a high risk of potential bias. All studies introduced Curos at the same time as elements of education, disinfection protocol awareness and audit, all of which may have affected the outcomes. The studies used inconsistent classifications and definitions of bloodstream infections. They also included different populations, which makes it difficult to accurately compare results. The 9 unpublished abstracts describe studies done in a range of settings, but the details are limited. There was no evidence for the use of Curos in community settings. Only 1 of the before-and-after studies and 2 of the abstracts were done in the UK, which may limit the generalisability of the results to NHS practice. For full details of the clinical evidence, see sections 2.2 and 2.3 of the assessment report.
## The meta-analysis of 4 studies is likely to be imprecise because it is based on low quality evidence
The company submitted 2 meta-analyses: the first used data from 4 studies that reported rates of central line-associated bloodstream infection, and the second used data from 2 of the same 4 studies which were done in an intensive care setting. Because of the low quality of the individual studies and the differences between them, the external assessment centre (EAC) concluded that the meta-analysis of the 4 studies was at risk of serious imprecision. However, the results of both meta-analyses were used in the cost modelling because no better estimates were available (see appendix E of the assessment report for further details).
# Cost evidence
## The company's cost model shows that using Curos is cost saving in both general hospital and intensive care populations
The company presented a decision-tree model with 2 main branches: 1 for Curos and 1 for standard care (alcohol wipes). Patients in each branch can develop central line-associated bloodstream infections. Based on the company's 2 meta-analyses, the model can report results for either the whole hospital population or only the intensive care population. The EAC agreed with the overall structure, noting that there were no changes to the model care pathway other than exchanging 1 method of disinfecting for another. The company's model showed that using Curos saves around £28 per person in the general hospital population and around £134 per person in the intensive care population. For full details of the cost evidence, see section 4 of the assessment report.
## The EAC's revised model shows that Curos is only cost saving in the general hospital population
The EAC made some changes to the model, including increasing the number of needleless connector ports in the intensive care setting from 10 to 12 (based on expert advice). The EAC also reduced the nurse time for standard care from 45 seconds to 15 seconds (equal to Curos); it considered that nurses would use the 30-second drying time of alcohol wipes for other tasks, and so this should not be considered as time saved when using Curos. The EAC's revised model showed that using Curos saves around £17 in the general hospital population, but incurs additional costs of around £94 per person in the intensive care population.
## Sensitivity analyses suggest that Curos could be cost saving in the intensive care population but any results are uncertain
The EAC's sensitivity analyses showed that the main driver of cost savings in the general hospital population was baseline infection rate. No main driver of cost savings was identified in the intensive care population, but a threshold analysis showed that Curos could be cost saving in this population if there were a high enough difference in infection incidence between Curos and standard care (an incidence rate ratio of 0.75). However, any results are uncertain because the analyses are informed by data from the clinical evidence, which is of low quality.# Committee discussion
# Clinical-effectiveness overview
## Evidence for the clinical effectiveness of Curos is uncertain
Although the studies report a reduction in bloodstream infections with Curos, there are differences in the way in which this is measured between studies. The clinical experts explained that this variation in measuring and reporting bloodstream infections is a common problem in both clinical studies and NHS practice. The committee considered that this makes any judgement about the overall effectiveness of Curos less certain. The committee acknowledged the low quality of the evidence, noting that the before-and-after design of the studies was likely to introduce bias. Most of the studies were done outside of the UK so their generalisability to NHS practice is uncertain. The committee noted that the studies were insufficiently powered to detect any benefit with Curos independent of the existing bundle of care for preventing infections. The studies also provide few details about any other infection prevention techniques that were used.
## More evidence is needed about Curos in the context of the bundle of care
In NHS practice, Curos would be used as part of the standard bundle of care for preventing infections. The committee proposed that more NHS-based evidence was needed, exploring the potential clinical benefits of Curos when used as part of a bundle of care for preventing infections.
## There is insufficient evidence to support the adoption of Curos for any subgroups but those at high risk of infection are likely to benefit most
The committee concluded that because of the heterogeneity of the clinical evidence it could not recommend the adoption of Curos in any subgroup of people. Despite the lack of evidence, the committee considered that it was plausible Curos could provide benefits in certain situations. The external assessment centre (EAC) highlighted the fact that the evidence suggests that the benefits of Curos were most likely to be seen in people who are at high risk of infection. The clinical experts explained that there are a number of factors that can affect infection rates, including the nature of the underlying disease, the healthcare environment, the type of line in place, the nature of the administered drug or fluid and the frequency of administrations needed. The infection rate is also affected by staff compliance with infection reduction protocols. The clinical experts advised that people who are immunocompromised, such as those having bone marrow transplants or treatment for cancer, are likely to have a higher infection risk. The clinical experts also highlighted the potential benefits of using Curos in a community setting where many people have long-term vascular access devices in place. The committee agreed that future research should focus on people at high risk of infection, including those in community settings.
# NHS considerations overview
## Compliance with infection prevention protocols varies
The clinical experts explained that implementing any new infection prevention strategy is likely to increase staff compliance with protocols already in place, particularly when practice is being audited. The committee noted that compliance is likely to vary over time and that this was not adequately captured by the clinical evidence. The clinical experts also advised that compliance with standard infection prevention protocols varies in NHS practice and in some cases may be as low as 20%. The committee acknowledged that using Curos may increase compliance, but there was insufficient evidence for this.
## Misuse can be avoided through regular staff training
Curos is a single-use device: that is, the cap must be replaced each time the line is accessed. The clinical experts agreed that there is a potential risk of Curos being re-used when the line is accessed, but they advised that any misuse can be avoided through regular staff training.
## No procurement constraints are expected for Curos
The clinical experts noted that carefully planned stock control is important to ensure the continued availability of Curos. The company confirmed that Curos is readily available and that the NHS supply chain holds a 3- to 4-week stock. The committee raised concerns about the sustainability of the technology and if disposing the caps (which are not currently recyclable) would have a negative environmental impact. The company stated that Curos caps are treated as clinical waste on disposal.
# Cost modelling overview
## The EAC's revisions to the model are acceptable but uncertainties remain
The committee agreed with the EAC that the reliability of the cost modelling was limited because of the uncertainty in the clinical evidence. Clinical expert advice was mixed: although some experts agreed that Curos may save time compared with manual disinfection, others noted that compliance with manual disinfection protocols is very low in practice and using Curos would be unlikely to free up any staff time. The committee accepted the EAC's revisions to the cost model but concluded that further evidence is needed to show if using Curos releases staff resources or not.
# Main cost drivers
## More robust data are needed to understand the potential resource impact of Curos
The main driver in the cost model was baseline infection rate (that is, the higher the baseline infection rate, the greater the potential cost savings with Curos). The clinical experts explained that bloodstream infection rates are highly variable both within and between hospitals, and the way in which hospitals measure and report bloodstream infections varies. Having reviewed the cost evidence and accepting the uncertain clinical benefits, the committee concluded that more robust data were needed to understand the potential resource impact of using Curos in the NHS.
# Further research
## Curos shows promise and further research would help address the uncertainties
The committee concluded that further research would help resolve the uncertainties about the potential benefits of using Curos. The research should determine if Curos adds clinical value to the standard bundle of care for preventing infections when using needleless connectors. It should focus on people at high risk of infection. A community-based trial should be considered, and a prospective and randomised trial design would be appropriate to limit bias. The research should provide data to inform cost modelling and should be designed with a timeframe that would provide useful information before this guidance is reviewed.
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{'Recommendations': 'Curos disinfecting cap shows promise for preventing infections when using needleless connectors, but there is currently insufficient evidence to support the case for routine adoption in the NHS.\n\nResearch is therefore recommended to address uncertainties about the clinical benefits of using Curos. This research should:\n\ndetermine if Curos adds value to the standard bundle of care for preventing infections when using needleless connectors\n\nexplore the use of Curos in people at high risk of infection, including those whose condition is managed in the community\n\nclearly define the patient groups included and use consistent outcomes.NICE will facilitate this research, in collaboration with the company, clinical and academic partners, and will update this guidance if or when substantive new evidence becomes available.\n\nWhy the committee made these recommendations\n\nCuros is a disinfecting cap which, when placed on the needleless connector at the end of a vascular access line, is intended to reduce the risk of infection. Curos can stay in place for up to 7 days but must be replaced each time the line is used.\n\nEvidence for the clinical effectiveness of Curos is limited. The studies include a wide range of people in different clinical situations and use different definitions of bloodstream infection. It is not clear if Curos would provide any additional benefit to the standard bundle of care for preventing infections. There is also no evidence for its effectiveness in community settings and any cost benefits are uncertain.\n\nDespite these uncertainties, Curos shows promise for preventing infections when using needleless connectors, especially in people at high risk of infection. Because of this, further research on Curos is recommended.', 'The technology': "Technology\n\nThe Curos disinfecting cap (3M) is a single-use device which is placed over the needleless connector of vascular access lines. It contains a foam that is impregnated with 70% isopropyl alcohol, which acts as an antiseptic.\n\nThe cap can stay in place for up to 7 days, but must be replaced with a new cap if it is removed.\n\nCuros is supplied individually or in strips of 10. It received a class IIa CE mark in September 2016.\n\nInnovative aspects\n\nCuros avoids the need to manually disinfect needleless connectors. The company claims that it differs from technologies with a similar purpose because:\n\nit has a wide spectrum of antimicrobial action\n\nit is easy and convenient to use\n\nits design makes it easier to attach and harder to dislodge\n\nits distinctive green colour avoids confusion with other covers.\n\nIntended use\n\nCuros is twisted onto the end of a needleless connector and should be left in place for at least 1 minute. The company claims that, after 1 minute, the antiseptic will kill 6 microorganisms commonly associated with bloodstream infections.\n\nCuros would be used as part of a bundle of care for preventing infections when using vascular access lines. It is intended to replace the use of alcohol wipes or solution.\n\nThe company provides online training videos for staff using Curos, and further training if needed.\n\nCosts\n\nThe unit cost of a Curos cap in the company's submission is £0.32 (including VAT).\n\nFor more details, see the website for Curos disinfecting caps.", 'Evidence': "# Clinical evidence\n\n## The evidence for Curos is limited in quantity and quality and may not be generalisable to NHS practice\n\nThe clinical evidence for Curos comprises 6 uncontrolled before-and-after studies and 9 unpublished abstracts. Overall, the before-and-after studies reported a reduction in bloodstream infections but were of low quality and have a high risk of potential bias. All studies introduced Curos at the same time as elements of education, disinfection protocol awareness and audit, all of which may have affected the outcomes. The studies used inconsistent classifications and definitions of bloodstream infections. They also included different populations, which makes it difficult to accurately compare results. The 9 unpublished abstracts describe studies done in a range of settings, but the details are limited. There was no evidence for the use of Curos in community settings. Only 1 of the before-and-after studies and 2 of the abstracts were done in the UK, which may limit the generalisability of the results to NHS practice. For full details of the clinical evidence, see sections 2.2 and 2.3 of the assessment report.\n\n## The meta-analysis of 4 studies is likely to be imprecise because it is based on low quality evidence\n\nThe company submitted 2 meta-analyses: the first used data from 4 studies that reported rates of central line-associated bloodstream infection, and the second used data from 2 of the same 4 studies which were done in an intensive care setting. Because of the low quality of the individual studies and the differences between them, the external assessment centre (EAC) concluded that the meta-analysis of the 4 studies was at risk of serious imprecision. However, the results of both meta-analyses were used in the cost modelling because no better estimates were available (see appendix E of the assessment report for further details).\n\n# Cost evidence\n\n## The company's cost model shows that using Curos is cost saving in both general hospital and intensive care populations\n\nThe company presented a decision-tree model with 2 main branches: 1 for Curos and 1 for standard care (alcohol wipes). Patients in each branch can develop central line-associated bloodstream infections. Based on the company's 2 meta-analyses, the model can report results for either the whole hospital population or only the intensive care population. The EAC agreed with the overall structure, noting that there were no changes to the model care pathway other than exchanging 1 method of disinfecting for another. The company's model showed that using Curos saves around £28 per person in the general hospital population and around £134 per person in the intensive care population. For full details of the cost evidence, see section 4 of the assessment report.\n\n## The EAC's revised model shows that Curos is only cost saving in the general hospital population\n\nThe EAC made some changes to the model, including increasing the number of needleless connector ports in the intensive care setting from 10 to 12 (based on expert advice). The EAC also reduced the nurse time for standard care from 45\xa0seconds to 15\xa0seconds (equal to Curos); it considered that nurses would use the 30-second drying time of alcohol wipes for other tasks, and so this should not be considered as time saved when using Curos. The EAC's revised model showed that using Curos saves around £17 in the general hospital population, but incurs additional costs of around £94 per person in the intensive care population.\n\n## Sensitivity analyses suggest that Curos could be cost saving in the intensive care population but any results are uncertain\n\nThe EAC's sensitivity analyses showed that the main driver of cost savings in the general hospital population was baseline infection rate. No main driver of cost savings was identified in the intensive care population, but a threshold analysis showed that Curos could be cost saving in this population if there were a high enough difference in infection incidence between Curos and standard care (an incidence rate ratio of 0.75). However, any results are uncertain because the analyses are informed by data from the clinical evidence, which is of low quality.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Evidence for the clinical effectiveness of Curos is uncertain\n\nAlthough the studies report a reduction in bloodstream infections with Curos, there are differences in the way in which this is measured between studies. The clinical experts explained that this variation in measuring and reporting bloodstream infections is a common problem in both clinical studies and NHS practice. The committee considered that this makes any judgement about the overall effectiveness of Curos less certain. The committee acknowledged the low quality of the evidence, noting that the before-and-after design of the studies was likely to introduce bias. Most of the studies were done outside of the UK so their generalisability to NHS practice is uncertain. The committee noted that the studies were insufficiently powered to detect any benefit with Curos independent of the existing bundle of care for preventing infections. The studies also provide few details about any other infection prevention techniques that were used.\n\n## More evidence is needed about Curos in the context of the bundle of care\n\nIn NHS practice, Curos would be used as part of the standard bundle of care for preventing infections. The committee proposed that more NHS-based evidence was needed, exploring the potential clinical benefits of Curos when used as part of a bundle of care for preventing infections.\n\n## There is insufficient evidence to support the adoption of Curos for any subgroups but those at high risk of infection are likely to benefit most\n\nThe committee concluded that because of the heterogeneity of the clinical evidence it could not recommend the adoption of Curos in any subgroup of people. Despite the lack of evidence, the committee considered that it was plausible Curos could provide benefits in certain situations. The external assessment centre (EAC) highlighted the fact that the evidence suggests that the benefits of Curos were most likely to be seen in people who are at high risk of infection. The clinical experts explained that there are a number of factors that can affect infection rates, including the nature of the underlying disease, the healthcare environment, the type of line in place, the nature of the administered drug or fluid and the frequency of administrations needed. The infection rate is also affected by staff compliance with infection reduction protocols. The clinical experts advised that people who are immunocompromised, such as those having bone marrow transplants or treatment for cancer, are likely to have a higher infection risk. The clinical experts also highlighted the potential benefits of using Curos in a community setting where many people have long-term vascular access devices in place. The committee agreed that future research should focus on people at high risk of infection, including those in community settings.\n\n# NHS considerations overview\n\n## Compliance with infection prevention protocols varies\n\nThe clinical experts explained that implementing any new infection prevention strategy is likely to increase staff compliance with protocols already in place, particularly when practice is being audited. The committee noted that compliance is likely to vary over time and that this was not adequately captured by the clinical evidence. The clinical experts also advised that compliance with standard infection prevention protocols varies in NHS practice and in some cases may be as low as 20%. The committee acknowledged that using Curos may increase compliance, but there was insufficient evidence for this.\n\n## Misuse can be avoided through regular staff training\n\nCuros is a single-use device: that is, the cap must be replaced each time the line is accessed. The clinical experts agreed that there is a potential risk of Curos being re-used when the line is accessed, but they advised that any misuse can be avoided through regular staff training.\n\n## No procurement constraints are expected for Curos\n\nThe clinical experts noted that carefully planned stock control is important to ensure the continued availability of Curos. The company confirmed that Curos is readily available and that the NHS supply chain holds a 3- to 4-week stock. The committee raised concerns about the sustainability of the technology and if disposing the caps (which are not currently recyclable) would have a negative environmental impact. The company stated that Curos caps are treated as clinical waste on disposal.\n\n# Cost modelling overview\n\n## The EAC's revisions to the model are acceptable but uncertainties remain\n\nThe committee agreed with the EAC that the reliability of the cost modelling was limited because of the uncertainty in the clinical evidence. Clinical expert advice was mixed: although some experts agreed that Curos may save time compared with manual disinfection, others noted that compliance with manual disinfection protocols is very low in practice and using Curos would be unlikely to free up any staff time. The committee accepted the EAC's revisions to the cost model but concluded that further evidence is needed to show if using Curos releases staff resources or not.\n\n# Main cost drivers\n\n## More robust data are needed to understand the potential resource impact of Curos\n\nThe main driver in the cost model was baseline infection rate (that is, the higher the baseline infection rate, the greater the potential cost savings with Curos). The clinical experts explained that bloodstream infection rates are highly variable both within and between hospitals, and the way in which hospitals measure and report bloodstream infections varies. Having reviewed the cost evidence and accepting the uncertain clinical benefits, the committee concluded that more robust data were needed to understand the potential resource impact of using Curos in the NHS.\n\n# Further research\n\n## Curos shows promise and further research would help address the uncertainties\n\nThe committee concluded that further research would help resolve the uncertainties about the potential benefits of using Curos. The research should determine if Curos adds clinical value to the standard bundle of care for preventing infections when using needleless connectors. It should focus on people at high risk of infection. A community-based trial should be considered, and a prospective and randomised trial design would be appropriate to limit bias. The research should provide data to inform cost modelling and should be designed with a timeframe that would provide useful information before this guidance is reviewed."}
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https://www.nice.org.uk/guidance/mtg44
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Evidence-based recommendations on Curos for preventing infections when using needleless connectors.
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65265145ceb8c2b52fb3c97da831c7b2973fd7a6
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nice
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Lead-I ECG devices for detecting symptomatic atrial fibrillation using single time point testing in primary care
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Lead-I ECG devices for detecting symptomatic atrial fibrillation using single time point testing in primary care
Evidence-based recommendations on lead-I electrocardiogram (ECG) devices (imPulse, Kardia Mobile, MyDiagnostick and Zenicor-ECG) for detecting symptomatic atrial fibrillation using single time point testing in primary care.
# Recommendations
There is not enough evidence to recommend the routine adoption of lead-I electrocardiogram (ECG) devices (imPulse, Kardia Mobile, MyDiagnostick and Zenicor-ECG) to detect atrial fibrillation when used for single time point testing in primary care for people with signs or symptoms of the condition and an irregular pulse. Further research is recommended to show how using lead‑I ECG devices in this way affects:
the number of people with atrial fibrillation detected, compared with current practice (see section 6.1) and
primary and secondary care services, particularly how ECGs generated by the devices would be interpreted in practice, including staff time needed to interpret the ECG traces and associated costs (see section 6.2).
Centres currently using these devices for this indication are encouraged to take part in research and data collection (see sections 6.1 and 6.2).# Clinical need and practice
# The problem addressed
Lead-I electrocardiogram (ECG) devices can be used in primary care to help detect atrial fibrillation in people presenting with signs or symptoms of the condition, who have an irregular pulse on manual pulse palpation. The devices include electrodes, internal storage for ECG recordings and automated software to interpret the ECG trace. Data can be transferred to a local or remote computer for further analysis by a healthcare professional.
Using lead-I ECG devices may improve detection of atrial fibrillation. This would lead to earlier identification of people who are at a higher risk of having a stroke and who would benefit from anticoagulant treatment. Using lead‑I ECG devices would also allow ECGs to be quickly recorded when atrial fibrillation is suspected. This may help identify people with intermittent (paroxysmal) atrial fibrillation, which might have stopped before a 12‑lead ECG can be done. The scope of this assessment is the use of the devices for single time point testing for people presenting in primary care with signs or symptoms of atrial fibrillation, and an irregular pulse.
# The condition
## Atrial fibrillation
Atrial fibrillation is a type of arrhythmia that causes an irregular or abnormally fast heart rate. It is the most common arrhythmia and has a higher incidence in older people. When a person has atrial fibrillation the upper chambers of the heart (the atria) beat irregularly, making the heart less effective at moving blood into the ventricles. This can cause blood clots to form, which may cause a stroke. Early detection of atrial fibrillation allows preventative treatment to be started, for example, oral anticoagulants to reduce the risk of stroke.
The abnormal electrical impulses that cause the condition can result in persistent, permanent or intermittent atrial fibrillation:
permanent atrial fibrillation: atrial fibrillation is present all the time
persistent atrial fibrillation: episodes last longer than 7 days (if left untreated)
paroxysmal atrial fibrillation: intermittent episodes that usually last less than 2 days and stop without treatment.
Signs and symptoms of atrial fibrillation include feeling dizzy, being short of breath, feeling tired, having chest discomfort and heart palpitations. Atrial fibrillation can also be asymptomatic.
# The diagnostics and care pathways
## Diagnosis
NICE's guideline on atrial fibrillation recommends that manual pulse palpation should be used to assess for an irregular pulse, which may indicate underlying atrial fibrillation in people presenting with any of the following: breathlessness (dyspnoea), palpitations, syncope (dizziness), chest discomfort, stroke or transient ischaemic attack.
The guideline also recommends doing an ECG in all people, whether symptomatic or not, when atrial fibrillation is suspected because an irregular pulse has been detected. In current practice a 12‑lead ECG can be done in primary or secondary care and is interpreted by a trained healthcare professional. This would be used to confirm atrial fibrillation that is suspected based on manual pulse palpation, before treatment is started. When atrial fibrillation has already been diagnosed, a 12‑lead ECG is important to identify any additional abnormalities, such as left ventricular hypertrophy, which need to be considered when deciding on further treatment.
After an irregular pulse is detected, if there is a delay until a 12‑lead ECG is done, paroxysmal atrial fibrillation may have stopped and therefore won't be detected by the ECG. Clinical experts advised that lead‑I ECGs would be used in the diagnostic pathway for people with signs and symptoms of atrial fibrillation after manual pulse palpation has revealed an irregular pulse.
## Care pathway
NICE's guideline on atrial fibrillation makes recommendations for the care of people diagnosed with atrial fibrillation:
Assessment of risk and treatment to lower risk of stroke: This includes assessing stroke and bleeding risk using the CHA2DS2VASc and HAS-BLED scores, and treatments to lower the risk of stroke (apixaban, dabigatran etexilate, rivaroxaban or a vitamin K antagonist). NICE has produced technology appraisal guidance on the direct oral anticoagulants apixaban, dabigatran etexilate and rivaroxaban and on edoxaban.
Treatment to control heart rate and rhythm: This includes different interventions that are offered as part of a rate control strategy (beta blockers, calcium channel blocker, digoxin) or rhythm control strategy (pharmacological or electrical rhythm control or both), when appropriate.The guideline also covers the use of left atrial ablation if drug treatment has failed to control atrial fibrillation symptoms or is unsuitable.# The diagnostic tests
The assessment compared 5 interventions with 1 comparator.
# The interventions
The lead-I electrocardiogram (ECG) devices were assessed when they were used in addition to 12‑lead ECGs. Clinical experts advised that a 12‑lead ECG would still be used after lead-I ECGs to identify any additional abnormalities, such as left ventricular hypertrophy, which need to be considered when deciding on further treatment. One of the 5 lead‑I ECG devices in the scope, the RhythmPad GP (Cardiocity Ltd), was removed from this guidance after consultation. This was because the company informed NICE that, following a change in the CE mark, the device is no longer intended for detecting atrial fibrillation in people with signs or symptoms using single time point testing in primary care.
## imPulse
imPulse (Plessey Semiconductors Ltd) is a CE-marked lead‑I ECG device, which is provided with downloadable software for data analysis (imPulse Viewer). The software has to be installed on a personal computer or tablet. ECGs are taken by holding the device in both hands and placing each thumb on a separate sensor on the device for a pre-set length of time (from 30 seconds to 10 minutes). Data are transferred to the hardware hosting the analytical software using Bluetooth, with the recorded ECG trace being displayed in real time.
Once the recording has finished, the generated ECG trace can be saved in the imPulse viewer. Previously recorded ECG traces can also be loaded into this viewer and can be saved as PDFs. The software's atrial fibrillation algorithm analyses the trace and states whether atrial fibrillation is unlikely, possible or probable. For a 'possible' or 'probable' result, the company recommends that the person should have further investigations, and that the algorithm should not be used to definitively diagnose atrial fibrillation.
## Kardia Mobile
Kardia Mobile (AliveCor Ltd) is a CE-marked lead-I ECG device that works with the Kardia app to record and interpret ECGs. A compatible Android or Apple smartphone or tablet is also needed. Two fingers from each hand are placed on the Kardia Mobile to record an ECG, which is sent wirelessly to the device hosting the Kardia app. The default length of recording is 30 seconds, but this can be extended up to 5 minutes. The ECG trace is then automatically sent as an anonymous file to a server in the European Union for storage as an encrypted file.
The app's algorithm classifies ECG traces as:
normal
possible atrial fibrillation detected
unclassified.The instructions for use state that the Kardia app assesses for atrial fibrillation only, and the device will not necessarily detect other cardiac arrhythmias. Any non-atrial fibrillation arrhythmias detected, including sinus tachycardia, are labelled as unclassified. The company states that any ECG labelled as 'possible atrial fibrillation' or 'unclassified' should be reviewed by a cardiologist or qualified clinician. ECG traces recorded by the device can be sent from a smartphone or tablet by email as a PDF attachment and stored in a patient's records.
## MyDiagnostick
MyDiagnostick (MyDiagnostick Medical BV) is a CE-marked handheld lead‑I ECG device that can produce and interpret an ECG trace. The ECG is generated by holding metal electrodes at each end of the device for 1 minute. The device activates automatically when gripped and deactivates automatically when released. A light on the device turns green if no atrial fibrillation is detected, or red if atrial fibrillation is detected. If an error occurs during the reading, the device produces both an audible warning and a visible warning from the light on the device. Up to 140 ECG traces can be stored in the device before it starts to overwrite previous traces.
MyDiagnostick can be connected to a computer via a USB connection to download the generated ECG trace for review and storage using free software (downloaded from the MyDiagnostick website). The company states that the device automatically interprets ECGs, but that a clinical professional should examine the ECG trace to confirm the diagnosis.
## Zenicor-ECG
Zenicor-ECG (Zenicor Medical Systems AB) is a CE-marked system with 2 components: a lead‑I ECG device (Zenicor-EKG 2) and an online system for analysis and storage (Zenicor-EKG Backend System version 3.2). The online system sends data to a server in the European Union. This can be accessed using a web browser without prior installation of software and requires a user licence. ECGs are taken by placing both thumbs on the device for 30 seconds.
Once an ECG is taken using Zenicor-EKG 2, the trace can be transferred from the device (using a built-in mobile network modem) to a Zenicor server in Sweden. Here the ECG is analysed using the Zenicor‑EKG Backend System, which includes an automated algorithm. This categorises an ECG into 1 of 12 groups of potential arrhythmias; 1 of which includes atrial fibrillation. The algorithm also reports if the ECG cannot be analysed. The company states that a clinician needs to manually interpret the ECG trace generated by the Zenicor‑ECG to make a final diagnosis of atrial fibrillation. Clinicians can view the analysis using the Zenicor Doctor System user interface via a web browser. The ECG trace is also available via this interface and can be downloaded or printed as a PDF.
# The comparator
## -lead ECG after an irregular pulse is detected
The comparator for this assessment is a 12-lead ECG, used to check for atrial fibrillation after an irregular pulse has been detected by manual pulse palpation. Clinical experts commented that an irregular pulse on manual pulse palpation is not thought to be sufficient to start anticoagulant treatment, so in this diagnostic pathway patients do not have treatment until a 12‑lead ECG confirms atrial fibrillation.
Clinical experts commented that there can be delays in arranging 12‑lead ECGs after an irregular pulse is detected, which can delay diagnosis of atrial fibrillation, or potentially miss paroxysmal atrial fibrillation because the initial examination did not include an ECG recording. The length of this delay will vary and depends on local arrangements for doing 12‑lead ECGs, for example, if this can be done in primary care or if a referral to secondary care is needed.# Evidence
The diagnostics advisory committee (section 8) considered evidence on lead-I electrocardiogram (ECG) devices (imPulse, Kardia Mobile, MyDiagnostick and Zenicor-ECG) for detecting atrial fibrillation using single time point testing in primary care from several sources. Full details of all the evidence are in the committee papers. Evidence on the RhythmPad GP was removed from this guidance after consultation (see section 3.1). To make sure the committee papers are clear, the published diagnostics assessment report and extra relevant documents include the evidence assessed on RhythmPad GP.
# Clinical effectiveness
The external assessment group (EAG) did a systematic review to identify evidence on the diagnostic accuracy and clinical effectiveness of using the lead‑I ECG devices to detect atrial fibrillation. Included studies were those that used the devices at a single time point to detect atrial fibrillation (rather than repeated use over a period of time). Because no studies were identified in the population of interest (people with signs and symptoms of atrial fibrillation and an irregular pulse on manual palpation), the EAG included studies done in a population who were asymptomatic. The EAG included in this definition people who did not present with signs and symptoms of atrial fibrillation (for example, breathlessness or palpitations) with or without a previous diagnosis of atrial fibrillation. It included people with other cardiovascular comorbidities and people who were attending a cardiovascular clinic.
The EAG divided their review into 2 parts; studies reporting diagnostic accuracy of the devices and studies reporting the clinical effectiveness of the devices.
## Diagnostic accuracy
In the diagnostic test accuracy review, 9 studies were included. There is an overview of the included studies in table 1. All the studies either enrolled people with a known atrial fibrillation status (that is, people known to have atrial fibrillation and people with no history of the condition), or who were recruited from cardiology services. Only Desteghe et al. (2017) provided the reasons people were admitted to a cardiology service, with 3.4% admitted because of symptomatic atrial fibrillation.
Only 1 study was done in primary care (Vaes et al. 2014), with the rest in secondary or tertiary care. There was 1 study done in the UK (Williams et al. 2015). No published studies assessed the imPulse device.
In all studies the reference standard was a 12‑lead ECG interpreted by a trained healthcare professional (a cardiologist, electrophysiologist or GP with a special interest in cardiology). The index test (lead‑I ECG) and reference standard (12‑lead ECG) were both done within 6 hours of each other in all but 1 study (Vaes et al.). In this study the interval between tests was not reported.
## Table 1 Overview of studies included in the EAG's diagnostic accuracy review
Device
Study
Population in study
Interpreter of device output
Kardia Mobile
Desteghe et al. 2017a
(Belgium)
Inpatients in a cardiology ward (35.6% had a history of atrial fibrillation)
Electrophysiologists
Algorithm
Results presented separately
Haberman et al. 2015
(USA)
Cardiology clinic patientsb
Electrophysiologist
Koltowski et al. 2017c
(Poland)
People in tertiary care
Cardiologist
Lau et al. 2013
(Australia)
People at a cardiology department (24% had a history of atrial fibrillation)
Algorithm
Williams et al. 2015
(UK)
People attending an atrial fibrillation clinic who were known to have atrial fibrillation and people with unknown atrial fibrillation status (who were attending the clinic for reasons unrelated to atrial fibrillation)
Cardiologist
GP with special interest in cardiology
Results presented separately
MyDiagnostick
Desteghe et al. 2017a
(Belgium)
Inpatients in a cardiology ward (35.6% had a history of atrial fibrillation)
Electrophysiologists
Algorithm
Results presented separately
Tieleman et al. 2014
(Netherlands)
People attending an outpatient cardiology clinic or a specialised atrial fibrillation outpatient clinic
Algorithm
Vaes et al. 2014
(Belgium)
People known to have atrial fibrillation (83.4%) and people with no history of the condition invited to take part by GPs
Algorithm
Zenicor-ECG
Doliwa et al. 2009
(Sweden)
People with atrial fibrillation, atrial flutter or sinus rhythm attending a cardiology outpatient clinic
Cardiologist
a Desteghe et al. assessed both Kardia Mobile and MyDiagnostick.
b Results from additional study participants (healthy young adults and elite athletes) were not included in the EAG's analyses.
c Koltowski et al. was only available as a conference proceeding.
The QUADAS-2 tool was used to assess study quality. For patient selection, the EAG judged that all 9 studies had an unclear risk of bias and a high level of concern for applicability (because none were done in a population who had symptoms). For 1 study there was limited information available in the publication; Koltowski et al. (2017) was only available as a conference proceeding.
The included studies varied in how the devices gave a positive result for atrial fibrillation. This was either based on the lead‑I ECG device's diagnostic algorithm or on clinician interpretation of an ECG trace generated by the devices. The EAG judged that studies in which the device output was interpreted by a trained healthcare professional were more applicable (low concern) than those in which a lead‑I ECG device algorithm alone was used (high concern; Lau et al. 2013, Tieleman et al. 2014 and Vaes et al. 2014). The EAG presented results in 2 sections depending on how atrial fibrillation was identified (by a clinician or by the device's algorithm alone).
Data were included from 4 studies, which assessed Kardia Mobile alone (Haberman et al. 2014; Williams et al. 2015), Kardia Mobile and MyDiagnostick (Desteghe et al. 2017) and Zenicor‑ECG alone (Doliwa et al. 2009).
Desteghe et al. reported separate accuracy estimates from lead‑I ECGs interpreted by 2 electrophysiologists; only pooled estimates using data from electrophysiologist 1 are shown in table 2 (values were similar when data from electrophysiologist 2 were used). Williams et al. reported separate accuracy estimates from lead‑I ECGs interpreted by a cardiologist or by a GP with a special interest in cardiology. Pooled accuracy estimates in table 3 used data from Williams et al. when the lead‑I ECG interpreter was a cardiologist (interpreters in other studies were cardiologists or electrophysiologists). Pooled accuracy estimates using data from Williams et al. when the interpreter was a GP with a special interest in cardiology (not shown) were similar. However, the study showed a decrease in specificity when the GP interpreted the lead‑I ECG; 76% (95% confidence interval 64% to 85%) compared with 86% (95% CI 76% to 94%) when the cardiologist interpreted them.
## Table 2 Pooled diagnostic accuracy estimates for lead-I ECGs interpreted by a trained healthcare professional
Meta-analysis
Lead-I devices in included studies (number of studies)
Pooled sensitivity % (95% CI)
Pooled specificity % (95% CI)
All devicesa,c
Kardia Mobile (3b,d), Zenicor-ECG (1e)
(86.2 to 97.4)
(90.4 to 98.8)
All devicesa,c
Kardia Mobile (2), MyDiagnostick (1b,f), Zenicor-ECG (1e)
(83.8 to 95.0)
(89.4 to 98.3)
Kardia Mobilea,c
Kardia Mobile (3d)
(85.1 to 97.7)
(88.0 to 99.2)
a Data from electrophysiologist 1 from Desteghe et al. 2017.
b Data from Desteghe et al. 2017 from either Kardia Mobile or MyDiagnostick.
c Data from Williams et al. 2015 from cardiologist interpreting lead-I ECG.
d Desteghe et al. 2017; Haberman et al. 2015; Williams et al. 2015.
e Doliwa et al. 2009.
f Desteghe et al. 2017.
Only Kardia Mobile had sufficient studies to produce a device‑specific pooled estimate (see table 2). Accuracy estimates from individual studies for other devices are presented in table 3. The EAG commented that there were insufficient data to formally assess differences between the lead-I ECG devices.
## Table 3 Individual study diagnostic accuracy estimates for lead-I ECGs interpreted by a trained healthcare professional
Lead-I ECG device
Study
Sensitivity % (95% CI)
Specificity % (95% CI)
MyDiagnosticka
Desteghe et al. 2017
(62.0 to 97.0)
(92.0 to 98.0)
Zenicor-ECG
Doliwa et al. 2009
(81.0 to 98.0)
(86.0 to 100.0)
a Data from electrophysiologist 1 from Desteghe et al.
Four studies that reported sensitivity and specificity of the lead‑I ECG device when the trace was interpreted by the device's algorithm alone were included in meta-analyses. Two studies reported data for MyDiagnostick alone (Tieleman et al. 2014; Vaes et al. 2014), 1 study for Kardia Mobile alone (Lau et al. 2013) and 1 study for both MyDiagnostick and Kardia Mobile (Desteghe et al. 2017). Pooled sensitivity and specificity estimates from meta‑analyses are presented in table 4.
## Table 4 Pooled diagnostic accuracy estimates for lead-I ECG traces interpreted by device algorithm alone
Meta-analysis
Lead-I devices in included studies (number of studies)
Pooled sensitivity % (95% CI)
Pooled specificity % (95% CI)
All devicesa
Kardia Mobile (1b), MyDiagnostick (3c)
(86.0 to 99.0)
(92.9 to 96.8)
All devicesa
Kardia Mobile (2d), MyDiagnostick (2e)
(70.4 to 99.4)
(94.2 to 97.6)
MyDiagnostick
MyDiagnostick (3c)
(79.0 to 99.1)
(91.9 to 96.2)
Kardia Mobile
Kardia Mobile (2d)
(32.3 to 99.1)
(95.1 to 98.5)
a Data from Desteghe et al. 2017 from either Kardia Mobile or MyDiagnostick.
b Lau et al. 2013.
c Desteghe et al. 2017; Tieleman et al. 2014; Vaes et al. 2014.
d Desteghe et al. 2017; Lau et al. 2013.
e Tieleman et al. 2014; Vaes et al. 2014.
The EAG noted that the companies who make the lead‑I ECG devices stated that atrial fibrillation should not be diagnosed using the algorithm alone; ECG traces produced by the devices should be reviewed by a qualified healthcare professional.
The EAG commented that the available data were not sufficient to formally assess differences between the different lead-I ECG devices. Desteghe et al. (2017) assessed the concordance between Kardia Mobile and MyDiagnostick. There was no statistically significant difference in agreement between the devices (based on kappa values) when assessing all patients (p=0.677) or after excluding those with an implanted device (for example, a pacemaker or implantable cardiac defibrillator; p=0.411).
The EAG commented that the pooled sensitivity and specificity values were similar across all the meta-analyses done, irrespective of how the lead‑I ECG trace was interpreted (algorithm or healthcare professional) or which lead‑I ECG devices were used (pooled estimates produced by the EAG used Kardia Mobile, MyDiagnostick and Zenicor-ECG).
The EAG identified further studies that reported sensitivity and specificity estimates of the lead‑I ECG devices. However, it did not include them in its main report because they did not meet 1 of the eligibility criteria for inclusion, that is, that the reference standard in the studies was not a 12‑lead ECG interpreted by a trained healthcare professional. Results were presented in appendix 6 of the diagnostics assessment report. They included 1 unpublished study which assessed imPulse (no other studies were identified for this device). Ranges were reported for sensitivity (67% to 100%) and specificity (83% to 100%). These data were used in the economic model.
## Evidence on clinical effectiveness of the lead-I ECG devices
The EAG included 19 studies in its clinical effectiveness review. Of these, 7 studies were done in primary care (Orchard et al. 2014; Chan et al. 2016; Chan et al. 2017; Gibson et al. 2017; Hussain and Thakrar, 2016; Kaasenbrood et al. 2016; Orchard et al. 2016). There were 2 studies done in the UK (Gibson et al. 2017; Hussain and Thakrar, 2016). Of the studies, 13 included data for Kardia Mobile, 5 for MyDiagnostick, 1 for Zenicor-ECG and 1 for imPulse. No studies were identified that assessed the clinical effectiveness of lead‑I ECG devices when used for people with signs and symptoms of atrial fibrillation presenting in primary care.
There were 13 studies that reported diagnostic yield of atrial fibrillation detection by lead‑I ECG devices (various devices), which ranged from 0.38% to 5.84%. However, the location of testing varied between studies; primary care (6 studies), secondary care (2 studies), tertiary care (1 study) and in the community (4 studies). In the primary care studies, the range was 0.49% to 5.84%. None of the studies assessed people with signs and symptoms of atrial fibrillation. The enrolled populations varied from the general population or people who were attending primary care for a reason unrelated to atrial fibrillation (for example, for flu vaccination) to people admitted to a cardiology ward and people with known atrial fibrillation. The prevalence of atrial fibrillation in these populations is likely to vary and may not be applicable to the population that is the focus of this assessment. No data were found on any benefit of lead‑I ECGs in identifying people with paroxysmal atrial fibrillation, compared with later ECG testing.
Test failure rate (which included both the device failing to produce a result and producing a poor-quality ECG trace) varied between 0.1% and 9% (various devices). Reasons suggested for uninterpretable lead‑I ECGs were sinus tachycardia or bradycardia, that patients had a tremor or that hospitalised patients were unable to hold the devices firmly enough.
A study done in Australia (Lowres et al. 2014) reported a time to diagnosis of atrial fibrillation of 16.6 days (standard deviation of 14.3 days) from detection by an initial lead‑I ECG diagnostic test at a pharmacy to confirmed diagnosis with a 12‑lead ECG.
Tieleman et al. (2014) reported that people were able to use MyDiagnostick with minimal instructions. Chan et al. (2017) reported that Kardia Mobile was easy to use. Orchard et al. (2016) commented that it may be difficult for older people to hold the Kardia Mobile device still enough to take a reading. In Desteghe et al. (2017), 7% of people were excluded from the study because they could not hold the devices as intended (the study used both MyDiagnostick and Kardia Mobile).
In Hussain and Thakrar (2016), 5 out of 6 people had a change in the clinical management of their condition after atrial fibrillation was detected by Kardia Mobile (1 person died as an inpatient after referral to hospital). In Lowres et al. (2014), oral anticoagulants were prescribed for 6 out of 10 new patients with atrial fibrillation detected by a lead‑I ECG followed by a 12‑lead ECG interpreted by a cardiologist.
In Orchard et al. (2016), which used Kardia Mobile, patients and GPs commented that they liked using the device. Chan et al. (2017) reported that all patients asked were willing to have further testing with Kardia Mobile at future GP visits, and 86% of GPs surveyed considered that the device was useful for atrial fibrillation screening and they would use it in their daily practice. Gibson et al. (2017) reported generally positive responses to using MyDiagnostick, although some issues with implementing use of the device were raised. A further study reported that Kardia Mobile was easily administered and that no one declined testing with the device (Hussain and Thakrar 2016). In Chan et al. (2017), interviewed patients commented that having access to the lead-I ECG device in the surgery was more convenient than having to attend another healthcare facility for a 12‑lead ECG.
The EAG also looked at unpublished evidence from a quality control audit on the use of Kardia Mobile across Eastbourne, Hailsham and Seaford clinical commissioning group and Hastings and Rother clinical commissioning group. This was provided by a specialist committee member as an example of an ongoing audit. Over a 2-year period the device was used in primary care or for home visits if people had an irregular pulse or signs of atrial fibrillation. There were 183 ECG traces reported, identifying 128 cases of atrial fibrillation from the lead‑I ECG trace alone. The proportion of people newly diagnosed with atrial fibrillation (69.9%) was considerably higher than the diagnostic yield in studies identified by the EAG (0.38% to 5.84%), although the audit was designed for quality control, and not to assess atrial fibrillation yield.
# Cost effectiveness
## Systematic review of cost-effectiveness evidence
The EAG did a systematic review to identify published full economic evaluations of lead‑I ECG devices for detecting atrial fibrillation. Studies were excluded if they assessed the devices for repeated ECG measurements (rather than at a single time point) or if they assessed the devices for screening a population or for an asymptomatic 'silent atrial fibrillation' population. The EAG did not identify any published studies that met their inclusion criteria. However, the EAG highlighted 2 recently published economic evaluations (Welton et al. 2017 and Jacobs et al. 2018) that suggested that lead-I ECG devices may represent a cost-effective use of resources for systematic, opportunistic screening of people aged 65 years and over during a routine GP appointment.
## Modelling approach
The EAG developed a de novo economic model designed to evaluate the cost effectiveness of using the lead‑I ECG devices for single time point testing of people presenting in primary care with signs and symptoms of atrial fibrillation and who have an irregular pulse.
The model compared the effect of using a lead‑I ECG device in primary care for people with signs and symptoms of atrial fibrillation who have an irregular pulse (detected by manual pulse palpation) with standard diagnostic testing (that is, without the use of a lead‑I ECG device). The model was in 2 phases: a diagnostic phase followed by a post-diagnostic phase.
This phase covered the initial assessment of people presenting in primary care with signs and symptoms of atrial fibrillation, and who have had manual pulse palpation that shows an irregular pulse. The model compared 2 strategies: referral for a subsequent 12‑lead ECG to check for atrial fibrillation (standard diagnostic pathway) or having a lead‑I ECG in primary care at the same primary care appointment to check for atrial fibrillation (lead‑I ECG pathway) followed by a 12‑lead ECG if the clinician thought this was appropriate.
The diagnostic phase model covered the first 3 months after the initial primary care appointment. By the end of the diagnostic phase, people have either been diagnosed as having atrial fibrillation, or no atrial fibrillation has been detected (either correctly or incorrectly). People diagnosed with atrial fibrillation can have anticoagulants and rate control treatment (beta blockers).
People can have up to 2 cerebrovascular events (transient ischaemic attack, ischaemic or haemorrhagic stroke), a non-major bleeding event, or die. This was modelled using a Markov model. The probability of having a cerebrovascular event for people with atrial fibrillation is reduced if they are taking anticoagulants. However, anyone taking anticoagulants has an associated higher risk of having a bleeding event.
After the 3-month diagnostic phase model, people entered a second Markov model. This had the same structure as the Markov model in the diagnostic phase after a diagnosis has been made, but ran over a 30‑year timespan (with 3‑month cycles). People entered based on their history of cerebrovascular events (none, 1 or 2) and they could have further cerebrovascular events, non‑major bleeding events, or die.
## Model inputs
The starting age of the modelled cohort was 70 years, and the model was run over 30 years. The cohort consisted of people with signs and symptoms of atrial fibrillation including an irregular pulse. This included people with atrial fibrillation (assumed to be 20% based on clinical advice) and people without the condition (assumed to have either atrial or ventricular ectopy).
Estimates of the diagnostic accuracy of the 4 lead‑I ECG devices were obtained from the EAG's systematic review and meta-analyses. The EAG used estimates of accuracy based on healthcare professionals interpreting the ECG traces, because it assumed that atrial fibrillation would not be diagnosed based on a device's algorithm alone.
## Table 5 Sensitivity and specificity values of lead-I ECG devices used in the economic model
Lead-I ECG
Interpreter of ECG
Data source
Sensitivity %
Specificity %
imPulse
Healthcare professional
Reeves (unpublished)
a
a
Kardia Mobileb
Healthcare professional
Pooled analysisc
MyDiagnostick
Healthcare professional
Desteghe et al. (2017)d
Zenicor-ECG
Healthcare professional
Doliwa et al. (2009)
a EAG used the midpoint from the range reported in the Reeves report.
b Alternative accuracy estimates based on a pooled estimate in which data from electrophysiologist 2 from Desteghe et al. were used in a scenario analysis; sensitivity 91.3%, specificity 97.4%.
c Pooled estimate from 3 studies; see table 2.
d Desteghe et al. reported accuracy estimates from 2 electrophysiologists. Estimates used in the base case were from electrophysiologist 1 (see table 3); values from electrophysiologist 2 were used in a scenario analysis (sensitivity of 80.0%, specificity of 98.0%).
For people with atrial fibrillation, the rate of mortality and cerebrovascular events (transient ischaemic attack, ischaemic or haemorrhagic stroke) in people who did not have anticoagulants was taken from Sterne et al. (2017). The effect of anticoagulants on the incidence of these events in people with atrial fibrillation was also taken from this study. For people without atrial fibrillation the rate of mortality and cerebrovascular events was taken from various sources (for example, Public Health England report, Office for National Statistics report, Rothwell et al. 2005). The risk of cerebrovascular events and mortality for people with untreated atrial fibrillation does not vary by type of atrial fibrillation. That is, risk is the same for paroxysmal, permanent and persistent atrial fibrillation. After people have a cerebrovascular event, their risk of mortality increases. The EAG assumed that this risk was 2.6 times greater based on a study of stroke survivors in Norway (Mathisen et al. 2016). The risk of having a further cerebrovascular event was based on a meta-analysis of stroke survivors (Mohan et al. 2011) with increased risk in the first year, then a lower risk from year 2 onwards.
The risk of clinically relevant bleeding is increased for people who have anticoagulants, based on Sterne et al. (2017). This is the case for people with or without atrial fibrillation.
## Costs
Annual costs of the devices used in the base-case model are shown in table 6. Because the lead‑I ECG could be used outside the scope of this assessment, the EAG also did a scenario analysis that excluded the costs of the devices. No extra cost was included for administering and interpreting the lead‑I ECG because it was assumed that this could be done during a standard GP consultation.
## Table 6 Estimated annual costs of lead-I ECG devices
Lead-I ECG
Item
Unit cost (£)
c
Expected lifespan (years)
Annual cost (£)
Unit cost per test
b
imPulse
Device
Kardia Mobile
Device
a
MyDiagnostick
Device
Zenicor-ECG
Device and 36-month licence
Extra 36-month licence
a Costs of any additional tablet or device needed not included (the effect of this additional cost is assessed in scenario analysis F).
b Assumes 54 people tested per year.
c Excluding VAT.
The EAG devised base cases that differed depending on where 12‑lead ECGs were done. If a 12‑lead ECG was done in primary care, the cost of administering it was assumed to be £12.34. This was based on the costs of the device, disposables and staff time to do and interpret the ECG. The cost of administering a 12‑lead ECG in secondary care was assumed to be £52 (from NHS reference costs). The cost of Holter monitoring (for 7 days) was assumed to be £120.23.
Costs for anticoagulant (apixaban) and rate control (beta blockers) treatment were obtained from the British national formulary and NHS drug tariff. Costs of bleeding events and transient ischaemic attack were taken from NHS reference costs. Age and sex-adjusted 1- and 5‑year costs for strokes were from the Sentinel Stroke National Audit Programme's cost and cost-effectiveness report (2016).
Berg et al. (2010) was used to provide utility values for people with atrial fibrillation (see table 7). Beta blockers were assumed to improve symptoms for people with atrial fibrillation.
## Table 7 Utility values used in base-case economic model (at age 70; age- and sex-adjusted)
Atrial fibrillation status (95% CI)
Atrial fibrillation
No atrial fibrillation
Untreated
(0.537 to 0.881)
(0.480 to 0.942)
Treated
(0.480 to 0.942)
(0.480 to 0.942)
People without atrial fibrillation were assumed to be having a short symptomatic episode caused by atrial or ventricular ectopy that resolved quickly. For people who had an ischaemic or haemorrhagic stroke, a lifetime utility decrement was applied at the time of the first stroke (no further decrements were applied for subsequent strokes). The size of the decrement was −0.272 (95% CI −0.345 to −0.198) for both types of stroke. Transient ischaemic attacks and bleeding events were assumed to have no long-term effect on health-related quality of life, and no utility decrement was applied for these events.
## Base-case assumptions
The following assumptions were applied in the base-case analyses:
Of the people presenting in primary care with signs and symptoms of atrial fibrillation, and who have an irregular pulse, 20% have atrial fibrillation.
Of the people with atrial fibrillation, 50% have paroxysmal atrial fibrillation. The EAG commented that there is a lack of evidence on the prevalence of paroxysmal atrial fibrillation in people with symptoms, and noted that a recent study (Welton et al. 2017) had reported wide variation in prevalence (although not necessarily in a symptomatic population). The effect of varying this prevalence was investigated in sensitivity analysis.
Additional interpretation by a cardiologist is needed for 10% of lead‑I ECG tests.
The 12-lead ECGs have 100% sensitivity and specificity for atrial fibrillation (if a person is in atrial fibrillation at the time of the test).
For 48% of people with paroxysmal atrial fibrillation the episode will have stopped by the time a 12‑lead ECG is done (2 or 14 days after the initial primary care consultation when an irregular pulse is detected). This is based on data from Israel et al. (2004).
Holter testing for paroxysmal atrial fibrillation is assumed to have 100% sensitivity and specificity (if atrial fibrillation occurs during testing). Holter testing is assumed to be for 7 days and 70% people with atrial fibrillation are assumed to have an episode in that time (based on data from Kirchoff et al. 2006).
In the standard diagnostic pathway, 50% of people who have a negative 12‑lead ECG have Holter testing. In the lead‑I ECG pathway, 80% of people who have a negative lead‑I ECG have a 12‑lead ECG. If the 12-lead ECG is negative, 50% of people have Holter testing. Of the 20% of people who are not referred for a 12‑lead ECG after a negative lead‑I ECG, 50% have Holter testing.
Only people who are diagnosed with atrial fibrillation and who have a CHA2DS2-VASc score of 2 or more have anticoagulants. There are 82.4% of people with atrial fibrillation assumed to have a CHA2DS2-VASc score of 2 or more, and 81.2% of these are assumed to take anticoagulants (based on NHS Quality and Outcomes Framework 2016/2017 indicator AF007).
People having anticoagulants have apixaban (simplifying assumption).
Treatment with anticoagulants starts immediately after a positive lead-I ECG result (simplifying assumption).
People whose atrial fibrillation is undetected and who have a cerebrovascular event are assumed to have their atrial fibrillation diagnosed as part of treatment.
## Base-case results
The EAG produced 4 base cases, depending on when and where 12‑lead ECGs were done:
base case 1: 12-lead ECG in primary care (2 days later)
base case 2: 12-lead ECG in primary care (14 days later)
base case 3: 12-lead ECG in secondary care (2 days later)
base case 4: 12-lead ECG in secondary care (14 days later).
In pairwise analyses, all the lead-I ECG devices were compared independently with the standard pathway (that is, no use of a lead-I ECG device). Results were similar across the 4 base cases, and in probabilistic analyses. The results from base-case 1 are shown in table 8.
## Table 8 Base case 1: Pairwise cost-effectiveness analysis (compared with standard pathway)
Total costs (£)
Total QALYs
Incremental costs (£)
Incremental QALYs
ICER (£)
Standard pathway
Kardia Mobile
imPulse
MyDiagnostick
Zenicor-ECG
In fully incremental analyses across all the base cases, all lead‑I ECG devices were dominated by Kardia Mobile (that is, Kardia Mobile cost less but produced more quality-adjusted life years ). The incremental cost-effectiveness ratios (ICERs) for Kardia Mobile compared with the standard pathway were the same as for the pairwise comparison (less than £1,100 per QALY gained). At consultation, the company who makes MyDiagnostick proposed new costs for their device. The EAG ran the base-case analysis again using these costs in an addendum to the diagnostics assessment report. This resulted in lower costs for MyDiagnostick, but did not affect the EAG's overall conclusions on the pairwise cost-effectiveness analysis.
## Analysis of alternative scenarios
The EAG investigated the effect of varying some of the base-case assumptions in scenario analyses. This included assessing the effect of adding the cost of a smartphone or tablet (including the cost of a data network) for Kardia Mobile in a threshold analysis. The EAG commented that a smartphone or tablet would need to cost more than £2,850 for Kardia Mobile to no longer dominate the other lead-I ECG devices. The ICER for Kardia Mobile compared with the standard pathway remained less than £20,000 per QALY gained if a smartphone or tablet costs less than £24,362. Using alternative accuracy estimates for MyDiagnostick and Kardia Mobile (using results from electrophysiologist 2 from Desteghe et al.) resulted in Kardia Mobile having an ICER of £5,503 per QALY gained compared with MyDiagnostick. Compared with the standard pathway MyDiagnostick dominated. The Zenicor‑ECG was no longer dominated, but had an ICER of £242,994 per QALY gained when compared with Kardia Mobile.
The model was most sensitive to the proportion of patients whose atrial fibrillation was paroxysmal (assumed to be 50% in the base case) in one-way analyses for all of the lead-I ECG devices. Cost effectiveness improved as the proportion of paroxysmal atrial fibrillation increased. Conversely, lower estimates of the proportion of paroxysmal atrial fibrillation made the devices less cost effective (increased incremental costs and decreased incremental QALYs).
In a probabilistic sensitivity analysis (done in base case 1) all other lead‑I ECG devices were dominated by Kardia Mobile in a fully incremental analysis. In pairwise comparisons with the standard pathway, ICERs were similar to the deterministic results, and all were less than £17,000 per QALY gained.# Committee discussion
The committee discussed the effects of atrial fibrillation. The clinical experts commented that earlier diagnosis of atrial fibrillation may reduce a person's risk of stroke because anticoagulation treatment could be started sooner, if appropriate. Also, earlier treatment with rate control drugs, such as beta blockers, can stop associated symptoms and may improve quality of life, although both types of treatment are associated with a risk of side effects. Comments submitted by a patient expert highlighted that atrial fibrillation can go undiagnosed for months or even years. It is common for people to have anxiety, depression and fear while living with the symptoms of atrial fibrillation, particularly when the cause of the symptoms is unknown. If atrial fibrillation is not treated, people are at higher risk of a stroke. The clinical experts commented that atrial fibrillation‑related stroke can be extremely disabling and debilitating, with family members often becoming full-time carers to the people affected. The committee was aware that improving detection of atrial fibrillation is therefore a priority for the healthcare system. It concluded that earlier diagnosis could be important to reduce the risk of stroke and its associated effects for people with the condition.
The committee asked how suspected atrial fibrillation is currently investigated in people presenting in primary care. The clinical experts commented that an electrocardiogram (ECG) is needed to determine whether atrial fibrillation is present, but delays in doing an ECG often prevent atrial fibrillation being diagnosed, particularly if it is paroxysmal. They explained that episodes of paroxysmal atrial fibrillation usually stop within 48 hours without treatment. This can lead to it being missed if an ECG is not done immediately. Earlier access to an ECG, such as a lead‑I ECG that can be done during a GP consultation, would increase the chances of atrial fibrillation that is causing symptoms being detected. It would also mean that preventative treatment is not delayed. Alternatively, if symptoms are present but no arrhythmia can be seen on an ECG this can help to rule out atrial fibrillation as a cause. The clinical experts also commented that many GP practices cannot do a 12‑lead ECG immediately because they do not have the equipment on site or because staff are not available to do, or interpret, the test. Ambulatory ECG monitoring may need to be done, which needs multiple visits to a hospital. The committee concluded that the availability of lead-I ECGs could improve access to testing for people with symptoms of atrial fibrillation.
# Clinical effectiveness
The committee considered the studies included in the diagnostic accuracy review. It noted that the external assessment group (EAG) had concerns over the applicability of several of the studies because lead‑I ECG traces were interpreted by the device's algorithms alone, rather than by a trained healthcare professional. It noted that the companies stated that the algorithms alone should not be used to diagnose atrial fibrillation. Clinical experts highlighted the importance of having trained healthcare professionals review ECG traces generated by the lead‑I ECG devices. This is to confirm or exclude atrial fibrillation and to check any algorithm outputs, and therefore inform treatment decisions. The committee noted that the trained healthcare professionals interpreting the ECGs in the identified studies were generally cardiologists or electrophysiologists, who may be more experienced in interpreting ECG traces than GPs. In 1 study (Williams et al. 2015), in which the interpreter was a GP with a special interest in cardiology, specificity estimates were lower than those obtained when a cardiologist interpreted the trace. Also, accuracy estimates of the devices varied between the 2 electrophysiologists in Desteghe et al. (2017), suggesting that interpretation of the lead‑I ECG traces is likely to be subject to inter-observer variability. The committee concluded that it was important that decisions about treatment based on lead‑I ECG traces are made only after review by a trained healthcare professional, because this may have a substantial effect on false results.
The committee noted that the populations varied in the studies included in the EAG's diagnostic accuracy review. Most of the studies were done in people who did not report symptoms of atrial fibrillation, but who were attending cardiology services because of an underlying cardiac problem. It recalled that the EAG had highlighted this as a generalisability issue. The clinical experts explained that because the populations in the included studies tended to be older, the burden of atrial fibrillation would be expected to be greater than in a truly asymptomatic population. The committee considered that the absence of studies that were directly applicable to the population in this assessment was not ideal. But it concluded that the available studies provided a reasonable estimate of the ability of the devices to correctly identify atrial fibrillation.
The committee considered the diagnostic accuracy data that were available for each of the devices. It noted that 5 studies were available for Kardia Mobile, 3 for MyDiagnostick and 1 for Zenicor-ECG. The committee also noted that there was uncertainty about whether current versions of the algorithms had been used in the diagnostic accuracy studies for the lead‑I ECG devices. Most of the studies compared each of the devices with a 12‑lead ECG and did not include formal comparisons of the devices. There was 1 study (Desteghe et al. 2017) that assessed concordance between MyDiagnostick and Kardia Mobile and reported no statistically significant difference. The committee concluded that the available accuracy data were limited and were not sufficient to assess differences in accuracy between the lead-I ECG devices.
The committee considered the reference standard used in the identified diagnostic accuracy studies: a 12‑lead ECG done within about 6 hours of the lead‑I ECGs. It noted that the comparator for this assessment was a 12‑lead ECG done several days after the initial GP appointment where the irregular pulse was detected. The EAG identified no studies showing that lead‑I ECGs increased detection of atrial fibrillation when compared with 12‑lead ECGs done later after an irregular pulse was detected. It noted that studies identified by the EAG that reported diagnostic yield of atrial fibrillation were not done in a population who had symptoms, which is the focus of this assessment. The committee recalled that the potential value of the devices in this context was increased detection of atrial fibrillation, particularly paroxysmal, compared with a 12‑lead ECG done later (see section 5.2). It concluded that the identified data did not allow the committee to assess the likely clinical effect of the lead‑I ECG devices in increasing detection of atrial fibrillation compared with current practice (that is, a 12‑lead ECG done later).
# Cost effectiveness
The committee considered the cost per use of the lead‑I ECG devices assumed in the model. It heard that the lifespan of MyDiagnostick was incorrect in the original report, but noted that the EAG had corrected this. The committee questioned the expected average number of people seen by a full-time GP per year that the EAG had used to estimate the cost per use of the devices, noting evidence from NHS Digital that the average number of people per GP is potentially higher. The EAG commented that its estimate was conservative and that if the average number of people per GP was higher this would reduce the cost per use of the devices and improve the cost-effectiveness estimates. The committee also questioned whether the model included the costs of training to use the device. The EAG explained that this was not explicitly included, but it had looked at the effect of increasing the costs of using the lead‑I ECG devices and the cost-effectiveness estimates were robust to increases in the costs per use. The committee concluded that, although there were uncertainties in the costs per use assumed in the model, they were not a key driver of the results.
The committee discussed the costs associated with interpreting the lead-I ECG traces in practice and considered whether these had been adequately captured in the model. It noted its conclusion that the ECG traces from the devices need to be interpreted by a trained healthcare professional to diagnose atrial fibrillation and make decisions about treatment (see section 5.3). The clinical experts explained that there is likely to be wide variation in the ability of GPs to interpret ECGs, and that some practices may use centralised services for this. The committee concluded that there was uncertainty about how lead‑I ECGs generated in primary care would be interpreted in practice, and therefore the effect on staff time and costs associated with introducing lead‑I ECGs into primary care. Further research was recommended to assess this (see section 6.2).
The committee considered the risk of bleeding associated with anticoagulant treatment, and noted that the model assumed that all patients have direct oral anticoagulants. It noted that people incorrectly identified as having atrial fibrillation by the lead‑I ECG devices in the model (false positive results) were assumed to have anticoagulants, and so were at risk of bleeding. The clinical experts explained that false positive results were likely to be caused by atrial ectopy, a benign condition that is not associated with an increased risk of stroke. They also commented that this group of people was likely to continue anticoagulants over the longer term, unless they chose to stop treatment. The committee questioned whether the risk of bleeding had been adequately captured in the analyses. The EAG explained that the model did allow for people to have bleeding events, and that a scenario analysis in the addendum including a quality-adjusted life year (QALY) decrement for minor bleeds had very similar results to the base-case analysis. The committee noted that the EAG's model did not account for any excess mortality in people who had a haemorrhagic stroke because of anticoagulants. The EAG commented that the increase in the number of bleeds in the model caused by adopting lead‑I ECGs was very small. The clinical experts commented that lead‑I ECG traces are reviewed by trained healthcare professionals, which helps to minimise the risk of false positive diagnoses. The committee concluded that there was some uncertainty about whether the model had captured all the adverse effects caused by anticoagulants.
The committee noted that the model was sensitive to an assumption about the proportion of cases of atrial fibrillation that are paroxysmal. The EAG explained that because of a lack of evidence this had been assumed to be 50% in the base case. The clinical experts commented that about 25% of atrial fibrillation is likely to be paroxysmal, and that the proportion in the modelled population is unlikely to be less than this. If the proportion of paroxysmal atrial fibrillation was set to 25% in the model, the incremental cost-effectiveness ratio (ICER) for Kardia Mobile compared with the standard pathway was about £7,500 per QALY gained, an increase from £1,060 per QALY gained in base case 1, in which it dominated the other lead‑I ECG devices. As the proportion of paroxysmal atrial fibrillation was decreased the ICER increased, to around £250,000 per QALY gained when the prevalence was set to 0. The committee concluded that because there were no data on the proportion of people with symptomatic atrial fibrillation that is paroxysmal the cost-effectiveness estimates were highly uncertain.
The EAG commented that most of the patient benefits in the model (from the use of the lead‑I ECG devices compared with the standard pathway) came from an estimated increase in detection of people with paroxysmal atrial fibrillation. However, the committee recalled that no clinical evidence had been identified that showed that lead‑I ECG devices increased the detection of people with atrial fibrillation compared with a later 12‑lead ECG in practice (see section 5.6). The EAG had made assumptions in the model to estimate the effect of the likely increase in detection of paroxysmal atrial fibrillation associated with the lead‑I ECG devices. However, because of a lack of data, it was unclear whether this increase would occur in clinical practice. The committee concluded that although there is plausible potential for the lead‑I ECG devices to be cost effective when used for single time point testing in primary care (for people with signs and symptoms of atrial fibrillation with an irregular pulse), there was insufficient evidence at present to determine if the predicted benefits of using the devices would be realised in practice. The committee considered that further research would help to address this (see section 6.1).
The committee considered the usability of the devices and noted that the EAG identified several studies reporting that the devices were easy to use and were liked by patients and healthcare professionals. However, it noted that 1 study (Desteghe et al.) reported that up to 7% of people were not able to use the devices because they were unable to hold them as recommended by the companies. A patient expert submitted comments that some people may need help in holding the devices while a recording is taken, for example people who have had a stroke or people with arthritis. The committee concluded that healthcare professionals should bear this in mind when using the devices and encouraged the companies to improve the usability of their devices for these groups of people.
The committee considered the results of the fully incremental economic analyses (see sections 4.43 and 4.46). It noted that all lead-I ECG devices were dominated by Kardia Mobile (that is, using the Kardia Mobile cost less but produced more QALYs). However, the committee recalled its earlier conclusion that the available accuracy data for the lead‑I ECG devices were limited and were not sufficient to assess differences in accuracy between the lead-I ECG devices (see section 5.5). It also noted that the Kardia Mobile did not dominate in all simulations in the probabilistic sensitivity analysis. The committee concluded that there was considerable uncertainty about the relative cost effectiveness of the different lead‑I ECG devices, and that a conclusion about which device was most cost effective could not be made from the available data.
# Research considerations
The clinical experts explained that lead‑I ECG devices were increasingly being used in primary care settings. The committee noted that Academic Health Science Networks (AHSNs) are assessing the effect of introducing lead‑I ECG devices into primary and community care, although their project is broader than the scope of this assessment. The committee considered consultation responses on the AHSN project. It noted that data collected as part of the project may be relevant to the population covered by this guidance and could help answer some of the uncertainties identified on the system impact of adopting the devices (see section 6.2). Clinical experts explained their processes to ensure appropriate governance of patient information when using these devices to detect atrial fibrillation. The committee noted the importance of this and concluded that centres should ensure appropriate information governance is in place for these devices.
The committee heard that the focus of the AHSN project is to evaluate the extent of spread and adoption of the mobile ECG technology and to describe the optimum environment for implementing a national procured innovation. It is not an evaluation of the technology itself. The committee concluded that data collected as part of the AHSN project were unlikely to resolve uncertainty about the extent of any increased detection of atrial fibrillation by the devices compared with current practice (see section 6.1) and that further research would be needed to address this.# Recommendations for further research
The committee recommended further research to determine if using the lead‑I electrocardiogram (ECG) devices in primary care for people with signs or symptoms of atrial fibrillation, and an irregular pulse, increases the number of people with atrial fibrillation (including paroxysmal) detected, compared with current practice (that is, a 12‑lead ECG done later). The committee considered the feasibility of collecting data to see if using the lead‑I ECG devices increased the detection of atrial fibrillation that would be missed if only 12‑lead ECGs done later were available. It noted that even if a lead‑I ECG is used and atrial fibrillation is detected, a subsequent 12‑lead ECG would still be done to check for structural cardiac abnormalities and inform further management decisions. The committee concluded that practices using lead‑I ECG devices could determine the number of additional cases of atrial fibrillation detected by the devices. This can be done by identifying people with a confirmed positive lead‑I ECG for atrial fibrillation who subsequently had a 12‑lead ECG that was negative because the atrial fibrillation had stopped. The committee also considered that data collected on the time between the initial lead‑I ECG and the subsequent 12‑lead ECG would be useful.
The committee recommended that data should be collected to evaluate the system impact of adopting the lead‑I ECGs on both primary and secondary care. In particular, data should be collected on how ECGs generated by the devices would be interpreted in practice, including staff time needed to interpret the ECG traces and associated costs.
|
{'Recommendations': 'There is not enough evidence to recommend the routine adoption of lead-I electrocardiogram (ECG) devices (imPulse, Kardia Mobile, MyDiagnostick and Zenicor-ECG) to detect atrial fibrillation when used for single time point testing in primary care for people with signs or symptoms of the condition and an irregular pulse. Further research is recommended to show how using lead‑I ECG devices in this way affects:\n\nthe number of people with atrial fibrillation detected, compared with current practice (see section\xa06.1) and\n\nprimary and secondary care services, particularly how ECGs generated by the devices would be interpreted in practice, including staff time needed to interpret the ECG traces and associated costs (see section\xa06.2).\n\nCentres currently using these devices for this indication are encouraged to take part in research and data collection (see sections\xa06.1 and\xa06.2).', 'Clinical need and practice': "# The problem addressed\n\nLead-I electrocardiogram (ECG) devices can be used in primary care to help detect atrial fibrillation in people presenting with signs or symptoms of the condition, who have an irregular pulse on manual pulse palpation. The devices include electrodes, internal storage for ECG recordings and automated software to interpret the ECG trace. Data can be transferred to a local or remote computer for further analysis by a healthcare professional.\n\nUsing lead-I ECG devices may improve detection of atrial fibrillation. This would lead to earlier identification of people who are at a higher risk of having a stroke and who would benefit from anticoagulant treatment. Using lead‑I ECG devices would also allow ECGs to be quickly recorded when atrial fibrillation is suspected. This may help identify people with intermittent (paroxysmal) atrial fibrillation, which might have stopped before a 12‑lead ECG can be done. The scope of this assessment is the use of the devices for single time point testing for people presenting in primary care with signs or symptoms of atrial fibrillation, and an irregular pulse.\n\n# The condition\n\n## Atrial fibrillation\n\nAtrial fibrillation is a type of arrhythmia that causes an irregular or abnormally fast heart rate. It is the most common arrhythmia and has a higher incidence in older people. When a person has atrial fibrillation the upper chambers of the heart (the atria) beat irregularly, making the heart less effective at moving blood into the ventricles. This can cause blood clots to form, which may cause a stroke. Early detection of atrial fibrillation allows preventative treatment to be started, for example, oral anticoagulants to reduce the risk of stroke.\n\nThe abnormal electrical impulses that cause the condition can result in persistent, permanent or intermittent atrial fibrillation:\n\npermanent atrial fibrillation: atrial fibrillation is present all the time\n\npersistent atrial fibrillation: episodes last longer than 7\xa0days (if left untreated)\n\nparoxysmal atrial fibrillation: intermittent episodes that usually last less than 2\xa0days and stop without treatment.\n\nSigns and symptoms of atrial fibrillation include feeling dizzy, being short of breath, feeling tired, having chest discomfort and heart palpitations. Atrial fibrillation can also be asymptomatic.\n\n# The diagnostics and care pathways\n\n## Diagnosis\n\nNICE's guideline on atrial fibrillation recommends that manual pulse palpation should be used to assess for an irregular pulse, which may indicate underlying atrial fibrillation in people presenting with any of the following: breathlessness (dyspnoea), palpitations, syncope (dizziness), chest discomfort, stroke or transient ischaemic attack.\n\nThe guideline also recommends doing an ECG in all people, whether symptomatic or not, when atrial fibrillation is suspected because an irregular pulse has been detected. In current practice a 12‑lead ECG can be done in primary or secondary care and is interpreted by a trained healthcare professional. This would be used to confirm atrial fibrillation that is suspected based on manual pulse palpation, before treatment is started. When atrial fibrillation has already been diagnosed, a 12‑lead ECG is important to identify any additional abnormalities, such as left ventricular hypertrophy, which need to be considered when deciding on further treatment.\n\nAfter an irregular pulse is detected, if there is a delay until a 12‑lead ECG is done, paroxysmal atrial fibrillation may have stopped and therefore won't be detected by the ECG. Clinical experts advised that lead‑I ECGs would be used in the diagnostic pathway for people with signs and symptoms of atrial fibrillation after manual pulse palpation has revealed an irregular pulse.\n\n## Care pathway\n\nNICE's guideline on atrial fibrillation makes recommendations for the care of people diagnosed with atrial fibrillation:\n\nAssessment of risk and treatment to lower risk of stroke: This includes assessing stroke and bleeding risk using the CHA2DS2VASc and HAS-BLED scores, and treatments to lower the risk of stroke (apixaban, dabigatran etexilate, rivaroxaban or a vitamin K antagonist). NICE has produced technology appraisal guidance on the direct oral anticoagulants apixaban, dabigatran etexilate and rivaroxaban and on edoxaban.\n\nTreatment to control heart rate and rhythm: This includes different interventions that are offered as part of a rate control strategy (beta blockers, calcium channel blocker, digoxin) or rhythm control strategy (pharmacological or electrical rhythm control or both), when appropriate.The guideline also covers the use of left atrial ablation if drug treatment has failed to control atrial fibrillation symptoms or is unsuitable.", 'The diagnostic tests': "The assessment compared 5\xa0interventions with 1\xa0comparator.\n\n# The interventions\n\nThe lead-I electrocardiogram (ECG) devices were assessed when they were used in addition to 12‑lead ECGs. Clinical experts advised that a 12‑lead ECG would still be used after lead-I ECGs to identify any additional abnormalities, such as left ventricular hypertrophy, which need to be considered when deciding on further treatment. One of the 5\xa0lead‑I ECG devices in the scope, the RhythmPad GP (Cardiocity Ltd), was removed from this guidance after consultation. This was because the company informed NICE that, following a change in the CE mark, the device is no longer intended for detecting atrial fibrillation in people with signs or symptoms using single time point testing in primary care.\n\n## imPulse\n\nimPulse (Plessey Semiconductors Ltd) is a CE-marked lead‑I ECG device, which is provided with downloadable software for data analysis (imPulse Viewer). The software has to be installed on a personal computer or tablet. ECGs are taken by holding the device in both hands and placing each thumb on a separate sensor on the device for a pre-set length of time (from 30\xa0seconds to 10\xa0minutes). Data are transferred to the hardware hosting the analytical software using Bluetooth, with the recorded ECG trace being displayed in real time.\n\nOnce the recording has finished, the generated ECG trace can be saved in the imPulse viewer. Previously recorded ECG traces can also be loaded into this viewer and can be saved as PDFs. The software's atrial fibrillation algorithm analyses the trace and states whether atrial fibrillation is unlikely, possible or probable. For a 'possible' or 'probable' result, the company recommends that the person should have further investigations, and that the algorithm should not be used to definitively diagnose atrial fibrillation.\n\n## Kardia Mobile\n\nKardia Mobile (AliveCor Ltd) is a CE-marked lead-I ECG device that works with the Kardia app to record and interpret ECGs. A compatible Android or Apple smartphone or tablet is also needed. Two fingers from each hand are placed on the Kardia Mobile to record an ECG, which is sent wirelessly to the device hosting the Kardia app. The default length of recording is 30\xa0seconds, but this can be extended up to 5\xa0minutes. The ECG trace is then automatically sent as an anonymous file to a server in the European Union for storage as an encrypted file.\n\nThe app's algorithm classifies ECG traces as:\n\nnormal\n\npossible atrial fibrillation detected\n\nunclassified.The instructions for use state that the Kardia app assesses for atrial fibrillation only, and the device will not necessarily detect other cardiac arrhythmias. Any non-atrial fibrillation arrhythmias detected, including sinus tachycardia, are labelled as unclassified. The company states that any ECG labelled as 'possible atrial fibrillation' or 'unclassified' should be reviewed by a cardiologist or qualified clinician. ECG traces recorded by the device can be sent from a smartphone or tablet by email as a PDF attachment and stored in a patient's records.\n\n## MyDiagnostick\n\nMyDiagnostick (MyDiagnostick Medical BV) is a CE-marked handheld lead‑I ECG device that can produce and interpret an ECG trace. The ECG is generated by holding metal electrodes at each end of the device for 1\xa0minute. The device activates automatically when gripped and deactivates automatically when released. A light on the device turns green if no atrial fibrillation is detected, or red if atrial fibrillation is detected. If an error occurs during the reading, the device produces both an audible warning and a visible warning from the light on the device. Up to 140\xa0ECG traces can be stored in the device before it starts to overwrite previous traces.\n\nMyDiagnostick can be connected to a computer via a USB connection to download the generated ECG trace for review and storage using free software (downloaded from the MyDiagnostick website). The company states that the device automatically interprets ECGs, but that a clinical professional should examine the ECG trace to confirm the diagnosis.\n\n## Zenicor-ECG\n\nZenicor-ECG (Zenicor Medical Systems AB) is a CE-marked system with 2\xa0components: a lead‑I ECG device (Zenicor-EKG 2) and an online system for analysis and storage (Zenicor-EKG Backend System version\xa03.2). The online system sends data to a server in the European Union. This can be accessed using a web browser without prior installation of software and requires a user licence. ECGs are taken by placing both thumbs on the device for 30\xa0seconds.\n\nOnce an ECG is taken using Zenicor-EKG 2, the trace can be transferred from the device (using a built-in mobile network modem) to a Zenicor server in Sweden. Here the ECG is analysed using the Zenicor‑EKG Backend System, which includes an automated algorithm. This categorises an ECG into 1 of 12\xa0groups of potential arrhythmias; 1 of which includes atrial fibrillation. The algorithm also reports if the ECG cannot be analysed. The company states that a clinician needs to manually interpret the ECG trace generated by the Zenicor‑ECG to make a final diagnosis of atrial fibrillation. Clinicians can view the analysis using the Zenicor Doctor System user interface via a web browser. The ECG trace is also available via this interface and can be downloaded or printed as a PDF.\n\n# The comparator\n\n## -lead ECG after an irregular pulse is detected\n\nThe comparator for this assessment is a 12-lead ECG, used to check for atrial fibrillation after an irregular pulse has been detected by manual pulse palpation. Clinical experts commented that an irregular pulse on manual pulse palpation is not thought to be sufficient to start anticoagulant treatment, so in this diagnostic pathway patients do not have treatment until a 12‑lead ECG confirms atrial fibrillation.\n\nClinical experts commented that there can be delays in arranging 12‑lead ECGs after an irregular pulse is detected, which can delay diagnosis of atrial fibrillation, or potentially miss paroxysmal atrial fibrillation because the initial examination did not include an ECG recording. The length of this delay will vary and depends on local arrangements for doing 12‑lead ECGs, for example, if this can be done in primary care or if a referral to secondary care is needed.", 'Evidence': "The diagnostics advisory committee (section\xa08) considered evidence on lead-I electrocardiogram (ECG) devices (imPulse, Kardia Mobile, MyDiagnostick and Zenicor-ECG) for detecting atrial fibrillation using single time point testing in primary care from several sources. Full details of all the evidence are in the committee papers. Evidence on the RhythmPad GP was removed from this guidance after consultation (see section\xa03.1). To make sure the committee papers are clear, the published diagnostics assessment report and extra relevant documents include the evidence assessed on RhythmPad GP.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) did a systematic review to identify evidence on the diagnostic accuracy and clinical effectiveness of using the lead‑I ECG devices to detect atrial fibrillation. Included studies were those that used the devices at a single time point to detect atrial fibrillation (rather than repeated use over a period of time). Because no studies were identified in the population of interest (people with signs and symptoms of atrial fibrillation and an irregular pulse on manual palpation), the EAG included studies done in a population who were asymptomatic. The EAG included in this definition people who did not present with signs and symptoms of atrial fibrillation (for example, breathlessness or palpitations) with or without a previous diagnosis of atrial fibrillation. It included people with other cardiovascular comorbidities and people who were attending a cardiovascular clinic.\n\nThe EAG divided their review into 2\xa0parts; studies reporting diagnostic accuracy of the devices and studies reporting the clinical effectiveness of the devices.\n\n## Diagnostic accuracy\n\nIn the diagnostic test accuracy review, 9\xa0studies were included. There is an overview of the included studies in table\xa01. All the studies either enrolled people with a known atrial fibrillation status (that is, people known to have atrial fibrillation and people with no history of the condition), or who were recruited from cardiology services. Only Desteghe et al. (2017) provided the reasons people were admitted to a cardiology service, with 3.4% admitted because of symptomatic atrial fibrillation.\n\nOnly 1\xa0study was done in primary care (Vaes et al. 2014), with the rest in secondary or tertiary care. There was 1\xa0study done in the UK (Williams et al. 2015). No published studies assessed the imPulse device.\n\nIn all studies the reference standard was a 12‑lead ECG interpreted by a trained healthcare professional (a cardiologist, electrophysiologist or GP with a special interest in cardiology). The index test (lead‑I ECG) and reference standard (12‑lead ECG) were both done within 6\xa0hours of each other in all but 1\xa0study (Vaes et al.). In this study the interval between tests was not reported.\n\n## Table 1 Overview of studies included in the EAG's diagnostic accuracy review\n\nDevice\n\nStudy\n\nPopulation in study\n\nInterpreter of device output\n\nKardia Mobile\n\nDesteghe et al. 2017a\n\n(Belgium)\n\nInpatients in a cardiology ward (35.6% had a history of atrial fibrillation)\n\nElectrophysiologists\n\nAlgorithm\n\nResults presented separately\n\nHaberman et al. 2015\n\n(USA)\n\nCardiology clinic patientsb\n\nElectrophysiologist\n\nKoltowski et al. 2017c\n\n(Poland)\n\nPeople in tertiary care\n\nCardiologist\n\nLau et al. 2013\n\n(Australia)\n\nPeople at a cardiology department (24% had a history of atrial fibrillation)\n\nAlgorithm\n\nWilliams et al. 2015\n\n(UK)\n\nPeople attending an atrial fibrillation clinic who were known to have atrial fibrillation and people with unknown atrial fibrillation status (who were attending the clinic for reasons unrelated to atrial fibrillation)\n\nCardiologist\n\nGP with special interest in cardiology\n\nResults presented separately\n\nMyDiagnostick\n\nDesteghe et al. 2017a\n\n(Belgium)\n\nInpatients in a cardiology ward (35.6% had a history of atrial fibrillation)\n\nElectrophysiologists\n\nAlgorithm\n\nResults presented separately\n\nTieleman et al. 2014\n\n(Netherlands)\n\nPeople attending an outpatient cardiology clinic or a specialised atrial fibrillation outpatient clinic\n\nAlgorithm\n\nVaes et al. 2014\n\n(Belgium)\n\nPeople known to have atrial fibrillation (83.4%) and people with no history of the condition invited to take part by GPs\n\nAlgorithm\n\nZenicor-ECG\n\nDoliwa et al. 2009\n\n(Sweden)\n\nPeople with atrial fibrillation, atrial flutter or sinus rhythm attending a cardiology outpatient clinic\n\nCardiologist\n\na Desteghe et al. assessed both Kardia Mobile and MyDiagnostick.\n\nb Results from additional study participants (healthy young adults and elite athletes) were not included in the EAG's analyses.\n\nc Koltowski et al. was only available as a conference proceeding.\n\nThe QUADAS-2 tool was used to assess study quality. For patient selection, the EAG judged that all 9\xa0studies had an unclear risk of bias and a high level of concern for applicability (because none were done in a population who had symptoms). For 1\xa0study there was limited information available in the publication; Koltowski et al. (2017) was only available as a conference proceeding.\n\nThe included studies varied in how the devices gave a positive result for atrial fibrillation. This was either based on the lead‑I ECG device's diagnostic algorithm or on clinician interpretation of an ECG trace generated by the devices. The EAG judged that studies in which the device output was interpreted by a trained healthcare professional were more applicable (low concern) than those in which a lead‑I ECG device algorithm alone was used (high concern; Lau et al. 2013, Tieleman et al. 2014 and Vaes et al. 2014). The EAG presented results in 2\xa0sections depending on how atrial fibrillation was identified (by a clinician or by the device's algorithm alone).\n\nData were included from 4\xa0studies, which assessed Kardia Mobile alone (Haberman et al. 2014; Williams et al. 2015), Kardia Mobile and MyDiagnostick (Desteghe et al. 2017) and Zenicor‑ECG alone (Doliwa et al. 2009).\n\nDesteghe et al. reported separate accuracy estimates from lead‑I ECGs interpreted by 2\xa0electrophysiologists; only pooled estimates using data from electrophysiologist\xa01 are shown in table\xa02 (values were similar when data from electrophysiologist\xa02 were used). Williams et al. reported separate accuracy estimates from lead‑I ECGs interpreted by a cardiologist or by a GP with a special interest in cardiology. Pooled accuracy estimates in table\xa03 used data from Williams et al. when the lead‑I ECG interpreter was a cardiologist (interpreters in other studies were cardiologists or electrophysiologists). Pooled accuracy estimates using data from Williams et al. when the interpreter was a GP with a special interest in cardiology (not shown) were similar. However, the study showed a decrease in specificity when the GP interpreted the lead‑I ECG; 76% (95% confidence interval [CI] 64% to 85%) compared with 86% (95% CI 76% to 94%) when the cardiologist interpreted them.\n\n## Table 2 Pooled diagnostic accuracy estimates for lead-I ECGs interpreted by a trained healthcare professional\n\nMeta-analysis\n\nLead-I devices in included studies (number of studies)\n\nPooled sensitivity % (95% CI)\n\nPooled specificity % (95% CI)\n\nAll devicesa,c\n\nKardia Mobile (3b,d), Zenicor-ECG (1e)\n\n\n\n(86.2 to 97.4)\n\n\n\n(90.4 to 98.8)\n\nAll devicesa,c\n\nKardia Mobile (2), MyDiagnostick (1b,f), Zenicor-ECG (1e)\n\n\n\n(83.8 to 95.0)\n\n\n\n(89.4 to 98.3)\n\nKardia Mobilea,c\n\nKardia Mobile (3d)\n\n\n\n(85.1 to 97.7)\n\n\n\n(88.0 to 99.2)\n\na Data from electrophysiologist 1 from Desteghe et al. 2017.\n\nb Data from Desteghe et al. 2017 from either Kardia Mobile or MyDiagnostick.\n\nc Data from Williams et al. 2015 from cardiologist interpreting lead-I ECG.\n\nd Desteghe et al. 2017; Haberman et al. 2015; Williams et al. 2015.\n\ne Doliwa et al. 2009.\n\nf Desteghe et al. 2017.\n\nOnly Kardia Mobile had sufficient studies to produce a device‑specific pooled estimate (see table\xa02). Accuracy estimates from individual studies for other devices are presented in table\xa03. The EAG commented that there were insufficient data to formally assess differences between the lead-I ECG devices.\n\n## Table 3 Individual study diagnostic accuracy estimates for lead-I ECGs interpreted by a trained healthcare professional\n\nLead-I ECG device\n\nStudy\n\nSensitivity % (95% CI)\n\nSpecificity % (95% CI)\n\nMyDiagnosticka\n\nDesteghe et al. 2017\n\n\n\n(62.0 to 97.0)\n\n\n\n(92.0 to 98.0)\n\nZenicor-ECG\n\nDoliwa et al. 2009\n\n\n\n(81.0 to 98.0)\n\n\n\n(86.0 to 100.0)\n\na Data from electrophysiologist 1 from Desteghe et al.\n\nFour\xa0studies that reported sensitivity and specificity of the lead‑I ECG device when the trace was interpreted by the device's algorithm alone were included in meta-analyses. Two studies reported data for MyDiagnostick alone (Tieleman et al. 2014; Vaes et al. 2014), 1\xa0study for Kardia Mobile alone (Lau et al. 2013) and 1\xa0study for both MyDiagnostick and Kardia Mobile (Desteghe et al. 2017). Pooled sensitivity and specificity estimates from meta‑analyses are presented in table\xa04.\n\n## Table 4 Pooled diagnostic accuracy estimates for lead-I ECG traces interpreted by device algorithm alone\n\nMeta-analysis\n\nLead-I devices in included studies (number of studies)\n\nPooled sensitivity % (95% CI)\n\nPooled specificity % (95% CI)\n\nAll devicesa\n\nKardia Mobile (1b), MyDiagnostick (3c)\n\n\n\n(86.0 to 99.0)\n\n\n\n(92.9 to 96.8)\n\nAll devicesa\n\nKardia Mobile (2d), MyDiagnostick (2e)\n\n\n\n(70.4 to 99.4)\n\n\n\n(94.2 to 97.6)\n\nMyDiagnostick\n\nMyDiagnostick (3c)\n\n\n\n(79.0 to 99.1)\n\n\n\n(91.9 to 96.2)\n\nKardia Mobile\n\nKardia Mobile (2d)\n\n\n\n(32.3 to 99.1)\n\n\n\n(95.1 to 98.5)\n\na Data from Desteghe et al. 2017 from either Kardia Mobile or MyDiagnostick.\n\nb Lau et al. 2013.\n\nc Desteghe et al. 2017; Tieleman et al. 2014; Vaes et al. 2014.\n\nd Desteghe et al. 2017; Lau et al. 2013.\n\ne Tieleman et al. 2014; Vaes et al. 2014.\n\nThe EAG noted that the companies who make the lead‑I ECG devices stated that atrial fibrillation should not be diagnosed using the algorithm alone; ECG traces produced by the devices should be reviewed by a qualified healthcare professional.\n\nThe EAG commented that the available data were not sufficient to formally assess differences between the different lead-I ECG devices. Desteghe et al. (2017) assessed the concordance between Kardia Mobile and MyDiagnostick. There was no statistically significant difference in agreement between the devices (based on kappa values) when assessing all patients (p=0.677) or after excluding those with an implanted device (for example, a pacemaker or implantable cardiac defibrillator; p=0.411).\n\nThe EAG commented that the pooled sensitivity and specificity values were similar across all the meta-analyses done, irrespective of how the lead‑I ECG trace was interpreted (algorithm or healthcare professional) or which lead‑I ECG devices were used (pooled estimates produced by the EAG used Kardia Mobile, MyDiagnostick and Zenicor-ECG).\n\nThe EAG identified further studies that reported sensitivity and specificity estimates of the lead‑I ECG devices. However, it did not include them in its main report because they did not meet 1 of the eligibility criteria for inclusion, that is, that the reference standard in the studies was not a 12‑lead ECG interpreted by a trained healthcare professional. Results were presented in appendix\xa06 of the diagnostics assessment report. They included 1\xa0unpublished study which assessed imPulse (no other studies were identified for this device). Ranges were reported for sensitivity (67% to 100%) and specificity (83% to 100%). These data were used in the economic model.\n\n## Evidence on clinical effectiveness of the lead-I ECG devices\n\nThe EAG included 19\xa0studies in its clinical effectiveness review. Of these, 7\xa0studies were done in primary care (Orchard et al. 2014; Chan et al. 2016; Chan et al. 2017; Gibson et al. 2017; Hussain and Thakrar, 2016; Kaasenbrood et al. 2016; Orchard et al. 2016). There were 2\xa0studies done in the UK (Gibson et al. 2017; Hussain and Thakrar, 2016). Of the studies, 13 included data for Kardia Mobile, 5\xa0for MyDiagnostick, 1\xa0for Zenicor-ECG and 1\xa0for imPulse. No studies were identified that assessed the clinical effectiveness of lead‑I ECG devices when used for people with signs and symptoms of atrial fibrillation presenting in primary care.\n\nThere were 13\xa0studies that reported diagnostic yield of atrial fibrillation detection by lead‑I ECG devices (various devices), which ranged from 0.38% to 5.84%. However, the location of testing varied between studies; primary care (6\xa0studies), secondary care (2\xa0studies), tertiary care (1\xa0study) and in the community (4\xa0studies). In the primary care studies, the range was 0.49% to 5.84%. None of the studies assessed people with signs and symptoms of atrial fibrillation. The enrolled populations varied from the general population or people who were attending primary care for a reason unrelated to atrial fibrillation (for example, for flu vaccination) to people admitted to a cardiology ward and people with known atrial fibrillation. The prevalence of atrial fibrillation in these populations is likely to vary and may not be applicable to the population that is the focus of this assessment. No data were found on any benefit of lead‑I ECGs in identifying people with paroxysmal atrial fibrillation, compared with later ECG testing.\n\nTest failure rate (which included both the device failing to produce a result and producing a poor-quality ECG trace) varied between 0.1% and 9% (various devices). Reasons suggested for uninterpretable lead‑I ECGs were sinus tachycardia or bradycardia, that patients had a tremor or that hospitalised patients were unable to hold the devices firmly enough.\n\nA study done in Australia (Lowres et al. 2014) reported a time to diagnosis of atrial fibrillation of 16.6\xa0days (standard deviation of 14.3\xa0days) from detection by an initial lead‑I ECG diagnostic test at a pharmacy to confirmed diagnosis with a 12‑lead ECG.\n\nTieleman et al. (2014) reported that people were able to use MyDiagnostick with minimal instructions. Chan et al. (2017) reported that Kardia Mobile was easy to use. Orchard et al. (2016) commented that it may be difficult for older people to hold the Kardia Mobile device still enough to take a reading. In Desteghe et al. (2017), 7% of people were excluded from the study because they could not hold the devices as intended (the study used both MyDiagnostick and Kardia Mobile).\n\nIn Hussain and Thakrar (2016), 5 out of 6\xa0people had a change in the clinical management of their condition after atrial fibrillation was detected by Kardia Mobile (1\xa0person died as an inpatient after referral to hospital). In Lowres et al. (2014), oral anticoagulants were prescribed for 6 out of 10\xa0new patients with atrial fibrillation detected by a lead‑I ECG followed by a 12‑lead ECG interpreted by a cardiologist.\n\nIn Orchard et al. (2016), which used Kardia Mobile, patients and GPs commented that they liked using the device. Chan et al. (2017) reported that all patients asked were willing to have further testing with Kardia Mobile at future GP visits, and 86% of GPs surveyed considered that the device was useful for atrial fibrillation screening and they would use it in their daily practice. Gibson et al. (2017) reported generally positive responses to using MyDiagnostick, although some issues with implementing use of the device were raised. A further study reported that Kardia Mobile was easily administered and that no one declined testing with the device (Hussain and Thakrar 2016). In Chan et al. (2017), interviewed patients commented that having access to the lead-I ECG device in the surgery was more convenient than having to attend another healthcare facility for a 12‑lead ECG.\n\nThe EAG also looked at unpublished evidence from a quality control audit on the use of Kardia Mobile across Eastbourne, Hailsham and Seaford clinical commissioning group and Hastings and Rother clinical commissioning group. This was provided by a specialist committee member as an example of an ongoing audit. Over a 2-year period the device was used in primary care or for home visits if people had an irregular pulse or signs of atrial fibrillation. There were 183\xa0ECG traces reported, identifying 128\xa0cases of atrial fibrillation from the lead‑I ECG trace alone. The proportion of people newly diagnosed with atrial fibrillation (69.9%) was considerably higher than the diagnostic yield in studies identified by the EAG (0.38% to 5.84%), although the audit was designed for quality control, and not to assess atrial fibrillation yield.\n\n# Cost effectiveness\n\n## Systematic review of cost-effectiveness evidence\n\nThe EAG did a systematic review to identify published full economic evaluations of lead‑I ECG devices for detecting atrial fibrillation. Studies were excluded if they assessed the devices for repeated ECG measurements (rather than at a single time point) or if they assessed the devices for screening a population or for an asymptomatic 'silent atrial fibrillation' population. The EAG did not identify any published studies that met their inclusion criteria. However, the EAG highlighted 2\xa0recently published economic evaluations (Welton et al. 2017 and Jacobs et al. 2018) that suggested that lead-I ECG devices may represent a cost-effective use of resources for systematic, opportunistic screening of people aged 65\xa0years and over during a routine GP appointment.\n\n## Modelling approach\n\nThe EAG developed a de novo economic model designed to evaluate the cost effectiveness of using the lead‑I ECG devices for single time point testing of people presenting in primary care with signs and symptoms of atrial fibrillation and who have an irregular pulse.\n\nThe model compared the effect of using a lead‑I ECG device in primary care for people with signs and symptoms of atrial fibrillation who have an irregular pulse (detected by manual pulse palpation) with standard diagnostic testing (that is, without the use of a lead‑I ECG device). The model was in 2\xa0phases: a diagnostic phase followed by a post-diagnostic phase.\n\nThis phase covered the initial assessment of people presenting in primary care with signs and symptoms of atrial fibrillation, and who have had manual pulse palpation that shows an irregular pulse. The model compared 2\xa0strategies: referral for a subsequent 12‑lead ECG to check for atrial fibrillation (standard diagnostic pathway) or having a lead‑I ECG in primary care at the same primary care appointment to check for atrial fibrillation (lead‑I ECG pathway) followed by a 12‑lead ECG if the clinician thought this was appropriate.\n\nThe diagnostic phase model covered the first 3\xa0months after the initial primary care appointment. By the end of the diagnostic phase, people have either been diagnosed as having atrial fibrillation, or no atrial fibrillation has been detected (either correctly or incorrectly). People diagnosed with atrial fibrillation can have anticoagulants and rate control treatment (beta blockers).\n\nPeople can have up to 2\xa0cerebrovascular events (transient ischaemic attack, ischaemic or haemorrhagic stroke), a non-major bleeding event, or die. This was modelled using a Markov model. The probability of having a cerebrovascular event for people with atrial fibrillation is reduced if they are taking anticoagulants. However, anyone taking anticoagulants has an associated higher risk of having a bleeding event.\n\nAfter the 3-month diagnostic phase model, people entered a second Markov model. This had the same structure as the Markov model in the diagnostic phase after a diagnosis has been made, but ran over a 30‑year timespan (with 3‑month cycles). People entered based on their history of cerebrovascular events (none, 1\xa0or\xa02) and they could have further cerebrovascular events, non‑major bleeding events, or die.\n\n## Model inputs\n\nThe starting age of the modelled cohort was 70\xa0years, and the model was run over 30\xa0years. The cohort consisted of people with signs and symptoms of atrial fibrillation including an irregular pulse. This included people with atrial fibrillation (assumed to be 20% based on clinical advice) and people without the condition (assumed to have either atrial or ventricular ectopy).\n\nEstimates of the diagnostic accuracy of the 4\xa0lead‑I ECG devices were obtained from the EAG's systematic review and meta-analyses. The EAG used estimates of accuracy based on healthcare professionals interpreting the ECG traces, because it assumed that atrial fibrillation would not be diagnosed based on a device's algorithm alone.\n\n## Table 5 Sensitivity and specificity values of lead-I ECG devices used in the economic model\n\nLead-I ECG\n\nInterpreter of ECG\n\nData source\n\nSensitivity %\n\nSpecificity %\n\nimPulse\n\nHealthcare professional\n\nReeves (unpublished)\n\na\n\na\n\nKardia Mobileb\n\nHealthcare professional\n\nPooled analysisc\n\n\n\n\n\nMyDiagnostick\n\nHealthcare professional\n\nDesteghe et al. (2017)d\n\n\n\n\n\nZenicor-ECG\n\nHealthcare professional\n\nDoliwa et al. (2009)\n\n\n\n\n\na EAG used the midpoint from the range reported in the Reeves report.\n\nb Alternative accuracy estimates based on a pooled estimate in which data from electrophysiologist\xa02 from Desteghe et al. were used in a scenario analysis; sensitivity 91.3%, specificity 97.4%.\n\nc Pooled estimate from 3 studies; see table 2.\n\nd Desteghe et al. reported accuracy estimates from 2 electrophysiologists. Estimates used in the base case were from electrophysiologist\xa01 (see table 3); values from electrophysiologist\xa02 were used in a scenario analysis (sensitivity of 80.0%, specificity of 98.0%).\n\nFor people with atrial fibrillation, the rate of mortality and cerebrovascular events (transient ischaemic attack, ischaemic or haemorrhagic stroke) in people who did not have anticoagulants was taken from Sterne et al. (2017). The effect of anticoagulants on the incidence of these events in people with atrial fibrillation was also taken from this study. For people without atrial fibrillation the rate of mortality and cerebrovascular events was taken from various sources (for example, Public Health England report, Office for National Statistics report, Rothwell et al. 2005). The risk of cerebrovascular events and mortality for people with untreated atrial fibrillation does not vary by type of atrial fibrillation. That is, risk is the same for paroxysmal, permanent and persistent atrial fibrillation. After people have a cerebrovascular event, their risk of mortality increases. The EAG assumed that this risk was 2.6\xa0times greater based on a study of stroke survivors in Norway (Mathisen et al. 2016). The risk of having a further cerebrovascular event was based on a meta-analysis of stroke survivors (Mohan et al. 2011) with increased risk in the first year, then a lower risk from year\xa02 onwards.\n\nThe risk of clinically relevant bleeding is increased for people who have anticoagulants, based on Sterne et al. (2017). This is the case for people with or without atrial fibrillation.\n\n## Costs\n\nAnnual costs of the devices used in the base-case model are shown in table 6. Because the lead‑I ECG could be used outside the scope of this assessment, the EAG also did a scenario analysis that excluded the costs of the devices. No extra cost was included for administering and interpreting the lead‑I ECG because it was assumed that this could be done during a standard GP consultation.\n\n## Table 6 Estimated annual costs of lead-I ECG devices\n\nLead-I ECG\n\nItem\n\nUnit cost (£)\n \n c\n\nExpected lifespan (years)\n\nAnnual cost (£)\n\nUnit cost per test\n \n b\n \n (£)\n\nimPulse\n\nDevice\n\n\n\n\n\n\n\n\n\nKardia Mobile\n\nDevice\n\n\n\n\n\na\n\n\n\nMyDiagnostick\n\nDevice\n\n\n\n\n\n\n\n\n\nZenicor-ECG\n\nDevice and 36-month licence\n\n,980\n\n\n\n\n\n\n\nExtra 36-month licence\n\n,780\n\n\n\na Costs of any additional tablet or device needed not included (the effect of this additional cost is assessed in scenario analysis F).\n\nb Assumes 54\xa0people tested per year.\n\nc Excluding VAT.\n\nThe EAG devised base cases that differed depending on where 12‑lead ECGs were done. If a 12‑lead ECG was done in primary care, the cost of administering it was assumed to be £12.34. This was based on the costs of the device, disposables and staff time to do and interpret the ECG. The cost of administering a 12‑lead ECG in secondary care was assumed to be £52 (from NHS reference costs). The cost of Holter monitoring (for 7\xa0days) was assumed to be £120.23.\n\nCosts for anticoagulant (apixaban) and rate control (beta blockers) treatment were obtained from the British national formulary and NHS drug tariff. Costs of bleeding events and transient ischaemic attack were taken from NHS reference costs. Age and sex-adjusted 1-\xa0and 5‑year costs for strokes were from the Sentinel Stroke National Audit Programme's cost and cost-effectiveness report (2016).\n\nBerg et al. (2010) was used to provide utility values for people with atrial fibrillation (see table\xa07). Beta blockers were assumed to improve symptoms for people with atrial fibrillation.\n\n## Table 7 Utility values used in base-case economic model (at age\xa070; age- and sex-adjusted)\n\n\n\nAtrial fibrillation status (95% CI)\n\nAtrial fibrillation\n\nNo atrial fibrillation\n\nUntreated\n\n(0.537 to 0.881)\n\n(0.480 to 0.942)\n\nTreated\n\n(0.480 to 0.942)\n\n(0.480 to 0.942)\n\nPeople without atrial fibrillation were assumed to be having a short symptomatic episode caused by atrial or ventricular ectopy that resolved quickly. For people who had an ischaemic or haemorrhagic stroke, a lifetime utility decrement was applied at the time of the first stroke (no further decrements were applied for subsequent strokes). The size of the decrement was −0.272 (95% CI −0.345 to −0.198) for both types of stroke. Transient ischaemic attacks and bleeding events were assumed to have no long-term effect on health-related quality of life, and no utility decrement was applied for these events.\n\n## Base-case assumptions\n\nThe following assumptions were applied in the base-case analyses:\n\nOf the people presenting in primary care with signs and symptoms of atrial fibrillation, and who have an irregular pulse, 20% have atrial fibrillation.\n\nOf the people with atrial fibrillation, 50% have paroxysmal atrial fibrillation. The EAG commented that there is a lack of evidence on the prevalence of paroxysmal atrial fibrillation in people with symptoms, and noted that a recent study (Welton et al. 2017) had reported wide variation in prevalence (although not necessarily in a symptomatic population). The effect of varying this prevalence was investigated in sensitivity analysis.\n\nAdditional interpretation by a cardiologist is needed for 10% of lead‑I ECG tests.\n\nThe 12-lead ECGs have 100% sensitivity and specificity for atrial fibrillation (if a person is in atrial fibrillation at the time of the test).\n\nFor 48% of people with paroxysmal atrial fibrillation the episode will have stopped by the time a 12‑lead ECG is done (2 or 14\xa0days after the initial primary care consultation when an irregular pulse is detected). This is based on data from Israel et al. (2004).\n\nHolter testing for paroxysmal atrial fibrillation is assumed to have 100% sensitivity and specificity (if atrial fibrillation occurs during testing). Holter testing is assumed to be for 7\xa0days and 70% people with atrial fibrillation are assumed to have an episode in that time (based on data from Kirchoff et al. 2006).\n\nIn the standard diagnostic pathway, 50% of people who have a negative 12‑lead ECG have Holter testing. In the lead‑I ECG pathway, 80% of people who have a negative lead‑I ECG have a 12‑lead ECG. If the 12-lead ECG is negative, 50% of people have Holter testing. Of the 20% of people who are not referred for a 12‑lead ECG after a negative lead‑I ECG, 50% have Holter testing.\n\nOnly people who are diagnosed with atrial fibrillation and who have a CHA2DS2-VASc score of\xa02 or more have anticoagulants. There are 82.4% of people with atrial fibrillation assumed to have a CHA2DS2-VASc score of\xa02 or more, and 81.2% of these are assumed to take anticoagulants (based on NHS Quality and Outcomes Framework 2016/2017 indicator AF007).\n\nPeople having anticoagulants have apixaban (simplifying assumption).\n\nTreatment with anticoagulants starts immediately after a positive lead-I ECG result (simplifying assumption).\n\nPeople whose atrial fibrillation is undetected and who have a cerebrovascular event are assumed to have their atrial fibrillation diagnosed as part of treatment.\n\n## Base-case results\n\nThe EAG produced 4\xa0base cases, depending on when and where 12‑lead ECGs were done:\n\nbase case 1: 12-lead ECG in primary care (2\xa0days later)\n\nbase case 2: 12-lead ECG in primary care (14\xa0days later)\n\nbase case 3: 12-lead ECG in secondary care (2\xa0days later)\n\nbase case 4: 12-lead ECG in secondary care (14\xa0days later).\n\nIn pairwise analyses, all the lead-I ECG devices were compared independently with the standard pathway (that is, no use of a lead-I ECG device). Results were similar across the 4\xa0base cases, and in probabilistic analyses. The results from base-case\xa01 are shown in table\xa08.\n\n## Table 8 Base case 1: Pairwise cost-effectiveness analysis (compared with standard pathway)\n\n\n\nTotal costs (£)\n\nTotal QALYs\n\nIncremental costs (£)\n\nIncremental QALYs\n\nICER (£)\n\nStandard pathway\n\n,187\n\n\n\n–\n\n–\n\n–\n\nKardia Mobile\n\n,551\n\n\n\n,364\n\n\n\n,060\n\nimPulse\n\n,745\n\n\n\n,557\n\n\n\n,165\n\nMyDiagnostick\n\n,233\n\n\n\n,046\n\n\n\n,638\n\nZenicor-ECG\n\n,468\n\n\n\n,281\n\n\n\n,462\n\nIn fully incremental analyses across all the base cases, all lead‑I ECG devices were dominated by Kardia Mobile (that is, Kardia Mobile cost less but produced more quality-adjusted life years [QALYs]). The incremental cost-effectiveness ratios (ICERs) for Kardia Mobile compared with the standard pathway were the same as for the pairwise comparison (less than £1,100 per QALY gained). At consultation, the company who makes MyDiagnostick proposed new costs for their device. The EAG ran the base-case analysis again using these costs in an addendum to the diagnostics assessment report. This resulted in lower costs for MyDiagnostick, but did not affect the EAG's overall conclusions on the pairwise cost-effectiveness analysis.\n\n## Analysis of alternative scenarios\n\nThe EAG investigated the effect of varying some of the base-case assumptions in scenario analyses. This included assessing the effect of adding the cost of a smartphone or tablet (including the cost of a data network) for Kardia Mobile in a threshold analysis. The EAG commented that a smartphone or tablet would need to cost more than £2,850 for Kardia Mobile to no longer dominate the other lead-I ECG devices. The ICER for Kardia Mobile compared with the standard pathway remained less than £20,000 per QALY gained if a smartphone or tablet costs less than £24,362. Using alternative accuracy estimates for MyDiagnostick and Kardia Mobile (using results from electrophysiologist\xa02 from Desteghe et al.) resulted in Kardia Mobile having an ICER of £5,503 per QALY gained compared with MyDiagnostick. Compared with the standard pathway MyDiagnostick dominated. The Zenicor‑ECG was no longer dominated, but had an ICER of £242,994 per QALY gained when compared with Kardia Mobile.\n\nThe model was most sensitive to the proportion of patients whose atrial fibrillation was paroxysmal (assumed to be 50% in the base case) in one-way analyses for all of the lead-I ECG devices. Cost effectiveness improved as the proportion of paroxysmal atrial fibrillation increased. Conversely, lower estimates of the proportion of paroxysmal atrial fibrillation made the devices less cost effective (increased incremental costs and decreased incremental QALYs).\n\nIn a probabilistic sensitivity analysis (done in base case\xa01) all other lead‑I ECG devices were dominated by Kardia Mobile in a fully incremental analysis. In pairwise comparisons with the standard pathway, ICERs were similar to the deterministic results, and all were less than £17,000 per QALY gained.", 'Committee discussion': "The committee discussed the effects of atrial fibrillation. The clinical experts commented that earlier diagnosis of atrial fibrillation may reduce a person's risk of stroke because anticoagulation treatment could be started sooner, if appropriate. Also, earlier treatment with rate control drugs, such as beta blockers, can stop associated symptoms and may improve quality of life, although both types of treatment are associated with a risk of side effects. Comments submitted by a patient expert highlighted that atrial fibrillation can go undiagnosed for months or even years. It is common for people to have anxiety, depression and fear while living with the symptoms of atrial fibrillation, particularly when the cause of the symptoms is unknown. If atrial fibrillation is not treated, people are at higher risk of a stroke. The clinical experts commented that atrial fibrillation‑related stroke can be extremely disabling and debilitating, with family members often becoming full-time carers to the people affected. The committee was aware that improving detection of atrial fibrillation is therefore a priority for the healthcare system. It concluded that earlier diagnosis could be important to reduce the risk of stroke and its associated effects for people with the condition.\n\nThe committee asked how suspected atrial fibrillation is currently investigated in people presenting in primary care. The clinical experts commented that an electrocardiogram (ECG) is needed to determine whether atrial fibrillation is present, but delays in doing an ECG often prevent atrial fibrillation being diagnosed, particularly if it is paroxysmal. They explained that episodes of paroxysmal atrial fibrillation usually stop within 48\xa0hours without treatment. This can lead to it being missed if an ECG is not done immediately. Earlier access to an ECG, such as a lead‑I ECG that can be done during a GP consultation, would increase the chances of atrial fibrillation that is causing symptoms being detected. It would also mean that preventative treatment is not delayed. Alternatively, if symptoms are present but no arrhythmia can be seen on an ECG this can help to rule out atrial fibrillation as a cause. The clinical experts also commented that many GP practices cannot do a 12‑lead ECG immediately because they do not have the equipment on site or because staff are not available to do, or interpret, the test. Ambulatory ECG monitoring may need to be done, which needs multiple visits to a hospital. The committee concluded that the availability of lead-I ECGs could improve access to testing for people with symptoms of atrial fibrillation.\n\n# Clinical effectiveness\n\nThe committee considered the studies included in the diagnostic accuracy review. It noted that the external assessment group (EAG) had concerns over the applicability of several of the studies because lead‑I ECG traces were interpreted by the device's algorithms alone, rather than by a trained healthcare professional. It noted that the companies stated that the algorithms alone should not be used to diagnose atrial fibrillation. Clinical experts highlighted the importance of having trained healthcare professionals review ECG traces generated by the lead‑I ECG devices. This is to confirm or exclude atrial fibrillation and to check any algorithm outputs, and therefore inform treatment decisions. The committee noted that the trained healthcare professionals interpreting the ECGs in the identified studies were generally cardiologists or electrophysiologists, who may be more experienced in interpreting ECG traces than GPs. In 1\xa0study (Williams et al. 2015), in which the interpreter was a GP with a special interest in cardiology, specificity estimates were lower than those obtained when a cardiologist interpreted the trace. Also, accuracy estimates of the devices varied between the 2\xa0electrophysiologists in Desteghe et al. (2017), suggesting that interpretation of the lead‑I ECG traces is likely to be subject to inter-observer variability. The committee concluded that it was important that decisions about treatment based on lead‑I ECG traces are made only after review by a trained healthcare professional, because this may have a substantial effect on false results.\n\nThe committee noted that the populations varied in the studies included in the EAG's diagnostic accuracy review. Most of the studies were done in people who did not report symptoms of atrial fibrillation, but who were attending cardiology services because of an underlying cardiac problem. It recalled that the EAG had highlighted this as a generalisability issue. The clinical experts explained that because the populations in the included studies tended to be older, the burden of atrial fibrillation would be expected to be greater than in a truly asymptomatic population. The committee considered that the absence of studies that were directly applicable to the population in this assessment was not ideal. But it concluded that the available studies provided a reasonable estimate of the ability of the devices to correctly identify atrial fibrillation.\n\nThe committee considered the diagnostic accuracy data that were available for each of the devices. It noted that 5\xa0studies were available for Kardia Mobile, 3\xa0for MyDiagnostick and 1\xa0for Zenicor-ECG. The committee also noted that there was uncertainty about whether current versions of the algorithms had been used in the diagnostic accuracy studies for the lead‑I ECG devices. Most of the studies compared each of the devices with a 12‑lead ECG and did not include formal comparisons of the devices. There was 1\xa0study (Desteghe et al. 2017) that assessed concordance between MyDiagnostick and Kardia Mobile and reported no statistically significant difference. The committee concluded that the available accuracy data were limited and were not sufficient to assess differences in accuracy between the lead-I ECG devices.\n\nThe committee considered the reference standard used in the identified diagnostic accuracy studies: a 12‑lead ECG done within about 6\xa0hours of the lead‑I ECGs. It noted that the comparator for this assessment was a 12‑lead ECG done several days after the initial GP appointment where the irregular pulse was detected. The EAG identified no studies showing that lead‑I ECGs increased detection of atrial fibrillation when compared with 12‑lead ECGs done later after an irregular pulse was detected. It noted that studies identified by the EAG that reported diagnostic yield of atrial fibrillation were not done in a population who had symptoms, which is the focus of this assessment. The committee recalled that the potential value of the devices in this context was increased detection of atrial fibrillation, particularly paroxysmal, compared with a 12‑lead ECG done later (see section\xa05.2). It concluded that the identified data did not allow the committee to assess the likely clinical effect of the lead‑I ECG devices in increasing detection of atrial fibrillation compared with current practice (that is, a 12‑lead ECG done later).\n\n# Cost effectiveness\n\nThe committee considered the cost per use of the lead‑I ECG devices assumed in the model. It heard that the lifespan of MyDiagnostick was incorrect in the original report, but noted that the EAG had corrected this. The committee questioned the expected average number of people seen by a full-time GP per year that the EAG had used to estimate the cost per use of the devices, noting evidence from NHS Digital that the average number of people per GP is potentially higher. The EAG commented that its estimate was conservative and that if the average number of people per GP was higher this would reduce the cost per use of the devices and improve the cost-effectiveness estimates. The committee also questioned whether the model included the costs of training to use the device. The EAG explained that this was not explicitly included, but it had looked at the effect of increasing the costs of using the lead‑I ECG devices and the cost-effectiveness estimates were robust to increases in the costs per use. The committee concluded that, although there were uncertainties in the costs per use assumed in the model, they were not a key driver of the results.\n\nThe committee discussed the costs associated with interpreting the lead-I ECG traces in practice and considered whether these had been adequately captured in the model. It noted its conclusion that the ECG traces from the devices need to be interpreted by a trained healthcare professional to diagnose atrial fibrillation and make decisions about treatment (see section\xa05.3). The clinical experts explained that there is likely to be wide variation in the ability of GPs to interpret ECGs, and that some practices may use centralised services for this. The committee concluded that there was uncertainty about how lead‑I ECGs generated in primary care would be interpreted in practice, and therefore the effect on staff time and costs associated with introducing lead‑I ECGs into primary care. Further research was recommended to assess this (see section\xa06.2).\n\nThe committee considered the risk of bleeding associated with anticoagulant treatment, and noted that the model assumed that all patients have direct oral anticoagulants. It noted that people incorrectly identified as having atrial fibrillation by the lead‑I ECG devices in the model (false positive results) were assumed to have anticoagulants, and so were at risk of bleeding. The clinical experts explained that false positive results were likely to be caused by atrial ectopy, a benign condition that is not associated with an increased risk of stroke. They also commented that this group of people was likely to continue anticoagulants over the longer term, unless they chose to stop treatment. The committee questioned whether the risk of bleeding had been adequately captured in the analyses. The EAG explained that the model did allow for people to have bleeding events, and that a scenario analysis in the addendum including a quality-adjusted life year (QALY) decrement for minor bleeds had very similar results to the base-case analysis. The committee noted that the EAG's model did not account for any excess mortality in people who had a haemorrhagic stroke because of anticoagulants. The EAG commented that the increase in the number of bleeds in the model caused by adopting lead‑I ECGs was very small. The clinical experts commented that lead‑I ECG traces are reviewed by trained healthcare professionals, which helps to minimise the risk of false positive diagnoses. The committee concluded that there was some uncertainty about whether the model had captured all the adverse effects caused by anticoagulants.\n\nThe committee noted that the model was sensitive to an assumption about the proportion of cases of atrial fibrillation that are paroxysmal. The EAG explained that because of a lack of evidence this had been assumed to be 50% in the base case. The clinical experts commented that about 25% of atrial fibrillation is likely to be paroxysmal, and that the proportion in the modelled population is unlikely to be less than this. If the proportion of paroxysmal atrial fibrillation was set to 25% in the model, the incremental cost-effectiveness ratio (ICER) for Kardia Mobile compared with the standard pathway was about £7,500 per QALY gained, an increase from £1,060 per QALY gained in base case\xa01, in which it dominated the other lead‑I ECG devices. As the proportion of paroxysmal atrial fibrillation was decreased the ICER increased, to around £250,000 per QALY gained when the prevalence was set to\xa00. The committee concluded that because there were no data on the proportion of people with symptomatic atrial fibrillation that is paroxysmal the cost-effectiveness estimates were highly uncertain.\n\nThe EAG commented that most of the patient benefits in the model (from the use of the lead‑I ECG devices compared with the standard pathway) came from an estimated increase in detection of people with paroxysmal atrial fibrillation. However, the committee recalled that no clinical evidence had been identified that showed that lead‑I ECG devices increased the detection of people with atrial fibrillation compared with a later 12‑lead ECG in practice (see section\xa05.6). The EAG had made assumptions in the model to estimate the effect of the likely increase in detection of paroxysmal atrial fibrillation associated with the lead‑I ECG devices. However, because of a lack of data, it was unclear whether this increase would occur in clinical practice. The committee concluded that although there is plausible potential for the lead‑I ECG devices to be cost effective when used for single time point testing in primary care (for people with signs and symptoms of atrial fibrillation with an irregular pulse), there was insufficient evidence at present to determine if the predicted benefits of using the devices would be realised in practice. The committee considered that further research would help to address this (see section\xa06.1).\n\nThe committee considered the usability of the devices and noted that the EAG identified several studies reporting that the devices were easy to use and were liked by patients and healthcare professionals. However, it noted that 1\xa0study (Desteghe et al.) reported that up to 7% of people were not able to use the devices because they were unable to hold them as recommended by the companies. A patient expert submitted comments that some people may need help in holding the devices while a recording is taken, for example people who have had a stroke or people with arthritis. The committee concluded that healthcare professionals should bear this in mind when using the devices and encouraged the companies to improve the usability of their devices for these groups of people.\n\nThe committee considered the results of the fully incremental economic analyses (see sections\xa04.43 and 4.46). It noted that all lead-I ECG devices were dominated by Kardia Mobile (that is, using the Kardia Mobile cost less but produced more QALYs). However, the committee recalled its earlier conclusion that the available accuracy data for the lead‑I ECG devices were limited and were not sufficient to assess differences in accuracy between the lead-I ECG devices (see section\xa05.5). It also noted that the Kardia Mobile did not dominate in all simulations in the probabilistic sensitivity analysis. The committee concluded that there was considerable uncertainty about the relative cost effectiveness of the different lead‑I ECG devices, and that a conclusion about which device was most cost effective could not be made from the available data.\n\n# Research considerations\n\nThe clinical experts explained that lead‑I ECG devices were increasingly being used in primary care settings. The committee noted that Academic Health Science Networks (AHSNs) are assessing the effect of introducing lead‑I ECG devices into primary and community care, although their project is broader than the scope of this assessment. The committee considered consultation responses on the AHSN project. It noted that data collected as part of the project may be relevant to the population covered by this guidance and could help answer some of the uncertainties identified on the system impact of adopting the devices (see section\xa06.2). Clinical experts explained their processes to ensure appropriate governance of patient information when using these devices to detect atrial fibrillation. The committee noted the importance of this and concluded that centres should ensure appropriate information governance is in place for these devices.\n\nThe committee heard that the focus of the AHSN project is to evaluate the extent of spread and adoption of the mobile ECG technology and to describe the optimum environment for implementing a national procured innovation. It is not an evaluation of the technology itself. The committee concluded that data collected as part of the AHSN project were unlikely to resolve uncertainty about the extent of any increased detection of atrial fibrillation by the devices compared with current practice (see section\xa06.1) and that further research would be needed to address this.", 'Recommendations for further research': 'The committee recommended further research to determine if using the lead‑I electrocardiogram (ECG) devices in primary care for people with signs or symptoms of atrial fibrillation, and an irregular pulse, increases the number of people with atrial fibrillation (including paroxysmal) detected, compared with current practice (that is, a 12‑lead ECG done later). The committee considered the feasibility of collecting data to see if using the lead‑I ECG devices increased the detection of atrial fibrillation that would be missed if only 12‑lead ECGs done later were available. It noted that even if a lead‑I ECG is used and atrial fibrillation is detected, a subsequent 12‑lead ECG would still be done to check for structural cardiac abnormalities and inform further management decisions. The committee concluded that practices using lead‑I ECG devices could determine the number of additional cases of atrial fibrillation detected by the devices. This can be done by identifying people with a confirmed positive lead‑I ECG for atrial fibrillation who subsequently had a 12‑lead ECG that was negative because the atrial fibrillation had stopped. The committee also considered that data collected on the time between the initial lead‑I ECG and the subsequent 12‑lead ECG would be useful.\n\nThe committee recommended that data should be collected to evaluate the system impact of adopting the lead‑I ECGs on both primary and secondary care. In particular, data should be collected on how ECGs generated by the devices would be interpreted in practice, including staff time needed to interpret the ECG traces and associated costs.'}
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https://www.nice.org.uk/guidance/dg35
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Evidence-based recommendations on lead-I electrocardiogram (ECG) devices (imPulse, Kardia Mobile, MyDiagnostick and Zenicor-ECG) for detecting symptomatic atrial fibrillation using single time point testing in primary care.
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nice
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Crohn's disease: management
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Crohn's disease: management
This guideline covers managing Crohn’s disease in children, young people and adults. It aims to reduce people’s symptoms and maintain or improve their quality of life.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Providing information and support
Ensure that information and advice about Crohn's disease:
is age appropriate
is of the appropriate cognitive and literacy level
meets the cultural and linguistic needs of the local community.
Discuss treatment options and monitoring with the person with Crohn's disease, with their family members or carers (as appropriate), and within the multidisciplinary team. Apply the principles in the NICE guideline on patient experience in adult NHS services.
Discuss the possible nature, frequency and severity of side effects of drug treatment with people with Crohn's disease and their family members or carers (as appropriate). Appendices L and M of the full guideline contain observational data on adverse events associated with aminosalicylate treatment and immunosuppressives.
Give all people with Crohn's disease and their family members or carers (as appropriate) information, advice and support in line with published NICE guidance on:
smoking cessation
patient experience
medicines adherence
fertility.
Give people with Crohn's disease and their family members or carers additional information on the following when appropriate:
possible delay of growth and puberty in children and young people
diet and nutrition
fertility and sexual relationships
prognosis
side effects of their treatment
cancer risk
surgery
transition between paediatric and adult services
contact details for support groups.
Offer people with Crohn's disease and their family members or carers (as appropriate) age‑appropriate multidisciplinary support to deal with any concerns about the disease and its treatment, including concerns about body image, living with a chronic illness, and attending school and higher education.
# Inducing remission in Crohn's disease
## Monotherapy
In May 2019, the use of some medicines was off label:
: budesonide in children and young people
: mesalazine, olsalazine and balsalazide.
See NICE's information on prescribing medicines.
Offer monotherapy with a conventional glucocorticosteroid (prednisolone, methylprednisolone or intravenous hydrocortisone) to induce remission in people with a first presentation or a single inflammatory exacerbation of Crohn's disease in a 12‑month period.
Consider enteral nutrition as an alternative to a conventional glucocorticosteroid to induce remission for:
children in whom there is concern about growth or side effects
young people in whom there is concern about growth.
Consider budesonide for a first presentation or a single inflammatory exacerbation in a 12‑month period for people:
who have one or more of distal ileal, ileocaecal or right-sided colonic disease (see the recommendations on when to consider surgery early in the course of the disease in the section on Crohn's disease limited to the distal ileum) and
if conventional glucocorticosteroids are contraindicated, or if the person declines or cannot tolerate them. Explain that budesonide is less effective than a conventional glucocorticosteroid, but may have fewer side effects.
Consider aminosalicylate treatment for a first presentation or a single inflammatory exacerbation in a 12‑month period if conventional glucocorticosteroids are contraindicated, or if the person declines or cannot tolerate them. Explain that aminosalicylates are less effective than a conventional glucocorticosteroid or budesonide but may have fewer side effects than a conventional glucocorticosteroid.
Do not offer budesonide or aminosalicylate treatment for severe presentations or exacerbations.
Do not offer azathioprine, mercaptopurine or methotrexate as monotherapy to induce remission.
## Add‑on treatment
In May 2019, the use of some medicines was off label:
: budesonide (in children and young people), mercaptopurine, and most preparations of azathioprine
: mercaptopurine and most preparations of azathioprine
: some formulations of methotrexate (in adults), all formulations of methotrexate (in children and young people), and budesonide (in children and young people)
: some formulations of methotrexate (in adults), all formulations of methotrexate (in children and young people), mercaptopurine, and most preparations of azathioprine.
See NICE's information on prescribing medicines.
Consider adding azathioprine or mercaptopurine to a conventional glucocorticosteroid or budesonide to induce remission of Crohn's disease if:
there are 2 or more inflammatory exacerbations in a 12‑month period or
the glucocorticosteroid dose cannot be tapered.
Assess thiopurine methyltransferase (TPMT) activity before offering azathioprine or mercaptopurine. Do not offer azathioprine or mercaptopurine if TPMT activity is deficient (very low or absent). Consider azathioprine or mercaptopurine at a lower dose if TPMT activity is below normal but not deficient (according to local laboratory reference values).
Consider adding methotrexate (follow British national formulary /British national formulary for children cautions) to a conventional glucocorticosteroid or budesonide to induce remission in people who cannot tolerate azathioprine or mercaptopurine, or in whom TPMT activity is deficient, if:
there are 2 or more inflammatory exacerbations in a 12‑month period or
the glucocorticosteroid dose cannot be tapered.
Monitor the effects of azathioprine, mercaptopurine and methotrexate as advised in the BNF or BNFC. Consult the monographs of individual drugs for advice on monitoring immunosuppressives. Monitor for neutropenia in people taking azathioprine or mercaptopurine even if they have normal TPMT activity.
Ensure that there are documented local safety monitoring policies and procedures (including audit) for people receiving treatment that needs monitoring. Nominate a member of staff to act on abnormal results and communicate with GPs, people with Crohn's disease and their family members or carers (as appropriate).
## Infliximab and adalimumab
The recommendations in the following section (except for the recommendation on discussing the options of monotherapy or combined therapy) are from the NICE technology appraisal guidance on infliximab and adalimumab for the treatment of Crohn's disease.
Infliximab and adalimumab, within their licensed indications, are recommended as treatment options for adults with severe active Crohn's disease (see recommendation 1.2.18) whose disease has not responded to conventional therapy (including immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab or adalimumab should be given as a planned course of treatment until treatment failure (including the need for surgery), or until 12 months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see recommendation 1.2.16) to determine whether ongoing treatment is still clinically appropriate.
Treatment as described in recommendation 1.2.12 should normally be started with the less expensive drug (taking into account drug administration costs, required dose and product price per dose). This may need to be varied for individuals because of differences in the method of administration and treatment schedules.
When a person with Crohn's disease is starting infliximab or adalimumab (in line with recommendations 1.2.12, 1.2.15, 1.2.17 and 1.2.20), discuss options of:
monotherapy with one of these drugs or
combined therapy (either infliximab or adalimumab, combined with an immunosuppressant). Tell the person there is uncertainty about the comparative effectiveness and long‑term adverse effects of monotherapy and combined therapy.
Infliximab, within its licensed indication, is recommended as a treatment option for people with active fistulising Crohn's disease whose disease has not responded to conventional therapy (including antibiotics, drainage and immunosuppressive treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab should be given as a planned course of treatment until treatment failure (including the need for surgery) or until 12 months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see recommendation 1.2.16) to determine whether ongoing treatment is still clinically appropriate.
Treatment with infliximab or adalimumab (see recommendations 1.2.12 and 1.2.15) should only be continued if there is clear evidence of ongoing active disease as determined by clinical symptoms, biological markers and investigation, including endoscopy if necessary. Specialists should discuss the risks and benefits of continued treatment with patients and consider a trial withdrawal from treatment for all patients who are in stable clinical remission. People who continue treatment with infliximab or adalimumab should have their disease reassessed at least every 12 months to determine whether ongoing treatment is still clinically appropriate. People whose disease relapses after treatment is stopped should have the option to start treatment again.
Infliximab, within its licensed indication, is recommended for the treatment of people aged 6 to 17 years with severe active Crohn's disease whose disease has not responded to conventional therapy (including corticosteroids, immunomodulators and primary nutrition therapy), or who are intolerant of or have contraindications to conventional therapy. The need to continue treatment should be reviewed at least every 12 months.
For the purposes of this guidance, severe active Crohn's disease is defined as very poor general health and one or more symptoms such as weight loss, fever, severe abdominal pain and usually frequent (3 to 4 or more) diarrhoeal stools daily. People with severe active Crohn's disease may or may not develop new fistulae or have extra‑intestinal manifestations of the disease. This clinical definition normally, but not exclusively, corresponds to a Crohn's Disease Activity Index (CDAI) score of 300 or more, or a Harvey‑Bradshaw score of 8 to 9 or above.
When using the CDAI and Harvey‑Bradshaw Index, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the scores and make any adjustments they consider appropriate.
Treatment with infliximab or adalimumab should only be started and reviewed by clinicians with experience of TNF inhibitors and of managing Crohn's disease.
## Ustekinumab and vedolizumab
For guidance on using ustekinumab, see the NICE technology appraisal guidance on ustekinumab for moderately to severely active Crohn's disease after previous treatment.
For guidance on using vedolizumab, see the NICE technology appraisal guidance on vedolizumab for treating moderately to severely active Crohn's disease after prior therapy.
# Maintaining remission in Crohn's disease
Discuss with people with Crohn's disease and their family members or carers (as appropriate) options for managing their disease when they are in remission, including both no treatment and treatment. The discussion should include the risk of inflammatory exacerbations (with and without drug treatment) and the potential side effects of drug treatment. Record the person's views in their notes.
Offer colonoscopic surveillance in line with the NICE guideline on colorectal cancer prevention: colonoscopic surveillance in adults with ulcerative colitis, Crohn's disease or adenomas.
## Follow‑up during remission for people who choose not to have maintenance treatment
When people choose not to receive maintenance treatment:
discuss and agree with them and their family members or carers (as appropriate) plans for follow‑up, including the frequency of follow‑up and who they should see
ensure they know which symptoms may suggest a relapse and should prompt a consultation with their healthcare professional (most frequently, unintended weight loss, abdominal pain, diarrhoea, general ill‑health)
ensure they know how to access the healthcare system if they experience a relapse
discuss the importance of not smoking.
## Maintenance treatment for people who choose this option
In May 2019, the use of some medicines was off label:
and 1.3.5: mercaptopurine and most preparations of azathioprine
: some formulations of methotrexate (in adults), all formulations of methotrexate (in children and young people).
See NICE's information on prescribing medicines.
Offer azathioprine or mercaptopurine as monotherapy to maintain remission when previously used with a conventional glucocorticosteroid or budesonide to induce remission.
Consider azathioprine or mercaptopurine to maintain remission in people who have not previously received these drugs (particularly people with adverse prognostic factors such as early age of onset, perianal disease, glucocorticosteroid use at presentation and severe presentations).
Consider methotrexate (follow BNF/BNFC cautions) to maintain remission only in people who:
needed methotrexate to induce remission or
have tried but did not tolerate azathioprine or mercaptopurine for maintenance or
have contraindications to azathioprine or mercaptopurine (for example, deficient thiopurine methyltransferase activity or previous episodes of pancreatitis).
Do not offer a conventional glucocorticosteroid or budesonide to maintain remission.
See recommendations 1.2.10 and 1.2.11 for guidance on monitoring the effects of azathioprine, mercaptopurine and methotrexate.
See recommendation 1.2.16 for when to continue infliximab or adalimumab during remission.
# Maintaining remission in Crohn's disease after surgery
In May 2019, the use of some medicines was off label:
and 1.4.3: some preparations of azathioprine, and of the combination of azathioprine and metronidazole
: some preparations of azathioprine.
See NICE's information on prescribing medicines.
To maintain remission in people with ileocolonic Crohn's disease who have had complete macroscopic resection within the last 3 months, consider azathioprine in combination with up to 3 months' postoperative metronidazole.
Consider azathioprine alone for people who cannot tolerate metronidazole.
Monitor the effects of azathioprine and metronidazole as advised in the BNF or BNFC. Monitor for neutropenia in people taking azathioprine even if they have normal thiopurine methyltransferase (TPMT) activity (see also recommendation 1.2.11 for ensuring that there are documented local safety monitoring policies and procedures in place).
Do not offer biologics to maintain remission after complete macroscopic resection of ileocolonic Crohn's disease.
For people who have had surgery and started taking biologics before this guideline was published (May 2019), continue with their current treatment until both they and their NHS healthcare professional agree it is appropriate to change.
Do not offer budesonide to maintain remission in people with ileocolonic Crohn's disease who have had complete macroscopic resection.
To find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on maintaining remission in Crohn's disease after surgery .
Full details of the evidence and the committee's discussion are in the evidence review: Crohn's disease management – post surgical maintenance of remission.
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# Surgery
## Crohn's disease limited to the distal ileum
Consider surgery as an alternative to medical treatment early in the course of the disease for people whose disease is limited to the distal ileum, taking into account the following:
benefits and risks of medical treatment and surgery
risk of recurrence after surgery (appendix N of the full guideline contains observational data on recurrence rates after surgery)
individual preferences and any personal or cultural considerations. Record the person's views in their notes.
Consider surgery early in the course of the disease, or before or early in puberty, for children and young people whose disease is limited to the distal ileum and who have:
growth impairment despite optimal medical treatment and/or
refractory disease. Discuss treatment options with the child or young person and their family members or carers (as appropriate), and within the multidisciplinary team.
## Managing strictures
Consider balloon dilation, particularly for people with a single stricture that is short, straight and accessible by colonoscopy.
Discuss the benefits and risks of balloon dilation and surgical interventions for managing strictures with:
the person with Crohn's disease and their family members or carers (as appropriate) and
a surgeon and
a gastroenterologist.Appendix O of the full guideline contains observational data on efficacy, safety, quality of life and time to recurrence for balloon dilation and surgery for stricture.
Take into account the following factors when assessing options for managing a stricture:
whether medical treatment has been optimised
the number and extent of previous resections
the rapidity of past recurrence (if appropriate)
the potential for further resections
the consequence of short bowel syndrome
the person's preference, and how their lifestyle and cultural background might affect management.
Ensure that abdominal surgery is available for managing complications or failure of balloon dilation.
# Monitoring for osteopenia and assessing fracture risk
Refer to the NICE guideline on osteoporosis: assessing the risk of fragility fracture for recommendations on assessing the risk of fragility fracture in adults. Crohn's disease is a cause of secondary osteoporosis.
Do not routinely monitor for changes in bone mineral density in children and young people.
Consider monitoring for changes in bone mineral density in children and young people with risk factors, such as low body mass index (BMI), low trauma fracture or continued or repeated glucocorticosteroid use.
# Conception and pregnancy
Give information about the possible effects of Crohn's disease on pregnancy, including the potential risks and benefits of medical treatment and the possible effects of Crohn's disease on fertility.
Ensure effective communication and information‑sharing across specialties (for example, primary care, obstetrics and gastroenterology) in the care of pregnant women with Crohn's disease.
# Terms used in this guideline
## Complete macroscopic resection
The surgical removal of the section of bowel with visible (rather than microscopic) disease.# Recommendations for research
The 2019 guideline committee has made the following recommendation for research.
# Enteral nutrition after surgery
What are the benefits, risk and cost effectiveness of enteral nutrition in maintaining remission in the post-surgical period of Crohn's disease?
For a short explanation of why the committee made the research recommendation, see the rationale on maintaining remission in Crohn's disease after surgery .
Full details of the evidence and the committee's discussion are in the evidence review: Crohn's disease management – post surgical maintenance of remission.
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# Other recommendations for research
## From the 2012 guideline
Does the addition of azathioprine to systemic glucocorticosteroid treatment at diagnosis improve the long-term outcome compared with glucocorticosteroid treatment alone for patients with intestinal Crohn's disease?
Following successful medical induction of remission of Crohn's disease of the colon, is mesalazine more clinically and cost effective than no treatment?
What is the effect on quality of life of medical treatment compared with early surgery for Crohn's disease limited to the distal ileum?
What are the benefits, risks and cost effectiveness of enteral nutrition compared to glucocorticosteroid treatment in adults, children and young people?
What are the information needs of people with Crohn's disease, as defined by people with the condition, and can education and support based on these needs lead to better clinical and quality-of-life outcomes?# Rationale and impact
This section briefly explains why the committee made the recommendations and how they might affect practice. It links to details of the evidence and a full description of the committee's discussion.
# Maintaining remission in Crohn's disease after surgery
Recommendations 1.4.1 to 1.4.6
## Why the committee made the recommendations
The recommendations apply to people with ileocolonic Crohn's disease who have had complete macroscopic resection and who have no residual active disease. This is the population covered in the studies the committee reviewed. The committee was aware that a proportion of people could still have residual active disease after surgery. It agreed that in these people, their disease is not in remission and the recommendations in the section on inducing remission in Crohn's disease would apply.
The evidence showed that azathioprine in combination with up to 3 months' metronidazole was effective in maintaining endoscopic remission. While there was some evidence of clinical benefit with azathioprine on its own, the effect was less certain. However, the committee included it as an option because some people have trouble tolerating metronidazole. The committee did not recommend metronidazole alone because, based on the evidence and their clinical experience, the potential benefits did not outweigh the potential harms (or adverse effects). Azathioprine can also be difficult to tolerate, and can cause adverse effects, so the committee looked at mercaptopurine as an alternative. However, mercaptopurine is not cost effective for maintaining remission because it has a high cost relative to the limited benefits it provides. The committee also reviewed the evidence for aminosalicylates (such as mesalazine). The evidence on relapse rates (assessed endoscopically) showed that aminosalicylates were not clinically or cost effective. Because of this, the 2012 recommendation on aminosalicylates was removed.
The committee made a recommendation on monitoring because of the tolerability issues and potential adverse effects of azathioprine and metronidazole. This is based on the 2012 recommendation on monitoring azathioprine when using it to induce remission.
There was limited evidence available for biologics, and a lot of uncertainty around how much benefit they provide. Biologics are also expensive, and all these factors together mean that they are not currently cost effective when compared with the other options for maintaining remission. To avoid unnecessarily changing treatments for people who started taking biologics before this guideline was published, the committee made a recommendation to cover this group.
The committee made a recommendation against offering budesonide because evidence shows that it is not beneficial in maintaining remission after surgery.
None of the included studies looked specifically at maintaining remission for children and young people after surgery, so the committee did not make separate recommendations for this population. In their experience children and young people are offered the same post-surgery treatment as adults.
There was no randomised controlled trial evidence on enteral nutrition. The committee made a research recommendation on enteral nutrition after surgery because it is sometimes used alone or with other maintenance therapy for maintaining remission after surgery.
## How the recommendations might affect practice
The committee noted that the recommendations made are in line with current practice. There is variation across the UK in whether people receive 3 months of metronidazole after surgery.
The committee believe that the recommendation to not start biologics after surgery could potentially result in cost savings and maintain consistency in clinical practice.
Return to recommendations# Context
Crohn's disease is a chronic inflammatory disease that mainly affects the gastrointestinal tract. The disease may be progressive in some people, and a proportion may develop extra‑intestinal manifestations. Crohn's & Colitis UK estimate there are at least 115,000 people in the UK with Crohn's disease. The causes of Crohn's disease are widely debated. Smoking and genetic predisposition are 2 important factors that are likely to play a role.
Typically people with Crohn's disease have recurrent relapses, with acute exacerbations interspersed with periods of remission or less active disease. Whether a relapse refers to a recurrence of symptoms or the appearance of mucosal abnormalities before the development of symptoms remains the subject of dispute. Treatment is largely directed at symptom relief rather than cure, and active treatment of acute disease (inducing remission) should be distinguished from preventing relapse (maintaining remission).
Management options for Crohn's disease include drug therapy, attention to nutrition, smoking cessation and, in severe or chronic active disease, surgery.
The aims of drug treatment are to reduce symptoms, promote mucosal healing, and maintain or improve quality of life, while minimising toxicity related to drugs over both the short‑ and long‑term. Glucocorticosteroid treatment, aminosalicylate treatment, antibiotics, immunosuppressants and tumour necrosis factor (TNF)‑alpha inhibitors are currently considered to be options for treating Crohn's disease. Enteral nutrition has also been used widely as first‑line therapy in children and young people to facilitate growth and development, but its use in adults is less common. Between 50 and 80% of people with Crohn's disease will eventually need surgery for strictures causing symptoms of obstruction, other complications such as fistula formation, perforation or failure of medical therapy.
The 2015 routine surveillance review of the guideline highlighted evidence on the combined use of TNF‑alpha inhibitor and immunosuppressant medications for inducing remission in people with severe active Crohn's disease. The recommendations were updated in May 2016, to provide guidance on the combined use of TNF‑alpha inhibitor biologics (infliximab or adalimumab) together with an immunosuppressant medication, compared with biologic medication given alone. An update in May 2019 made new recommendations on maintaining remission after surgery.# Finding more information and resources
You can see everything NICE says on Crohn's disease in the NICE Pathway on Crohn's disease.
To find out what we have said on topics related to this guideline, see the NICE web page on inflammatory bowel disease.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice see practical steps to improving the quality of care and services using NICE guidance.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Providing information and support\n\nEnsure that information and advice about Crohn's disease:\n\nis age appropriate\n\nis of the appropriate cognitive and literacy level\n\nmeets the cultural and linguistic needs of the local community. \n\nDiscuss treatment options and monitoring with the person with Crohn's disease, with their family members or carers (as appropriate), and within the multidisciplinary team. Apply the principles in the NICE guideline on patient experience in adult NHS services. \n\nDiscuss the possible nature, frequency and severity of side effects of drug treatment with people with Crohn's disease and their family members or carers (as appropriate). Appendices L and M of the full guideline contain observational data on adverse events associated with aminosalicylate treatment and immunosuppressives. \n\nGive all people with Crohn's disease and their family members or carers (as appropriate) information, advice and support in line with published NICE guidance on:\n\nsmoking cessation\n\npatient experience\n\nmedicines adherence\n\nfertility. \n\nGive people with Crohn's disease and their family members or carers additional information on the following when appropriate:\n\npossible delay of growth and puberty in children and young people\n\ndiet and nutrition\n\nfertility and sexual relationships\n\nprognosis\n\nside effects of their treatment\n\ncancer risk\n\nsurgery\n\ntransition between paediatric and adult services\n\ncontact details for support groups. \n\nOffer people with Crohn's disease and their family members or carers (as appropriate) age‑appropriate multidisciplinary support to deal with any concerns about the disease and its treatment, including concerns about body image, living with a chronic illness, and attending school and higher education. \n\n# Inducing remission in Crohn's disease\n\n## Monotherapy\n\nIn May 2019, the use of some medicines was off label:\n\n: budesonide in children and young people\n\n: mesalazine, olsalazine and balsalazide.\n\nSee NICE's information on prescribing medicines.\n\nOffer monotherapy with a conventional glucocorticosteroid (prednisolone, methylprednisolone or intravenous hydrocortisone) to induce remission in people with a first presentation or a single inflammatory exacerbation of Crohn's disease in a 12‑month period. \n\nConsider enteral nutrition as an alternative to a conventional glucocorticosteroid to induce remission for:\n\nchildren in whom there is concern about growth or side effects\n\nyoung people in whom there is concern about growth. \n\nConsider budesonide for a first presentation or a single inflammatory exacerbation in a 12‑month period for people:\n\nwho have one or more of distal ileal, ileocaecal or right-sided colonic disease (see the recommendations on when to consider surgery early in the course of the disease in the section on Crohn's disease limited to the distal ileum)\xa0and\n\nif conventional glucocorticosteroids are contraindicated, or if the person declines or cannot tolerate them. Explain that budesonide is less effective than a conventional glucocorticosteroid, but may have fewer side effects. \n\nConsider aminosalicylate treatment for a first presentation or a single inflammatory exacerbation in a 12‑month period if conventional glucocorticosteroids are contraindicated, or if the person declines or cannot tolerate them. Explain that aminosalicylates are less effective than a conventional glucocorticosteroid or budesonide but may have fewer side effects than a conventional glucocorticosteroid. \n\nDo not offer budesonide or aminosalicylate treatment for severe presentations or exacerbations. \n\nDo not offer azathioprine, mercaptopurine or methotrexate as monotherapy to induce remission. \n\n## Add‑on treatment\n\nIn May 2019, the use of some medicines was off label:\n\n: budesonide (in children and young people), mercaptopurine, and most preparations of azathioprine\n\n: mercaptopurine and most preparations of azathioprine\n\n: some formulations of methotrexate (in adults), all formulations of methotrexate (in children and young people), and budesonide (in children and young people)\n\n: some formulations of methotrexate (in adults), all formulations of methotrexate (in children and young people), mercaptopurine, and most preparations of azathioprine.\n\nSee NICE's information on prescribing medicines.\n\nConsider adding azathioprine or mercaptopurine to a conventional glucocorticosteroid or budesonide to induce remission of Crohn's disease if:\n\nthere are 2 or more inflammatory exacerbations in a 12‑month period or\n\nthe glucocorticosteroid dose cannot be tapered. \n\nAssess thiopurine methyltransferase (TPMT) activity before offering azathioprine or mercaptopurine. Do not offer azathioprine or mercaptopurine if TPMT activity is deficient (very low or absent). Consider azathioprine or mercaptopurine at a lower dose if TPMT activity is below normal but not deficient (according to local laboratory reference values). \n\nConsider adding methotrexate (follow British national formulary [BNF]/British national formulary for children [BNFC] cautions) to a conventional glucocorticosteroid or budesonide to induce remission in people who cannot tolerate azathioprine or mercaptopurine, or in whom TPMT activity is deficient, if:\n\nthere are 2 or more inflammatory exacerbations in a 12‑month period or\n\nthe glucocorticosteroid dose cannot be tapered. \n\nMonitor the effects of azathioprine, mercaptopurine and methotrexate as advised in the BNF or BNFC. Consult the monographs of individual drugs for advice on monitoring immunosuppressives. Monitor for neutropenia in people taking azathioprine or mercaptopurine even if they have normal TPMT activity. \n\nEnsure that there are documented local safety monitoring policies and procedures (including audit) for people receiving treatment that needs monitoring. Nominate a member of staff to act on abnormal results and communicate with GPs, people with Crohn's disease and their family members or carers (as appropriate). \n\n## Infliximab and adalimumab\n\nThe recommendations in the following section (except for the recommendation on discussing the options of monotherapy or combined therapy) are from the NICE technology appraisal guidance on infliximab and adalimumab for the treatment of Crohn's disease.\n\nInfliximab and adalimumab, within their licensed indications, are recommended as treatment options for adults with severe active Crohn's disease (see recommendation 1.2.18) whose disease has not responded to conventional therapy (including immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab or adalimumab should be given as a planned course of treatment until treatment failure (including the need for surgery), or until 12\xa0months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see recommendation 1.2.16) to determine whether ongoing treatment is still clinically appropriate. \n\nTreatment as described in recommendation 1.2.12 should normally be started with the less expensive drug (taking into account drug administration costs, required dose and product price per dose). This may need to be varied for individuals because of differences in the method of administration and treatment schedules. \n\nWhen a person with Crohn's disease is starting infliximab or adalimumab (in line with recommendations 1.2.12, 1.2.15, 1.2.17 and 1.2.20), discuss options of:\n\nmonotherapy with one of these drugs or\n\ncombined therapy (either infliximab or adalimumab, combined with an immunosuppressant). Tell the person there is uncertainty about the comparative effectiveness and long‑term adverse effects of monotherapy and combined therapy. \n\nInfliximab, within its licensed indication, is recommended as a treatment option for people with active fistulising Crohn's disease whose disease has not responded to conventional therapy (including antibiotics, drainage and immunosuppressive treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab should be given as a planned course of treatment until treatment failure (including the need for surgery) or until 12\xa0months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see recommendation 1.2.16) to determine whether ongoing treatment is still clinically appropriate. \n\nTreatment with infliximab or adalimumab (see recommendations 1.2.12 and 1.2.15) should only be continued if there is clear evidence of ongoing active disease as determined by clinical symptoms, biological markers and investigation, including endoscopy if necessary. Specialists should discuss the risks and benefits of continued treatment with patients and consider a trial withdrawal from treatment for all patients who are in stable clinical remission. People who continue treatment with infliximab or adalimumab should have their disease reassessed at least every 12\xa0months to determine whether ongoing treatment is still clinically appropriate. People whose disease relapses after treatment is stopped should have the option to start treatment again. \n\nInfliximab, within its licensed indication, is recommended for the treatment of people aged 6 to 17\xa0years with severe active Crohn's disease whose disease has not responded to conventional therapy (including corticosteroids, immunomodulators and primary nutrition therapy), or who are intolerant of or have contraindications to conventional therapy. The need to continue treatment should be reviewed at least every 12\xa0months. \n\nFor the purposes of this guidance, severe active Crohn's disease is defined as very poor general health and one or more symptoms such as weight loss, fever, severe abdominal pain and usually frequent (3 to 4 or more) diarrhoeal stools daily. People with severe active Crohn's disease may or may not develop new fistulae or have extra‑intestinal manifestations of the disease. This clinical definition normally, but not exclusively, corresponds to a Crohn's Disease Activity Index (CDAI) score of 300 or more, or a Harvey‑Bradshaw score of 8 to 9 or above. \n\nWhen using the CDAI and Harvey‑Bradshaw Index, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the scores and make any adjustments they consider appropriate. \n\nTreatment with infliximab or adalimumab should only be started and reviewed by clinicians with experience of TNF inhibitors and of managing Crohn's disease. \n\n## Ustekinumab and vedolizumab\n\nFor guidance on using ustekinumab, see the NICE technology appraisal guidance on ustekinumab for moderately to severely active Crohn's disease after previous treatment. \n\nFor guidance on using vedolizumab, see the NICE technology appraisal guidance on vedolizumab for treating moderately to severely active Crohn's disease after prior therapy. \n\n# Maintaining remission in Crohn's disease\n\nDiscuss with people with Crohn's disease and their family members or carers (as appropriate) options for managing their disease when they are in remission, including both no treatment and treatment. The discussion should include the risk of inflammatory exacerbations (with and without drug treatment) and the potential side effects of drug treatment. Record the person's views in their notes. \n\nOffer colonoscopic surveillance in line with the NICE guideline on colorectal cancer prevention: colonoscopic surveillance in adults with ulcerative colitis, Crohn's disease or adenomas. \n\n## Follow‑up during remission for people who choose not to have maintenance treatment\n\nWhen people choose not to receive maintenance treatment:\n\ndiscuss and agree with them and their family members or carers (as appropriate) plans for follow‑up, including the frequency of follow‑up and who they should see\n\nensure they know which symptoms may suggest a relapse and should prompt a consultation with their healthcare professional (most frequently, unintended weight loss, abdominal pain, diarrhoea, general ill‑health)\n\nensure they know how to access the healthcare system if they experience a relapse\n\ndiscuss the importance of not smoking. \n\n## Maintenance treatment for people who choose this option\n\nIn May 2019, the use of some medicines was off label:\n\nand 1.3.5: mercaptopurine and most preparations of azathioprine\n\n: some formulations of methotrexate (in adults), all formulations of methotrexate (in children and young people).\n\nSee NICE's information on prescribing medicines.\n\nOffer azathioprine or mercaptopurine as monotherapy to maintain remission when previously used with a conventional glucocorticosteroid or budesonide to induce remission. \n\nConsider azathioprine or mercaptopurine to maintain remission in people who have not previously received these drugs (particularly people with adverse prognostic factors such as early age of onset, perianal disease, glucocorticosteroid use at presentation and severe presentations). \n\nConsider methotrexate (follow BNF/BNFC cautions) to maintain remission only in people who:\n\nneeded methotrexate to induce remission or\n\nhave tried but did not tolerate azathioprine or mercaptopurine for maintenance or\n\nhave contraindications to azathioprine or mercaptopurine (for example, deficient thiopurine methyltransferase [TPMT] activity or previous episodes of pancreatitis). \n\nDo not offer a conventional glucocorticosteroid or budesonide to maintain remission. \n\nSee recommendations 1.2.10 and 1.2.11 for guidance on monitoring the effects of azathioprine, mercaptopurine and methotrexate.\n\nSee recommendation 1.2.16 for when to continue infliximab or adalimumab during remission.\n\n# Maintaining remission in Crohn's disease after surgery\n\nIn May 2019, the use of some medicines was off label:\n\nand 1.4.3: some preparations of azathioprine, and of the combination of azathioprine and metronidazole\n\n: some preparations of azathioprine.\n\nSee NICE's information on prescribing medicines.\n\nTo maintain remission in people with ileocolonic Crohn's disease who have had complete macroscopic resection within the last 3\xa0months, consider azathioprine in combination with up to 3\xa0months' postoperative metronidazole. \n\nConsider azathioprine alone for people who cannot tolerate metronidazole. \n\nMonitor the effects of azathioprine and metronidazole as advised in the BNF or BNFC. Monitor for neutropenia in people taking azathioprine even if they have normal thiopurine methyltransferase (TPMT) activity (see also recommendation 1.2.11 for ensuring that there are documented local safety monitoring policies and procedures in place). \n\nDo not offer biologics to maintain remission after complete macroscopic resection of ileocolonic Crohn's disease. \n\nFor people who have had surgery and started taking biologics before this guideline was published (May 2019), continue with their current treatment until both they and their NHS healthcare professional agree it is appropriate to change. \n\nDo not offer budesonide to maintain remission in people with ileocolonic Crohn's disease who have had complete macroscopic resection. \n\nTo find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on maintaining remission in Crohn's disease after surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence review: Crohn's disease management – post surgical maintenance of remission.\n\nLoading. Please wait.\n\n# Surgery\n\n## Crohn's disease limited to the distal ileum\n\nConsider surgery as an alternative to medical treatment early in the course of the disease for people whose disease is limited to the distal ileum, taking into account the following:\n\nbenefits and risks of medical treatment and surgery\n\nrisk of recurrence after surgery (appendix N of the full guideline contains observational data on recurrence rates after surgery)\n\nindividual preferences and any personal or cultural considerations. Record the person's views in their notes. \n\nConsider surgery early in the course of the disease, or before or early in puberty, for children and young people whose disease is limited to the distal ileum and who have:\n\ngrowth impairment despite optimal medical treatment and/or\n\nrefractory disease. Discuss treatment options with the child or young person and their family members or carers (as appropriate), and within the multidisciplinary team. \n\n## Managing strictures\n\nConsider balloon dilation, particularly for people with a single stricture that is short, straight and accessible by colonoscopy. \n\nDiscuss the benefits and risks of balloon dilation and surgical interventions for managing strictures with:\n\nthe person with Crohn's disease and their family members or carers (as appropriate) and\n\na surgeon and\n\na gastroenterologist.Appendix O of the full guideline contains observational data on efficacy, safety, quality of life and time to recurrence for balloon dilation and surgery for stricture. \n\nTake into account the following factors when assessing options for managing a stricture:\n\nwhether medical treatment has been optimised\n\nthe number and extent of previous resections\n\nthe rapidity of past recurrence (if appropriate)\n\nthe potential for further resections\n\nthe consequence of short bowel syndrome\n\nthe person's preference, and how their lifestyle and cultural background might affect management. \n\nEnsure that abdominal surgery is available for managing complications or failure of balloon dilation. \n\n# Monitoring for osteopenia and assessing fracture risk\n\nRefer to the NICE guideline on osteoporosis: assessing the risk of fragility fracture for recommendations on assessing the risk of fragility fracture in adults. Crohn's disease is a cause of secondary osteoporosis.\n\nDo not routinely monitor for changes in bone mineral density in children and young people. \n\nConsider monitoring for changes in bone mineral density in children and young people with risk factors, such as low body mass index (BMI), low trauma fracture or continued or repeated glucocorticosteroid use. \n\n# Conception and pregnancy\n\nGive information about the possible effects of Crohn's disease on pregnancy, including the potential risks and benefits of medical treatment and the possible effects of Crohn's disease on fertility. \n\nEnsure effective communication and information‑sharing across specialties (for example, primary care, obstetrics and gastroenterology) in the care of pregnant women with Crohn's disease. \n\n# Terms used in this guideline\n\n## Complete macroscopic resection\n\nThe surgical removal of the section of bowel with visible (rather than microscopic) disease.", 'Recommendations for research': "The 2019 guideline committee has made the following recommendation for research.\n\n# Enteral nutrition after surgery\n\nWhat are the benefits, risk and cost effectiveness of enteral nutrition in maintaining remission in the post-surgical period of Crohn's disease?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on maintaining remission in Crohn's disease after surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence review: Crohn's disease management – post surgical maintenance of remission.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## From the 2012 guideline\n\nDoes the addition of azathioprine to systemic glucocorticosteroid treatment at diagnosis improve the long-term outcome compared with glucocorticosteroid treatment alone for patients with intestinal Crohn's disease?\n\nFollowing successful medical induction of remission of Crohn's disease of the colon, is mesalazine more clinically and cost effective than no treatment?\n\nWhat is the effect on quality of life of medical treatment compared with early surgery for Crohn's disease limited to the distal ileum?\n\nWhat are the benefits, risks and cost effectiveness of enteral nutrition compared to glucocorticosteroid treatment in adults, children and young people?\n\nWhat are the information needs of people with Crohn's disease, as defined by people with the condition, and can education and support based on these needs lead to better clinical and quality-of-life outcomes?", 'Rationale and impact': "This section briefly explains why the committee made the recommendations and how they might affect practice. It links to details of the evidence and a full description of the committee's discussion.\n\n# Maintaining remission in Crohn's disease after surgery\n\nRecommendations 1.4.1 to 1.4.6\n\n## Why the committee made the recommendations\n\nThe recommendations apply to people with ileocolonic Crohn's disease who have had complete macroscopic resection and who have no residual active disease. This is the population covered in the studies the committee reviewed. The committee was aware that a proportion of people could still have residual active disease after surgery. It agreed that in these people, their disease is not in remission and the recommendations in the section on inducing remission in Crohn's disease would apply.\n\nThe evidence showed that azathioprine in combination with up to 3\xa0months' metronidazole was effective in maintaining endoscopic remission. While there was some evidence of clinical benefit with azathioprine on its own, the effect was less certain. However, the committee included it as an option because some people have trouble tolerating metronidazole. The committee did not recommend metronidazole alone because, based on the evidence and their clinical experience, the potential benefits did not outweigh the potential harms (or adverse effects). Azathioprine can also be difficult to tolerate, and can cause adverse effects, so the committee looked at mercaptopurine as an alternative. However, mercaptopurine is not cost effective for maintaining remission because it has a high cost relative to the limited benefits it provides. The committee also reviewed the evidence for aminosalicylates (such as mesalazine). The evidence on relapse rates (assessed endoscopically) showed that aminosalicylates were not clinically or cost effective. Because of this, the 2012 recommendation on aminosalicylates was removed.\n\nThe committee made a recommendation on monitoring because of the tolerability issues and potential adverse effects of azathioprine and metronidazole. This is based on the 2012 recommendation on monitoring azathioprine when using it to induce remission.\n\nThere was limited evidence available for biologics, and a lot of uncertainty around how much benefit they provide. Biologics are also expensive, and all these factors together mean that they are not currently cost effective when compared with the other options for maintaining remission. To avoid unnecessarily changing treatments for people who started taking biologics before this guideline was published, the committee made a recommendation to cover this group.\n\nThe committee made a recommendation against offering budesonide because evidence shows that it is not beneficial in maintaining remission after surgery.\n\nNone of the included studies looked specifically at maintaining remission for children and young people after surgery, so the committee did not make separate recommendations for this population. In their experience children and young people are offered the same post-surgery treatment as adults.\n\nThere was no randomised controlled trial evidence on enteral nutrition. The committee made a research recommendation on enteral nutrition after surgery because it is sometimes used alone or with other maintenance therapy for maintaining remission after surgery.\n\n## How the recommendations might affect practice\n\nThe committee noted that the recommendations made are in line with current practice. There is variation across the UK in whether people receive 3\xa0months of metronidazole after surgery.\n\nThe committee believe that the recommendation to not start biologics after surgery could potentially result in cost savings and maintain consistency in clinical practice.\n\nReturn to recommendations", 'Context': "Crohn's disease is a chronic inflammatory disease that mainly affects the gastrointestinal tract. The disease may be progressive in some people, and a proportion may develop extra‑intestinal manifestations. Crohn's & Colitis UK estimate there are at least 115,000\xa0people in the UK with Crohn's disease. The causes of Crohn's disease are widely debated. Smoking and genetic predisposition are 2 important factors that are likely to play a role.\n\nTypically people with Crohn's disease have recurrent relapses, with acute exacerbations interspersed with periods of remission or less active disease. Whether a relapse refers to a recurrence of symptoms or the appearance of mucosal abnormalities before the development of symptoms remains the subject of dispute. Treatment is largely directed at symptom relief rather than cure, and active treatment of acute disease (inducing remission) should be distinguished from preventing relapse (maintaining remission).\n\nManagement options for Crohn's disease include drug therapy, attention to nutrition, smoking cessation and, in severe or chronic active disease, surgery.\n\nThe aims of drug treatment are to reduce symptoms, promote mucosal healing, and maintain or improve quality of life, while minimising toxicity related to drugs over both the short‑ and long‑term. Glucocorticosteroid treatment, aminosalicylate treatment, antibiotics, immunosuppressants and tumour necrosis factor (TNF)‑alpha inhibitors are currently considered to be options for treating Crohn's disease. Enteral nutrition has also been used widely as first‑line therapy in children and young people to facilitate growth and development, but its use in adults is less common. Between 50 and 80% of people with Crohn's disease will eventually need surgery for strictures causing symptoms of obstruction, other complications such as fistula formation, perforation or failure of medical therapy.\n\nThe 2015 routine surveillance review of the guideline highlighted evidence on the combined use of TNF‑alpha inhibitor and immunosuppressant medications for inducing remission in people with severe active Crohn's disease. The recommendations were updated in May 2016, to provide guidance on the combined use of TNF‑alpha inhibitor biologics (infliximab or adalimumab) together with an immunosuppressant medication, compared with biologic medication given alone. An update in May 2019 made new recommendations on maintaining remission after surgery.", 'Finding more information and resources': "You can see everything NICE says on Crohn's disease in the NICE Pathway on Crohn's disease.\n\nTo find out what we have said on topics related to this guideline, see the NICE web page on inflammatory bowel disease.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice see practical steps to improving the quality of care and services using NICE guidance."}
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https://www.nice.org.uk/guidance/ng129
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This guideline covers managing Crohn’s disease in children, young people and adults. It aims to reduce people’s symptoms and maintain or improve their quality of life.
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98279a8bfb918a4f4aaeaad65a0a1ae00d009a88
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nice
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Ulcerative colitis: management
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Ulcerative colitis: management
This guideline covers managing ulcerative colitis in children, young people and adults. It aims to help professionals to provide consistent high-quality care and it highlights the importance of advice and support for people with ulcerative colitis.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Patient information and support
Discuss the disease and associated symptoms, treatment options and monitoring:
with the person with ulcerative colitis and their family members or carers (as appropriate) and
within the multidisciplinary team (the composition of which should be appropriate for the age of the person) at every opportunity.Apply the principles in the NICE guideline on patient experience in adult NHS services.
Discuss the possible nature, frequency and severity of side effects of drug treatment for ulcerative colitis with the person, and their family members or carers (as appropriate). Refer to the NICE guideline on medicines adherence.
Give the person, and their family members or carers (as appropriate) information about their risk of developing colorectal cancer and about colonoscopic surveillance, in line with the NICE guidelines on colorectal cancer prevention: colonoscopic surveillance in adults with ulcerative colitis, Crohn's disease or adenomas and suspected cancer: recognition and referral.
# Inducing remission in people with ulcerative colitis
## Treating mild-to-moderate ulcerative colitis
To induce remission in people with a mild-to-moderate first presentation or inflammatory exacerbation of proctitis, offer a topical aminosalicylate as first-line treatment. In May 2019, this was an off-label use of some topical aminosalicylates for children and young people. See NICE's information on prescribing medicines.
If remission is not achieved within 4 weeks, consider adding an oral aminosalicylate. In May 2019, this was an off-label use of some oral aminosalicylates for children and young people. See NICE's information on prescribing medicines.
If further treatment is needed, consider adding a time-limited course of a topical or an oral corticosteroid. In May 2019, this was an off-label use of beclometasone dipropionate in most situations. See NICE's information on prescribing medicines.
For people who decline a topical aminosalicylate:
consider an oral aminosalicylate as first-line treatment, and explain that this is not as effective as a topical aminosalicylate
if remission is not achieved within 4 weeks, consider adding a time-limited course of a topical or an oral corticosteroid. In May 2019, this was an off-label use of beclometasone dipropionate in most situations. See NICE's information on prescribing medicines.
For people who cannot tolerate aminosalicylates, consider a time-limited course of a topical or an oral corticosteroid.
To induce remission in people with a mild-to-moderate first presentation or inflammatory exacerbation of proctosigmoiditis or left-sided ulcerative colitis, offer a topical aminosalicylate as first-line treatment.
If remission is not achieved within 4 weeks, consider:
adding a high-dose oral aminosalicylate to the topical aminosalicylate or
switching to a high-dose oral aminosalicylate and a time-limited course of a topical corticosteroid.
If further treatment is needed, stop topical treatments and offer an oral aminosalicylate and a time-limited course of an oral corticosteroid.
For people who decline any topical treatment:
consider a high-dose oral aminosalicylate alone, and explain that this is not as effective as a topical aminosalicylate
if remission is not achieved within 4 weeks, offer a time-limited course of an oral corticosteroid in addition to the high-dose aminosalicylate.
For people who cannot tolerate aminosalicylates, consider a time-limited course of a topical or an oral corticosteroid.
To induce remission in people with a mild-to-moderate first presentation or inflammatory exacerbation of extensive ulcerative colitis, offer a topical aminosalicylate and a high-dose oral aminosalicylate as first-line treatment.
If remission is not achieved within 4 weeks, stop the topical aminosalicylate and offer a high-dose oral aminosalicylate with a time-limited course of an oral corticosteroid.
For people who cannot tolerate aminosalicylates, consider a time-limited course of an oral corticosteroid.
## Biologics and Janus kinase inhibitors for moderately to severely active ulcerative colitis: all extents of disease
For guidance on biologics and Janus kinase inhibitors for treating moderately to severely active ulcerative colitis, see the:
NICE technology appraisal guidance on infliximab, adalimumab and golimumab for moderately to severely active ulcerative colitis
NICE technology appraisal guidance on vedolizumab for treating moderately to severely active ulcerative colitis
NICE technology appraisal guidance on tofacitinib for moderately to severely active ulcerative colitis.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on inducing remission in people with mild-to-moderate ulcerative colitis .
Full details of the evidence and the committee's discussion are in evidence review: induction of remission in mild-to-moderate ulcerative colitis.
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## Treating acute severe ulcerative colitis: all extents of disease
For people admitted to hospital with acute severe ulcerative colitis:
ensure that a gastroenterologist and a colorectal surgeon collaborate to provide treatment and management
ensure that the composition of the multidisciplinary team is appropriate for the age of the person
seek advice from a paediatrician with expertise in gastroenterology when treating a child or young person
ensure that the obstetric and gynaecology team is included when treating a pregnant woman.
For people admitted to hospital with acute severe ulcerative colitis (either a first presentation or an inflammatory exacerbation):
-ffer intravenous corticosteroids to induce remission and
assess the likelihood that the person will need surgery (see the recommendation on assess and document in the section on assessing likelihood of needing surgery).
Consider intravenous ciclosporin or surgery for people:
who cannot tolerate or who decline intravenous corticosteroids or
for whom treatment with intravenous corticosteroids is contraindicated.Take into account the person's preferences when choosing treatment. In May 2019, this was an off-label use of ciclosporin. See NICE's information on prescribing medicines.
Consider adding intravenous ciclosporin to intravenous corticosteroids or consider surgery for people:
who have little or no improvement within 72 hours of starting intravenous corticosteroids or
whose symptoms worsen at any time despite corticosteroid treatment.Take into account the person's preferences when choosing treatment. In May 2019, this was an off-label use of ciclosporin. See NICE's information on prescribing medicines
Infliximab is recommended as an option for the treatment of acute exacerbations of severely active ulcerative colitis only in patients in whom ciclosporin is contraindicated or clinically inappropriate, based on a careful assessment of the risks and benefits of treatment in the individual patient.
In people who do not meet the criterion in the recommendation above on the use of infliximab in patients in whom ciclosporin is contraindicated or clinically inappropriate, infliximab should only be used for the treatment of acute exacerbations of severely active ulcerative colitis in clinical trials.
## Monitoring treatment
Ensure that there are documented local safety monitoring policies and procedures (including audit) for adults, children and young people receiving treatment that needs monitoring (aminosalicylates, tacrolimus, ciclosporin, infliximab, azathioprine and mercaptopurine). Nominate a member of staff to act on abnormal results and communicate with GPs and people with ulcerative colitis and their family members or carers (as appropriate).
## Assessing likelihood of needing surgery
Assess and document on admission, and then daily, the likelihood of needing surgery for people admitted to hospital with acute severe ulcerative colitis.
Be aware that there may be an increased likelihood of needing surgery for people with any of the following:
stool frequency more than 8 per day
pyrexia
tachycardia
an abdominal X‑ray showing colonic dilatation
low albumin, low haemoglobin, high platelet count or C‑reactive protein above 45 mg/litre (bear in mind that normal values may be different in pregnant women).
# Information about treatment options for people who are considering surgery
These recommendations apply to anyone with ulcerative colitis considering elective surgery. The principles can also be applied to people requiring emergency surgery.
## Information when considering surgery
For people with ulcerative colitis who are considering surgery, ensure that a specialist (such as a gastroenterologist or a nurse specialist) gives the person and their family members or carers (as appropriate) information about all available treatment options, and discusses this with them. Information should include the benefits and risks of the different treatments and the potential consequences of no treatment.
Ensure that the person and their family members or carers (as appropriate) have sufficient time and opportunities to think about the options and the implications of the different treatments.
Ensure that a colorectal surgeon gives any person who is considering surgery and their family members or carers (as appropriate) specific information about what they can expect in the short and long term after surgery, and discusses this with them.
Ensure that a specialist (such as a colorectal surgeon, a gastroenterologist, an inflammatory bowel disease nurse specialist or a stoma nurse) gives any person who is considering surgery and their family members or carers (as appropriate) information about:
diet
sensitive topics such as sexual function
effects on lifestyle
psychological wellbeing
the type of surgery, the possibility of needing a stoma and stoma care.
Ensure that a specialist who is knowledgeable about stomas (such as a stoma nurse or a colorectal surgeon) gives any person who is having surgery and their family members or carers (as appropriate) specific information about the siting, care and management of stomas.
## Information after surgery
After surgery, ensure that a specialist who is knowledgeable about stomas (such as a stoma nurse or a colorectal surgeon) gives the person and their family members or carers (as appropriate) information about managing the effects on bowel function. This should be specific to the type of surgery performed (ileostomy or ileoanal pouch) and could include the following:
strategies to deal with the impact on their physical, psychological and social wellbeing
where to go for help if symptoms occur
sources of support and advice.
# Maintaining remission in people with ulcerative colitis
## Proctitis and proctosigmoiditis
To maintain remission after a mild-to-moderate inflammatory exacerbation of proctitis or proctosigmoiditis, consider the following options, taking into account the person's preferences:
a topical aminosalicylate alone (daily or intermittent) or
an oral aminosalicylate plus a topical aminosalicylate (daily or intermittent) or
an oral aminosalicylate alone, explaining that this may not be as effective as combined treatment or an intermittent topical aminosalicylate alone. In May 2019, note that this was an off-label use of some aminosalicylates for children and young people. See NICE's information on prescribing medicines
## Left-sided and extensive ulcerative colitis
To maintain remission in adults after a mild-to-moderate inflammatory exacerbation of left-sided or extensive ulcerative colitis:
-ffer a low maintenance dose of an oral aminosalicylate
when deciding which oral aminosalicylate to use, take into account the person's preferences, side effects and cost.
To maintain remission in children and young people after a mild-to-moderate inflammatory exacerbation of left-sided or extensive ulcerative colitis:
-ffer an oral aminosalicylate (dosing requirements for children should be calculated by body weight, as described in the BNF)
when deciding which oral aminosalicylate to use, take into account the person's preferences (and those of their parents or carers as appropriate), side effects and cost. In May 2019, this was an off-label use of some oral aminosalicylates for children and young people. See NICE's information on prescribing medicines.
## All extents of disease
Consider oral azathioprine or oral mercaptopurine to maintain remission:
after 2 or more inflammatory exacerbations in 12 months that require treatment with systemic corticosteroids or
if remission is not maintained by aminosalicylates. In May 2019, this was an off-label use of some brands of azathioprine and mercaptopurine. See NICE's information on prescribing medicines.
To maintain remission after a single episode of acute severe ulcerative colitis:
consider oral azathioprine or oral mercaptopurine
consider oral aminosalicylates if azathioprine and/or mercaptopurine are contraindicated or the person cannot tolerate them. In May 2019, this was an off-label use of some brands of azathioprine and mercaptopurine. See NICE's information on prescribing medicines.
## Dosing regimen for oral aminosalicylates
Consider a once-daily dosing regimen for oral aminosalicylates when used for maintaining remission. Take into account the person's preferences, and explain that once-daily dosing can be more effective, but may result in more side effects. In May 2019, this was an off-label use of some oral aminosalicylates. See NICE's information on prescribing medicines.
# Pregnant women
When caring for a pregnant woman with ulcerative colitis:
Ensure effective communication and information-sharing across specialties (for example, primary care, obstetrics and gynaecology, and gastroenterology).
Give her information about the potential risks and benefits of medical treatment to induce or maintain remission and of not having treatment, and discuss this with her. Include information relevant to a potential admission for an acute severe inflammatory exacerbation.
# Monitoring
## Monitoring bone health
For recommendations on assessing the risk of fragility fracture in adults, refer to the NICE guideline on osteoporosis: assessing the risk of fragility fracture.
Consider monitoring bone health in children and young people with ulcerative colitis in the following circumstances:
during chronic active disease
after treatment with systemic corticosteroids
after recurrent active disease.
## Monitoring growth and pubertal development in children and young people
Monitor the height and body weight of children and young people with ulcerative colitis against expected values on centile charts (and/or z scores) at the following intervals according to disease activity:
every 3 to 6 months:
if they have an inflammatory exacerbation and are approaching or undergoing puberty or
if there is chronic active disease or
if they are being treated with systemic corticosteroids
every 6 months during pubertal growth if the disease is inactive
every 12 months if none of the criteria above are met.
Monitor pubertal development in young people with ulcerative colitis using the principles of Tanner staging, by asking screening questions and/or carrying out a formal examination.
Consider referral to a secondary care paediatrician for pubertal assessment and investigation of the underlying cause if a young person with ulcerative colitis:
has slow pubertal progress or
has not developed pubertal features appropriate for their age.
Monitoring of growth and pubertal development:
can be done in a range of locations (for example, at routine appointments, acute admissions or urgent appointments in primary care, community services or secondary care)
should be carried out by appropriately trained healthcare professionals as part of the overall clinical assessment (including disease activity) to help inform the need for timely investigation, referral and/or interventions, particularly during pubertal growth.If the young person prefers self-assessment for monitoring pubertal development, this should be allowed if possible and they should be instructed on how to do this.
Ensure that relevant information about monitoring of growth and pubertal development and about disease activity is shared across services (for example, community, primary, secondary and specialist services). Apply the principles in the NICE guideline on patient experience in adult NHS services in relation to continuity of care.
# Terms used in this guideline
## Mild, moderate and severe ulcerative colitis
In this guideline, the categories of mild, moderate and severe are used to describe ulcerative colitis:
In adults these categories are based on the Truelove and Witts' severity index (see table 1). This table is adapted from the Truelove and Witts' criteria.
In children and young people these categories are based on the Paediatric Ulcerative Colitis Activity Index (PUCAI; see table 2).
Mild
Moderate
Severe
Bowel movements (number per day)
Fewer than 4
-r more plus at least 1 of the features of systemic upset (marked with - below)
Blood in stools
No more than small amounts of blood
Between mild and severe
Visible blood
Pyrexia (temperature greater than 37.8°C) *
No
No
Yes
Pulse rate greater than 90 bpm *
No
No
Yes
Anaemia *
No
No
Yes
Erythrocyte sedimentation rate (mm/hour) *
-r below
-r below
Above 30
© Copyright British Medical Journal, 29 October 1955. Reproduced with permission.
Disease severity in table 2 is defined by the following scores:
severe: 65 or above
moderate: 35–64
mild: 10–34
remission (disease not active): below 10.
Item
Points
Abdominal pain
No pain
Pain can be ignored
Pain cannot be ignored
Rectal bleeding
None
Small amount only, in less than 50% of stools
Small amount with most stools
Large amount (50% of the stool content)
Stool consistency of most stools
Formed
Partially formed
Completely unformed
Number of stools per 24 hours
Nocturnal stools (any episode causing wakening)
No
Yes
Activity level
No limitation of activity
Occasional limitation of activity
Severe restricted activity
Sum of PUCAI (0–85)
© Copyright The Hospital for Sick Children, Toronto, Canada, 2006. Reproduced with permission.
## Time-limited course of oral corticosteroids
A course of corticosteroids used to treat active disease, normally given for 4 to 8 weeks (depending on the steroid).# Recommendations for research
The guideline committee has made the following recommendations for research. As part of the 2019 update, the guideline committee made an additional 3 research recommendations on inducing remission in mild-to-moderate ulcerative colitis.
# Key recommendations for research
## The effectiveness of immunomodulators in inducing remission in proctitis
In a mild-to-moderate first presentation or inflammatory exacerbation of proctitis that is resistant to standard treatment, what is the effectiveness of topical immunomodulators, such as tacrolimus, in achieving clinical remission and what is the most effective formulation (suppository/ointment)?
For a short explanation of why the committee made the recommendation for research, see the rationale on proctitis .
Full details of the evidence and the committee's discussion are in evidence review: induction of remission in mild-to-moderate ulcerative colitis.
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## The effectiveness of immunomodulators in unresponsive ulcerative colitis
What is the effectiveness of oral tacrolimus and systemic (intramuscular/subcutaneous/oral) methotrexate in the induction of remission in mild-to-moderate ulcerative colitis unresponsive to aminosalicylates?
For a short explanation of why the committee made the recommendation for research, see the rationale on extensive ulcerative colitis .
Full details of the evidence and the committee's discussion are in evidence review: induction of remission in mild-to-moderate ulcerative colitis.
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## The relative effectiveness of corticosteroids for inducing remission in ulcerative colitis
What is the clinical and cost effectiveness of prednisolone, budesonide, and beclometasone in addition to aminosalicylates compared with each other and with aminosalicylate monotherapy for the induction of remission for people with mild-to-moderate ulcerative colitis?
For a short explanation of why the committee made the recommendation for research, see the rationale on all extents of disease .
Full details of the evidence and the committee's discussion are in evidence review: induction of remission in mild-to-moderate ulcerative colitis.
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# Other recommendations for research
## From the 2019 update
What is the clinical and cost effectiveness of prednisolone compared with aminosalicylates for the induction of remission for people with moderate ulcerative colitis?
What is the clinical and cost effectiveness of prednisolone plus an aminosalicylate compared with beclometasone plus an aminosalicylate for induction of remission for people with moderate ulcerative colitis?
What are the benefits, risks and cost effectiveness of methotrexate, ciclosporin, tacrolimus, adalimumab and infliximab compared with each other and with placebo for induction of remission for people with subacute ulcerative colitis that is refractory to systemic corticosteroids?
## From the 2013 guideline
What are the benefits, risks and cost effectiveness of methotrexate, ciclosporin, tacrolimus, adalimumab and infliximab compared with each other and with placebo for induction of remission for people with subacute ulcerative colitis that is refractory to systemic corticosteroids?
What is the clinical and cost effectiveness of regular maintenance treatment compared with no regular treatment (but rapid standard treatment if a relapse occurs) in specific populations with mild to moderate ulcerative colitis?
To develop and validate a risk tool that predicts the likelihood of needing surgery for adults admitted to hospital with acute severe ulcerative colitis.
In children and young people with ulcerative colitis receiving steroid treatment, what are the clinical benefits of routine monitoring of bone density, what tests should be done and how frequently?
A registry to collect data to answer 'What are the potential harms or benefits of drug treatments in pregnant women with ulcerative colitis?'
What are the information needs of people with ulcerative colitis when they are considering surgery?
What is the clinical and cost effectiveness of sulphasalazine compared to high-dose branded mesalazine for induction of remission for people with mild moderate ulcerative colitis?
What is the validity, reliability and accuracy of available adult risk tools as a predictor for the need for surgery in people admitted into hospital with acute severe ulcerative colitis?
What is the validity, reliability and accuracy of the paediatric ulcerative colitis activity index (PUCAI) as a predictor for surgery for children and young people admitted to hospital with acute severe colitis?
In people with mild to moderate ulcerative colitis, what are the best second-line treatment strategies for induction of remission after people have failed to respond to ASA mono or combination therapies?
In people with subacute ulcerative colitis, what are the best second-line treatment strategies for induction of remission after people have failed to respond to oral prednisolone?
In people with mild to moderate ulcerative colitis, what are the best strategies for the induction of remission after people have failed to respond to tacrolimus?
Establish a national registry to identify the incidence of growth failure and/or pubertal delay in ulcerative colitis and the relationship with treatment (to record treatment and growth ).# Rationale and impact
This section briefly explains why the committee made the recommendations and how they might affect practice. It links to details of the evidence and a full description of the committee's discussion.
# Inducing remission in people with mild-to-moderate ulcerative colitis
Recommendations 1.2.1 to 1.2.14
## Why the committee made the recommendations
The evidence showed that topical aminosalicylates (suppositories or enema) are the most effective treatments for achieving remission in people with mild-to-moderate proctitis, so these were recommended as first-line treatments. The evidence did not show any difference in effectiveness between enema and suppository.
Topical aminosalicylates alone are recommended for up to 4 weeks because the evidence showed that they were the most effective treatment within this timeframe. There was no direct evidence for combining topical and oral aminosalicylates for people with proctitis. However, evidence showed that this combination was effective for people with proctosigmoiditis, and the committee agreed that this evidence was also applicable to people with proctitis alone. The committee chose not to specify a dose for the oral aminosalicylate. It preferred to leave it open to clinical judgment depending on the specific situation (for example, the clinician could give a low dose if the person had not taken an aminosalicylate before, or a high dose if the person was already taking a low dose).
Some people will not achieve remission with topical and oral aminosalicylates. In clinical practice, oral or topical corticosteroids are commonly added at this stage, but there was no evidence on this combination. The committee agreed that, based on their experience, adding a topical or oral corticosteroid should be an option at this stage.
Despite the lack of direct evidence for the effectiveness of topical or oral corticosteroids, the committee agreed that, based on their experience, these should also be an option for people who cannot tolerate aminosalicylates.
Some people decline topical treatment, preferring oral to topical aminosalicylates. This is more common in children and young people, although proctitis is not common in this group. As the evidence showed that oral aminosalicylates are not as effective at inducing remission, the committee thought it was important to explain this to people who decline topical aminosalicylates.
There was cost-effectiveness evidence showing that using an immunomodulator as the next line of treatment after oral or topical corticosteroids and oral aminosalicylate produced greater health benefits at lower total costs than other strategies. However, the clinical evidence on topical immunomodulators was limited and it was unclear how applicable it was to UK clinical practice. Because of this, the committee recommended the sequence without this final treatment, and made a research recommendation on topical immunomodulators.
There is evidence that topical aminosalicylates are effective for achieving remission in people with mild-to-moderate proctosigmoiditis or left-sided ulcerative colitis. In the committee's experience topical aminosalicylates also work faster and more effectively than topical corticosteroids. Topical aminosalicylates alone are recommended for up to 4 weeks because the evidence showed that they were effective within this timeframe. Cost-effectiveness evidence also showed that treatment sequences starting with topical aminosalicylates produced greater health benefits and incurred lower total costs than other strategies.
There is no direct evidence for the effectiveness of high-dose oral aminosalicylates combined with either topical aminosalicylates or topical corticosteroids. However, there is evidence that topical treatments or high-dose oral aminosalicylates individually provide some benefit. Therefore, the committee agreed it was reasonable to recommend combinations of these if remission is not achieved. While there was limited evidence for oral corticosteroids, in the committee's experience an oral corticosteroid may benefit people with proctosigmoiditis or left-sided disease if further treatment is needed. As a result, they recommended oral corticosteroids with oral aminosalicylates instead of topical treatment for these people. This reflects current practice for people who do not achieve remission with topical treatments and high-dose oral aminosalicylates.
The evidence showed that people with mild-to-moderate extensive ulcerative colitis would benefit most from a combination of high-dose oral aminosalicylates with topical aminosalicylates as first-line treatment. High-dose oral aminosalicylates combined with topical aminosalicylates are recommended for up to 4 weeks, because in the committee's experience they are the most effective treatment within this timeframe. There is evidence that an oral corticosteroid combined with a high-dose oral aminosalicylate is also effective, so the committee recommended this combination if remission is not achieved with aminosalicylates alone. In people who cannot tolerate aminosalicylates, oral corticosteroids are recommended as they are also an effective treatment option.
The sequence of drugs recommended was more effective than starting with a high-dose oral aminosalicylate alone. There was some uncertainty around the cost effectiveness of this sequence. The data on the effectiveness of high-dose oral aminosalicylates combined with topical aminosalicylates was from an 8‑week clinical trial. The committee believed that in practice, people whose disease did not respond to treatment within 4 weeks would switch to another treatment. When the cost-effectiveness analysis allowed for early switching, the combination of a high-dose oral aminosalicylate and topical aminosalicylate was not cost effective. However, if it was assumed that everyone continued treatment as described in the trial, the combination of a high-dose oral aminosalicylate and topical aminosalicylate was more likely to be cost effective. The committee took the uncertainty about the cost-effectiveness results in the different scenarios into account in recommending the combination as first-line treatment.
There was some evidence on methotrexate for inducing remission, but it did not show a clear benefit, and there was no evidence on oral tacrolimus. To address these gaps in the evidence, the committee made a research recommendation on the effectiveness of immunomodulators in unresponsive ulcerative colitis.
Most of the evidence was for adults. However, the committee agreed to generalise the recommendations to all people with a mild-to-moderate exacerbation or first presentation of ulcerative colitis.
There is limited evidence on oral corticosteroids. In addition, the committee agreed that the use of oral corticosteroids is generally reserved for later lines of treatment because of concerns about side effects. It is not clear which corticosteroid is most effective for each extent of disease. There is also limited evidence on immunomodulators, specifically oral tacrolimus and systemic methotrexate for each extent of disease. The committee made a research recommendation on corticosteroids for the induction of remission in mild-to-moderate ulcerative colitis to address these uncertainties.
## How the recommendations might affect practice
The new recommendations classify the extents of ulcerative colitis differently. This more closely reflects current practice, so will be clearer and more informative for people with mild-to-moderate ulcerative colitis and healthcare professionals.
The recommendations in the 2013 guideline referred to specific corticosteroids. To better reflect the available evidence, the updated recommendations refer to aminosalicylates and corticosteroids as a class rather than recommending individual treatments. This allows healthcare professionals and people with mild-to-moderate ulcerative colitis to choose the most appropriate corticosteroid or aminosalicylate, depending on patient preference, availability and acquisition cost.
The new recommendations specify that courses of oral corticosteroids should be time-limited. This should address varying practice in prescribing for some corticosteroids.
Return to recommendations# Context
Ulcerative colitis is the most common type of inflammatory bowel disease. There are around 146,000 people in the UK with a diagnosis of ulcerative colitis (Crohn's & Colitis UK). The cause of ulcerative colitis is unknown. It can develop at any age, but peak incidence is between the ages of 15 and 25 years, with a second, smaller peak between 55 and 65 years (although this second peak has not been universally demonstrated).
Ulcerative colitis usually affects the rectum, and a variable extent of the colon proximal to the rectum. The inflammation is continuous in extent. Inflammation of the rectum is referred to as proctitis, and inflammation of the rectum and sigmoid as proctosigmoiditis. Left-sided colitis refers to disease involving the colon distal to the splenic flexure. Extensive colitis affects the colon proximal to the splenic flexure, and includes pan-colitis, where the whole colon is involved.
Symptoms of active disease or relapse include bloody diarrhoea, an urgent need to defecate and abdominal pain.
Ulcerative colitis is a lifelong disease that is associated with significant morbidity. It can also affect a person's social and psychological wellbeing, particularly if poorly controlled. Typically, it has a relapsing-remitting pattern.
Current medical approaches focus on treating active disease to address symptoms, to improve quality of life, and thereafter to maintain remission. The long-term benefits of achieving mucosal healing remain unclear. The treatment chosen for active disease is likely to depend on clinical severity, extent of disease and the person's preference, and may include the use of aminosalicylates, corticosteroids or biological drugs. These drugs can be oral or topical (into the rectum), and corticosteroids may be administered intravenously in people with acute severe disease. Surgery may be considered as emergency treatment for severe ulcerative colitis that does not respond to drug treatment. People may also choose to have elective surgery for unresponsive or frequently relapsing disease that is affecting their quality of life.
Advice and support for people with ulcerative colitis is important, in terms of discussing the effects of the condition and its course, medical treatment options, the effects of medication and the monitoring required. Around 10% of inpatients with inflammatory bowel disease reported a lack of information about drug side effects on discharge from hospital. Information to support decisions about surgery is also essential, both for clinicians and for people facing the possibility of surgery. This includes recognising adverse prognostic factors for people admitted with acute severe colitis to enable timely decisions about escalating medical therapy or predicting the need for surgery. It is also very important to provide relevant information to support people considering elective surgery.
The wide choice of drug preparations and dosing regimens, the judgement required in determining the optimum timing for surgery (both electively and as an emergency) and the importance of support and information may lead to variation in practice across the UK. This guideline aims to address this variation, and to help healthcare professionals to provide consistent high-quality care. Managing ulcerative colitis in adults and children overlaps in many regards, so the guideline incorporates advice that is applicable to children and young people, which again should help to address potential inconsistencies in practice.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Patient information and support\n\nDiscuss the disease and associated symptoms, treatment options and monitoring:\n\nwith the person with ulcerative colitis and their family members or carers (as appropriate) and\n\nwithin the multidisciplinary team (the composition of which should be appropriate for the age of the person) at every opportunity.Apply the principles in the NICE guideline on patient experience in adult NHS services. \n\nDiscuss the possible nature, frequency and severity of side effects of drug treatment for ulcerative colitis with the person, and their family members or carers (as appropriate). Refer to the NICE guideline on medicines adherence. \n\nGive the person, and their family members or carers (as appropriate) information about their risk of developing colorectal cancer and about colonoscopic surveillance, in line with the NICE guidelines on colorectal cancer prevention: colonoscopic surveillance in adults with ulcerative colitis, Crohn's disease or adenomas and suspected cancer: recognition and referral. \n\n# Inducing remission in people with ulcerative colitis\n\n## Treating mild-to-moderate ulcerative colitis\n\nTo induce remission in people with a mild-to-moderate first presentation or inflammatory exacerbation of proctitis, offer a topical aminosalicylate as first-line treatment. In May 2019, this was an off-label use of some topical aminosalicylates for children and young people. See NICE's information on prescribing medicines.\n\nIf remission is not achieved within 4\xa0weeks, consider adding an oral aminosalicylate. In May 2019, this was an off-label use of some oral aminosalicylates for children and young people. See NICE's information on prescribing medicines.\n\nIf further treatment is needed, consider adding a time-limited course of a topical or an oral corticosteroid. In May 2019, this was an off-label use of beclometasone dipropionate in most situations. See NICE's information on prescribing medicines.\n\nFor people who decline a topical aminosalicylate:\n\nconsider an oral aminosalicylate as first-line treatment, and explain that this is not as effective as a topical aminosalicylate\n\nif remission is not achieved within 4\xa0weeks, consider adding a time-limited course of a topical or an oral corticosteroid. In May 2019, this was an off-label use of beclometasone dipropionate in most situations. See NICE's information on prescribing medicines.\n\nFor people who cannot tolerate aminosalicylates, consider a time-limited course of a topical or an oral corticosteroid. \n\nTo induce remission in people with a mild-to-moderate first presentation or inflammatory exacerbation of proctosigmoiditis or left-sided ulcerative colitis, offer a topical aminosalicylate as first-line treatment. \n\nIf remission is not achieved within 4\xa0weeks, consider:\n\nadding a high-dose oral aminosalicylate to the topical aminosalicylate or\n\nswitching to a high-dose oral aminosalicylate and a time-limited course of a topical corticosteroid. \n\nIf further treatment is needed, stop topical treatments and offer an oral aminosalicylate and a time-limited course of an oral corticosteroid. \n\nFor people who decline any topical treatment:\n\nconsider a high-dose oral aminosalicylate alone, and explain that this is not as effective as a topical aminosalicylate\n\nif remission is not achieved within 4\xa0weeks, offer a time-limited course of an oral corticosteroid in addition to the high-dose aminosalicylate. \n\nFor people who cannot tolerate aminosalicylates, consider a time-limited course of a topical or an oral corticosteroid. \n\nTo induce remission in people with a mild-to-moderate first presentation or inflammatory exacerbation of extensive ulcerative colitis, offer a topical aminosalicylate and a high-dose oral aminosalicylate as first-line treatment. \n\nIf remission is not achieved within 4\xa0weeks, stop the topical aminosalicylate and offer a high-dose oral aminosalicylate with a time-limited course of an oral corticosteroid. \n\nFor people who cannot tolerate aminosalicylates, consider a time-limited course of an oral corticosteroid. \n\n## Biologics and Janus kinase inhibitors for moderately to severely active ulcerative colitis: all extents of disease\n\nFor guidance on biologics and Janus\xa0kinase inhibitors for treating moderately to severely active ulcerative colitis, see the:\n\nNICE technology appraisal guidance on infliximab, adalimumab and golimumab for moderately to severely active ulcerative colitis\n\nNICE technology appraisal guidance on vedolizumab for treating moderately to severely active ulcerative colitis\n\nNICE technology appraisal guidance on tofacitinib for moderately to severely active ulcerative colitis. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on inducing remission in people with mild-to-moderate ulcerative colitis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review: induction of remission in mild-to-moderate ulcerative colitis.\n\nLoading. Please wait.\n\n## Treating acute severe ulcerative colitis: all extents of disease\n\nFor people admitted to hospital with acute severe ulcerative colitis:\n\nensure that a gastroenterologist and a colorectal surgeon collaborate to provide treatment and management\n\nensure that the composition of the multidisciplinary team is appropriate for the age of the person\n\nseek advice from a paediatrician with expertise in gastroenterology when treating a child or young person\n\nensure that the obstetric and gynaecology team is included when treating a pregnant woman. \n\nFor people admitted to hospital with acute severe ulcerative colitis (either a first presentation or an inflammatory exacerbation):\n\noffer intravenous corticosteroids to induce remission and\n\nassess the likelihood that the person will need surgery (see the recommendation on assess and document in the section on assessing likelihood of needing surgery). \n\nConsider intravenous ciclosporin or surgery for people:\n\nwho cannot tolerate or who decline intravenous corticosteroids or\n\nfor whom treatment with intravenous corticosteroids is contraindicated.Take into account the person's preferences when choosing treatment. In May 2019, this was an off-label use of ciclosporin. See NICE's information on prescribing medicines.\n\nConsider adding intravenous ciclosporin to intravenous corticosteroids or consider surgery for people:\n\nwho have little or no improvement within 72\xa0hours of starting intravenous corticosteroids or\n\nwhose symptoms worsen at any time despite corticosteroid treatment.Take into account the person's preferences when choosing treatment. In May 2019, this was an off-label use of ciclosporin. See NICE's information on prescribing medicines\n\nInfliximab is recommended as an option for the treatment of acute exacerbations of severely active ulcerative colitis only in patients in whom ciclosporin is contraindicated or clinically inappropriate, based on a careful assessment of the risks and benefits of treatment in the individual patient. [This recommendation is from NICE technology appraisal guidance on infliximab for acute exacerbations of ulcerative colitis]\n\nIn people who do not meet the criterion in the recommendation above on the use of infliximab in patients in whom ciclosporin is contraindicated or clinically inappropriate, infliximab should only be used for the treatment of acute exacerbations of severely active ulcerative colitis in clinical trials. [This recommendation is from NICE technology appraisal guidance on infliximab for acute exacerbations of ulcerative colitis]\n\n## Monitoring treatment\n\nEnsure that there are documented local safety monitoring policies and procedures (including audit) for adults, children and young people receiving treatment that needs monitoring (aminosalicylates, tacrolimus, ciclosporin, infliximab, azathioprine and mercaptopurine). Nominate a member of staff to act on abnormal results and communicate with GPs and people with ulcerative colitis and their family members or carers (as appropriate). \n\n## Assessing likelihood of needing surgery\n\nAssess and document on admission, and then daily, the likelihood of needing surgery for people admitted to hospital with acute severe ulcerative colitis. \n\nBe aware that there may be an increased likelihood of needing surgery for people with any of the following:\n\nstool frequency more than 8\xa0per day\n\npyrexia\n\ntachycardia\n\nan abdominal X‑ray showing colonic dilatation\n\nlow albumin, low haemoglobin, high platelet count or C‑reactive protein above 45\xa0mg/litre (bear in mind that normal values may be different in pregnant women). \n\n# Information about treatment options for people who are considering surgery\n\nThese recommendations apply to anyone with ulcerative colitis considering elective surgery. The principles can also be applied to people requiring emergency surgery.\n\n## Information when considering surgery\n\nFor people with ulcerative colitis who are considering surgery, ensure that a specialist (such as a gastroenterologist or a nurse specialist) gives the person and their family members or carers (as appropriate) information about all available treatment options, and discusses this with them. Information should include the benefits and risks of the different treatments and the potential consequences of no treatment. \n\nEnsure that the person and their family members or carers (as appropriate) have sufficient time and opportunities to think about the options and the implications of the different treatments. \n\nEnsure that a colorectal surgeon gives any person who is considering surgery and their family members or carers (as appropriate) specific information about what they can expect in the short and long term after surgery, and discusses this with them. \n\nEnsure that a specialist (such as a colorectal surgeon, a gastroenterologist, an inflammatory bowel disease nurse specialist or a stoma nurse) gives any person who is considering surgery and their family members or carers (as appropriate) information about:\n\ndiet\n\nsensitive topics such as sexual function\n\neffects on lifestyle\n\npsychological wellbeing\n\nthe type of surgery, the possibility of needing a stoma and stoma care. \n\nEnsure that a specialist who is knowledgeable about stomas (such as a stoma nurse or a colorectal surgeon) gives any person who is having surgery and their family members or carers (as appropriate) specific information about the siting, care and management of stomas. \n\n## Information after surgery\n\nAfter surgery, ensure that a specialist who is knowledgeable about stomas (such as a stoma nurse or a colorectal surgeon) gives the person and their family members or carers (as appropriate) information about managing the effects on bowel function. This should be specific to the type of surgery performed (ileostomy or ileoanal pouch) and could include the following:\n\nstrategies to deal with the impact on their physical, psychological and social wellbeing\n\nwhere to go for help if symptoms occur\n\nsources of support and advice. \n\n# Maintaining remission in people with ulcerative colitis\n\n## Proctitis and proctosigmoiditis\n\nTo maintain remission after a mild-to-moderate inflammatory exacerbation of proctitis or proctosigmoiditis, consider the following options, taking into account the person's preferences:\n\na topical aminosalicylate alone (daily or intermittent) or\n\nan oral aminosalicylate plus a topical aminosalicylate (daily or intermittent) or\n\nan oral aminosalicylate alone, explaining that this may not be as effective as combined treatment or an intermittent topical aminosalicylate alone. In May 2019, note that this was an off-label use of some aminosalicylates for children and young people. See NICE's information on prescribing medicines\n\n## Left-sided and extensive ulcerative colitis\n\nTo maintain remission in adults after a mild-to-moderate inflammatory exacerbation of left-sided or extensive ulcerative colitis:\n\noffer a low maintenance dose of an oral aminosalicylate\n\nwhen deciding which oral aminosalicylate to use, take into account the person's preferences, side effects and cost. \n\nTo maintain remission in children and young people after a mild-to-moderate inflammatory exacerbation of left-sided or extensive ulcerative colitis:\n\noffer an oral aminosalicylate (dosing requirements for children should be calculated by body weight, as described in the BNF)\n\nwhen deciding which oral aminosalicylate to use, take into account the person's preferences (and those of their parents or carers as appropriate), side effects and cost. In May 2019, this was an off-label use of some oral aminosalicylates for children and young people. See NICE's information on prescribing medicines.\n\n## All extents of disease\n\nConsider oral azathioprine or oral mercaptopurine to maintain remission:\n\nafter 2 or more inflammatory exacerbations in 12\xa0months that require treatment with systemic corticosteroids or\n\nif remission is not maintained by aminosalicylates. In May 2019, this was an off-label use of some brands of azathioprine and mercaptopurine. See NICE's information on prescribing medicines.\n\nTo maintain remission after a single episode of acute severe ulcerative colitis:\n\nconsider oral azathioprine or oral mercaptopurine\n\nconsider oral aminosalicylates if azathioprine and/or mercaptopurine are contraindicated or the person cannot tolerate them. In May 2019, this was an off-label use of some brands of azathioprine and mercaptopurine. See NICE's information on prescribing medicines.\n\n## Dosing regimen for oral aminosalicylates\n\nConsider a once-daily dosing regimen for oral aminosalicylates when used for maintaining remission. Take into account the person's preferences, and explain that once-daily dosing can be more effective, but may result in more side effects. In May 2019, this was an off-label use of some oral aminosalicylates. See NICE's information on prescribing medicines.\n\n# Pregnant women\n\nWhen caring for a pregnant woman with ulcerative colitis:\n\nEnsure effective communication and information-sharing across specialties (for example, primary care, obstetrics and gynaecology, and gastroenterology).\n\nGive her information about the potential risks and benefits of medical treatment to induce or maintain remission and of not having treatment, and discuss this with her. Include information relevant to a potential admission for an acute severe inflammatory exacerbation. \n\n# Monitoring\n\n## Monitoring bone health\n\nFor recommendations on assessing the risk of fragility fracture in adults, refer to the NICE guideline on osteoporosis: assessing the risk of fragility fracture. \n\nConsider monitoring bone health in children and young people with ulcerative colitis in the following circumstances:\n\nduring chronic active disease\n\nafter treatment with systemic corticosteroids\n\nafter recurrent active disease. \n\n## Monitoring growth and pubertal development in children and young people\n\nMonitor the height and body weight of children and young people with ulcerative colitis against expected values on centile charts (and/or z\xa0scores) at the following intervals according to disease activity:\n\nevery 3 to 6\xa0months:\n\n\n\nif they have an inflammatory exacerbation and are approaching or undergoing puberty or\n\nif there is chronic active disease or\n\nif they are being treated with systemic corticosteroids\n\n\n\nevery 6\xa0months during pubertal growth if the disease is inactive\n\nevery 12\xa0months if none of the criteria above are met. \n\nMonitor pubertal development in young people with ulcerative colitis using the principles of Tanner staging, by asking screening questions and/or carrying out a formal examination. \n\nConsider referral to a secondary care paediatrician for pubertal assessment and investigation of the underlying cause if a young person with ulcerative colitis:\n\nhas slow pubertal progress or\n\nhas not developed pubertal features appropriate for their age. \n\nMonitoring of growth and pubertal development:\n\ncan be done in a range of locations (for example, at routine appointments, acute admissions or urgent appointments in primary care, community services or secondary care)\n\nshould be carried out by appropriately trained healthcare professionals as part of the overall clinical assessment (including disease activity) to help inform the need for timely investigation, referral and/or interventions, particularly during pubertal growth.If the young person prefers self-assessment for monitoring pubertal development, this should be allowed if possible and they should be instructed on how to do this. \n\nEnsure that relevant information about monitoring of growth and pubertal development and about disease activity is shared across services (for example, community, primary, secondary and specialist services). Apply the principles in the NICE guideline on patient experience in adult NHS services in relation to continuity of care. \n\n# Terms used in this guideline\n\n## Mild, moderate and severe ulcerative colitis\n\nIn this guideline, the categories of mild, moderate and severe are used to describe ulcerative colitis:\n\nIn adults these categories are based on the Truelove and Witts' severity index (see table 1). This table is adapted from the Truelove and Witts' criteria.\n\nIn children and young people these categories are based on the Paediatric Ulcerative Colitis Activity Index (PUCAI; see table 2).\n\n–\n\nMild\n\nModerate\n\nSevere\n\nBowel movements (number per day)\n\nFewer than 4\n\n–6\n\nor more plus at least 1 of the features of systemic upset (marked with * below)\n\nBlood in stools\n\nNo more than small amounts of blood\n\nBetween mild and severe\n\nVisible blood\n\nPyrexia (temperature greater than 37.8°C) *\n\nNo\n\nNo\n\nYes\n\nPulse rate greater than 90\xa0bpm *\n\nNo\n\nNo\n\nYes\n\nAnaemia *\n\nNo\n\nNo\n\nYes\n\nErythrocyte sedimentation rate (mm/hour) *\n\nor below\n\nor below\n\nAbove 30\n\n© Copyright British Medical Journal, 29 October 1955. Reproduced with permission.\n\nDisease severity in table 2 is defined by the following scores:\n\nsevere: 65 or above\n\nmoderate: 35–64\n\nmild: 10–34\n\nremission (disease not active): below 10.\n\n\n\n\n\n\n\nItem\n\nPoints\n\n.\n\n\n\nAbdominal pain\n\n_\n\n\n\nNo pain\n\nPain can be ignored\n\nPain cannot be ignored\n\n\n\n\n\n\n\n.\n\nRectal bleeding\n\n_\n\n\n\nNone\n\nSmall amount only, in less than 50% of stools\n\nSmall amount with most stools\n\nLarge amount (50% of the stool content)\n\n\n\n\n\n\n\n\n\n.\n\nStool consistency of most stools\n\n_\n\n\n\nFormed\n\nPartially formed\n\nCompletely unformed\n\n\n\n\n\n\n\n.\n\nNumber of stools per 24 hours\n\n_\n\n\n\n–2\n\n–5\n\n–8\n\n>8\n\n\n\n\n\n\n\n\n\n.\n\nNocturnal stools (any episode causing wakening)\n\n_\n\n\n\nNo\n\nYes\n\n\n\n\n\n.\n\nActivity level\n\n_\n\n\n\nNo limitation of activity\n\nOccasional limitation of activity\n\nSevere restricted activity\n\n\n\n\n\n\n\n\n\nSum of PUCAI (0–85)\n\n_\n\n© Copyright The Hospital for Sick Children, Toronto, Canada, 2006. Reproduced with permission.\n\n## Time-limited course of oral corticosteroids\n\nA course of corticosteroids used to treat active disease, normally given for 4 to 8\xa0weeks (depending on the steroid).", 'Recommendations for research': "The guideline committee has made the following recommendations for research. As part of the 2019 update, the guideline committee made an additional 3 research recommendations on inducing remission in mild-to-moderate ulcerative colitis.\n\n# Key recommendations for research\n\n## The effectiveness of immunomodulators in inducing remission in proctitis\n\nIn a mild-to-moderate first presentation or inflammatory exacerbation of proctitis that is resistant to standard treatment, what is the effectiveness of topical immunomodulators, such as tacrolimus, in achieving clinical remission and what is the most effective formulation (suppository/ointment)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on proctitis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review: induction of remission in mild-to-moderate ulcerative colitis.\n\nLoading. Please wait.\n\n## The effectiveness of immunomodulators in unresponsive ulcerative colitis\n\nWhat is the effectiveness of oral tacrolimus and systemic (intramuscular/subcutaneous/oral) methotrexate in the induction of remission in mild-to-moderate ulcerative colitis unresponsive to aminosalicylates?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on extensive ulcerative colitis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review: induction of remission in mild-to-moderate ulcerative colitis.\n\nLoading. Please wait.\n\n## The relative effectiveness of corticosteroids for inducing remission in ulcerative colitis\n\nWhat is the clinical and cost effectiveness of prednisolone, budesonide, and beclometasone in addition to aminosalicylates compared with each other and with aminosalicylate monotherapy for the induction of remission for people with mild-to-moderate ulcerative colitis?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on all extents of disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review: induction of remission in mild-to-moderate ulcerative colitis.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## From the 2019 update\n\nWhat is the clinical and cost effectiveness of prednisolone compared with aminosalicylates for the induction of remission for people with moderate ulcerative colitis?\n\nWhat is the clinical and cost effectiveness of prednisolone plus an aminosalicylate compared with beclometasone plus an aminosalicylate for induction of remission for people with moderate ulcerative colitis?\n\nWhat are the benefits, risks and cost effectiveness of methotrexate, ciclosporin, tacrolimus, adalimumab and infliximab compared with each other and with placebo for induction of remission for people with subacute ulcerative colitis that is refractory to systemic corticosteroids?\n\n## From the 2013 guideline\n\nWhat are the benefits, risks and cost effectiveness of methotrexate, ciclosporin, tacrolimus, adalimumab and infliximab compared with each other and with placebo for induction of remission for people with subacute ulcerative colitis that is refractory to systemic corticosteroids?\n\nWhat is the clinical and cost effectiveness of regular maintenance treatment compared with no regular treatment (but rapid standard treatment if a relapse occurs) in specific populations with mild to moderate ulcerative colitis?\n\nTo develop and validate a risk tool that predicts the likelihood of needing surgery for adults admitted to hospital with acute severe ulcerative colitis.\n\nIn children and young people with ulcerative colitis receiving steroid treatment, what are the clinical benefits of routine monitoring of bone density, what tests should be done and how frequently?\n\nA registry to collect data to answer 'What are the potential harms or benefits of drug treatments in pregnant women with ulcerative colitis?'\n\nWhat are the information needs of people with ulcerative colitis when they are considering surgery?\n\nWhat is the clinical and cost effectiveness of sulphasalazine compared to high-dose branded mesalazine for induction of remission for people with mild moderate ulcerative colitis?\n\nWhat is the validity, reliability and accuracy of available adult risk tools as a predictor for the need for surgery in people admitted into hospital with acute severe ulcerative colitis?\n\nWhat is the validity, reliability and accuracy of the paediatric ulcerative colitis activity index (PUCAI) as a predictor for surgery for children and young people admitted to hospital with acute severe colitis?\n\nIn people with mild to moderate ulcerative colitis, what are the best second-line treatment strategies for induction of remission after people have failed to respond to ASA mono or combination therapies?\n\nIn people with subacute ulcerative colitis, what are the best second-line treatment strategies for induction of remission after people have failed to respond to oral prednisolone?\n\nIn people with mild to moderate ulcerative colitis, what are the best strategies for the induction of remission after people have failed to respond to tacrolimus?\n\nEstablish a national registry to identify the incidence of growth failure and/or pubertal delay in ulcerative colitis and the relationship with treatment (to record treatment [steroids, ASA, immunomodulators] and growth [z scores]).", 'Rationale and impact': "This section briefly explains why the committee made the recommendations and how they might affect practice. It links to details of the evidence and a full description of the committee's discussion.\n\n# Inducing remission in people with mild-to-moderate ulcerative colitis\n\nRecommendations 1.2.1 to 1.2.14\n\n## Why the committee made the recommendations\n\nThe evidence showed that topical aminosalicylates (suppositories or enema) are the most effective treatments for achieving remission in people with mild-to-moderate proctitis, so these were recommended as first-line treatments. The evidence did not show any difference in effectiveness between enema and suppository.\n\nTopical aminosalicylates alone are recommended for up to 4\xa0weeks because the evidence showed that they were the most effective treatment within this timeframe. There was no direct evidence for combining topical and oral aminosalicylates for people with proctitis. However, evidence showed that this combination was effective for people with proctosigmoiditis, and the committee agreed that this evidence was also applicable to people with proctitis alone. The committee chose not to specify a dose for the oral aminosalicylate. It preferred to leave it open to clinical judgment depending on the specific situation (for example, the clinician could give a low dose if the person had not taken an aminosalicylate before, or a high dose if the person was already taking a low dose).\n\nSome people will not achieve remission with topical and oral aminosalicylates. In clinical practice, oral or topical corticosteroids are commonly added at this stage, but there was no evidence on this combination. The committee agreed that, based on their experience, adding a topical or oral corticosteroid should be an option at this stage.\n\nDespite the lack of direct evidence for the effectiveness of topical or oral corticosteroids, the committee agreed that, based on their experience, these should also be an option for people who cannot tolerate aminosalicylates.\n\nSome people decline topical treatment, preferring oral to topical aminosalicylates. This is more common in children and young people, although proctitis is not common in this group. As the evidence showed that oral aminosalicylates are not as effective at inducing remission, the committee thought it was important to explain this to people who decline topical aminosalicylates.\n\nThere was cost-effectiveness evidence showing that using an immunomodulator as the next line of treatment after oral or topical corticosteroids and oral aminosalicylate produced greater health benefits at lower total costs than other strategies. However, the clinical evidence on topical immunomodulators was limited and it was unclear how applicable it was to UK clinical practice. Because of this, the committee recommended the sequence without this final treatment, and made a research recommendation on topical immunomodulators.\n\nThere is evidence that topical aminosalicylates are effective for achieving remission in people with mild-to-moderate proctosigmoiditis or left-sided ulcerative colitis. In the committee's experience topical aminosalicylates also work faster and more effectively than topical corticosteroids. Topical aminosalicylates alone are recommended for up to 4\xa0weeks because the evidence showed that they were effective within this timeframe. Cost-effectiveness evidence also showed that treatment sequences starting with topical aminosalicylates produced greater health benefits and incurred lower total costs than other strategies.\n\nThere is no direct evidence for the effectiveness of high-dose oral aminosalicylates combined with either topical aminosalicylates or topical corticosteroids. However, there is evidence that topical treatments or high-dose oral aminosalicylates individually provide some benefit. Therefore, the committee agreed it was reasonable to recommend combinations of these if remission is not achieved. While there was limited evidence for oral corticosteroids, in the committee's experience an oral corticosteroid may benefit people with proctosigmoiditis or left-sided disease if further treatment is needed. As a result, they recommended oral corticosteroids with oral aminosalicylates instead of topical treatment for these people. This reflects current practice for people who do not achieve remission with topical treatments and high-dose oral aminosalicylates.\n\nThe evidence showed that people with mild-to-moderate extensive ulcerative colitis would benefit most from a combination of high-dose oral aminosalicylates with topical aminosalicylates as first-line treatment. High-dose oral aminosalicylates combined with topical aminosalicylates are recommended for up to 4\xa0weeks, because in the committee's experience they are the most effective treatment within this timeframe. There is evidence that an oral corticosteroid combined with a high-dose oral aminosalicylate is also effective, so the committee recommended this combination if remission is not achieved with aminosalicylates alone. In people who cannot tolerate aminosalicylates, oral corticosteroids are recommended as they are also an effective treatment option.\n\nThe sequence of drugs recommended was more effective than starting with a high-dose oral aminosalicylate alone. There was some uncertainty around the cost effectiveness of this sequence. The data on the effectiveness of high-dose oral aminosalicylates combined with topical aminosalicylates was from an 8‑week clinical trial. The committee believed that in practice, people whose disease did not respond to treatment within 4\xa0weeks would switch to another treatment. When the cost-effectiveness analysis allowed for early switching, the combination of a high-dose oral aminosalicylate and topical aminosalicylate was not cost effective. However, if it was assumed that everyone continued treatment as described in the trial, the combination of a high-dose oral aminosalicylate and topical aminosalicylate was more likely to be cost effective. The committee took the uncertainty about the cost-effectiveness results in the different scenarios into account in recommending the combination as first-line treatment.\n\nThere was some evidence on methotrexate for inducing remission, but it did not show a clear benefit, and there was no evidence on oral tacrolimus. To address these gaps in the evidence, the committee made a research recommendation on the effectiveness of immunomodulators in unresponsive ulcerative colitis.\n\nMost of the evidence was for adults. However, the committee agreed to generalise the recommendations to all people with a mild-to-moderate exacerbation or first presentation of ulcerative colitis.\n\nThere is limited evidence on oral corticosteroids. In addition, the committee agreed that the use of oral corticosteroids is generally reserved for later lines of treatment because of concerns about side effects. It is not clear which corticosteroid is most effective for each extent of disease. There is also limited evidence on immunomodulators, specifically oral tacrolimus and systemic methotrexate for each extent of disease. The committee made a research recommendation on corticosteroids for the induction of remission in mild-to-moderate ulcerative colitis to address these uncertainties.\n\n## How the recommendations might affect practice\n\nThe new recommendations classify the extents of ulcerative colitis differently. This more closely reflects current practice, so will be clearer and more informative for people with mild-to-moderate ulcerative colitis and healthcare professionals.\n\nThe recommendations in the 2013 guideline referred to specific corticosteroids. To better reflect the available evidence, the updated recommendations refer to aminosalicylates and corticosteroids as a class rather than recommending individual treatments. This allows healthcare professionals and people with mild-to-moderate ulcerative colitis to choose the most appropriate corticosteroid or aminosalicylate, depending on patient preference, availability and acquisition cost.\n\nThe new recommendations specify that courses of oral corticosteroids should be time-limited. This should address varying practice in prescribing for some corticosteroids.\n\nReturn to recommendations", 'Context': "Ulcerative colitis is the most common type of inflammatory bowel disease. There are around 146,000\xa0people in the UK with a diagnosis of ulcerative colitis (Crohn's & Colitis UK). The cause of ulcerative colitis is unknown. It can develop at any age, but peak incidence is between the ages of 15 and 25\xa0years, with a second, smaller peak between 55 and 65\xa0years (although this second peak has not been universally demonstrated).\n\nUlcerative colitis usually affects the rectum, and a variable extent of the colon proximal to the rectum. The inflammation is continuous in extent. Inflammation of the rectum is referred to as proctitis, and inflammation of the rectum and sigmoid as proctosigmoiditis. Left-sided colitis refers to disease involving the colon distal to the splenic flexure. Extensive colitis affects the colon proximal to the splenic flexure, and includes pan-colitis, where the whole colon is involved.\n\nSymptoms of active disease or relapse include bloody diarrhoea, an urgent need to defecate and abdominal pain.\n\nUlcerative colitis is a lifelong disease that is associated with significant morbidity. It can also affect a person's social and psychological wellbeing, particularly if poorly controlled. Typically, it has a relapsing-remitting pattern.\n\nCurrent medical approaches focus on treating active disease to address symptoms, to improve quality of life, and thereafter to maintain remission. The long-term benefits of achieving mucosal healing remain unclear. The treatment chosen for active disease is likely to depend on clinical severity, extent of disease and the person's preference, and may include the use of aminosalicylates, corticosteroids or biological drugs. These drugs can be oral or topical (into the rectum), and corticosteroids may be administered intravenously in people with acute severe disease. Surgery may be considered as emergency treatment for severe ulcerative colitis that does not respond to drug treatment. People may also choose to have elective surgery for unresponsive or frequently relapsing disease that is affecting their quality of life.\n\nAdvice and support for people with ulcerative colitis is important, in terms of discussing the effects of the condition and its course, medical treatment options, the effects of medication and the monitoring required. Around 10% of inpatients with inflammatory bowel disease reported a lack of information about drug side effects on discharge from hospital. Information to support decisions about surgery is also essential, both for clinicians and for people facing the possibility of surgery. This includes recognising adverse prognostic factors for people admitted with acute severe colitis to enable timely decisions about escalating medical therapy or predicting the need for surgery. It is also very important to provide relevant information to support people considering elective surgery.\n\nThe wide choice of drug preparations and dosing regimens, the judgement required in determining the optimum timing for surgery (both electively and as an emergency) and the importance of support and information may lead to variation in practice across the UK. This guideline aims to address this variation, and to help healthcare professionals to provide consistent high-quality care. Managing ulcerative colitis in adults and children overlaps in many regards, so the guideline incorporates advice that is applicable to children and young people, which again should help to address potential inconsistencies in practice."}
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https://www.nice.org.uk/guidance/ng130
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This guideline covers managing ulcerative colitis in children, young people and adults. It aims to help professionals to provide consistent high-quality care and it highlights the importance of advice and support for people with ulcerative colitis.
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bde03f7407fa9b01dda90f7e4d3b363bb6ed124b
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nice
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Intrapartum care for women with existing medical conditions or obstetric complications and their babies
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Intrapartum care for women with existing medical conditions or obstetric complications and their babies
This guideline covers care during labour and birth for women who need extra support because they have a medical condition or complications in their current or previous pregnancy. The guideline also covers women who have had no antenatal care. It aims to improve experiences and outcomes for women and their babies.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Supporting women to make decisions about their care is particularly important during the intrapartum period. Healthcare professionals should ensure that women have the information they need to make decisions and to give consent in line with General Medical Council (GMC) guidance and the 2015 Montgomery ruling.
# Information for women with existing medical conditions
Clarify with women with existing medical conditions whether and how they would like their birth companion(s) involved in discussions about care during labour and birth. Review this regularly.
Offer pregnant women with medical conditions and their birth companion(s) information about intrapartum care. This should include:
general information as outlined in the NICE guideline on intrapartum care for healthy women and babies
how their medical condition may affect their care
how labour and birth may affect their medical condition
how their medical condition and its management may affect the baby.Information should be presented as recommended in the NICE guideline on patient experience in adult NHS services.
Offer information about intrapartum care in consultations before conception, if possible, and as early as possible during pregnancy. Allow extra time to discuss with the woman how her medical condition may affect her care.
Information about intrapartum care should be offered to women with medical conditions by a member of the multidisciplinary team (see the recommendation on team members in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team).
If a pregnant woman with a medical condition has not had any antenatal care (see the section on no antenatal care), give her information about intrapartum care at her first contact with healthcare services during pregnancy.
NICE has published a guideline on diabetes in pregnancy.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information for women with existing medical conditions .
Full details of the evidence and the committee's discussion are in evidence review A: information for women with existing medical conditions.
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# Planning for intrapartum care with women with existing medical conditions – involving a multidisciplinary team
A multidisciplinary team led by a named healthcare professional should involve a pregnant woman with a medical condition in preparing an individualised plan for intrapartum care. The plan should be:
formulated by following the principles of shared decision making outlined in the NICE guideline on shared decision making
reviewed with the woman and her birth companion(s) as early as possible throughout pregnancy and on admission for birth
updated with the woman if her medical condition changes during pregnancy
shared with the woman's GP and teams providing her antenatal and intrapartum care.
For pregnant women with a medical condition, the multidisciplinary team may include, as appropriate:
a midwife
an obstetrician
an obstetric anaesthetist
an obstetric physician or clinician with expertise in caring for pregnant women with the medical condition
a clinician with expertise in the medical condition
a specialty surgeon
a critical care specialist
a neonatologist
the woman's GP
allied health professionals.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on planning for intrapartum care with women with existing medical conditions – involving a multidisciplinary team .
Full details of the evidence and the committee's discussion are in evidence review B: antenatal care planning involving a multidisciplinary team for women with existing medical conditions.
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# Heart disease
## Risk assessment for women with heart disease
Risk assessment for women with heart disease should follow the principles of multidisciplinary team working (outlined in the recommendation in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Include a cardiologist with expertise in managing heart disease in pregnant women in the multidisciplinary team discussions.
For women with heart disease diagnosed in the intrapartum period, urgent multidisciplinary discussions are needed to ensure that the woman is offered the same level of care as a woman with an existing diagnosis of heart disease and, where possible, that her preferences are taken into account.
Be aware that some women with heart disease are at low risk of complications and their care should be in line with the NICE guideline on intrapartum care for healthy women and babies, whereas others need individualised specialist care.Risk is defined according to the modified World Health Organization (WHO) classification of maternal cardiovascular risk in the 2018 European Society of Cardiology guidelines published in the European Heart Journal.
For women with heart disease, reassess intrapartum risk regularly during pregnancy and the intrapartum period using all of the following:
comprehensive clinical assessment, including history and physical examination
the modified WHO classification of risk
New York Heart Association (NYHA) functional class (see American Heart Association's information about classes of heart failure).
Offer the same investigations to pregnant women with heart disease as to women who are not pregnant. Review the results and act on them without delay.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on risk assessment for women with heart disease .
Full details of the evidence and the committee's discussion are in evidence review C: heart disease.
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## Management of anticoagulation for women with mechanical heart valves
When pregnancy is confirmed:
involve women with mechanical heart valves in multidisciplinary discussion of plans for anticoagulation during the intrapartum period (see the recommendations in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team)
consider including a haematologist in the multidisciplinary discussion
explain to women that they will need individualised anticoagulation depending on their current treatment.
For women with mechanical heart valves who are taking warfarin in the third trimester, switch anticoagulation to low-molecular-weight heparin by 36+0 weeks of pregnancy or 2 weeks before planned birth (if this is earlier than 36+0 weeks). In hospital, consider doing this by:
stopping warfarin, and 24 hours later, starting low-molecular-weight heparin using a twice-daily regimen at a dose based on the most recent weight available
increasing the dose of low-molecular-weight heparin according to anti‑Xa levels; this should be done by:
checking anti‑Xa levels each day 3 to 4 hours after a dose of low-molecular-weight heparin, aiming for a peak anti‑Xa level between 1.0 and 1.2 IU/ml
checking that the anti‑Xa level before a dose of low-molecular-weight heparin (trough level) is above 0.6 IU/ml
rechecking anti‑Xa level weekly once the target anti‑Xa level is achieved.
For women with mechanical heart valves, stop therapeutic low-molecular-weight heparin 24 hours before a planned caesarean section and consider:
aiming to perform the caesarean section as near to 24 hours after stopping low-molecular-weight heparin as possible and no later than 30 hours after stopping or
switching to intravenous unfractionated heparin (aiming for an activated partial thromboplastin time of at least twice control), then 4 to 6 hours before caesarean section, stopping intravenous unfractionated heparin.
For women with mechanical heart valves who are having an induction of labour, a senior obstetrician should be involved in:
deciding when to stop low-molecular-weight heparin or intravenous unfractionated heparin in order to:
minimise the risk of maternal haemorrhage or valve thrombosis
enable the option of regional analgesia
reviewing the progress of labour and:
the need for low-molecular-weight heparin every 12 hours, aiming for birth as close to 12 hours from the last injection as possible or
the need for unfractionated heparin, aiming for birth as close to 4 to 6 hours after stopping the infusion.
For women with mechanical heart valves who are taking warfarin and who present in established labour:
check the international normalised ratio (INR) immediately and consult a haematologist
do not give anticoagulation until the woman has had an assessment by an obstetrician, which should happen within 2 hours
carry out a senior review (including at least a senior obstetrician, haematologist and a consultant obstetric anaesthetist) to discuss the mode of birth most likely to give the lowest risk of bleeding for the woman and the baby
consider reversal of anticoagulation.
For women with mechanical heart valves, carry out a postpartum review, involving at least a senior obstetrician and anaesthetist, of the risk of haemorrhage and valve thrombosis within 3 to 4 hours of birth. Aim to restart therapeutic low-molecular-weight heparin or unfractionated heparin 4 to 6 hours after birth.
For women with mechanical heart valves at high risk of peripartum haemorrhage, consider the following options until hourly review indicates that therapeutic anticoagulation can be re-established:
prophylactic low-molecular-weight heparin or
no low-molecular-weight heparin.
For women with mechanical heart valves, consider delaying restarting warfarin until at least 7 days after birth and arrange specialist follow‑up as outlined in the multidisciplinary care plan (see recommendation 1.3.6).
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management of anticoagulation for women with mechanical heart valves .
Full details of the evidence and the committee's discussion are in evidence review C: heart disease.
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## Mode of birth for women with heart disease
Develop an individualised birth plan with the woman with heart disease covering all 3 stages of labour following multidisciplinary discussion (outlined in the recommendation on the plan in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Consider including a cardiologist with expertise in managing heart disease in pregnant women in the multidisciplinary team discussions.
Throughout pregnancy, manage pulmonary arterial hypertension in consultation with a specialist pulmonary hypertension centre.
Offer planned birth (induction of labour or caesarean section) for women with mechanical heart valves.
Consider planned caesarean section for women with:
any disease of the aorta assessed as high risk
pulmonary arterial hypertension
NYHA class III or IV heart disease.Explain the benefits and risks of caesarean section. If the woman chooses not to have a caesarean section, explain the benefits and risks of an assisted second stage of labour compared with active pushing alone.
For women with heart disease who have a planned caesarean section, develop an individualised emergency care plan with the woman in case she presents in early labour, with new symptoms or with obstetric complications.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on mode of birth for women with heart disease .
Full details of the evidence and the committee's discussion are in evidence review C: heart disease.
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## Fluid management for women with heart disease
During pregnancy, plan the management of fluid balance during the intrapartum period for women with heart disease with the multidisciplinary team (outlined in the recommendation on team members in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Include a cardiologist with expertise in managing heart disease in pregnant women. Multidisciplinary discussion should include:
how the condition affects fluid balance
-ptimum fluid balance and how this might be achieved
plans for risk assessment and monitoring.
Identify women with heart disease for whom fluid balance is critical to cardiac function. These include women with:
severe left-sided stenotic lesions (for example, aortic stenosis and mitral stenosis)
hypertrophic cardiomyopathy
cardiomyopathy with systolic ventricular dysfunction
pulmonary arterial hypertension
Fontan circulation and other univentricular circulations
NYHA class IV heart disease.
For women with heart disease in whom fluid balance is critical for optimal cardiac function, offer tailored monitoring and clinical review during the intrapartum period, and consider escalation as follows:
hourly monitoring of fluid input and output (with at least 4‑hourly assessment by a senior clinician), blood pressure, pulse, respiratory rate and oxygen saturation
continuous electrocardiogram (ECG) and pulse oximetry with interpretation by trained staff
continuous intra-arterial blood pressure monitoring
cardiac output monitoring with non-invasive techniques, or serial echocardiography by trained staff.Advise women who need intensive monitoring that this may have to be carried out in an intensive care unit where the necessary equipment and expertise is available.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Offer standard fluid management during the intrapartum period for women with modified WHO 1 and NYHA class I heart disease.
Consider standard fluid management during the intrapartum period for women with modified WHO 2 to 3, or NYHA class II to III heart disease after a multidisciplinary discussion (outlined in the recommendation on the plan in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team).
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fluid management for women with heart disease .
Full details of the evidence and the committee's discussion are in evidence review C: heart disease.
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## Diagnosis and management of heart failure for all women in the intrapartum period
These recommendations cover the diagnosis and management of heart failure for all women in the intrapartum period. This includes women with existing heart disease, and women with no existing heart disease who develop symptoms and signs of heart failure.
Take a cardiac-specific history and suspect heart failure if there is not another likely cause of any of the following symptoms:
breathlessness when lying down (ruling out aortocaval compression) or at rest
unexplained cough, particularly when lying down or which produces frothy pink sputum
paroxysmal nocturnal dyspnoea – being woken from sleep by severe breathlessness and coughing, which may produce pink frothy sputum and is improved by moving to an upright position
palpitation (awareness of persistent fast heart rate at rest).
Consider heart failure in the intrapartum period if there are any of the following signs:
pale, sweaty, agitated with cool peripheries
heart rate persistently greater than 110 beats per minute at rest
respiratory rate persistently greater than 20 breaths per minute at rest
hypotension (systolic blood pressure less than 100 mmHg)
-xygen saturation less than 95% on air
elevated jugular venous pressure
added murmur or heart sound
reduced air entry, basal crackles or wheeze, on listening to the chest.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
If any of the symptoms or signs in recommendations 1.3.24 and 1.3.25 suggest heart failure, a senior clinician should review the woman's condition without delay.
When there is a clinical suspicion of heart failure in any woman in the intrapartum period:
establish peripheral venous access
measure urea and electrolytes, and perform a full blood count
measure arterial blood gases
perform an ECG
perform a chest X‑ray.
If clinical suspicion of heart failure in the intrapartum period cannot be ruled out by the investigations in recommendation 1.3.27, arrange:
review by a cardiologist (with interim review by a healthcare professional with expertise in this area if a cardiologist is not immediately available)
a transthoracic echocardiogram by a trained technician or cardiologist
measurement of N‑terminal pro‑brain natriuretic peptide (NT‑proBNP) levels.
Consider early birth for women with heart failure due to cardiomyopathy, depending on the severity of the condition and how well the condition has responded to treatment.
Optimise treatment for heart failure as soon as possible after birth even if the woman is breastfeeding.
If clinical suspicion of heart failure persists after birth, consider the continued involvement of a cardiologist.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on diagnosis and management of heart failure for all women in the intrapartum period .
Full details of the evidence and the committee's discussion are in evidence review C: heart disease.
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## Anaesthesia and analgesia for women with heart disease
During pregnancy, prepare a plan for managing anaesthesia and analgesia for women with heart disease involving a multidisciplinary team and the woman (outlined in the recommendation on the plan in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Consider including a haematologist for women on an anticoagulation regimen.
Consider offering the same information about anaesthesia and analgesia in labour to women with modified WHO 1 or modified WHO 2 heart disease as described in the NICE guideline on intrapartum care for healthy women and babies.
Consider regional anaesthesia for women with modified WHO 3 and modified WHO 4 heart disease, unless this is contraindicated.
Consider collaborative working in the intrapartum period between an obstetric anaesthetist and a cardiac anaesthetist for women with modified WHO 3 and modified WHO 4 heart disease.
When using regional anaesthesia for women with heart disease, aim to preserve cardiovascular stability by, for example, using a sequential combined spinal–epidural technique.
Offer intrapartum monitoring of the heart and circulation to all women with modified WHO 3 and modified WHO 4 heart disease; this will usually include continuous invasive intra-arterial pressure monitoring and may include central venous pressure monitoring and advanced cardiac output monitoring.
Offer low-dose regional analgesia to women with modified WHO 3 or modified WHO 4 heart disease because this is less likely to cause cardiac instability during labour and birth.
Consider regional analgesia for women who have been on low-molecular-weight heparin and who have not had a prophylactic dose for at least 12 hours, or a therapeutic dose for at least 24 hours.
For women taking low-molecular-weight heparin:
wait 12 hours after a prophylactic dose before siting an epidural, or removing an epidural catheter
wait 24 hours after a therapeutic dose before siting an epidural or spinal, or removing an epidural catheter
after siting an epidural or a spinal, or removing an epidural catheter, wait 4 hours before administering a further dose of low-molecular-weight heparin
do not administer therapeutic dose low-molecular-weight heparin while an epidural catheter is in place.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and analgesia for women with heart disease .
Full details of the evidence and the committee's discussion are in evidence review C: heart disease.
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## Management of the third stage of labour for women with heart disease
During pregnancy, prepare an individualised plan for managing the third stage of labour for women with heart disease, involving a multidisciplinary team and the woman (outlined in the recommendation on the plan in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Consider including a cardiologist with expertise in managing heart disease in pregnant women.
Treat women with modified WHO 1 heart disease as low risk and consider the full range of care options for healthy women in the third stage of labour described in the NICE guideline on intrapartum care for healthy women and babies.
Advise active management of the third stage of labour for women with modified WHO 2 heart disease, in line with the NICE guideline on intrapartum care for healthy women and babies.
Consider management of the third stage of labour for women with modified WHO 3 or modified WHO 4 heart disease according to table 1.
Condition
First-line uterotonic
Second-line uterotonics
Drugs to avoid because of potential harm
Significant aortopathy
Marfan syndrome and Loeys–Dietz with aortic dilatation >40 mm
Bicuspid aortopathy and aortic dilatation >45 mm
Previous aortic dissection
Turner syndrome and aortic size index >25 cm/m2
Oxytocin
Misoprostol
Carboprost
Ergometrine (because of risk of hypertension-induced aortic dissection or rupture)
Limited or fixed low cardiac output, or preload-dependent circulation
Severe systemic ventricular dysfunction (ejection fraction <30%)
Severe valvular stenosis
Hypertrophic cardiomyopathy with diastolic dysfunction or significant outflow tract obstruction
Fontan circulation
Cyanotic heart disease
Slow infusion of oxytocin to avoid sudden haemodynamic change
Misoprostol
Carboprost
Long-acting oxytocin analogues and ergometrine (because of risk of hypertension-induced heart failure)
Pulmonary arterial hypertension
Oxytocin
Misoprostol
Ergometrine, carboprost and long-acting oxytocin analogues (because of risk of worsening pulmonary hypertension)
Coronary artery disease
Oxytocin
Misoprostol
Ergometrine (because of risk of coronary ischaemia)
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management of the third stage of labour for women with heart disease .
Full details of the evidence and the committee's discussion are in evidence review C: heart disease.
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# Asthma
## Analgesia for women with asthma
Offer women with asthma the same options for pain relief during labour as women without asthma, including:
Entonox (50% nitrous oxide plus 50% oxygen)
intravenous and intramuscular opioids
epidural
combined spinal–epidural analgesia.
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on pain relief during labour for women with asthma .
Full details of the evidence and the committee's discussion are in evidence review D: asthma.
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## Prostaglandins for women with asthma
Do not offer prostaglandin F2 alpha (carboprost) to women with asthma because of the risk of bronchospasm.
Consider prostaglandin E1 or prostaglandin E2 as options for inducing labour in women with asthma because there is no evidence that they worsen asthma.
Consider prostaglandin E1 as an option for treating postpartum haemorrhage in women with asthma because there is no evidence it worsens asthma.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on prostaglandins for women with asthma .
Full details of the evidence and the committee's discussion are in evidence review D: asthma.
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# Long-term systemic steroids
## Steroid replacement regimens
Be aware that maternal corticosteroids given antenatally for fetal lung maturation should not affect the advice given in recommendations 1.5.2 to 1.5.4.
For women planning a vaginal birth who have adrenal insufficiency or who are taking long-term oral steroids (equivalent to 5 mg or more prednisolone daily for more than 3 weeks):
continue their regular oral steroids and
when they are in established first stage of labour, add intravenous or intramuscular hydrocortisone and consider a minimum dose of 50 mg every 6 hours until 6 hours after the baby is born.
For women having a planned or emergency caesarean section who have adrenal insufficiency or who are taking long-term oral steroids (equivalent to 5 mg or more prednisolone daily for more than 3 weeks):
continue their regular oral steroids and
give intravenous hydrocortisone when starting anaesthesia; the dose will depend on whether the woman has received hydrocortisone in labour, for example:
consider giving 50 mg if she has had hydrocortisone in labour
consider giving 100 mg if she has not had hydrocortisone in labour
give a further dose of hydrocortisone 6 hours after the baby is born (for example, 50 mg intravenously or intramuscularly).
Do not offer supplemental hydrocortisone in the intrapartum period to women taking inhaled or topical steroids.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on steroid replacement for women on long-term steroids .
Full details of the evidence and the committee's discussion are in evidence review E: long-term systemic steroids.
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# Bleeding disorders
## Regional anaesthesia and analgesia for women with bleeding disorders
Discuss the balance of benefits and risks of regional analgesia and anaesthesia with women with bleeding disorders.
When considering regional analgesia and anaesthesia for women with bleeding disorders, take into account:
the overall risk of bleeding and opportunity for corrective treatment
therapeutic and prophylactic anticoagulation
the risk of bleeding associated with the technique to be used
the difficulty of needle siting or insertion
the comparative risks associated with no analgesia or non-regional analgesia
the comparative risks of general anaesthesia.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on regional anaesthesia and analgesia for women with bleeding disorders .
Full details of the evidence and the committee's discussion are in evidence review F: bleeding disorders.
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## Modifying the birth plan according to platelet count or function
For woman with known immune thrombocytopenic purpura, before admission for birth:
plan birth in an obstetric-led unit with a neonatal unit that routinely provides high-dependency care
plan as if the baby will be at risk of bleeding irrespective of the woman's platelet count
consider monitoring maternal platelet count weekly from 36 weeks, and if the platelet count is below 50:
discuss and agree a plan for intrapartum care with the multidisciplinary team, including a haematologist
consider giving steroids or intravenous immunoglobulin to raise the maternal platelet count.
For women with known immune thrombocytopenic purpura, on admission for birth:
measure maternal platelet count
manage intrapartum care according to table 2.
For women with known or suspected immune thrombocytopenic purpura, take the following precautions to reduce the risk of bleeding for the baby:
inform the neonatal team of the imminent birth of a baby at risk
do not carry out fetal blood sampling
use fetal scalp electrodes with caution
do not use ventouse
use mid-cavity or rotational forceps with caution
bear in mind that a caesarean section may not protect the baby from bleeding
measure the platelet count in the umbilical cord blood at birth.
Modify the birth plan based on maternal platelet count, using table 2 as a guide, for women with:
gestational thrombocytopenia (without pre-eclampsia and HELLP syndrome, and otherwise well)
an uncertain diagnosis of immune thrombocytopenic purpura.
Maternal platelet count
Maternal care
Platelet count above 80×109/l
Treat the woman as healthy for the purpose of considering regional analgesia and anaesthesia
Platelet count 50 to 80×109/l
Before considering regional analgesia and anaesthesia, take into account:
clinical history
the woman's preferences
anaesthetic expertise
Platelet count below 50×109/l
Avoid regional analgesia and anaesthesia under most circumstances
If the woman has known or suspected immune thrombocytopenic purpura, assume the baby is at risk of bleeding and take the precautions outlined in recommendation 1.6.5. If the woman has gestational thrombocytopenia, assume the baby has a normal risk of bleeding.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on modifying the birth plan according to platelet count or function .
Full details of the evidence and the committee's discussion are in evidence review F: bleeding disorders.
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## Management of the third stage of labour for women with bleeding disorders
Be aware that women with bleeding disorders are at increased risk of primary and secondary postpartum haemorrhage.
Offer active management rather than physiological management of the third stage of labour for women with bleeding disorders, in line with the NICE guideline on intrapartum care for healthy women and babies.
For women with bleeding disorders, avoid giving uterotonics by intramuscular injection.
Offer individualised postpartum care, as discussed with a senior haematologist, for women with bleeding disorders, to include:
measurement of blood loss
monitoring obstetric complications
monitoring haematological parameters.
Be aware that non-steroidal anti-inflammatory drugs can add to the risk of bleeding.
Before discharge from hospital, inform women with bleeding disorders of the risk of secondary bleeding postpartum and how to access care.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on managing the third stage of labour for women with bleeding disorders .
Full details of the evidence and the committee's discussion are in evidence review F: bleeding disorders.
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# Subarachnoid haemorrhage or arteriovenous malformation of the brain
## Mode of birth and management of the second stage of labour for women with subarachnoid haemorrhage or arteriovenous malformation of the brain
Involve the multidisciplinary team in risk assessment for women with a cerebrovascular malformation or a history of intracranial bleeding. Include the woman in care planning and a clinician with expertise in managing neurovascular conditions in pregnant women.
Classify the risk of intrapartum intracranial bleeding as low if a woman has:
a fully treated cerebrovascular malformation or
intracranial bleeding of unknown cause following investigation, which occurred more than 2 years ago.
For women with a cerebrovascular malformation at low risk of intracranial bleeding, base decisions on the mode of birth on the woman's preference and obstetric indications.
For women with a cerebrovascular malformation at low risk of intracranial bleeding, manage the second stage of labour based on the woman's preference and obstetric indications.
Classify the risk of intrapartum intracranial bleeding as high if a woman has:
an untreated or partially treated cerebrovascular malformation that has bled previously
a large aneurysm (7 mm or more) or an aneurysm with other high-risk features as defined by a neuroradiologist
a complex arteriovenous malformation
cavernoma with high-risk features
intracranial bleeding within the past 2 years.
Consider caesarean section for women who are at high risk of cerebral haemorrhage, after a full discussion with the woman of the benefits and risks of all the options.
For women at high risk of cerebral haemorrhage who prefer to aim for a vaginal birth or are in the second stage of labour:
-ffer regional analgesia and
explain the benefits and risks of an assisted second stage of labour compared with active pushing alone.
For women who present for the first time in labour with a history of cerebrovascular malformation or intracranial bleeding and unknown risk of intracranial bleeding, manage as high risk and follow recommendations 1.7.6 and 1.7.7.
Do not withhold regional analgesia or anaesthesia from women with an isolated cerebrovascular malformation unless they have a genetic predisposition to multiple vascular malformations or unknown genetic history.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on care of women at risk of intracranial bleeding .
Full details of the evidence and the committee's discussion are in evidence review G: subarachnoid haemorrhage or arterio-venous malformation of the brain.
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# Acute kidney injury or chronic kidney disease
## Fluid management for women with kidney disease
During pregnancy, involve the multidisciplinary team in risk assessment for women with kidney disease. Include a clinician with expertise in managing renal conditions in pregnant women.
Ensure that women with chronic kidney disease stage 4 or 5 before pregnancy or women with progressive or active kidney disease are cared for in the intrapartum period by a midwife, obstetrician and obstetric anaesthetist with input from a clinician with expertise in managing renal conditions in pregnant women.
Ensure that a clinician with expertise in managing renal conditions in pregnant women is available for consultation during the intrapartum period for women with chronic kidney disease stage 4 or 5 before pregnancy or women with progressive or active kidney disease.
Manage acute kidney injury secondary to pre-eclampsia in line with the NICE guideline on hypertension in pregnancy.
For women with chronic kidney disease with or without pre-eclampsia, monitor fluid balance in the intrapartum period. Measure heart rate hourly and the following at least every 4 hours:
blood pressure
respiratory rate with chest auscultation
fluid output and fluid intake
-xygen saturation.After each assessment, develop an individualised plan for managing fluid balance, which may involve additional monitoring techniques, with the aim of maintaining normal fluid volume to reduce the risks of acute kidney injury and pulmonary oedema.
Assess renal function at least every 24 hours during the intrapartum period in all women with chronic kidney disease because prolonged labour may lead to dehydration and acute kidney injury.
For women with acute kidney injury:
identify and correct the cause of the acute kidney injury
measure heart rate hourly and monitor fluid balance in the intrapartum period by assessing the following at least every 4 hours:
blood pressure
respiratory rate and chest auscultation
fluid output and fluid intake
-xygen saturation
develop an individualised plan for managing fluid balance, which may involve additional monitoring techniques, with the aim of maintaining normal fluid volume and avoiding both dehydration and pulmonary oedema
consider giving a single small bolus of fluid (for example, 250 ml) as crystalloid if the woman is dehydrated and review the fluid status and urine output within an hour of giving the first fluid bolus and before considering giving a second
continue to monitor fluid balance and renal function until the acute kidney injury has recovered.
Do not offer nephrotoxic drugs (for example, non-steroidal anti-inflammatory drugs) in the intrapartum period to women with kidney disease.
For all women with kidney disease during pregnancy:
monitor the following at least every 4 hours for at least 24 hours after the birth:
heart rate and blood pressure
respiratory rate and chest auscultation
fluid output and fluid intake
-xygen saturation
ensure postpartum assessment of renal function and follow‑up for women with persistent kidney disease.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fluid management for women with kidney disease .
Full details of the evidence and the committee's discussion are in evidence review H: acute kidney injury or chronic kidney disease.
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## Timing and mode of birth for women with kidney disease
As early as possible during pregnancy, plan intrapartum care for women with kidney disease due to lupus nephritis, vasculitis or glomerulonephritis with the woman and a clinician with expertise in managing renal conditions in pregnant women.
As early as possible during pregnancy, plan intrapartum care for women with a kidney transplant with the woman, a clinician with expertise in managing renal conditions in pregnant women and a kidney transplant surgeon.
For women with chronic kidney disease stage 1, stable renal function and non-nephrotic-range proteinuria (urine protein:creatinine ratio less than 300 mg/mmol), base decisions on timing and mode of birth on the woman's preference and obstetric indications.
Consider planned birth by 40+0 weeks of pregnancy for women with:
chronic kidney disease stage 1 and nephrotic-range proteinuria (urine protein:creatinine ratio greater than 300 mg/mmol) or
chronic kidney disease stage 2 to 4 with stable renal function.
For women with chronic kidney disease stage 5 or deteriorating stage 3b and stage 4, before 34+0 weeks of pregnancy, discuss the option of dialysis with the woman and the multidisciplinary team in an effort to prolong the pregnancy to at least 34+0 weeks.
For women with chronic kidney disease stage 5 or deteriorating stage 3b and stage 4, after 34+0 weeks of pregnancy, discuss the option of planned birth with the woman and the multidisciplinary team and consider birth no later than 38+0 weeks.
For all women with kidney disease, including those with a kidney transplant, base decisions on mode of birth on the woman's preference and obstetric indications.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on timing and mode of birth for women with kidney disease .
Full details of the evidence and the committee's discussion are in evidence review H: acute kidney injury or chronic kidney disease.
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# Obesity
## Assessing fetal presentation early in labour for women with a BMI over 30
Consider ultrasound scanning at the start of established labour if the baby's presentation is uncertain for women with a BMI over 30 kg/m2 at the booking appointment, particularly those with a BMI over 35 kg/m2.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on assessing fetal presentation early in labour for women with a BMI over 30 kg/m2 .
Full details of the evidence and the committee's discussion are in evidence review I: obesity.
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## Fetal monitoring for women with a BMI over 30
Base intrapartum fetal monitoring on the woman's preference and obstetric indications (including no antenatal care), in line with the NICE guideline on fetal monitoring in labour, for women with a BMI over 30 kg/m2 at the booking appointment and no medical complications.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal monitoring for women with a BMI over 30 kg/m2 .
Full details of the evidence and the committee's discussion are in evidence review I: obesity.
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## Position in labour for women with a BMI over 30
For women with a BMI over 30 kg/m2 at the booking appointment, carry out a risk assessment in the third trimester. When developing the birth plan with the woman, take into account:
the woman's preference
the woman's mobility
comorbidities
the woman's current or most recent weight.
For women with a BMI over 30 kg/m2 at the booking appointment and reduced mobility in the third trimester, consider advising the lateral position in the second stage of labour.
For women with a BMI over 30 kg/m2 at the booking appointment and adequate mobility, provide care in the second stage of labour in line with the NICE guideline on intrapartum care for healthy women and babies.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on position during the second stage of labour for women with a BMI over 30 kg/m2 .
Full details of the evidence and the committee's discussion are in evidence review I: obesity.
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## Equipment needs for women in labour with a BMI over 30
All obstetric units should have 'birthing beds' able to take a safe working load of 250 kg.
Carry out a risk assessment to ensure that essential equipment, in a size-appropriate form, is available for the intrapartum care of women with a BMI over 30 kg/m2 at the booking appointment, including:
surgical, obstetric and anaesthetic equipment
blood pressure cuffs
-perating theatre tables
lifting and lateral transfer equipment
anti-embolism stockings
wheelchairs
monitoring and measuring equipment.
For women with a BMI over 50 kg/m2 at the booking appointment, offer referral to an obstetric unit with suitable equipment and expertise as early as possible in pregnancy, if this is not available in their current unit.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on equipment needs for women in labour with a BMI over 30 kg/m2 .
Full details of the evidence and the committee's discussion are in evidence review I: obesity.
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# Information for women with obstetric complications or no antenatal care
Follow the recommendations on communication in the NICE guideline on intrapartum care for healthy women and babies for women in labour with obstetric complications or no antenatal care.
Recognise that women in labour with obstetric complications or no antenatal care:
may be more anxious than other women in labour and
are likely to have a better experience of labour and birth if they receive information about the benefits and risks of options for their care and are fully involved in decision making.
Provide information about care in labour and mode of birth, which:
is personalised to the woman's circumstances and needs
uses local and national figures where possible
expresses benefits and risks in a way that the woman can understand
is presented as recommended in the NICE guideline on patient experience in adult NHS services.
Recognise that individual views about risk vary, and support a woman's decision making and choices.
Clarify with women with obstetric complications or no antenatal care whether and how they would like their birth companion(s) involved in discussions about care during labour and birth. Review this regularly.
Involve the woman in planning her care by asking about her preferences and expectations for labour and birth. Take account of previous discussions, planning, decisions and choices, and keep the woman and her birth companion(s) fully informed.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information for women with obstetric complications or no antenatal care .
Full details of the evidence and the committee's discussion are in evidence review J: information for women with obstetric complications or no antenatal care.
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# Risk assessment for women with obstetric complications or no antenatal care
Take account of symptoms reported and concerns expressed by women in labour with any of the following:
pyrexia
sepsis
intrapartum haemorrhage
breech presentation
suspected small-for-gestational-age baby
suspected large-for-gestational-age baby
previous caesarean section
labour after 42 weeks of pregnancy
no antenatal care.
Ensure that a healthcare professional with skills and experience in managing obstetric complications reviews and assesses the condition of a woman with any of the complications in recommendation 1.11.1, including any observations recorded, and escalates care as needed.
Take account of the whole clinical picture when discussing options for care with the woman during the intrapartum period.
Carry out and record maternal observations (pulse, blood pressure, temperature and urine output), as recommended in the NICE guideline on intrapartum care for healthy women and babies and shown in table 3, for women in labour with any of the following and no other reasons for concern:
breech presentation
suspected small-for-gestational-age baby
suspected large-for-gestational-age baby
previous caesarean section
labour after 42 weeks of pregnancy
no antenatal care.
Pulse
Blood pressure
Respiratory rate
Temperature
Level of consciousness (AVPU)
Oxygen saturation
Urine
Hourly
‑hourly, and hourly in the second stage
Not required routinely
‑hourly
Not required routinely
Not required routinely
Record output
Abbreviations: AVPU, alert, voice, pain, unresponsive.
The frequency of observations should be adjusted if necessary based on the level of clinical concern.
For women in labour with fever, a temperature of 38°C or above on a single reading or 37.5°C or above on 2 consecutive readings (1 hour apart), carry out maternal observations as shown in table 4.
For women in labour with sepsis or suspected sepsis, carry out maternal observations as shown in table 4.
For women with intrapartum haemorrhage, continuously monitor vaginal blood loss and carry out maternal observations as shown in table 4.
Maternal observation
Fever
Suspected sepsis – concern insufficient for antibiotic treatment
Sepsis or suspected sepsis – on antibiotic treatment
Intrapartum haemorrhage
Pulse
Hourly
Hourly
Continuous, or at least every 30 minutes
At least hourly
Blood pressure
-hourly, and hourly in the second stage
-hourly, and hourly in the second stage
Continuous, or at least every 30 minutes
At least 4-hourly, and at least hourly in the second stage
Respiratory rate
-hourly
-hourly
Continuous, or at least every 30 minutes
At least 4-hourly
Temperature
Hourly
Hourly
Hourly
At least 4-hourly
Level of consciousness (AVPU)
Hourly
Hourly
Every 30 minutes
Hourly
Oxygen saturation
-hourly
-hourly
Continuous, or at least every 30 minutes
At least 4-hourly
Urine
Record output
Record output
Record output, hourly if catheterised
Record output, hourly if catheterised
Abbreviations: AVPU, alert, voice, pain, unresponsive.
The frequency of observations should be adjusted if necessary based on the level of clinical concern.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on risk assessment for women with obstetric complications or no antenatal care .
Full details of the evidence and the committee's discussion are in evidence review K: risk assessment for women with obstetric complications or no antenatal care.
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# Pyrexia
## Use of antipyretics for women in labour with a fever
Consider paracetamol for women in labour with a fever, a temperature of 38°C or above on a single reading, or 37.5°C or above on 2 consecutive readings (1 hour apart).
Be aware that paracetamol is not a treatment for sepsis and should not delay investigation if sepsis is suspected.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on the use of antipyretics for women in labour with a fever .
Full details of the evidence and the committee's discussion are in evidence review L: pyrexia.
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## Fetal blood sampling for women in labour with a fever
For women in labour with a fever, a temperature of 38°C or above on a single reading, or 37.5°C or above on 2 consecutive readings (1 hour apart), follow the recommendations in the section on fetal monitoring for women in labour with sepsis or suspected sepsis on fetal blood sampling for women with suspected sepsis.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal blood sampling for women in labour with a fever .
Full details of the evidence and the committee's discussion are in evidence review L: pyrexia.
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# Sepsis
## Mode of birth for women with sepsis or suspected sepsis
Follow the NICE guideline on sepsis for the recognition of sepsis in pregnant women.
Take into account the normal physiological changes in labour when thinking about the possibility of sepsis, for example, increased maternal pulse rate.
Recognise that women in labour with sepsis (see the NICE guideline on sepsis) are at higher risk of severe illness or death.
For women in labour with suspected sepsis, ensure ongoing multidisciplinary review from a team with a named lead, including:
a senior obstetrician
a senior obstetric anaesthetist
a senior midwife
a labour ward coordinator.
For women in labour with sepsis, ensure ongoing multidisciplinary review from a team with a named lead, including:
a senior obstetrician
a senior obstetric anaesthetist
a senior neonatologist
a senior microbiologist
a senior midwife
a labour ward coordinator.
Include a senior intensivist (critical care specialist), if a woman in labour with sepsis has any of the following signs of organ dysfunction:
altered consciousness
hypotension (systolic blood pressure less than 90 mmHg)
reduced urine output (less than 0.5 ml/kg per hour)
need for 40% oxygen to maintain oxygen saturation above 92%
tympanic temperature of less than 36°C.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
For women with sepsis or suspected sepsis in the intrapartum period:
agree a clear multidisciplinary care plan with the woman
document the agreed plan
review the plan regularly, taking account of the whole clinical picture, including response to treatment.
Involve the woman with sepsis or suspected sepsis and her birth companion(s) in shared decision making about her care, including the following options:
induction of labour
continuing labour
augmenting labour
instrumental birth
caesarean section.
When discussing timing and mode of birth with a woman with sepsis or suspected sepsis, take into account the woman's preferences, concerns and expectations, and the whole clinical picture, including:
the source and severity of sepsis, if known
weeks of pregnancy
fetal wellbeing
stage and progress of labour
parity
response to treatment.
If the source of sepsis is thought to be the genital tract, expedite the birth.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on mode of birth for women with sepsis or suspected sepsis .
Full details of the evidence and the committee's discussion are in evidence review M: sepsis.
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## Anaesthesia and analgesia for women in labour with sepsis or suspected sepsis
For women in labour with sepsis and any signs of organ dysfunction (see recommendation 1.13.6), regional anaesthesia should only be used with caution and advice from a consultant obstetric anaesthetist, and with a senior anaesthetist present.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on anaesthesia for women in labour with sepsis and signs of organ dysfunction .
Full details of the evidence and the committee's discussion are in evidence review M: sepsis.
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For women in labour with sepsis and any signs of organ dysfunction (see recommendation 1.13.6), regional analgesia should only be used with caution and advice from a consultant obstetric anaesthetist.
For women in labour with suspected sepsis where concern is insufficient for antibiotic treatment, consider the birthing pool as a form of analgesia only after discussion with a senior midwife and a senior obstetrician.
For women in labour who need antibiotics for suspected sepsis (see the NICE guideline on sepsis), start the antibiotics before inserting the needle for regional analgesia.
For women in labour with suspected sepsis, carry out a multidisciplinary review of options for pain relief at least every 4 hours.
If there are concerns about providing a woman's choice of regional analgesia, this should be discussed with the consultant obstetric anaesthetist.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on analgesia for women in labour with sepsis or suspected sepsis .
Full details of the evidence and the committee's discussion are in evidence review M: sepsis.
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## Fetal monitoring for women in labour with sepsis or suspected sepsis
Advise continuous cardiotocography during labour for:
women with suspected sepsis and
women with confirmed sepsisin line with the section on the use of cardiotocography for monitoring during labour in the NICE guideline on fetal monitoring in labour.
Explain to the woman and her birth companion(s) what fetal blood sampling involves and the uncertainty of the significance of the results, and support her decision to accept or decline testing.
Be aware that for women in labour with sepsis or suspected sepsis, fetal blood sample results may be falsely reassuring, and always discuss with a consultant obstetrician:
whether fetal blood sampling is needed
the results of any fetal blood sampling carried out.
For women in labour with sepsis or suspected sepsis and an abnormal cardiotocograph trace, think about the whole clinical picture and take account of the following before performing any fetal blood sampling and when interpreting the results:
the woman's preferences
stage and progress of labour
parity
likelihood of chorioamnionitis.
If sepsis continues to be suspected, only repeat fetal blood sampling with caution and in discussion with a consultant obstetrician.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal monitoring for women in labour with sepsis or suspected sepsis .
Full details of the evidence and the committee's discussion are in evidence review M: sepsis.
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## Antimicrobial treatment for women in labour with sepsis or suspected sepsis
For women in labour with sepsis or suspected sepsis:
Take into account the whole clinical picture when thinking about antimicrobial treatment.
Document the rationale for any decision to start antimicrobial treatment and the choice of antimicrobial.
Take specimens for microbiological culture, including blood cultures, before starting antimicrobials in line with the NICE guideline on sepsis.
For women in labour with sepsis or suspected sepsis and a clear source of infection, use existing local antimicrobial guidance when offering an antimicrobial.
For women in labour with sepsis or suspected sepsis and an unclear source of infection, offer a broad-spectrum intravenous antimicrobial from the agreed local formulary and in line with local (where available) or national guidelines.
Explain to the woman in labour with sepsis or suspected sepsis and her birth companion(s):
there is no evidence to support the use of one broad-spectrum antimicrobial over another
the choice of antimicrobial will be guided by local antimicrobial guidelines.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on antimicrobial treatment for women in labour with sepsis or suspected sepsis .
Full details of the evidence and the committee's discussion are in evidence review M: sepsis.
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## Care for women with sepsis or suspected sepsis immediately after the birth
For women with sepsis or suspected sepsis, ensure that there is ongoing multidisciplinary review (see the recommendations in the sections on multidisciplinary review for women in labour with suspected sepsis and with sepsis) in the first 24 hours after the birth. This should include a discussion about the need for:
microbiological specimens for culture
antimicrobial treatment
increased frequency of monitoring
an enhanced level of care and monitoring
further investigations such as imaging
support to enable the woman to feed her baby as she chooses (including keeping the woman and baby together wherever possible and maintaining skin-to-skin contact)
additional support for the woman and her family.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on care for women with sepsis or suspected sepsis immediately after the birth .
Full details of the evidence and the committee's discussion are in evidence review M: sepsis.
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# Intrapartum haemorrhage
## Management of intrapartum haemorrhage
If there are signs of shock in a woman with intrapartum haemorrhage, proceed with immediate resuscitation.
The maternity service and ambulance service should have strategies in place to respond quickly and appropriately if a woman has an intrapartum haemorrhage in any setting.
If a woman in labour has any vaginal blood loss other than a 'show', transfer her to obstetric-led care, in line with the NICE guideline on intrapartum care for healthy women and babies.
If a woman in labour has any vaginal blood loss other than a 'show', explain to her and her birth companion(s) what is happening.
If a woman in labour has any vaginal blood loss other than a 'show':
Take a history of the bleeding, asking about:
any associated symptoms, including pain
any specific concerns the woman may have
any previous uterine surgery.
Check previous scans for placental position.
Assess the volume of blood loss and characteristics of the blood, such as colour, and presence of clots or amniotic fluid.
Carry out a physical examination, including:
vital signs
abdominal palpation
speculum examination
vaginal examination if placenta praevia has been excluded
fetal heart auscultation.
Start continuous cardiotocography.
Take a blood sample to determine full blood count and blood group.
Think about the possible causes of bleeding, for example:
placental abruption
placenta praevia
uterine rupture
vasa praevia.Recognise that in many cases, no cause will be identifiable.
If a woman in labour has any vaginal blood loss other than a 'show', agree a multidisciplinary care plan with the woman and document the plan. Include the following in plans for multidisciplinary care:
a senior obstetrician
a senior obstetric anaesthetist
a senior midwife
a labour ward coordinator.
If a woman has intrapartum bleeding and her condition is stable, management should include:
establishing venous access
maternal monitoring (see the recommendation on continuously monitoring vaginal blood loss in the section on risk assessment for women with obstetric complications or no antenatal care and table 4)
monitoring the fetal heart rate with continuous cardiotocography.
If a woman with intrapartum bleeding has a large blood loss or her condition causes concern, management should be in line with recommendation 1.14.8 and also include:
giving intravenous fluids urgently
taking blood for full blood count and cross-matching
seeking medical advice from a more experienced healthcare professional.Management may also include:
triggering the local major haemorrhage protocol
taking blood for clotting studies and blood gases
use of amniotomy or oxytocin
expediting the birth.
If a woman in labour has vaginal blood loss typical of a 'show', follow the NICE guideline on intrapartum care for healthy women and babies.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management of intrapartum haemorrhage .
Full details of the evidence and the committee's discussion are in evidence review N: intrapartum haemorrhage.
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# Breech presenting in labour
## Mode of birth for women presenting with a breech position in labour
Discuss with women in labour with breech presentation the possible benefits and risks of vaginal birth and caesarean section, including:
an increase in the chance of serious medical problems for the woman with caesarean section
an increase in the chance of serious medical problems for the baby with vaginal birth
what it might mean for them and the baby if such problems did occur.
Explain to women in labour with breech presentation that any benefit of caesarean section in reducing the chance of serious medical problems for the baby may be greater in early labour.
Offer women in labour with breech presentation a choice between continuing labour and caesarean section.
Assess progress of labour in line with the NICE guideline on intrapartum care for healthy women and babies.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on mode of birth for women presenting with a breech position in labour .
Full details of the evidence and the committee's discussion are in evidence review O: breech presenting in labour.
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# Small-for-gestational-age baby
## Fetal monitoring in labour for babies suspected to be small for gestational age
Discuss with a woman whose baby is suspected to be small for gestational age:
the chance of serious medical problems for her baby
what it might mean for her and her baby if such problems did occur.
When discussing risk, explain that when a baby is suspected to be small for gestational age:
it is sometimes difficult to be certain the suspicion is correct until the baby is born
the chance of serious medical problems for the baby is greater with:
growth restriction
additional risk factors, such as preterm birth
complications during labour or birth.
Offer continuous cardiotocography to women whose babies are suspected to be small for gestational age after a full discussion of the benefits and risks (see recommendations 1.16.1 and 1.16.2). Respect the woman's decision if she declines continuous cardiotocography.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal monitoring in labour for babies suspected to be small for gestational age .
Full details of the evidence and the committee's discussion are in evidence review P: small-for-gestational-age baby.
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# Large-for-gestational-age baby
## Mode of birth for babies suspected to be large for gestational age
Explain to women in labour whose babies are suspected to be large for gestational age that:
it is sometimes difficult to be certain the suspicion is correct until the baby is born
when making decisions about mode of birth (for example, vaginal birth or caesarean section), this uncertainty needs to be taken into account.
Discuss with women in labour whose babies are suspected to be large for gestational age the possible benefits and risks of vaginal birth and caesarean section, including:
a higher chance of maternal medical problems such as infection with emergency caesarean section
a higher chance of shoulder dystocia and brachial plexus injury with vaginal birth
a higher chance of instrumental birth and perineal trauma with vaginal birth.Explain to the woman and her birth companion(s) what it might mean for her and her baby if such problems did occur.
Offer women in labour whose babies are suspected to be large for gestational age a choice between continuing labour, including augmented labour, and caesarean section.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on mode of birth for babies suspected to be large for gestational age .
Full details of the evidence and the committee's discussion are in evidence review Q: large-for-gestational-age baby.
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# No antenatal care
## Risk assessment and management of labour for women with no antenatal care
For women who have had no antenatal care, be aware of the particular importance of following the recommendations on establishing rapport and treating with respect in the NICE guideline on intrapartum care for healthy women and babies.
Provide obstetric-led intrapartum care for women who have had no antenatal care, and alert the neonatal team and, if relevant, the anaesthetic team. If the woman presents to a midwifery unit, arrange urgent transfer to an obstetric-led unit if appropriate.
For a woman with no antenatal care who has difficulty understanding, speaking and reading English, provide an interpreter (who may be a link worker or advocate and should not be a member of her family, her legal guardian or her partner), who can communicate with her in her preferred language.
If possible, take a full medical, psychological and social history from women who have had no antenatal care.
Try to find out why there has been no care during pregnancy.
Ask the woman who, if anyone, she would like to support her as her birth companion(s) during labour.
Explore sensitively any possible vulnerability or safeguarding concerns, including:
young maternal age
maternal mental health
maternal learning disability
maternal substance misuse
domestic or sexual abuse
homelessness
human trafficking
undocumented migrant status
female genital mutilation
the woman or family members being known to children's services or social services.
Carry out an obstetric and general medical examination of a woman with no antenatal care as soon as possible. This should include the initial assessment described in the NICE guideline on intrapartum care for healthy women and babies.
Carry out an assessment of the unborn baby, including ultrasound if possible, to determine:
viability
the presentation
an estimate of gestational age
the possibility of multiple pregnancy
the placental site.
Offer women who have had no antenatal care, tests for:
anaemia (full blood count)
haemoglobinopathies
blood group and rhesus D status
atypical red cell alloantibodies
random blood glucose
asymptomatic bacteriuria
HIV, hepatitis B and syphilis.
Offer rapid HIV testing to women thought to be at high risk of infection, which might include:
recent migrants from countries with high rates of HIV infection
women who misuse substances intravenously
suspected sexual abuse.
Explain to a woman who has had no antenatal care why and when information about her pregnancy may need to be shared with other agencies.
Contact the woman's GP and, if appropriate, other health or social care professionals for more information about the woman's history and to plan ongoing care.
If there are safeguarding concerns, refer the woman to safeguarding services, document the referral and inform healthcare professionals such as the GP, health visitor and paediatric teams, and social care professionals (see the NICE guidelines on pregnancy and complex social factors, child maltreatment and child abuse and neglect).
Follow the recommendations in the NICE guideline on intrapartum care for healthy women and babies when no medical conditions or obstetric complications are identified in women who present in labour with no antenatal care.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on risk assessment and management of labour for women with no antenatal care .
Full details of the evidence and the committee's discussion are in evidence review R: no antenatal care.
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# Previous caesarean section
## Management of the first and second stages of labour for women with a previous caesarean section
Do not routinely insert an intravenous cannula for women in labour who have had a previous caesarean section.
Explain to women in labour who have had a previous caesarean section that:
a vaginal birth is associated with a small chance of uterine rupture
an emergency caesarean section may mean a higher chance of:
heavy bleeding needing a blood transfusion
infection, for example, intrauterine infection
a longer hospital stay
complications in a future pregnancy, for example, placenta praevia and placenta accreta (see the NICE guideline on caesarean birth).
Explain to women in labour who have had a previous caesarean section that there is little evidence of a difference in outcomes for the baby between a vaginal birth or another caesarean section.
Explain to women who have had a previous caesarean section that they are likely to have a lower chance of complications in labour if they have also had a previous vaginal birth.
When discussing oxytocin for delay in the first or second stage of labour, explain to women who have had a previous caesarean section that this:
increases the chance of uterine rupture
reduces the chance of another caesarean section
increases the chance of an instrumental birth.
For guidance on continuous cardiotocography in labour for women with a previous caesarean section, see NICE's guideline on caesarean birth.
Support informed choice of a full range of options for pain relief for women who have had a previous caesarean section, including labour and birth in water.
Explain to women in labour who have had a previous caesarean section that regional analgesia is associated with:
a reduced chance of another caesarean section
an increased chance of an instrumental birth.
Do not routinely offer amniotomy to women in labour who have had a previous caesarean section.
This recommendation on continuous cardiotocography has been withdrawn (see recommendation 1.19.6).
For women who have had a previous caesarean section, be aware of the particular importance of following the recommendations from the NICE guideline on intrapartum care for healthy women and babies on:
food and drink in labour
controlling gastric acidity
position in labour, including the latent first stage, and birth.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management of the first and second stages of labour for women with a previous caesarean section .
Full details of the evidence and the committee's discussion are in evidence review S: previous caesarean section.
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# Labour after 42 weeks of pregnancy
## Fetal and maternal monitoring for women in labour after 42 weeks of pregnancy
Offer continuous cardiotocography to women in labour after 42 weeks of pregnancy after a full discussion of the benefits and risks to the woman and her baby. Respect the woman's decision if she declines continuous cardiotocography.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal and maternal monitoring for women in labour after 42 weeks of pregnancy .
Full details of the evidence and the committee's discussion are in evidence review T: labour after 42 weeks of pregnancy.
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# Terms used in this guideline
## Chronic kidney disease stages
Classified according to estimated glomerular filtration rate (eGFR) measured before pregnancy. See glomerular filtration rate (GFR) categories in table 1 in the NICE guideline on chronic kidney disease in adults.
## Intrapartum period
The intrapartum period is from the onset of labour (spontaneous or induced) to 24 hours after birth.
## Mechanical heart valves
A mechanical heart valve refers to a prosthetic heart valve that requires long-term anticoagulation to prevent heart valve thrombosis. This is different from a bioprosthetic heart valve, which does not need long-term anticoagulation.
## Regional anaesthesia
Regional anaesthesia includes spinal, epidural and combined spinal–epidural techniques.
## Regional analgesia
Regional analgesia includes spinal, epidural and combined spinal–epidural techniques.# Recommendations for research
The guideline committee has made the following high-priority recommendations for research. For details of all the committee's recommendations for research, see the evidence reviews.
# Subarachnoid haemorrhage or arteriovenous malformation of the brain
Does caesarean section protect against cerebral haemorrhage in women with a history of subarachnoid haemorrhage or cerebrovascular malformation?
For a short explanation of why the committee made the recommendation for research, see the rationale on mode of birth and management of the second stage of labour for women with subarachnoid haemorrhage or arteriovenous malformation of the brain .
Full details of the evidence and the committee's discussion are in evidence review G: subarachnoid haemorrhage or arterio-venous malformation of the brain.
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# Needle siting in pregnant women who are obese
Does the use of ultrasound of the lumbar spine improve siting of regional anaesthetic needles in pregnant women with a BMI over 30 kg/m2 at the booking appointment?
For a short explanation of why the committee made the recommendation for research, see the rationale on anaesthesia and analgesia for women with a BMI over 30 .
Full details of the evidence and the committee's discussion are in evidence review I: obesity.
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# Obesity as a risk factor for perinatal morbidity and mortality
Is obesity an independent risk factor for perinatal morbidity and mortality?
For a short explanation of why the committee made the recommendation for research, see the rationale on fetal monitoring for women with a BMI over 30 .
Full details of the evidence and the committee's discussion are in evidence review I: obesity.
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# Risk assessment for women in labour with signs of sepsis
What clinical features and laboratory investigations can be used to better stratify risk for women in labour with signs of sepsis (including fever and tachycardia)?
For a short explanation of why the committee made the recommendation for research, see the rationale on risk assessment for women with obstetric complications or no antenatal care .
Full details of the evidence and the committee's discussion are in evidence review K: risk assessment for women with obstetric complications or no antenatal care.
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# Previous caesarean section
What is the clinical and cost effectiveness of intermittent auscultation compared with continuous cardiotocography for women in labour who have had a previous caesarean section?
For a short explanation of why the committee made the recommendation for research, see the rationale on previous caesarean section .
Full details of the evidence and the committee's discussion are in evidence review S: previous caesarean section.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Information for women with existing medical conditions
Recommendations 1.1.1 to 1.1.5
## Why the committee made the recommendations
Evidence was very limited, but the committee knew from their experience that providing information is extremely important for pregnant women with medical conditions. They agreed that women would need the general information outlined in the NICE guideline on intrapartum care for healthy women and babies as well as additional information related to the medical condition. Extra time may be needed in a consultation to discuss how the medical condition may affect intrapartum care. It was agreed that information should be delivered by a healthcare professional from the multidisciplinary team who can answer questions the woman may have about the intrapartum period and the medical condition. It is up to the woman to decide whether and how her birth companion(s) are involved in these discussions.
## How the recommendations might affect practice
The committee did not expect a significant change in practice because the recommendations are in line with what is generally happening in most centres. However, in centres where this is not happening, consultations will take longer.
Return to recommendations
# Planning for intrapartum care with women with existing medical conditions – involving a multidisciplinary team
Recommendations 1.2.1 and 1.2.2
## Why the committee made the recommendations
Evidence did not show a difference in outcomes for women with a BMI over 40 or their babies when care was given by a specialist antenatal multidisciplinary team. However, the committee recognised that women with medical conditions have an increased risk of adverse outcomes, and a lack of multidisciplinary working has been repeatedly cited in the Confidential Enquiries into Maternal Deaths and Morbidity as contributing to maternal deaths. To minimise risk, the committee recommended that a standard obstetric team be extended (when appropriate) by involving healthcare professionals with expertise in managing the woman's medical condition, and that teams involved in the woman's care share their intrapartum care plans.
## How the recommendations might affect practice
Multidisciplinary teams are not currently in place in all settings, including settings where care is delivered to women at high risk because of medical conditions. However, multidisciplinary working with other medical or surgical specialties is currently expected within the intermediate and intensive pathways for more complex pregnancies. The recommendations are expected to result in a relatively modest change in practice because most modern multidisciplinary teams are 'virtual' (communicating by telephone or email rather than in person). Obstetric teams and specialists will be seeing the same women that they would see anyway, but multidisciplinary working will give them the opportunity to deliver more holistic care. However, establishing the relationships and ways of working may involve extra organisation and increase the antenatal involvement of obstetric anaesthetists.
Return to recommendations
# Risk assessment for women with heart disease
Recommendations 1.3.1 to 1.3.5
## Why the committee made the recommendations
The committee drew on their knowledge and experience to recommend that intrapartum care planning should start early in pregnancy for women with heart disease. Pregnancy and birth are associated with dramatic changes in the performance of the heart and the circulation. Early risk assessment is needed to plan for birth and agree any additional management. Women who present in the intrapartum period with a previously unrecognised heart problem pose a particular challenge. Urgent multidisciplinary discussions are needed to ensure that they are offered comparable intrapartum care to women with an existing diagnosis.
The committee agreed that multidisciplinary care should include a cardiologist with expertise in managing heart conditions during pregnancy because they were concerned that not all pregnant women with heart disease have appropriate cardiac referrals. Only a few cardiologists in the UK have an interest in managing heart disease in pregnancy and the Confidential Enquiries into Maternal Deaths and Morbidity identified deficient care when non-specialist cardiologists had given inappropriate advice. The benefit of specialist cardiology advice also includes encouraging women with low-risk conditions towards vaginal birth with no medical intervention, in line with the NICE guideline on intrapartum care for healthy women and babies.
Based on the available evidence and their knowledge and experience, the committee agreed that risk assessment should include diagnostic classification, cardiac functional capacity and clinical assessment. For some women, this can mean reassurance that no additional precautions are needed; for others, a full discussion of the risks and a comprehensive plan will be required. The committee recognised the importance of thorough clinical assessment as raised in the confidential enquiries and the need to provide prompt investigation identified in the 2016 MBBRACE‑UK report.
Based on their knowledge and experience, the committee recommended that the woman's clinical condition is reassessed regularly during pregnancy and the intrapartum period. Many changes in performance of the heart and circulation occur gradually during pregnancy, but the intrapartum period and early postpartum period (including the first hours and days after birth) sees changes that can trigger a deterioration in cardiac function and therefore it is vital that investigations are undertaken and acted on promptly.
## How the recommendations might affect practice
The committee agreed that the recommendations will reduce variation in practice and encourage best practice that already exists in many areas of the country. In some areas, there may be more referrals to tertiary level services for specialist advice from a cardiologist with expertise in managing heart conditions during pregnancy. However, specialist advice should better determine which women need additional intervention and provide reassurance for those women whose heart condition would not affect their birth plans.
The committee believed that cardiac investigations are not rapidly available in all areas of the UK and this is reinforced by delays to investigations being identified by the Confidential Enquiries into Maternal Deaths and Morbidity in some cases of maternal death. There is variation in access to echocardiography, an investigation that can be crucial to making a diagnosis when symptoms of heart disease develop in the intrapartum period. A plan to ensure urgent access to echocardiography (including out of hours) for pregnant women with heart disease should be considered.
The recommendation that vaginal birth is safe for women with mild heart disease may reduce unnecessary medical intervention.
Return to recommendations
# Management of anticoagulation for women with mechanical heart valves
Recommendations 1.3.6 to 1.3.13
## Why the committee made the recommendations
The evidence looked at the effects of different anticoagulants throughout pregnancy on maternal and neonatal outcomes rather than their effects during labour. The evidence was also limited to women with mechanical heart valves. Therefore, the committee based recommendations on their experience and advice from a cardiac specialist.
They noted that a woman with a mechanical heart valve is prone to thrombosis if she has inadequate anticoagulation, but is vulnerable to excessive bleeding with too much anticoagulation. Either can lead to devastating fatal incidents for the woman and her baby. It is therefore important that planning for the management of anticoagulation during the intrapartum period starts when pregnancy is confirmed. The committee agreed that a woman with a mechanical heart valve should be switched to low-molecular-weight heparin by 36 weeks of pregnancy, or 2 weeks before planned birth, because heparin has a shorter half-life than warfarin and it does not cross the placenta so reducing the risk of bleeding in the baby.
The committee acknowledged that intravenous unfractionated heparin continues to be used in some centres, although recognised that use of unfractionated heparin has declined in the UK. Recommendations on newer anticoagulants were not made because their use is limited in practice. The committee agreed, based on the once-daily dosing of warfarin, that low-molecular-weight heparin should be started 24 hours after stopping warfarin. Monitoring of anti‑Xa level and dose adjustments are needed to ensure that an appropriate level of anticoagulation is achieved. The committee agreed trough levels might be useful and should be checked.
For women who have a planned caesarean section, the risk of an epidural haematoma can be reduced by stopping low-molecular-weight heparin 24 hours before. For women having an induction of labour, the decision of when to stop low-molecular-weight heparin should balance the risk of valve thrombosis against the possibility of having regional analgesia. A senior obstetrician should be involved in this decision and review the progress of induction.
For a woman presenting in labour on warfarin, the committee agreed that anticoagulation be stopped immediately to minimise the risks of excessive bleeding for the woman and baby during labour. The committee recommended that obstetric assessment should occur within 2 hours, recognising that although assessment was urgent, it would not always be possible to do this immediately. The committee agreed that the international normalised ratio (INR) be checked immediately and a haematologist consulted. The INR determines the degree of anticoagulation in the woman and baby and indicates how anticoagulation should be managed. A haematologist would advise how to reverse anticoagulation if this was needed. Senior review, involving a senior obstetrician, haematologist and consultant obstetric anaesthetist, should ensure the safest birth for the woman and baby.
The committee acknowledged that reintroducing therapeutic anticoagulation 4 to 6 hours after birth (rather than 48 hours) increases the risk of uterine haemorrhage. They considered data from the European Registry of Pregnancy and Cardiac Disease (ROPAC) on anticoagulation in pregnancy for women with mechanical heart valves. Although not addressing peripartum anticoagulation, the study confirmed the high risk of haemorrhage with anticoagulation but also indicated a higher risk of mechanical heart valve thrombosis in pregnancy. With limited evidence, the committee, supported by specialist cardiac and haematology input, agreed to follow the European Society of Cardiology (ESC) guidelines and recommend that therapeutic anticoagulation is reintroduced 4 to 6 hours after birth. They considered the risk of peripartum mechanical heart valve thrombosis to be higher in pregnancy and to be of greater consequence than the increased risk of uterine haemorrhage with earlier reintroduction of anticoagulation.
## How the recommendations might affect practice
The committee believed that these recommendations reflect modern UK practice and the growing clinical use of low-molecular-weight heparin, and acknowledge some continued use of unfractionated heparin. Anti‑Xa assays are essential for the monitoring and titration of low-molecular-weight heparin and the committee recognised that access to this test may need to be improved.
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# Mode of birth for women with heart disease
Recommendations 1.3.14 to 1.3.18
## Why the committee made the recommendations
Evidence was very limited so the committee drew on their knowledge and experience to make recommendations. They agreed that risk assessment is necessary to understand how well the woman's heart is functioning and is likely to cope with the exertion of labour and the circulatory changes that take place after birth. Women should be involved in formulating an individualised birth plan, with advice from a team with experience of intrapartum care for women with heart conditions. This will usually involve doctors from at least 3 specialties (obstetrics, cardiology and anaesthesia). In this way, the woman's wishes for labour and birth can be discussed in relation to the specific risks of her condition.
In the UK, the management of pulmonary arterial hypertension is concentrated in a small number of specialist pulmonary hypertension centres. Pulmonary arterial hypertension is a life-threatening condition that requires expert management. The multidisciplinary team planning for a woman with pulmonary hypertension must include a respiratory clinician from 1 of these centres.
In order to minimise the time without anticoagulation, planned caesarean section or induction of labour should be offered to women with mechanical heart valves. The risks of valve thrombosis cannot be overstated but this needs to be balanced against the risks of bleeding around the time of birth.
Planned caesarean section should be considered for women with high-risk aortic disease or the most severe cardiac conditions, but the committee recognised that some of these women may prefer to plan for a vaginal birth. When this is the woman's preference, she should be fully informed of the benefits and risks of assisted second stage of labour compared with active pushing alone, in order to reduce the risk of aortic dissection, aortic rupture or acute heart failure.
Although the exertion of labour and the fluid shifts at birth may be detrimental to some heart conditions, this is not true for all women. The committee considered that many women with mild heart disease can be reassured that a normal vaginal birth is safe.
## How the recommendations might affect practice
It is thought that the recommendations largely reflect current UK practice. The committee recognised that most women with more severe heart disease are already managed in large obstetric-led units by clinical teams with experience in this area. By attempting to define the conditions that pose the highest risk, the recommendations may result in further centralisation of specialist services.
Women with pulmonary hypertension are already offered care in specialist centres. Pregnancy and childbirth hold such serious risks for women with this condition and the committee agreed that liaison with specialist respiratory clinicians was essential.
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# Fluid management for women with heart disease
Recommendations 1.3.19 to 1.3.23
## Why the committee made the recommendations
In the absence of evidence, the committee used their knowledge and experience to make recommendations for haemodynamic monitoring during birth for women with heart disease. Risk assessment and planning of intrapartum monitoring needs specialist multidisciplinary input. Discussions should take place during pregnancy and involve the woman so that she knows how her condition might be affected by changes in blood pressure, blood volume and fluid shifts during labour and birth, and the type of monitoring needed to manage this.
For women with mild heart disease, management of fluid balance does not mean a change from standard care. For those with more severe conditions, standard care may still be suitable but decisions need to be based on specialist assessment of the type and severity of the condition and the woman's views. There are some heart conditions in which fluid balance is critical to cardiac function, and frequent monitoring and assessment by a clinician with expertise in management of heart disease in pregnancy, such as a consultant anaesthetist, obstetrician, cardiologist or intensivist, are needed as a minimum. For these conditions, more invasive monitoring may also be needed. As part of the clinical review, this should be discussed with the woman, and those who need intensive monitoring should be made aware that they are likely to need to go to an intensive care unit or delivery suite where this expertise exists.
## How the recommendations might affect practice
The committee agreed that specialist planning for intrapartum monitoring to identify the monitoring needs of women with different heart conditions together with stepped escalation of monitoring intensity, would reduce variation in practice. It would allow NHS resources to be directed more effectively to reduce morbidity and mortality associated with fluid management during the intrapartum period for women with cardiac conditions and their babies. Women's experience of labour and birth would be improved through their involvement in management discussions and because they would receive a level of intervention appropriate to their needs, taking their priorities for birth into account where possible.
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# Diagnosis and management of heart failure for all women in the intrapartum period
Recommendations 1.3.24 to 1.3.31
## Why the committee made the recommendations
Although most of the recommendations were based on the committee's experience because of the limited evidence, there was some evidence to inform the recommendations on heart rate and using N‑terminal pro‑brain natriuretic peptide (NT‑proBNP) levels. The committee agreed that symptoms and signs suggesting heart failure should be assessed initially by a member of the obstetric team and if present, confirmed by a senior clinician. When clinical examination raises the suspicion of heart failure, imaging and blood tests are needed to assist review by a cardiologist or the most senior available clinician to make a definitive diagnosis. This recommendation arises from evidence from the Confidential Enquiries into Maternal Deaths and Morbidity, that the diagnosis may be missed or delayed.
The committee made recommendations to support prompt and accurate diagnosis of heart failure because it is difficult to distinguish between the symptoms and signs of the normal physiological changes of late pregnancy and the pathological symptoms and signs of heart failure. A basic but thorough history and examination are key to identifying women who are at risk and the committee wanted to stress the importance of these.
Although heart failure in the intrapartum period is rare, it is an important cause of maternal mortality. Prompt medical management is needed to stabilise the woman's immediate condition but a change to the obstetric management may also be necessary to improve or limit worsening of her heart condition.
## How the recommendations might affect practice
The recommendations largely reflect current best practice. The committee agreed they should reinforce practice as well as improving postnatal prescribing and encouraging these women to breastfeed.
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# Anaesthesia and analgesia for women with heart disease
Recommendations 1.3.32 to 1.3.40
## Why the committee made the recommendations
Evidence identified was very limited so the committee made recommendations based on their knowledge and experience. The committee wanted to promote the best medical opinion while also taking into account women's needs and wishes. Regional anaesthesia offers several benefits over general anaesthesia that are still relevant even when a woman has a heart condition.
The committee was aware that the type of anaesthesia that women with heart conditions receive can vary according to the attending anaesthetist's experience and technical expertise. Enhanced haemodynamic stability can be achieved using low-dose sequential combined spinal–epidural or carefully titrated continuous spinal catheter techniques. Therefore obstetric anaesthetists and cardiac anaesthetists should collaborate to provide the best anaesthetic option for cardiovascular stability for the woman. They agreed that information should be shared with the woman so the best outcomes can be achieved. Women with modified World Health Organization (WHO) 1 or modified WHO 2 heart disease should be given the same advice as described in the NICE guideline on intrapartum care for healthy women and babies.
Based on knowledge of the physiological consequences of pain and the evidence that regional analgesia provides the most complete pain relief in labour, the committee agreed that to minimise the risks of labour without adversely affecting the woman's heart condition, women with modified WHO 3 and modified WHO 4 heart disease should be offered regional analgesia for labour. These women have critical heart failure and life-threatening heart disease and need to be carefully monitored to avoid serious mortality and morbidity.
Women who have not had a prophylactic dose of low-molecular-weight heparin for 12 hours or a therapeutic dose for at least 24 hours could be considered for regional analgesia because, the committee agreed, after this time the risk of bleeding from regional analgesia is considered to be very low.
The committee also agreed it was important to acknowledge those women who remain on low-molecular-weight heparin, and to provide details regarding the appropriate timing for removal of the epidural catheter.
## How the recommendations might affect practice
Most pregnant women with severe heart disease are already offered care in large obstetric-led units with links to cardiac centres. Therefore, these recommendations reinforce current practice and are unlikely to lead to a change. The recommendation that women with WHO 1 and 2 heart disease should be treated as healthy women may reduce unnecessary change in routine intrapartum practice.
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# Management of the third stage of labour for women with heart disease
Recommendations 1.3.41 to 1.3.44
## Why the committee made the recommendations
The committee agreed that heart disease covers a spectrum of pathologies, which have different risks associated with management of the third stage of labour. The only evidence was limited, came from a single study and was not helpful in determining management options for women with various heart conditions. Therefore the committee made recommendations based on their knowledge and experience. A management plan developed with multidisciplinary expertise is needed for each woman. Women with less severe heart conditions have similar risks to normal healthy women in the third stage of labour and can be managed accordingly. Because the physiological management of the third stage of labour is associated with a higher risk of postpartum haemorrhage, women with WHO 2 heart disease should have the third stage actively managed. Active management is also needed for all women with more severe disease. Oxytocin is the uterotonic of first choice. Second-line options depend on the specific condition. Women with preload-dependent circulation are particularly vulnerable to falls in blood pressure and there is some evidence to suggest that oxytocin should be given as an infusion rather than bolus to avoid this.
Ergometrine and oxytocin, 2 of the most commonly administered uterotonic agents, are known to have significant cardiovascular side effects and may be contraindicated in some women with heart disease. However, management of the third stage of labour should not put women with heart disease at increased risk of postpartum haemorrhage because some of these women will tolerate even minor haemorrhage very poorly. The women at potential risk of adverse effects from oxytocin are also those who are at greatest risk if they have a postpartum haemorrhage. The committee took all these factors into account when developing recommendations.
## How the recommendations might affect practice
The recommendations largely reflect current practice. The committee agreed there should be little change, with the exception of reducing the use of long-acting forms of oxytocin.
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# Analgesia for women with asthma
Recommendation 1.4.1
## Why the committee made the recommendation
No evidence was found on harm from any form of pain relief during labour for women with asthma. In the absence of evidence, the committee drew on their knowledge and experience to agree that the risk of harm was theoretical, and women with asthma should have the same options for pain relief as women without asthma.
## How the recommendation might affect practice
The recommendation should not significantly alter practice, because many hospitals already offer all types of pain relief to women with asthma. Those that do not will have all the options available for women without asthma and so will be able to quickly implement the recommendation.
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# Prostaglandins for women with asthma
Recommendations 1.4.2 to 1.4.4
## Why the committee made the recommendations
Very limited evidence indicated that prostaglandins E1 and E2 did not worsen asthma and this was in line with the committee's experience. The committee agreed to recommend prostaglandins E1 and E2 as options for inducing labour in women with asthma, and prostaglandin E1 for postpartum haemorrhage, because these are the options for women without asthma. However, the committee was concerned about a risk of bronchospasm with prostaglandin F2 alpha and so recommended against it even though it would normally be offered to women without asthma.
## How the recommendations might affect practice
Current use of prostaglandins in the intrapartum period is not well documented, but it is thought that practice varies. These recommendations are expected to represent a change in practice, but not a significant resource impact because prostaglandins are already given to women without asthma. Prostaglandin use in women with asthma might increase intensive monitoring of respiratory function during labour or after birth. This would have a resource impact, but would be offset by the reduction in extremely prolonged labour or failed induction, and the impact of postpartum haemorrhage.
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# Long-term systemic steroids
Recommendations 1.5.1 to 1.5.4
## Why the committee made the recommendations
No evidence was found so the committee used their knowledge and experience to make recommendations. They agreed that women who have been taking long-term steroids (equivalent to 5 mg or more prednisolone daily for more than 3 weeks) are at risk of adrenal crisis when under the physiological stress of labour and birth. The committee recommended that these women continued their regular steroid dose during labour and birth, because the effects of stopping are uncertain and there could be problems restarting the dose in the postpartum period.
They agreed that additional steroids (on top of the normal dose) would be needed to protect against an adrenal crisis. These extra steroids should be given intravenously or intramuscularly because this allows better estimation of the dose absorbed, and avoids the risk of vomiting.
Women taking inhaled or topical steroids would not normally be at risk of adrenal crisis because of the lower doses. These women should not be offered additional steroids during labour and birth unless a specialist agrees this may be needed.
## How the recommendations might affect practice
The committee believe that steroids are likely overprescribed for women in labour. Therefore these recommendations might reduce the amount of steroids given, particularly for women taking inhaled or topical steroids. However, because steroids are inexpensive, this is unlikely to have a significant impact on resource use within the NHS in England.
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# Regional anaesthesia and analgesia for women with bleeding disorders
Recommendations 1.6.1 and 1.6.2
## Why the committee made the recommendations
The limited available evidence was not able to show at which level of platelet count or platelet function the risk of complications, such as epidural haematoma, starts to increase. Evidence reported no serious harm (such as epidural haematoma) from regional analgesia or anaesthesia even with a platelet count below 50×109/l. Bleeding complications are more likely with epidural rather than spinal techniques (because smaller needles are used for the latter). The committee agreed that sometimes they would consider regional analgesia and anaesthesia (especially spinal techniques) for women with low platelet counts. Because serious maternal complications are so rare, the evidence did not allow a definite conclusion that there was no significant risk associated with epidural analgesia when platelet count was low. The committee decided not to set a definitive platelet threshold below which epidural or spinal analgesia should not be considered, but agreed that overall bleeding risk (including, but not limited to, platelet count) should be taken into account. Benefits and risks should be discussed with women, because the risk-benefit ratio will be highly individual and could change in the intrapartum period.
## How the recommendations might affect practice
The recommendations are in line with current NHS practice.
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# Modifying the birth plan according to platelet count or function
Recommendations 1.6.3 to 1.6.6
## Why the committee made the recommendations
No evidence was identified on platelet count and level of platelet function at which risks for either the woman or her baby would increase. Therefore the committee made recommendations based on their knowledge and expertise. Women with gestational thrombocytopenia are generally considered at low risk of bleeding complications during birth, whereas women with immune thrombocytopenic purpura (ITP) are regarded as high risk. So the committee recommended significant changes to the birth plan only if the woman had ITP, or gestational thrombocytopenia with a low platelet count.
Women with ITP may have a low platelet count and high risk of bleeding while the baby has a normal platelet count and low risk of bleeding. Conversely, a woman with ITP may have a normal platelet count and a baby with a low platelet count and high risk of bleeding. In other words, for women with ITP, the bleeding risk of the woman does not correspond to the bleeding risk of the baby. Consequently, if the woman has ITP, it is safest to treat the baby as being at high risk of bleeding, and modify the birth plan to reduce the bleeding risk to the baby wherever possible, for example, by not carrying out any fetal blood sampling. The committee thought it important to remind the healthcare professional that, because of the risk of fetal bleeding, procedures using fetal scalp electrodes and mid-cavity or rotational forceps should be carried out with extra care.
Women with gestational thrombocytopenia do not have an alloantibody that affects the fetal platelet count. Gestational thrombocytopenia therefore only puts the woman at risk of bleeding, and not her baby.
## How the recommendations might affect practice
Women with ITP are at high risk of bleeding and so should give birth in an obstetric unit with a neonatal unit that routinely provides high-dependency care. However, the committee was aware that this does not always happen in practice, and so the recommendation could create more demand for high-dependency neonatal units. However, this might be offset by women at lower risk (for example, with gestational thrombocytopenia and a high platelet count) not being referred to these units.
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# Management of the third stage of labour for women with bleeding disorders
Recommendations 1.6.7 to 1.6.12
## Why the committee made the recommendations
The committee based the recommendations on their knowledge and experience because the evidence was very limited. A number of bleeding disorders can affect the third stage of labour but evidence was not found for all these conditions. In addition, it was not always possible to tell whether an outcome was linked to a treatment or a specific condition because conditions were sometimes grouped together according to severity.
The risk to a woman's life from postpartum haemorrhage is greater if she has a bleeding disorder. To reduce postpartum haemorrhage, the committee recommended active management of labour (rather than physiological management), which includes intramuscular oxytocin, clamping of the cord and controlled cord traction, as described in the NICE guideline on intrapartum care for healthy women and babies.
Women with bleeding disorders may need some adjustments to active management of labour. For example, there may be risks associated with intramuscular injections in these women. These considerations will need oversight from a senior haematologist, more frequent and possibly extended monitoring, and discussion of any changes in clinical condition.
## How the recommendations might affect practice
These recommendations should lead to fewer attempts at physiological management of the third stage in women with bleeding disorders, with fewer postpartum haemorrhages and reduced maternal morbidity. The recommendations will apply to a small number of women, so implementing them is unlikely to cause staffing or resource issues for hospitals.
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# Mode of birth and management of the second stage of labour for women with subarachnoid haemorrhage or arteriovenous malformation of the brain
Recommendations 1.7.1 to 1.7.9
## Why the committee made the recommendations
Although the available evidence showed that there were no maternal or neonatal deaths or morbidities related to maternal cerebrovascular malformation or a history of intracranial bleeding, the committee agreed that there was not enough evidence to justify changing practice for women at high risk of an intracranial bleed. Current practice is to manage the bleeding risk as conservatively as possible.
Although vaginal birth is an option for women at low risk of intracranial bleeding, the committee acknowledged that some women would choose a caesarean section because of the theoretical risk of a bleed. The committee agreed that mode of birth should be based on the woman's preference as well as obstetric indications.
In women at high risk, or unknown risk (for example, because they have presented in labour with no antenatal care), the committee decided that in theory a caesarean section reduces the risk of intracranial bleeding because it should reduce the risks of raised intracranial pressure. This theoretical reduction in risk justified caesarean section for this group. The committee added that if a woman at high risk wanted to go into labour, the benefits and risks of an assisted second stage of labour compared with active pushing alone should be explained to the woman to ensure that steps are taken to reduce the risk of intracranial bleeding.
The committee knew that there was sometimes a reluctance to offer regional analgesia and anaesthesia to women with a history of subarachnoid haemorrhage or arteriovenous malformation of the brain because of the possibility of provoking a bleed. They discussed that this was extremely unlikely unless there was a genetic predisposition to multiple cerebrovascular malformations or unknown genetic history. They agreed that most women should be able to choose regional analgesia if they wished.
The committee was aware that cerebrovascular malformations affect more than 3% of the population and that women with cerebrovascular malformations or a previous subarachnoid haemorrhage are at risk of a potentially life-threatening cerebral haemorrhage. In current practice, many women with cerebrovascular malformations will be offered a caesarean section. However, it is uncertain whether vaginal birth increases the risk of cerebral haemorrhage in these women and the committee agreed to make a recommendation for research on caesarean section for women with subarachnoid haemorrhage or arteriovenous malformation of the brain to inform future guidance.
## How the recommendations might affect practice
The recommendations are in line with current practice for women at high risk, but many healthcare professionals would currently offer an elective caesarean section to women at low risk. So these recommendations could lead to a major change in practice for these women, with fewer caesarean sections. This assumes that their obstetric indications and personal preferences are similar to those of the general population of women.
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# Fluid management for women with kidney disease
Recommendations 1.8.1 to 1.8.9
## Why the committee made the recommendations
Managing fluid balance in women with kidney disease during pregnancy is extremely difficult – dehydration can cause acute kidney injury, especially in those with underlying chronic kidney disease, but fluid overload can rapidly lead to pulmonary oedema, especially in women with superimposed pre-eclampsia.
Although there was limited evidence on fluid management, its importance has been emphasised by successive confidential enquiries. The committee agreed that fluid management would vary, depending on the clinical condition of the woman and her baby.
The committee knew from their experience that action could often be taken to improve outcomes if the issue was identified in time. Therefore they recommended regular frequent monitoring every 4 hours during the intrapartum period (in addition to routinely measuring hourly heart rate), including monitoring after birth. Because oliguria is very common in healthy women in the postpartum period, the assessment of urine output more frequently than every 4 hours can be misleading. Exactly what should be monitored would depend on the clinical condition of the woman, but would include observations to assess fluid status, including blood pressure, chest sounds, fluid intake and output, and oxygen saturation.
The committee agreed that it was important to remind professionals caring for women in labour and during birth that commonly used drugs that are known to be nephrotoxic (for example, non-steroidal anti-inflammatory drugs) should not be offered to women with chronic kidney disease or acute kidney injury.
## How the recommendations might affect practice
Current practice is highly variable. The recommendations will mean more observation of women with kidney disease, with increased work for healthcare professionals. But they should lead to significantly fewer instances of morbidity.
The committee agreed that women with pre-existing chronic kidney disease are particularly vulnerable to both acute kidney injury and pre-eclampsia. By managing fluid balance more effectively, the risk of acute kidney injury in women with chronic kidney disease can be reduced. This will improve short- and longer-term outcomes for women and benefit healthcare systems with reduced length of stay.
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# Timing and mode of birth for women with kidney disease
Recommendations 1.8.10 to 1.8.16
## Why the committee made the recommendations
No evidence was found for timing of birth for women with kidney disease but the committee agreed that this would depend on the extent of the impairment. Longer gestation leads to better outcomes for the baby but may lead to worse outcomes for the woman's kidney function. Therefore, when kidney disease is less severe (chronic kidney disease stage 1, or stages 2 to 4 with stable kidney function), the balance of benefits and harms favours allowing the baby as long as possible to develop without becoming overdue. The committee agreed that when there is a significant risk to the mother's life in allowing the pregnancy to continue, dialysis should be attempted to prolong the pregnancy until at least 34+0 weeks, with a planned birth after this. In the committee's experience, this offers the least risk to mother and baby, and allows as many women as possible to have the birth of their choice.
There was no evidence that any particular mode of birth was better or worse for women with kidney disease and this was in line with the committee's experience, and so decisions about the mode of birth should be based on the woman's preference and obstetric indications. However, the committee recommended that for women with a kidney transplant, a transplant surgeon should be involved in the intrapartum care planning early on in the antenatal period. This is important particularly if a caesarean section is planned because the transplanted kidney will often be positioned near the usual site of caesarean incision and is therefore at risk of damage. The committee agreed that access to a transplant surgeon, if the caesarean section was complicated, should be recommended.
## How the recommendations might affect practice
The recommendations are likely to lead to a change in practice in many areas. This is because currently some healthcare professionals only offer early birth to women with the most significant kidney disease. However, others recommend early birth to women who could safely carry the pregnancy a few weeks longer.
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# Assessing fetal presentation early in labour for women with a BMI over 30
Recommendation 1.9.1
## Why the committee made the recommendation
The NICE guideline on intrapartum care for healthy women and babies recommends that women with a BMI under 35 kg/m2 can give birth in a midwifery unit or at home. The committee agreed, based on their experience, that identifying the fetal position by palpation can be difficult in women who are obese, particularly when the BMI is over 35 kg/m2. The degree of confidence in palpation often decreases with increasing body weight.
Ultrasound scanning at the start of established labour can help with decision making when the baby's presentation is uncertain. The consequences of missing a malpresentation are more serious in women who are obese, who are already at a higher risk of operative interventions in labour. The committee agreed that healthcare professionals should consider ultrasound scanning at the start of established labour when presentation is uncertain and a woman is obese. This should reduce the likelihood of adverse outcomes for the woman and her baby.
## How the recommendation might affect practice
The recommendation reflects current practice.
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# Anaesthesia and analgesia for women with a BMI over 30
Recommendation for research 2
## Why the committee did not make a recommendation and made a research recommendation
The committee was aware that women who are obese are more likely to need anaesthesia during labour and birth. The rates of operative birth are much higher in this group, particularly in women with a BMI over 40 kg/m2. It's helpful for care planning if an anaesthetist is told when a woman with a BMI over 40 kg/m2 is admitted. Needle siting for anaesthesia is potentially more difficult in women who are obese because the surface landmark anatomy of the lumbar spine can be more difficult to identify. It is thought that there are more unsuccessful attempts to site regional analgesia, and ultrasound might be cost effective for needle siting in this group. The use of ultrasound for needle siting is increasing with resource implications for the NHS. The committee could not make a recommendation on the most appropriate technique for needle siting because the evidence was uncertain, but they agreed to make a recommendation for research on needle siting in pregnant women who are obese to inform future guidance.
# Fetal monitoring for women with a BMI over 30
Recommendation 1.9.2
## Why the committee made the recommendation
It is more difficult to monitor fetal heart rate, uterine contractions and fetal position in women who are obese. These women are likely to have more complications and growth restriction is more likely to have been missed from earlier scans, making accurate fetal monitoring particularly important in the intrapartum period.
However, there was no evidence that continuous cardiotocography improves outcomes compared with intermittent auscultation. So the committee agreed to recommend monitoring based on the woman's preference and obstetric indications in line with the NICE guideline on intrapartum care for health women and babies.
There is variation in management during the intrapartum period for women who are obese. This is because of a lack of agreement on whether women with uncomplicated obesity should be offered continuous fetal monitoring in labour, receive further antenatal ultrasound scanning, including amniotic fluid volume assessment and umbilical artery Doppler scans, or be offered early induction.
Research to date has not established the effect of stratified BMI on perinatal outcomes. Current research is mainly retrospective, using data dating back to the 1970s and 1980s when BMI was usually self-reported and not stratified according to WHO categorisation. The committee agreed to make a recommendation for research on obesity as a possible independent risk factor for perinatal morbidity and mortality to inform future guidance.
## How the recommendation might affect practice
There is a wide variation in the use of continuous cardiotocography and intermittent auscultation for women who are obese. However, the recommendation is unlikely to mean a large change in current practice.
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# Position in labour for women with a BMI over 30
Recommendations 1.9.3 to 1.9.5
## Why the committee made the recommendations
Based on their experience, the committee agreed that there was no reason to alter the advice on the position in the second stage of labour just because a woman is obese. But it is important that she has enough mobility to allow healthcare professionals access in an emergency (for example, the ability to get into the lateral position). For women who have significantly reduced mobility, the committee recommended the lateral position to begin with, because this allows good access and so reduces the risk of adverse events. The committee agreed that these decisions should be made in the third trimester after a risk assessment, to ensure that everyone is aware of the plans for managing the second stage.
## How the recommendations might affect practice
Most midwives know that the lateral position is the safest for women with reduced mobility in labour. Therefore the recommendations are unlikely to lead to a change in practice. The recommendations for women with sufficient mobility are the same as those in the NICE guideline on intrapartum care for healthy women and babies. They should not change practice unless healthcare professionals are unaware that the recommendations in this NICE guideline also apply to women who are obese.
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# Equipment needs for women in labour with a BMI over 30
Recommendations 1.9.6 to 1.9.8
## Why the committee made the recommendations
The committee agreed that women who are obese need specialist equipment for a safe birth. They described all the specialist equipment required; not just beds and wheelchairs but specialist surgical tools and monitoring equipment. The committee did not believe that every hospital would have all this equipment, particularly to deal with women with a BMI over 50 kg/m2. They agreed that referral to another obstetric unit should be considered when this is the case to ensure that the needs of the women are adequately met.
## How the recommendations might affect practice
A 2010 report from the Confidential Enquiry into Maternal and Child Health (CMACE) and the Royal College of Obstetrics and Gynaecologists identified major gaps in the provision of hospital equipment for pregnant women who are obese. The committee believed that this has significantly improved and therefore that – for the most part – the recommendations should not affect practice. They should, however, reinforce what hospitals should already be providing.
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# Information for women with obstetric complications or no antenatal care
Recommendations 1.10.1 to 1.10.6
## Why the committee made the recommendations
Evidence was limited but the committee agreed that good quality information is important for women who are at increased risk of serious medical problems for themselves or their babies. These women are likely to be more anxious than other women in labour and need information that presents risk in a way that they can understand. The information should be based on local and national data where possible to allow women to make informed choices. Healthcare professionals should recognise that individuals have their own views of risk and they should support women to make informed decisions about their care. The committee recognised that the evidence base was limited but showed that women felt they may be given biased information and that some options were not offered or were actively opposed. Women described having to search out information themselves. The evidence also suggested that there may be inequalities between women when it comes to making an informed decision and being in control of their care. Women who were not able to seek information could be disadvantaged in making informed choices. The committee noted that these themes were reflected by their own experiences and agreed that it is very important that information about all options is offered to women.
## How the recommendations might affect practice
The committee noted that there was variability in current practice relating to care of women in labour who have a higher chance of serious medical problems. The recommendations may result in a change in practice in some areas, with a change in focus from a risk-based approach to supporting informed decision making for all women.
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# Risk assessment for women with obstetric complications or no antenatal care
Recommendations 1.11.1 to 1.11.7
## Why the committee made the recommendations
No evidence was found on observations for women in labour with obstetric complications so the committee made recommendations based on their expertise and knowledge of good practice. They agreed that in order to understand the whole clinical picture, it is important to listen to the woman's concerns and her own account of her symptoms. The committee acknowledged that women in the following groups would only need routine maternal observations during labour if there were no other concerns:
breech presentation
suspected small-for-gestational-age baby
suspected large-for-gestational-age baby
previous caesarean section
labour after 42 weeks of pregnancy
no antenatal care.
The committee did not want to medicalise care for women with fever in labour and agreed that many of these women do not need additional maternal observations apart from hourly monitoring of temperature and level of consciousness (AVPU ), and 4‑hourly monitoring of respiratory rate and oxygen saturation. However, if other symptoms or signs develop, the possibility of sepsis should be considered.
The committee did not want to medicalise care for women with slight concerns about possible sepsis, but they agreed that if concerns are enough to warrant antibiotic treatment, more frequent observations are needed because of the risk of sudden deterioration. The committee recommended continuous or half-hourly measurement of pulse, blood pressure and respiratory rate in line with the NICE guideline on sepsis. Hourly monitoring of temperature is sufficient, but AVPU should be monitored every half hour, with continuous or 30‑minute monitoring of oxygen saturation. Hourly recording of urine output should be performed if the woman has a catheter.
The committee agreed that for women with intrapartum haemorrhage, continuous monitoring of vaginal blood loss is important because this is often underestimated and it can be difficult to decide when more action is needed. Therefore the committee recommended more frequent observations to detect possible changes in a woman's condition. They also recommended other observations such as respiratory rate, volume of urine output, AVPU and oxygen saturation to prompt transfer to an obstetric-led unit and involvement of a senior obstetrician if needed.
Because of the increased risk of serious medical problems in women with obstetric complications or no antenatal care and the need for timely action when indicated, it is important that the woman's condition is comprehensively reviewed by an experienced healthcare professional who should be responsible for deciding if there is a need to escalate care. The committee was aware that the risk of serious medical problems for the woman or the baby depends on the whole clinical picture. They recommended that this should be taken into account when discussing options for care with the woman during the intrapartum period.
The lack of evidence on maternal observations for women in labour with suspected sepsis prompted the committee to make a recommendation for research on risk assessment for women in labour with signs of sepsis to inform future guidance.
## How the recommendations might affect practice
The committee agreed that the recommendations reflect current best practice, but this may result in changing practice in some units.
Return to recommendations
# Use of antipyretics for women in labour with a fever
Recommendations 1.12.1 and 1.12.2
## Why the committee made the recommendations
Very limited evidence showed no difference in the rate of caesarean section or admission to neonatal intensive care when women had paracetamol for fever. However, the committee agreed that paracetamol is safe and can reduce discomfort when a woman has a temperature. They noted that fever can be a sign of sepsis and agreed that recognising and treating sepsis is a clinical priority. Because paracetamol may mask a worsening fever, they recommended that healthcare professionals should remember that paracetamol is not a treatment for sepsis and should not delay investigation and treatment when sepsis is suspected.
## How the recommendations might affect practice
The recommendations could reduce the inappropriate use of paracetamol and promote the prompt management of sepsis.
Return to recommendations
# Fetal blood sampling for women in labour with a fever
Recommendation 1.12.3
## Why the committee made the recommendation
No evidence was found on fetal blood sampling for women in labour with a fever so the committee made a recommendation based on their expertise and knowledge of good practice. Their view was that women with fever in labour should be treated as if they have suspected sepsis for the purpose of fetal blood sampling and so the recommendations in this section mirror those for sepsis and suspected sepsis.
## How the recommendation might affect practice
The recommendation should harmonise practice, potentially increasing use of fetal blood sampling in areas where healthcare professionals are overly cautious and decreasing use in places where multiple fetal blood samples are taken.
Return to recommendation
# Mode of birth for women with sepsis or suspected sepsis
Recommendations 1.13.1 to 1.13.10
## Why the committee made the recommendations
No evidence was found on mode of birth for women in labour with sepsis or suspected sepsis so the committee made recommendations based on their expertise and knowledge of good practice. They recognised that sepsis is an important cause of maternal mortality and that physiological changes during labour may mask the early signs of sepsis. There is no agreed definition of normal physiological adjustments occurring during pregnancy and labour and these can vary as labour progresses.
The committee agreed that the NICE guideline on sepsis should be followed for the recognition of sepsis in pregnant women and that normal physiological changes in labour (such as increased maternal pulse rate) should also be taken into account.
The committee agreed that there should be ongoing multidisciplinary review by a senior team with a named lead. Ongoing review means the team is prepared to react to a changing situation, which may alter very quickly. The committee agreed that inadequate or delayed maternal resuscitation may worsen organ dysfunction and have an impact on the safety of anaesthesia, so they recommended that a senior obstetric anaesthetist should be included in the team.
When a woman in labour has sepsis (rather than suspected sepsis), the team should be expanded to include a neonatologist and microbiologist, and for women with sepsis and manifestations of organ dysfunction, the team should be further expanded to include a senior intensivist (critical care specialist). The intention is that the multidisciplinary team may not meet face to face but that expert advice can be accessed when needed.
The committee noted that a clear management plan should be documented and reviewed on a regular basis because it is important not only for the multidisciplinary team but also for the woman to know what is happening.
The committee emphasised that the woman and her birth companion(s) should be involved in shared decision making about management because they need to be involved in decisions and choices about how to proceed.
All options for timing and mode of birth should be considered in discussion with the woman and it should not be assumed that caesarean section is the only option for women with sepsis or suspected sepsis. The committee agreed that when the source of sepsis is thought to be the genital tract, healthcare professionals should expedite the birth because there is an increased risk of adverse outcomes for the baby.
## How the recommendations might affect practice
The committee agreed that the recommendations reflect current best practice. This may result in changing practice in some units.
Return to recommendations
# Anaesthesia for women in labour with sepsis and signs of organ dysfunction
Recommendation 1.13.11
## Why the committee made the recommendation
No evidence was found on anaesthesia for women in labour with sepsis or suspected sepsis so the committee made recommendations based on their expertise and knowledge of good practice. They wanted to ensure that women in labour with sepsis and signs of organ dysfunction were offered anaesthesia appropriate to their clinical condition and noted that the default practice of using regional anaesthesia may not be appropriate for these women. The committee agreed that regional anaesthesia may be associated with cardiovascular instability when there is sepsis with signs of organ dysfunction. Other adverse outcomes may include epidural abscess and haematoma due to coagulopathy. This led the committee to recommend that regional anaesthesia should be used only with caution and advice from a consultant obstetric anaesthetist and in the presence of a senior anaesthetist.
## How the recommendation might affect practice
The committee agreed that the recommendation reflects current best practice so there should be no change in practice.
Return to recommendation
# Analgesia for women in labour with sepsis or suspected sepsis
Recommendations 1.13.12 to 1.13.16
## Why the committee made the recommendations
No evidence was found to recommend one form of pain relief over another for women in labour with sepsis or suspected sepsis. The committee was aware that women with sepsis and signs of organ dysfunction may have bacteraemia and an increased risk of local infection or meningitis when a needle is inserted for regional analgesia. Therefore they recommended that this should only be used with caution and only with advice from a consultant obstetric anaesthetist. The presence of a senior anaesthetist is not needed because of the lower dose of local anaesthetic used for a woman who is not having surgery.
Although there was no evidence that the use of the birthing pool is contraindicated for women in labour with suspected sepsis where concern is insufficient for antibiotic treatment, the committee used their clinical experience and expertise to recommend that for these women, the birthing pool should be considered only after discussion with a senior midwife and a senior obstetrician.
The committee also made a recommendation that for women needing antibiotics for suspected sepsis, the treatment should begin before inserting the needle for regional analgesia.
A multidisciplinary review of options for pain relief is recommended at least every 4 hours because usually the multidisciplinary team would not be involved this often.
## How the recommendations might affect practice
The committee was aware that currently the birthing pool would not be considered for some women with suspected sepsis where concern is insufficient for antibiotic treatment. The committee noted that there is variation in practice not only between units but also within obstetric units. Therefore the extent of change in practice will vary according to current practice.
The committee noted that use of prophylactic antibiotics in women with suspected sepsis before central neuraxial block is not currently universal practice in the UK. The committee's recommendation would reinforce current best practice.
Regular reviews with a minimum 4‑hour frequency are a change to current practice. Currently reviews are performed as and when needed. The committee agreed that recommending a minimum review frequency was a more proactive approach to supporting women's ongoing needs.
The committee was aware that a discussion with a senior anaesthetist did not always happen in current practice, and their recommendations would reinforce best practice.
Return to recommendations
# Fetal monitoring for women in labour with sepsis or suspected sepsis
Recommendations 1.13.17 to 1.13.21
## Why the committee made the recommendations
No evidence was found on fetal monitoring for women in labour with sepsis or suspected sepsis so the committee made recommendations based on their expertise and knowledge of good practice. The committee wanted healthcare professionals to explain to women with sepsis that there is uncertainty about the usefulness of fetal blood sampling so that women have more information when deciding whether to accept or decline testing. The committee also agreed that fetal blood sampling can be falsely reassuring when a woman has sepsis. They wished to emphasise that the whole clinical picture should influence the decision to perform sampling and should be taken into account when interpreting the results.
There is no evidence to support repeat fetal blood sampling so the committee wanted to highlight the need for caution and consultant obstetric input to guide decision making.
## How the recommendations might affect practice
The committee hoped the recommendations would harmonise practice, potentially increasing use of fetal blood sampling in areas where clinicians are overly cautious and decreasing use in places where multiple fetal blood samples are taken.
Return to recommendations
# Antimicrobial treatment for women in labour with sepsis or suspected sepsis
Recommendations 1.13.22 to 1.13.25
## Why the committee made the recommendations
No evidence was found on when to start antimicrobial treatment for women in labour with sepsis or suspected sepsis so the committee made recommendations based on their expertise and knowledge of good practice. The committee was aware that intrapartum sepsis presents unique diagnostic difficulties, including difficulties identifying the source of the infection, which can lead to under- or over-diagnosis of sepsis. The choice of antibiotics is influenced by concerns about safety for the baby.
No evidence was found to support the use of specific antimicrobials in labour when the source of infection is clear and therefore the committee decided to follow the NICE guideline on sepsis and recommend referring to local antimicrobial guidance.
When the source of infection is unclear, a broad-spectrum intravenous antimicrobial from the local formulary should be offered because intrauterine infection is the most likely source of the infection and is often due to multiple organisms (polymicrobial).
The committee was aware that local antimicrobial resistance patterns vary and that the choice of antimicrobial would be guided by this. The committee was keen to support shared decision making and to ensure that the woman and her birth companion(s) understood the reasons for the choice of antimicrobial.
## How the recommendations might affect practice
The recommendations reflect current best practice.
Return to recommendations
# Care for women with sepsis or suspected sepsis immediately after the birth
Recommendation 1.13.26
## Why the committee made the recommendation
No evidence was found on care for women with sepsis or suspected sepsis in the first 24 hours after the birth so the committee made recommendations based on their expertise and knowledge of good practice. They agreed that a team with a named lead should provide care. The committee felt that determining the need for antibiotics, frequency of monitoring and level of care were important both for the safety of the woman and avoiding separation from her baby. The committee was aware that the woman and baby are often separated if the woman is transferred to a general intensive care unit or high-dependency unit, and this can impact negatively on the developing relationship between the woman and her baby, and consequently on maternal emotional wellbeing and postnatal mental health.
Families expect women who have given birth to be discharged home in full health soon after the birth. If the woman develops intrapartum sepsis, additional practical and emotional support will be needed during the recovery from critical illness.
## How the recommendation might affect practice
The recommendation reflects current best practice and should improve practice in some areas, particularly around reducing separation of women and their babies.
Return to recommendations
# Intrapartum haemorrhage
Recommendations 1.14.1 to 1.14.10
## Why the committee made the recommendations
No evidence was found on management of intrapartum haemorrhage so the committee based recommendations on their expertise and knowledge of good practice and the recommendations for postpartum haemorrhage in the NICE guideline on intrapartum care for healthy women and babies. They agreed that a large blood loss may result in major shock, and this would be the first priority for treatment. They also agreed that it is good practice that all maternity settings are equipped to manage intrapartum haemorrhage.
The committee agreed that when vaginal blood loss is more than a show, it is important to transfer the woman to obstetric-led care. They also agreed that it was essential to talk with the woman and her birth companion(s) to explain what is happening, what may happen and understand her preferences. It is also important to determine the likely causes of the blood loss, and how the woman's health may deteriorate or stabilise. The committee agreed that speaking with the woman to gain the history, including any associated events, may help to determine the cause of bleeding.
The committee agreed that if a woman in labour has vaginal blood loss typical of a 'show', this is not detrimental to the woman or baby and for these women, the NICE guideline on intrapartum care for healthy women and babies should be followed.
## How the recommendations might affect practice
The recommendations reflect current best practice but this may mean a change practice in some units.
Return to recommendations
# Breech presenting in labour
Recommendations 1.15.1 to 1.15.4
## Why the committee made the recommendations
Evidence showed an increase in maternal infection and other maternal complications during the first 6 weeks after caesarean section in labour for breech presentation compared with vaginal breech birth. This was in line with the committee's experience.
Evidence showed fewer adverse outcomes for the baby after caesarean section in early labour for breech presentation compared with vaginal birth, but the benefit was less clear when caesarean section was performed in the later stages of labour. This was also in line with the committee's experience.
The committee acknowledged that offering a choice between continuing labour and emergency caesarean section may differ from the advice that women with breech presentation have received during pregnancy. This is because the balance of risks to the woman and baby have changed, with different considerations coming into play when the woman is in labour. For example, considerations will be different when breech presentation is first identified in labour, or when labour is more advanced. The committee wished to ensure that healthcare professionals give women the opportunity to make an informed choice about mode of birth in this situation. They agreed not to recommend one mode of birth over another, but that following discussion of the likely benefits and risks, a woman should be able to decide what is right for her.
Based on their knowledge and experience, the committee agreed that healthcare professionals should follow recommendations on assessing progress in labour in the NICE guideline on intrapartum care for healthy women and babies to avoid unnecessary intervention when there is a delay in labour.
## How the recommendations might affect practice
There is variation in practice regarding counselling in labour for women with breech presentation, following publication of the Term Breech Trial in 2000, which concluded that vaginal birth was associated with higher risks to the baby. The recommendation to offer women in labour with breech presentation a choice between continuing labour and emergency caesarean section will promote a more consistent approach and improved experience for women and their birth companion(s). Practice previously would frequently have been to recommend caesarean section for these women, whereas the guideline recommendations emphasise choice and informed decision making.
The committee was aware that training may be needed to fully implement the recommendations supporting vaginal breech birth.
Return to recommendations
# Small-for-gestational-age baby
Recommendations 1.16.1 to 1.16.3
## Why the committee made the recommendations
No evidence was found for monitoring in labour for babies suspected to be small for gestational age so the committee used their knowledge and experience to make recommendations. They agreed that babies who are small for gestational age are at risk of adverse outcomes and that this risk is higher when there is growth restriction or problems with birth. However, they acknowledged that it is difficult to be certain about the baby's size before birth. Healthcare professionals should explain the risks and uncertainties to women whose babies are suspected to be small for gestational age and such women should then be offered continuous cardiotocography so that any concerns for the baby can be picked up quickly.
## How the recommendations might affect practice
The committee agreed that the recommendations reflect current best practice so there should be no change. However, they acknowledged that women are currently often not informed about the uncertainty around diagnosis of small-for-gestational-age babies and the effectiveness of cardiotocography in preventing poor outcomes, so this will be a development in practice.
Return to recommendations
# Large-for-gestational-age baby
Recommendations 1.17.1 to 1.17.3
## Why the committee made the recommendations
There was no convincing evidence for one mode of birth over another for women in labour whose babies are suspected to be large for gestational age. The committee discussed the difficulty of estimating a baby's size when a woman is in labour. They acknowledged that ultrasound is difficult to perform in labour and is less accurate at estimating a baby's weight than in the antenatal period. They agreed that women should be told about this uncertainty. Evidence showed an increased risk of maternal infection when women in labour had an emergency caesarean section. In the committee's experience, there was a risk of shoulder dystocia and perineal trauma with vaginal birth. The committee agreed that women should be provided with information so that they can make their own decisions about mode of birth when their baby may be large for gestational age.
## How the recommendations might affect practice
The recommendations ensure that women are offered all the options available to them in labour. It is not anticipated that this will have a large impact on resource use.
Return to recommendations
# No antenatal care
Recommendations 1.18.1 to 1.18.12
## Why the committee made the recommendations
No evidence was found on intrapartum care for women who have had no antenatal care so the committee agreed to make recommendations based on their expertise and knowledge of good clinical practice.
Because of the lack of baseline information and a birth plan, intrapartum care for these women should be led by an obstetrician who will carry out a full assessment of the risks for the woman and her baby. The neonatal team should be alerted because the committee agreed that there is an increased risk of serious medical problems for the baby when a woman has had no antenatal care. Sometimes an anaesthetic team may also be needed.
Sensitive enquiry should be made to try to understand the reasons for the lack of antenatal care, as well as to identify any vulnerability and safeguarding issues. It is important to ask the woman who she would like as her birth companion(s) and to identify their relationship with her. If there is a language barrier, an independent interpreter should be used rather than the woman's birth companion(s).
Blood and urine tests normally performed as part of routine antenatal care should be offered to check for markers of anaemia and infection. Therefore, testing for HIV, hepatitis B and syphilis should be offered. Rapid HIV testing should be offered to women who are thought to be at high risk of HIV because steps can be taken to prevent vertical transmission of known HIV infection during vaginal birth. Evidence suggested that rapid HIV testing would offer a good balance of benefits and costs in women at high risk of infection. The test results would be used to plan care during labour, birth and postnatally.
The committee agreed that the woman's GP should be contacted to obtain more information about her history and to plan for her own and the baby's ongoing care. Safeguarding concerns should be considered and if necessary referrals made. The woman should be informed when other healthcare professionals, social care professionals, safeguarding teams or the police need to be contacted. It is also important to document and share information with relevant professionals, such as the paediatric team and local health providers, for continuation of care.
## How the recommendations might affect practice
The recommendations largely reflect good clinical practice and therefore will not mean a large change. However, rapid HIV testing is not always available. An assessment of local needs for such services should be done.
Return to recommendations
# Previous caesarean section
Recommendations 1.19.1 to 1.19.11
## Why the committee made the recommendations
No evidence was found for intravenous cannulation for women in labour with a previous caesarean section. The committee agreed that the chance of needing intravenous access for urgent blood transfusion was unlikely to be higher in these women, and so recommended that cannulation should not be routine.
The committee noted from the evidence and their expertise that the risk of uterine rupture with vaginal birth was small for women with a previous caesarean section. There was some evidence that performing an emergency caesarean section in labour is associated with an increased risk of heavy bleeding and the need for blood transfusion, infection and a longer hospital stay. The committee recommended that women should be told about this when making decisions about mode of birth.
The committee felt it was important that women should be made aware that there is no compelling evidence to recommend one mode of birth over another to improve outcomes for the baby.
Evidence indicated that women in labour with a previous caesarean section are likely to be at a lower risk of complications if they have also had a previous vaginal birth.
There was evidence that augmentation of labour with oxytocin and regional analgesia both reduced the chance of another caesarean section for women in labour who have had a caesarean section in the past. The likelihood of an instrumental vaginal birth (forceps or ventouse) was increased with both. The committee agreed that this should be explained to women so that they can make a fully informed decision.
No evidence was found to recommend one form of pain relief over another for women with a previous caesarean section. There was also no evidence that the use of the birthing pool for pain relief is contraindicated for these women. Therefore, the committee agreed to recommend that all forms of pain relief, including the birthing pool, should be offered.
No evidence was found for routine amniotomy in women in labour with previous caesarean section. The committee used their experience and expertise to recommend that this should not be offered.
The committee was aware that continuous cardiotocography is usually advised for women in labour who have had a previous caesarean section. However, it is uncertain whether continuous cardiotocography in these circumstances allows risk to be identified sooner than if intermittent auscultation is used. The committee made a recommendation for research on monitoring in labour for women with a previous caesarean section to inform future guidance.
## How the recommendations might affect practice
The committee recognised there was variation in practice and inequity in the choices available to women in labour with a previous caesarean section. The committee wanted to ensure that these women would be offered comprehensive information so that they could make informed decisions about their care and wellbeing, and would not be subjected to unnecessary interventions that may not improve outcomes for the woman or her baby. They noted that the extent of change in practice arising from the recommendations would vary across the UK based on current practice and that the recommendations may result in specific changes in practice around supporting women's choice of place of birth and routine cannulation in labour, which may in turn lead to cost savings for the healthcare system.
Return to recommendations
# Labour after 42 weeks of pregnancy
Recommendation 1.20.1
## Why the committee made the recommendation
No evidence was found for monitoring in labour after 42 weeks of pregnancy so the committee made the recommendation based on their knowledge and experience. The committee was aware of some evidence of an increased risk of stillbirth or neonatal death after 42 weeks and this was consistent with their own experience. Because of this, the committee agreed that continuous cardiotocography should be offered for all women in labour after 42 weeks so that any concerns for the baby can be identified quickly. The offer should be preceded by a full discussion of the benefits and risks to the woman and her baby.
## How the recommendation might affect practice
The recommendation to offer continuous cardiotocography to all women in labour after 42 weeks is in line with current practice.
Return to recommendation# Context
Risk assessment and planning are key components of individualised care for pregnant women, so that any factors likely to affect the pregnancy or birth can be identified in a timely manner. This guideline deals with care for women at higher risk of complications in labour and birth, either because of an existing medical condition or because obstetric complications develop. With appropriate risk assessment and care planning, care can be delivered to maximise the chances of good outcomes for both the woman and her baby. Assessment and planning start at the antenatal booking appointment and continue throughout pregnancy at each antenatal contact. During labour, routine monitoring of the woman and her unborn baby and of the progress of labour is a continuation of the risk-screening process. Findings from these assessments will affect the plan of care for labour, and may result in changes to the plan being made antenatally or during labour if new complications are identified.
A pregnancy is 'high risk' when the likelihood of an adverse outcome for the woman or the baby is greater than that of the 'normal population'. A labour is 'high risk' when the likelihood of an adverse outcome related to labour (for the woman or the baby) is greater than that of the 'normal population'.
The level of risk may be determined before pregnancy or arise during pregnancy or during labour, and can affect the woman or the baby:
A woman may have an existing medical condition that can be made worse by physiological changes that occur in labour.
Obstetric (pregnancy-related) problems can develop that increase the risk of adverse labour and/or birth outcomes.
A woman can enter labour with no identified complications and be considered at low risk of complications, but problems may arise during labour that can be associated with adverse outcomes.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nSupporting women to make decisions about their care is particularly important during the intrapartum period. Healthcare professionals should ensure that women have the information they need to make decisions and to give consent in line with General Medical Council (GMC) guidance and the 2015\xa0Montgomery ruling.\n\n# Information for women with existing medical conditions\n\nClarify with women with existing medical conditions whether and how they would like their birth companion(s) involved in discussions about care during labour and birth. Review this regularly.\n\nOffer pregnant women with medical conditions and their birth companion(s) information about intrapartum care. This should include:\n\ngeneral information as outlined in the NICE guideline on intrapartum care for healthy women and babies\n\nhow their medical condition may affect their care\n\nhow labour and birth may affect their medical condition\n\nhow their medical condition and its management may affect the baby.Information should be presented as recommended in the NICE guideline on patient experience in adult NHS services.\n\nOffer information about intrapartum care in consultations before conception, if possible, and as early as possible during pregnancy. Allow extra time to discuss with the woman how her medical condition may affect her care.\n\nInformation about intrapartum care should be offered to women with medical conditions by a member of the multidisciplinary team (see the recommendation on team members in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team).\n\nIf a pregnant woman with a medical condition has not had any antenatal care (see the section on no antenatal care), give her information about intrapartum care at her first contact with healthcare services during pregnancy.\n\nNICE has published a guideline on diabetes in pregnancy.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information for women with existing medical conditions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information for women with existing medical conditions.\n\nLoading. Please wait.\n\n# Planning for intrapartum care with women with existing medical conditions – involving a multidisciplinary team\n\nA multidisciplinary team led by a named healthcare professional should involve a pregnant woman with a medical condition in preparing an individualised plan for intrapartum care. The plan should be:\n\nformulated by following the principles of shared decision making outlined in the NICE guideline on shared decision making\n\nreviewed with the woman and her birth companion(s) as early as possible throughout pregnancy and on admission for birth\n\nupdated with the woman if her medical condition changes during pregnancy\n\nshared with the woman's GP and teams providing her antenatal and intrapartum care.\n\nFor pregnant women with a medical condition, the multidisciplinary team may include, as appropriate:\n\na midwife\n\nan obstetrician\n\nan obstetric anaesthetist\n\nan obstetric physician or clinician with expertise in caring for pregnant women with the medical condition\n\na clinician with expertise in the medical condition\n\na specialty surgeon\n\na critical care specialist\n\na neonatologist\n\nthe woman's GP\n\nallied health professionals.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on planning for intrapartum care with women with existing medical conditions – involving a multidisciplinary team\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: antenatal care planning involving a multidisciplinary team for women with existing medical conditions.\n\nLoading. Please wait.\n\n# Heart disease\n\n## Risk assessment for women with heart disease\n\nRisk assessment for women with heart disease should follow the principles of multidisciplinary team working (outlined in the recommendation in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Include a cardiologist with expertise in managing heart disease in pregnant women in the multidisciplinary team discussions.\n\nFor women with heart disease diagnosed in the intrapartum period, urgent multidisciplinary discussions are needed to ensure that the woman is offered the same level of care as a woman with an existing diagnosis of heart disease and, where possible, that her preferences are taken into account.\n\nBe aware that some women with heart disease are at low risk of complications and their care should be in line with the NICE guideline on intrapartum care for healthy women and babies, whereas others need individualised specialist care.Risk is defined according to the modified World Health Organization (WHO) classification of maternal cardiovascular risk in the 2018 European Society of Cardiology guidelines published in the European Heart Journal.\n\nFor women with heart disease, reassess intrapartum risk regularly during pregnancy and the intrapartum period using all of the following:\n\ncomprehensive clinical assessment, including history and physical examination\n\nthe modified WHO classification of risk\n\nNew York Heart Association (NYHA) functional class (see American Heart Association's information about classes of heart failure).\n\nOffer the same investigations to pregnant women with heart disease as to women who are not pregnant. Review the results and act on them without delay.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on risk assessment for women with heart disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: heart disease.\n\nLoading. Please wait.\n\n## Management of anticoagulation for women with mechanical heart valves\n\nWhen pregnancy is confirmed:\n\ninvolve women with mechanical heart valves in multidisciplinary discussion of plans for anticoagulation during the intrapartum period (see the recommendations in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team)\n\nconsider including a haematologist in the multidisciplinary discussion\n\nexplain to women that they will need individualised anticoagulation depending on their current treatment.\n\nFor women with mechanical heart valves who are taking warfarin in the third trimester, switch anticoagulation to low-molecular-weight heparin by 36+0\xa0weeks of pregnancy or 2\xa0weeks before planned birth (if this is earlier than 36+0\xa0weeks). In hospital, consider doing this by:\n\nstopping warfarin, and 24\xa0hours later, starting low-molecular-weight heparin using a twice-daily regimen at a dose based on the most recent weight available\n\nincreasing the dose of low-molecular-weight heparin according to anti‑Xa levels; this should be done by:\n\n\n\nchecking anti‑Xa levels each day 3\xa0to\xa04\xa0hours after a dose of low-molecular-weight heparin, aiming for a peak anti‑Xa level between 1.0\xa0and 1.2\xa0IU/ml\n\nchecking that the anti‑Xa level before a dose of low-molecular-weight heparin (trough level) is above 0.6\xa0IU/ml\n\n\n\nrechecking anti‑Xa level weekly once the target anti‑Xa level is achieved.\n\nFor women with mechanical heart valves, stop therapeutic low-molecular-weight heparin 24\xa0hours before a planned caesarean section and consider:\n\naiming to perform the caesarean section as near to 24\xa0hours after stopping low-molecular-weight heparin as possible and no later than 30\xa0hours after stopping or\n\nswitching to intravenous unfractionated heparin (aiming for an activated partial thromboplastin time [aPTT] of at least twice control), then 4\xa0to\xa06\xa0hours before caesarean section, stopping intravenous unfractionated heparin.\n\nFor women with mechanical heart valves who are having an induction of labour, a senior obstetrician should be involved in:\n\ndeciding when to stop low-molecular-weight heparin or intravenous unfractionated heparin in order to:\n\n\n\nminimise the risk of maternal haemorrhage or valve thrombosis\n\nenable the option of regional analgesia\n\n\n\nreviewing the progress of labour and:\n\n\n\nthe need for low-molecular-weight heparin every 12\xa0hours, aiming for birth as close to 12\xa0hours from the last injection as possible or\n\nthe need for unfractionated heparin, aiming for birth as close to 4\xa0to\xa06\xa0hours after stopping the infusion.\n\n\n\nFor women with mechanical heart valves who are taking warfarin and who present in established labour:\n\ncheck the international normalised ratio (INR) immediately and consult a haematologist\n\ndo not give anticoagulation until the woman has had an assessment by an obstetrician, which should happen within 2\xa0hours\n\ncarry out a senior review (including at least a senior obstetrician, haematologist and a consultant obstetric anaesthetist) to discuss the mode of birth most likely to give the lowest risk of bleeding for the woman and the baby\n\nconsider reversal of anticoagulation.\n\nFor women with mechanical heart valves, carry out a postpartum review, involving at least a senior obstetrician and anaesthetist, of the risk of haemorrhage and valve thrombosis within 3\xa0to\xa04\xa0hours of birth. Aim to restart therapeutic low-molecular-weight heparin or unfractionated heparin 4\xa0to\xa06\xa0hours after birth.\n\nFor women with mechanical heart valves at high risk of peripartum haemorrhage, consider the following options until hourly review indicates that therapeutic anticoagulation can be re-established:\n\nprophylactic low-molecular-weight heparin or\n\nno low-molecular-weight heparin.\n\nFor women with mechanical heart valves, consider delaying restarting warfarin until at least 7\xa0days after birth and arrange specialist follow‑up as outlined in the multidisciplinary care plan (see recommendation\xa01.3.6).\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management of anticoagulation for women with mechanical heart valves\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: heart disease.\n\nLoading. Please wait.\n\n## Mode of birth for women with heart disease\n\nDevelop an individualised birth plan with the woman with heart disease covering all 3\xa0stages of labour following multidisciplinary discussion (outlined in the recommendation on the plan in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Consider including a cardiologist with expertise in managing heart disease in pregnant women in the multidisciplinary team discussions.\n\nThroughout pregnancy, manage pulmonary arterial hypertension in consultation with a specialist pulmonary hypertension centre.\n\nOffer planned birth (induction of labour or caesarean section) for women with mechanical heart valves.\n\nConsider planned caesarean section for women with:\n\nany disease of the aorta assessed as high risk\n\npulmonary arterial hypertension\n\nNYHA class\xa0III or\xa0IV heart disease.Explain the benefits and risks of caesarean section. If the woman chooses not to have a caesarean section, explain the benefits and risks of an assisted second stage of labour compared with active pushing alone.\n\nFor women with heart disease who have a planned caesarean section, develop an individualised emergency care plan with the woman in case she presents in early labour, with new symptoms or with obstetric complications.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on mode of birth for women with heart disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: heart disease.\n\nLoading. Please wait.\n\n## Fluid management for women with heart disease\n\nDuring pregnancy, plan the management of fluid balance during the intrapartum period for women with heart disease with the multidisciplinary team (outlined in the recommendation on team members in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Include a cardiologist with expertise in managing heart disease in pregnant women. Multidisciplinary discussion should include:\n\nhow the condition affects fluid balance\n\noptimum fluid balance and how this might be achieved\n\nplans for risk assessment and monitoring.\n\nIdentify women with heart disease for whom fluid balance is critical to cardiac function. These include women with:\n\nsevere left-sided stenotic lesions (for example, aortic stenosis and mitral stenosis)\n\nhypertrophic cardiomyopathy\n\ncardiomyopathy with systolic ventricular dysfunction\n\npulmonary arterial hypertension\n\nFontan circulation and other univentricular circulations\n\nNYHA class\xa0IV heart disease.\n\nFor women with heart disease in whom fluid balance is critical for optimal cardiac function, offer tailored monitoring and clinical review during the intrapartum period, and consider escalation as follows:\n\nhourly monitoring of fluid input and output (with at least 4‑hourly assessment by a senior clinician), blood pressure, pulse, respiratory rate and oxygen saturation\n\ncontinuous electrocardiogram (ECG) and pulse oximetry with interpretation by trained staff\n\ncontinuous intra-arterial blood pressure monitoring\n\ncardiac output monitoring with non-invasive techniques, or serial echocardiography by trained staff.Advise women who need intensive monitoring that this may have to be carried out in an intensive care unit where the necessary equipment and expertise is available.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nOffer standard fluid management during the intrapartum period for women with modified WHO\xa01 and NYHA class\xa0I heart disease.\n\nConsider standard fluid management during the intrapartum period for women with modified WHO\xa02\xa0to\xa03, or NYHA class\xa0II\xa0to\xa0III heart disease after a multidisciplinary discussion (outlined in the recommendation on the plan in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team).\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fluid management for women with heart disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: heart disease.\n\nLoading. Please wait.\n\n## Diagnosis and management of heart failure for all women in the intrapartum period\n\nThese recommendations cover the diagnosis and management of heart failure for all women in the intrapartum period. This includes women with existing heart disease, and women with no existing heart disease who develop symptoms and signs of heart failure.\n\nTake a cardiac-specific history and suspect heart failure if there is not another likely cause of any of the following symptoms:\n\nbreathlessness when lying down (ruling out aortocaval compression) or at rest\n\nunexplained cough, particularly when lying down or which produces frothy pink sputum\n\nparoxysmal nocturnal dyspnoea – being woken from sleep by severe breathlessness and coughing, which may produce pink frothy sputum and is improved by moving to an upright position\n\npalpitation (awareness of persistent fast heart rate at rest).\n\nConsider heart failure in the intrapartum period if there are any of the following signs:\n\npale, sweaty, agitated with cool peripheries\n\nheart rate persistently greater than 110\xa0beats per minute at rest\n\nrespiratory rate persistently greater than 20\xa0breaths per minute at rest\n\nhypotension (systolic blood pressure less than 100\xa0mmHg)\n\noxygen saturation less than 95% on air\n\nelevated jugular venous pressure\n\nadded murmur or heart sound\n\nreduced air entry, basal crackles or wheeze, on listening to the chest.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nIf any of the symptoms or signs in recommendations 1.3.24 and 1.3.25 suggest heart failure, a senior clinician should review the woman's condition without delay.\n\nWhen there is a clinical suspicion of heart failure in any woman in the intrapartum period:\n\nestablish peripheral venous access\n\nmeasure urea and electrolytes, and perform a full blood count\n\nmeasure arterial blood gases\n\nperform an ECG\n\nperform a chest X‑ray.\n\nIf clinical suspicion of heart failure in the intrapartum period cannot be ruled out by the investigations in recommendation 1.3.27, arrange:\n\nreview by a cardiologist (with interim review by a healthcare professional with expertise in this area if a cardiologist is not immediately available)\n\na transthoracic echocardiogram by a trained technician or cardiologist\n\nmeasurement of N‑terminal pro‑brain natriuretic peptide (NT‑proBNP) levels.\n\nConsider early birth for women with heart failure due to cardiomyopathy, depending on the severity of the condition and how well the condition has responded to treatment.\n\nOptimise treatment for heart failure as soon as possible after birth even if the woman is breastfeeding.\n\nIf clinical suspicion of heart failure persists after birth, consider the continued involvement of a cardiologist.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on diagnosis and management of heart failure for all women in the intrapartum period\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: heart disease.\n\nLoading. Please wait.\n\n## Anaesthesia and analgesia for women with heart disease\n\nDuring pregnancy, prepare a plan for managing anaesthesia and analgesia for women with heart disease involving a multidisciplinary team and the woman (outlined in the recommendation on the plan in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Consider including a haematologist for women on an anticoagulation regimen.\n\nConsider offering the same information about anaesthesia and analgesia in labour to women with modified WHO\xa01\xa0or modified WHO\xa02 heart disease as described in the NICE guideline on intrapartum care for healthy women and babies.\n\nConsider regional anaesthesia for women with modified WHO\xa03 and modified WHO\xa04 heart disease, unless this is contraindicated.\n\nConsider collaborative working in the intrapartum period between an obstetric anaesthetist and a cardiac anaesthetist for women with modified WHO\xa03 and modified WHO\xa04 heart disease.\n\nWhen using regional anaesthesia for women with heart disease, aim to preserve cardiovascular stability by, for example, using a sequential combined spinal–epidural technique.\n\nOffer intrapartum monitoring of the heart and circulation to all women with modified WHO\xa03 and modified WHO\xa04 heart disease; this will usually include continuous invasive intra-arterial pressure monitoring and may include central venous pressure monitoring and advanced cardiac output monitoring.\n\nOffer low-dose regional analgesia to women with modified WHO\xa03 or modified WHO\xa04 heart disease because this is less likely to cause cardiac instability during labour and birth.\n\nConsider regional analgesia for women who have been on low-molecular-weight heparin and who have not had a prophylactic dose for at least 12\xa0hours, or a therapeutic dose for at least 24\xa0hours.\n\nFor women taking low-molecular-weight heparin:\n\nwait 12\xa0hours after a prophylactic dose before siting an epidural, or removing an epidural catheter\n\nwait 24\xa0hours after a therapeutic dose before siting an epidural or spinal, or removing an epidural catheter\n\nafter siting an epidural or a spinal, or removing an epidural catheter, wait 4\xa0hours before administering a further dose of low-molecular-weight heparin\n\ndo not administer therapeutic dose low-molecular-weight heparin while an epidural catheter is in place.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and analgesia for women with heart disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: heart disease.\n\nLoading. Please wait.\n\n## Management of the third stage of labour for women with heart disease\n\nDuring pregnancy, prepare an individualised plan for managing the third stage of labour for women with heart disease, involving a multidisciplinary team and the woman (outlined in the recommendation on the plan in the section on planning for intrapartum care with women with existing medical conditions - involving a multidisciplinary team). Consider including a cardiologist with expertise in managing heart disease in pregnant women.\n\nTreat women with modified WHO\xa01 heart disease as low risk and consider the full range of care options for healthy women in the third stage of labour described in the NICE guideline on intrapartum care for healthy women and babies.\n\nAdvise active management of the third stage of labour for women with modified WHO\xa02 heart disease, in line with the NICE guideline on intrapartum care for healthy women and babies.\n\nConsider management of the third stage of labour for women with modified WHO\xa03 or modified WHO\xa04 heart disease according to table\xa01.\n\nCondition\n\nFirst-line uterotonic\n\nSecond-line uterotonics\n\nDrugs to avoid because of potential harm\n\nSignificant aortopathy\n\nMarfan syndrome and Loeys–Dietz with aortic dilatation >40\xa0mm\n\nBicuspid aortopathy and aortic dilatation >45\xa0mm\n\nPrevious aortic dissection\n\nTurner syndrome and aortic size index >25\xa0cm/m2\n\nOxytocin\n\nMisoprostol\n\nCarboprost\n\nErgometrine (because of risk of hypertension-induced aortic dissection or rupture)\n\nLimited or fixed low cardiac output, or preload-dependent circulation\n\nSevere systemic ventricular dysfunction (ejection fraction <30%)\n\nSevere valvular stenosis\n\nHypertrophic cardiomyopathy with diastolic dysfunction or significant outflow tract obstruction\n\nFontan circulation\n\nCyanotic heart disease\n\nSlow infusion of oxytocin to avoid sudden haemodynamic change\n\nMisoprostol\n\nCarboprost\n\nLong-acting oxytocin analogues and ergometrine (because of risk of hypertension-induced heart failure)\n\nPulmonary arterial hypertension\n\nOxytocin\n\nMisoprostol\n\nErgometrine, carboprost and long-acting oxytocin analogues (because of risk of worsening pulmonary hypertension)\n\nCoronary artery disease\n\nOxytocin\n\nMisoprostol\n\nErgometrine (because of risk of coronary ischaemia)\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management of the third stage of labour for women with heart disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: heart disease.\n\nLoading. Please wait.\n\n# Asthma\n\n## Analgesia for women with asthma\n\nOffer women with asthma the same options for pain relief during labour as women without asthma, including:\n\nEntonox (50% nitrous oxide plus 50% oxygen)\n\nintravenous and intramuscular opioids\n\nepidural\n\ncombined spinal–epidural analgesia.\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on pain relief during labour for women with asthma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: asthma.\n\nLoading. Please wait.\n\n## Prostaglandins for women with asthma\n\nDo not offer prostaglandin\xa0F2 alpha (carboprost) to women with asthma because of the risk of bronchospasm.\n\nConsider prostaglandin\xa0E1 or prostaglandin\xa0E2 as options for inducing labour in women with asthma because there is no evidence that they worsen asthma.\n\nConsider prostaglandin\xa0E1 as an option for treating postpartum haemorrhage in women with asthma because there is no evidence it worsens asthma.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on prostaglandins for women with asthma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: asthma.\n\nLoading. Please wait.\n\n# Long-term systemic steroids\n\n## Steroid replacement regimens\n\nBe aware that maternal corticosteroids given antenatally for fetal lung maturation should not affect the advice given in recommendations 1.5.2 to\xa01.5.4.\n\nFor women planning a vaginal birth who have adrenal insufficiency or who are taking long-term oral steroids (equivalent to 5\xa0mg or more prednisolone daily for more than 3\xa0weeks):\n\ncontinue their regular oral steroids and\n\nwhen they are in established first stage of labour, add intravenous or intramuscular hydrocortisone and consider a minimum dose of 50\xa0mg every 6\xa0hours until 6\xa0hours after the baby is born.\n\nFor women having a planned or emergency caesarean section who have adrenal insufficiency or who are taking long-term oral steroids (equivalent to 5\xa0mg or more prednisolone daily for more than 3\xa0weeks):\n\ncontinue their regular oral steroids and\n\ngive intravenous hydrocortisone when starting anaesthesia; the dose will depend on whether the woman has received hydrocortisone in labour, for example:\n\n\n\nconsider giving 50\xa0mg if she has had hydrocortisone in labour\n\nconsider giving 100\xa0mg if she has not had hydrocortisone in labour\n\n\n\ngive a further dose of hydrocortisone 6\xa0hours after the baby is born (for example, 50\xa0mg intravenously or intramuscularly).\n\nDo not offer supplemental hydrocortisone in the intrapartum period to women taking inhaled or topical steroids.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on steroid replacement for women on long-term steroids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: long-term systemic steroids.\n\nLoading. Please wait.\n\n# Bleeding disorders\n\n## Regional anaesthesia and analgesia for women with bleeding disorders\n\nDiscuss the balance of benefits and risks of regional analgesia and anaesthesia with women with bleeding disorders.\n\nWhen considering regional analgesia and anaesthesia for women with bleeding disorders, take into account:\n\nthe overall risk of bleeding and opportunity for corrective treatment\n\ntherapeutic and prophylactic anticoagulation\n\nthe risk of bleeding associated with the technique to be used\n\nthe difficulty of needle siting or insertion\n\nthe comparative risks associated with no analgesia or non-regional analgesia\n\nthe comparative risks of general anaesthesia.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on regional anaesthesia and analgesia for women with bleeding disorders\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: bleeding disorders.\n\nLoading. Please wait.\n\n## Modifying the birth plan according to platelet count or function\n\nFor woman with known immune thrombocytopenic purpura, before admission for birth:\n\nplan birth in an obstetric-led unit with a neonatal unit that routinely provides high-dependency care\n\nplan as if the baby will be at risk of bleeding irrespective of the woman's platelet count\n\nconsider monitoring maternal platelet count weekly from 36\xa0weeks, and if the platelet count is below\xa050:\n\n\n\ndiscuss and agree a plan for intrapartum care with the multidisciplinary team, including a haematologist\n\n\n\nconsider giving steroids or intravenous immunoglobulin to raise the maternal platelet count.\n\nFor women with known immune thrombocytopenic purpura, on admission for birth:\n\nmeasure maternal platelet count\n\nmanage intrapartum care according to table\xa02.\n\nFor women with known or suspected immune thrombocytopenic purpura, take the following precautions to reduce the risk of bleeding for the baby:\n\ninform the neonatal team of the imminent birth of a baby at risk\n\ndo not carry out fetal blood sampling\n\nuse fetal scalp electrodes with caution\n\ndo not use ventouse\n\nuse mid-cavity or rotational forceps with caution\n\nbear in mind that a caesarean section may not protect the baby from bleeding\n\nmeasure the platelet count in the umbilical cord blood at birth.\n\nModify the birth plan based on maternal platelet count, using table\xa02 as a guide, for women with:\n\ngestational thrombocytopenia (without pre-eclampsia and HELLP syndrome, and otherwise well)\n\nan uncertain diagnosis of immune thrombocytopenic purpura.\n\nMaternal\xa0platelet count\n\nMaternal care\n\nPlatelet count above 80×109/l\n\nTreat the woman as healthy for the purpose of considering regional analgesia and anaesthesia\n\nPlatelet count 50 to 80×109/l\n\nBefore considering regional analgesia and anaesthesia, take into account:\n\nclinical history\n\nthe woman's preferences\n\nanaesthetic\xa0expertise\n\nPlatelet count below 50×109/l\n\nAvoid regional analgesia and anaesthesia under most circumstances\n\nIf the woman has known or suspected immune thrombocytopenic purpura, assume the baby is at risk of bleeding and take the precautions outlined in recommendation 1.6.5. If the woman has gestational thrombocytopenia, assume the baby has a normal risk of bleeding.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on modifying the birth plan according to platelet count or function\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: bleeding disorders.\n\nLoading. Please wait.\n\n## Management of the third stage of labour for women with bleeding disorders\n\nBe aware that women with bleeding disorders are at increased risk of primary and secondary postpartum haemorrhage.\n\nOffer active management rather than physiological management of the third stage of labour for women with bleeding disorders, in line with the NICE guideline on intrapartum care for healthy women and babies.\n\nFor women with bleeding disorders, avoid giving uterotonics by intramuscular injection.\n\nOffer individualised postpartum care, as discussed with a senior haematologist, for women with bleeding disorders, to include:\n\nmeasurement of blood loss\n\nmonitoring obstetric complications\n\nmonitoring haematological parameters.\n\nBe aware that non-steroidal anti-inflammatory drugs can add to the risk of bleeding.\n\nBefore discharge from hospital, inform women with bleeding disorders of the risk of secondary bleeding postpartum and how to access care.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on managing the third stage of labour for women with bleeding disorders\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: bleeding disorders.\n\nLoading. Please wait.\n\n# Subarachnoid haemorrhage or arteriovenous malformation of the brain\n\n## Mode of birth and management of the second stage of labour for women with subarachnoid haemorrhage or arteriovenous malformation of the brain\n\nInvolve the multidisciplinary team in risk assessment for women with a cerebrovascular malformation or a history of intracranial bleeding. Include the woman in care planning and a clinician with expertise in managing neurovascular conditions in pregnant women.\n\nClassify the risk of intrapartum intracranial bleeding as low if a woman has:\n\na fully treated cerebrovascular malformation or\n\nintracranial bleeding of unknown cause following investigation, which occurred more than 2\xa0years ago.\n\nFor women with a cerebrovascular malformation at low risk of intracranial bleeding, base decisions on the mode of birth on the woman's preference and obstetric indications.\n\nFor women with a cerebrovascular malformation at low risk of intracranial bleeding, manage the second stage of labour based on the woman's preference and obstetric indications.\n\nClassify the risk of intrapartum intracranial bleeding as high if a woman has:\n\nan untreated or partially treated cerebrovascular malformation that has bled previously\n\na large aneurysm (7\xa0mm or more) or an aneurysm with other high-risk features as defined by a neuroradiologist\n\na complex arteriovenous malformation\n\ncavernoma with high-risk features\n\nintracranial bleeding within the past 2\xa0years.\n\nConsider caesarean section for women who are at high risk of cerebral haemorrhage, after a full discussion with the woman of the benefits and risks of all the options.\n\nFor women at high risk of cerebral haemorrhage who prefer to aim for a vaginal birth or are in the second stage of labour:\n\noffer regional analgesia and\n\nexplain the benefits and risks of an assisted second stage of labour compared with active pushing alone.\n\nFor women who present for the first time in labour with a history of cerebrovascular malformation or intracranial bleeding and unknown risk of intracranial bleeding, manage as high risk and follow recommendations 1.7.6 and\xa01.7.7.\n\nDo not withhold regional analgesia or anaesthesia from women with an isolated cerebrovascular malformation unless they have a genetic predisposition to multiple vascular malformations or unknown genetic history.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on care of women at risk of intracranial bleeding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: subarachnoid haemorrhage or arterio-venous malformation of the brain.\n\nLoading. Please wait.\n\n# Acute kidney injury or chronic kidney disease\n\n## Fluid management for women with kidney disease\n\nDuring pregnancy, involve the multidisciplinary team in risk assessment for women with kidney disease. Include a clinician with expertise in managing renal conditions in pregnant women.\n\nEnsure that women with chronic kidney disease stage\xa04\xa0or\xa05 before pregnancy or women with progressive or active kidney disease are cared for in the intrapartum period by a midwife, obstetrician and obstetric anaesthetist with input from a clinician with expertise in managing renal conditions in pregnant women.\n\nEnsure that a clinician with expertise in managing renal conditions in pregnant women is available for consultation during the intrapartum period for women with chronic kidney disease stage\xa04\xa0or\xa05 before pregnancy or women with progressive or active kidney disease.\n\nManage acute kidney injury secondary to pre-eclampsia in line with the NICE guideline on hypertension in pregnancy.\n\nFor women with chronic kidney disease with or without pre-eclampsia, monitor fluid balance in the intrapartum period. Measure heart rate hourly and the following at least every 4\xa0hours:\n\nblood pressure\n\nrespiratory rate with chest auscultation\n\nfluid output and fluid intake\n\noxygen saturation.After each assessment, develop an individualised plan for managing fluid balance, which may involve additional monitoring techniques, with the aim of maintaining normal fluid volume to reduce the risks of acute kidney injury and pulmonary oedema.\n\nAssess renal function at least every 24\xa0hours during the intrapartum period in all women with chronic kidney disease because prolonged labour may lead to dehydration and acute kidney injury.\n\nFor women with acute kidney injury:\n\nidentify and correct the cause of the acute kidney injury\n\nmeasure heart rate hourly and monitor fluid balance in the intrapartum period by assessing the following at least every 4\xa0hours:\n\n\n\nblood pressure\n\nrespiratory rate and chest auscultation\n\nfluid output and fluid intake\n\noxygen saturation\n\n\n\ndevelop an individualised plan for managing fluid balance, which may involve additional monitoring techniques, with the aim of maintaining normal fluid volume and avoiding both dehydration and pulmonary oedema\n\nconsider giving a single small bolus of fluid (for example, 250\xa0ml) as crystalloid if the woman is dehydrated and review the fluid status and urine output within an hour of giving the first fluid bolus and before considering giving a second\n\ncontinue to monitor fluid balance and renal function until the acute kidney injury has recovered.\n\nDo not offer nephrotoxic drugs (for example, non-steroidal anti-inflammatory drugs) in the intrapartum period to women with kidney disease.\n\nFor all women with kidney disease during pregnancy:\n\nmonitor the following at least every 4\xa0hours for at least 24\xa0hours after the birth:\n\n\n\nheart rate and blood pressure\n\nrespiratory rate and chest auscultation\n\nfluid output and fluid intake\n\noxygen saturation\n\n\n\nensure postpartum assessment of renal function and follow‑up for women with persistent kidney disease.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fluid management for women with kidney disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: acute kidney injury or chronic kidney disease.\n\nLoading. Please wait.\n\n## Timing and mode of birth for women with kidney disease\n\nAs early as possible during pregnancy, plan intrapartum care for women with kidney disease due to lupus nephritis, vasculitis or glomerulonephritis with the woman and a clinician with expertise in managing renal conditions in pregnant women.\n\nAs early as possible during pregnancy, plan intrapartum care for women with a kidney transplant with the woman, a clinician with expertise in managing renal conditions in pregnant women and a kidney transplant surgeon.\n\nFor women with chronic kidney disease stage\xa01, stable renal function and non-nephrotic-range proteinuria (urine protein:creatinine ratio less than 300\xa0mg/mmol), base decisions on timing and mode of birth on the woman's preference and obstetric indications.\n\nConsider planned birth by 40+0\xa0weeks of pregnancy for women with:\n\nchronic kidney disease stage\xa01 and nephrotic-range proteinuria (urine protein:creatinine ratio greater than 300\xa0mg/mmol) or\n\nchronic kidney disease stage\xa02\xa0to\xa04 with stable renal function.\n\nFor women with chronic kidney disease stage\xa05 or deteriorating stage\xa03b and stage\xa04, before 34+0\xa0weeks of pregnancy, discuss the option of dialysis with the woman and the multidisciplinary team in an effort to prolong the pregnancy to at least 34+0\xa0weeks.\n\nFor women with chronic kidney disease stage\xa05 or deteriorating stage\xa03b and stage\xa04, after 34+0\xa0weeks of pregnancy, discuss the option of planned birth with the woman and the multidisciplinary team and consider birth no later than 38+0\xa0weeks.\n\nFor all women with kidney disease, including those with a kidney transplant, base decisions on mode of birth on the woman's preference and obstetric indications.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on timing and mode of birth for women with kidney disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: acute kidney injury or chronic kidney disease.\n\nLoading. Please wait.\n\n# Obesity\n\n## Assessing fetal presentation early in labour for women with a BMI over\xa030\n\nConsider ultrasound scanning at the start of established labour if the baby's presentation is uncertain for women with a BMI over 30\xa0kg/m2 at the booking appointment, particularly those with a BMI over 35\xa0kg/m2.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on assessing fetal presentation early in labour for women with a BMI over 30\xa0kg/m2\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: obesity.\n\nLoading. Please wait.\n\n## Fetal monitoring for women with a BMI over\xa030\n\nBase intrapartum fetal monitoring on the woman's preference and obstetric indications (including no antenatal care), in line with the NICE guideline on fetal monitoring in labour, for women with a BMI over 30\xa0kg/m2 at the booking appointment and no medical complications.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal monitoring for women with a BMI over 30\xa0kg/m2\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: obesity.\n\nLoading. Please wait.\n\n## Position in labour for women with a BMI over\xa030\n\nFor women with a BMI over 30\xa0kg/m2 at the booking appointment, carry out a risk assessment in the third trimester. When developing the birth plan with the woman, take into account:\n\nthe woman's preference\n\nthe woman's mobility\n\ncomorbidities\n\nthe woman's current or most recent weight.\n\nFor women with a BMI over 30\xa0kg/m2 at the booking appointment and reduced mobility in the third trimester, consider advising the lateral position in the second stage of labour.\n\nFor women with a BMI over 30\xa0kg/m2 at the booking appointment and adequate mobility, provide care in the second stage of labour in line with the NICE guideline on intrapartum care for healthy women and babies.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on position during the second stage of labour for women with a BMI over 30\xa0kg/m2\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: obesity.\n\nLoading. Please wait.\n\n## Equipment needs for women in labour with a BMI over\xa030\n\nAll obstetric units should have 'birthing beds' able to take a safe working load of 250\xa0kg.\n\nCarry out a risk assessment to ensure that essential equipment, in a size-appropriate form, is available for the intrapartum care of women with a BMI over 30\xa0kg/m2 at the booking appointment, including:\n\nsurgical, obstetric and anaesthetic equipment\n\nblood pressure cuffs\n\noperating theatre tables\n\nlifting and lateral transfer equipment\n\nanti-embolism stockings\n\nwheelchairs\n\nmonitoring and measuring equipment.\n\nFor women with a BMI over 50\xa0kg/m2 at the booking appointment, offer referral to an obstetric unit with suitable equipment and expertise as early as possible in pregnancy, if this is not available in their current unit.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on equipment needs for women in labour with a BMI over 30\xa0kg/m2\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: obesity.\n\nLoading. Please wait.\n\n# Information for women with obstetric complications or no antenatal care\n\nFollow the recommendations on communication in the NICE guideline on intrapartum care for healthy women and babies for women in labour with obstetric complications or no antenatal care.\n\nRecognise that women in labour with obstetric complications or no antenatal care:\n\nmay be more anxious than other women in labour and\n\nare likely to have a better experience of labour and birth if they receive information about the benefits and risks of options for their care and are fully involved in decision making.\n\nProvide information about care in labour and mode of birth, which:\n\nis personalised to the woman's circumstances and needs\n\nuses local and national figures where possible\n\nexpresses benefits and risks in a way that the woman can understand\n\nis presented as recommended in the NICE guideline on patient experience in adult NHS services.\n\nRecognise that individual views about risk vary, and support a woman's decision making and choices.\n\nClarify with women with obstetric complications or no antenatal care whether and how they would like their birth companion(s) involved in discussions about care during labour and birth. Review this regularly.\n\nInvolve the woman in planning her care by asking about her preferences and expectations for labour and birth. Take account of previous discussions, planning, decisions and choices, and keep the woman and her birth companion(s) fully informed.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information for women with obstetric complications or no antenatal care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: information for women with obstetric complications or no antenatal care.\n\nLoading. Please wait.\n\n# Risk assessment for women with obstetric complications or no antenatal care\n\nTake account of symptoms reported and concerns expressed by women in labour with any of the following:\n\npyrexia\n\nsepsis\n\nintrapartum haemorrhage\n\nbreech presentation\n\nsuspected small-for-gestational-age baby\n\nsuspected large-for-gestational-age baby\n\nprevious caesarean section\n\nlabour after 42\xa0weeks of pregnancy\n\nno antenatal care.\n\nEnsure that a healthcare professional with skills and experience in managing obstetric complications reviews and assesses the condition of a woman with any of the complications in recommendation 1.11.1, including any observations recorded, and escalates care as needed.\n\nTake account of the whole clinical picture when discussing options for care with the woman during the intrapartum period.\n\nCarry out and record maternal observations (pulse, blood pressure, temperature and urine output), as recommended in the NICE guideline on intrapartum care for healthy women and babies and shown in table\xa03, for women in labour with any of the following and no other reasons for concern:\n\nbreech presentation\n\nsuspected small-for-gestational-age baby\n\nsuspected large-for-gestational-age baby\n\nprevious caesarean section\n\nlabour after 42\xa0weeks of pregnancy\n\nno antenatal care.\n\nPulse\n\nBlood pressure\n\nRespiratory rate\n\nTemperature\n\nLevel of consciousness (AVPU)\n\nOxygen saturation\n\nUrine\n\nHourly\n\n‑hourly, and hourly in the second stage\n\nNot required routinely\n\n‑hourly\n\nNot required routinely\n\nNot required routinely\n\nRecord output\n\nAbbreviations: AVPU, alert, voice, pain, unresponsive.\n\nThe frequency of observations should be adjusted if necessary based on the level of clinical concern.\n\nFor women in labour with fever, a temperature of 38°C or above on a single reading or 37.5°C or above on 2\xa0consecutive readings (1\xa0hour apart), carry out maternal observations as shown in table\xa04.\n\nFor women in labour with sepsis or suspected sepsis, carry out maternal observations as shown in table\xa04.\n\nFor women with intrapartum haemorrhage, continuously monitor vaginal blood loss and carry out maternal observations as shown in table\xa04.\n\nMaternal observation\n\nFever\n\nSuspected sepsis – concern insufficient for antibiotic treatment\n\nSepsis or suspected sepsis – on antibiotic treatment\n\nIntrapartum haemorrhage\n\nPulse\n\nHourly\n\nHourly\n\nContinuous, or at least every 30 minutes\n\nAt least hourly\n\nBlood pressure\n\n-hourly, and hourly in the second stage\n\n-hourly, and hourly in the second stage\n\nContinuous, or at least every 30 minutes\n\nAt least 4-hourly, and at least hourly in the second stage\n\nRespiratory rate\n\n-hourly\n\n-hourly\n\nContinuous, or at least every 30 minutes\n\nAt least 4-hourly\n\nTemperature\n\nHourly\n\nHourly\n\nHourly\n\nAt least 4-hourly\n\nLevel of consciousness (AVPU)\n\nHourly\n\nHourly\n\nEvery 30 minutes\n\nHourly\n\nOxygen saturation\n\n-hourly\n\n-hourly\n\nContinuous, or at least every 30 minutes\n\nAt least 4-hourly\n\nUrine\n\nRecord output\n\nRecord output\n\nRecord output, hourly if catheterised\n\nRecord output, hourly if catheterised\n\nAbbreviations: AVPU, alert, voice, pain, unresponsive.\n\nThe frequency of observations should be adjusted if necessary based on the level of clinical concern.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on risk assessment for women with obstetric complications or no antenatal care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: risk assessment for women with obstetric complications or no antenatal care.\n\nLoading. Please wait.\n\n# Pyrexia\n\n## Use of antipyretics for women in labour with a fever\n\nConsider paracetamol for women in labour with a fever, a temperature of 38°C or above on a single reading, or 37.5°C or above on 2\xa0consecutive readings (1\xa0hour apart).\n\nBe aware that paracetamol is not a treatment for sepsis and should not delay investigation if sepsis is suspected.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on the use of antipyretics for women in labour with a fever\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: pyrexia.\n\nLoading. Please wait.\n\n## Fetal blood sampling for women in labour with a fever\n\nFor women in labour with a fever, a temperature of 38°C or above on a single reading, or 37.5°C or above on 2\xa0consecutive readings (1\xa0hour apart), follow the recommendations in the section on fetal monitoring for women in labour with sepsis or suspected sepsis on fetal blood sampling for women with suspected sepsis.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal blood sampling for women in labour with a fever\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: pyrexia.\n\nLoading. Please wait.\n\n# Sepsis\n\n## Mode of birth for women with sepsis or suspected sepsis\n\nFollow the NICE guideline on sepsis for the recognition of sepsis in pregnant women.\n\nTake into account the normal physiological changes in labour when thinking about the possibility of sepsis, for example, increased maternal pulse rate.\n\nRecognise that women in labour with sepsis (see the NICE guideline on sepsis) are at higher risk of severe illness or death.\n\nFor women in labour with suspected sepsis, ensure ongoing multidisciplinary review from a team with a named lead, including:\n\na senior obstetrician\n\na senior obstetric anaesthetist\n\na senior midwife\n\na labour ward coordinator.\n\nFor women in labour with sepsis, ensure ongoing multidisciplinary review from a team with a named lead, including:\n\na senior obstetrician\n\na senior obstetric anaesthetist\n\na senior neonatologist\n\na senior microbiologist\n\na senior midwife\n\na labour ward coordinator.\n\nInclude a senior intensivist (critical care specialist), if a woman in labour with sepsis has any of the following signs of organ dysfunction:\n\naltered consciousness\n\nhypotension (systolic blood pressure less than 90\xa0mmHg)\n\nreduced urine output (less than 0.5\xa0ml/kg per hour)\n\nneed for 40% oxygen to maintain oxygen saturation above\xa092%\n\ntympanic temperature of less than\xa036°C.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nFor women with sepsis or suspected sepsis in the intrapartum period:\n\nagree a clear multidisciplinary care plan with the woman\n\ndocument the agreed plan\n\nreview the plan regularly, taking account of the whole clinical picture, including response to treatment.\n\nInvolve the woman with sepsis or suspected sepsis and her birth companion(s) in shared decision making about her care, including the following options:\n\ninduction of labour\n\ncontinuing labour\n\naugmenting labour\n\ninstrumental birth\n\ncaesarean section.\n\nWhen discussing timing and mode of birth with a woman with sepsis or suspected sepsis, take into account the woman's preferences, concerns and expectations, and the whole clinical picture, including:\n\nthe source and severity of sepsis, if known\n\nweeks of pregnancy\n\nfetal wellbeing\n\nstage and progress of labour\n\nparity\n\nresponse to treatment.\n\nIf the source of sepsis is thought to be the genital tract, expedite the birth.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on mode of birth for women with sepsis or suspected sepsis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: sepsis.\n\nLoading. Please wait.\n\n## Anaesthesia and analgesia for women in labour with sepsis or suspected sepsis\n\nFor women in labour with sepsis and any signs of organ dysfunction (see recommendation 1.13.6), regional anaesthesia should only be used with caution and advice from a consultant obstetric anaesthetist, and with a senior anaesthetist present.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on anaesthesia for women in labour with sepsis and signs of organ dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: sepsis.\n\nLoading. Please wait.\n\nFor women in labour with sepsis and any signs of organ dysfunction (see recommendation 1.13.6), regional analgesia should only be used with caution and advice from a consultant obstetric anaesthetist.\n\nFor women in labour with suspected sepsis where concern is insufficient for antibiotic treatment, consider the birthing pool as a form of analgesia only after discussion with a senior midwife and a senior obstetrician.\n\nFor women in labour who need antibiotics for suspected sepsis (see the NICE guideline on sepsis), start the antibiotics before inserting the needle for regional analgesia.\n\nFor women in labour with suspected sepsis, carry out a multidisciplinary review of options for pain relief at least every 4\xa0hours.\n\nIf there are concerns about providing a woman's choice of regional analgesia, this should be discussed with the consultant obstetric anaesthetist.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on analgesia for women in labour with sepsis or suspected sepsis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: sepsis.\n\nLoading. Please wait.\n\n## Fetal monitoring for women in labour with sepsis or suspected sepsis\n\nAdvise continuous cardiotocography during labour for:\n\nwomen with suspected sepsis and\n\nwomen with confirmed sepsisin line with the section on the use of cardiotocography for monitoring during labour in the NICE guideline on fetal monitoring in labour.\n\nExplain to the woman and her birth companion(s) what fetal blood sampling involves and the uncertainty of the significance of the results, and support her decision to accept or decline testing.\n\nBe aware that for women in labour with sepsis or suspected sepsis, fetal blood sample results may be falsely reassuring, and always discuss with a consultant obstetrician:\n\nwhether fetal blood sampling is needed\n\nthe results of any fetal blood sampling carried out.[This recommendation is adapted from the NICE guideline on intrapartum care for healthy women and babies.]\n\nFor women in labour with sepsis or suspected sepsis and an abnormal cardiotocograph trace, think about the whole clinical picture and take account of the following before performing any fetal blood sampling and when interpreting the results:\n\nthe woman's preferences\n\nstage and progress of labour\n\nparity\n\nlikelihood of chorioamnionitis.\n\nIf sepsis continues to be suspected, only repeat fetal blood sampling with caution and in discussion with a consultant obstetrician.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal monitoring for women in labour with sepsis or suspected sepsis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: sepsis.\n\nLoading. Please wait.\n\n## Antimicrobial treatment for women in labour with sepsis or suspected sepsis\n\nFor women in labour with sepsis or suspected sepsis:\n\nTake into account the whole clinical picture when thinking about antimicrobial treatment.\n\nDocument the rationale for any decision to start antimicrobial treatment and the choice of antimicrobial.\n\nTake specimens for microbiological culture, including blood cultures, before starting antimicrobials in line with the NICE guideline on sepsis.\n\nFor women in labour with sepsis or suspected sepsis and a clear source of infection, use existing local antimicrobial guidance when offering an antimicrobial. [This recommendation is adapted from the NICE guideline on sepsis.]\n\nFor women in labour with sepsis or suspected sepsis and an unclear source of infection, offer a broad-spectrum intravenous antimicrobial from the agreed local formulary and in line with local (where available) or national guidelines. [This recommendation is adapted from the NICE guideline on sepsis.]\n\nExplain to the woman in labour with sepsis or suspected sepsis and her birth companion(s):\n\nthere is no evidence to support the use of one broad-spectrum antimicrobial over another\n\nthe choice of antimicrobial will be guided by local antimicrobial guidelines.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on antimicrobial treatment for women in labour with sepsis or suspected sepsis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: sepsis.\n\nLoading. Please wait.\n\n## Care for women with sepsis or suspected sepsis immediately after the birth\n\nFor women with sepsis or suspected sepsis, ensure that there is ongoing multidisciplinary review (see the recommendations in the sections on multidisciplinary review for women in labour with suspected sepsis and with sepsis) in the first 24\xa0hours after the birth. This should include a discussion about the need for:\n\nmicrobiological specimens for culture\n\nantimicrobial treatment\n\nincreased frequency of monitoring\n\nan enhanced level of care and monitoring\n\nfurther investigations such as imaging\n\nsupport to enable the woman to feed her baby as she chooses (including keeping the woman and baby together wherever possible and maintaining skin-to-skin contact)\n\nadditional support for the woman and her family.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on care for women with sepsis or suspected sepsis immediately after the birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: sepsis.\n\nLoading. Please wait.\n\n# Intrapartum haemorrhage\n\n## Management of intrapartum haemorrhage\n\nIf there are signs of shock in a woman with intrapartum haemorrhage, proceed with immediate resuscitation.\n\nThe maternity service and ambulance service should have strategies in place to respond quickly and appropriately if a woman has an intrapartum haemorrhage in any setting. [This recommendation is adapted from the NICE guideline on intrapartum care for healthy women and babies.]\n\nIf a woman in labour has any vaginal blood loss other than a 'show', transfer her to obstetric-led care, in line with the NICE guideline on intrapartum care for healthy women and babies.\n\nIf a woman in labour has any vaginal blood loss other than a 'show', explain to her and her birth companion(s) what is happening.\n\nIf a woman in labour has any vaginal blood loss other than a 'show':\n\nTake a history of the bleeding, asking about:\n\n\n\nany associated symptoms, including pain\n\nany specific concerns the woman may have\n\nany previous uterine surgery.\n\n\n\nCheck previous scans for placental position.\n\nAssess the volume of blood loss and characteristics of the blood, such as colour, and presence of clots or amniotic fluid.\n\nCarry out a physical examination, including:\n\n\n\nvital signs\n\nabdominal palpation\n\nspeculum examination\n\nvaginal examination if placenta praevia has been excluded\n\nfetal heart auscultation.\n\n\n\nStart continuous cardiotocography.\n\nTake a blood sample to determine full blood count and blood group.\n\nThink about the possible causes of bleeding, for example:\n\nplacental abruption\n\nplacenta praevia\n\nuterine rupture\n\nvasa praevia.Recognise that in many cases, no cause will be identifiable.\n\nIf a woman in labour has any vaginal blood loss other than a 'show', agree a multidisciplinary care plan with the woman and document the plan. Include the following in plans for multidisciplinary care:\n\na senior obstetrician\n\na senior obstetric anaesthetist\n\na senior midwife\n\na labour ward coordinator.\n\nIf a woman has intrapartum bleeding and her condition is stable, management should include:\n\nestablishing venous access\n\nmaternal monitoring (see the recommendation on continuously monitoring vaginal blood loss in the section on risk assessment for women with obstetric complications or no antenatal care and table 4)\n\nmonitoring the fetal heart rate with continuous cardiotocography.\n\nIf a woman with intrapartum bleeding has a large blood loss or her condition causes concern, management should be in line with recommendation 1.14.8 and also include:\n\ngiving intravenous fluids urgently\n\ntaking blood for full blood count and cross-matching\n\nseeking medical advice from a more experienced healthcare professional.Management may also include:\n\n\n\ntriggering the local major haemorrhage protocol\n\ntaking blood for clotting studies and blood gases\n\nuse of amniotomy or oxytocin\n\nexpediting the birth.\n\n\n\nIf a woman in labour has vaginal blood loss typical of a 'show', follow the NICE guideline on intrapartum care for healthy women and babies.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management of intrapartum haemorrhage\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: intrapartum haemorrhage.\n\nLoading. Please wait.\n\n# Breech presenting in labour\n\n## Mode of birth for women presenting with a breech position in labour\n\nDiscuss with women in labour with breech presentation the possible benefits and risks of vaginal birth and caesarean section, including:\n\nan increase in the chance of serious medical problems for the woman with caesarean section\n\nan increase in the chance of serious medical problems for the baby with vaginal birth\n\nwhat it might mean for them and the baby if such problems did occur.\n\nExplain to women in labour with breech presentation that any benefit of caesarean section in reducing the chance of serious medical problems for the baby may be greater in early labour.\n\nOffer women in labour with breech presentation a choice between continuing labour and caesarean section.\n\nAssess progress of labour in line with the NICE guideline on intrapartum care for healthy women and babies.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on mode of birth for women presenting with a breech position in labour\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: breech presenting in labour.\n\nLoading. Please wait.\n\n# Small-for-gestational-age baby\n\n## Fetal monitoring in labour for babies suspected to be small for gestational age\n\nDiscuss with a woman whose baby is suspected to be small for gestational age:\n\nthe chance of serious medical problems for her baby\n\nwhat it might mean for her and her baby if such problems did occur.\n\nWhen discussing risk, explain that when a baby is suspected to be small for gestational age:\n\nit is sometimes difficult to be certain the suspicion is correct until the baby is born\n\nthe chance of serious medical problems for the baby is greater with:\n\n\n\ngrowth restriction\n\nadditional risk factors, such as preterm birth\n\ncomplications during labour or birth.\n\n\n\nOffer continuous cardiotocography to women whose babies are suspected to be small for gestational age after a full discussion of the benefits and risks (see recommendations 1.16.1 and 1.16.2). Respect the woman's decision if she declines continuous cardiotocography.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal monitoring in labour for babies suspected to be small for gestational age\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0P: small-for-gestational-age baby.\n\nLoading. Please wait.\n\n# Large-for-gestational-age baby\n\n## Mode of birth for babies suspected to be large for gestational age\n\nExplain to women in labour whose babies are suspected to be large for gestational age that:\n\nit is sometimes difficult to be certain the suspicion is correct until the baby is born\n\nwhen making decisions about mode of birth (for example, vaginal birth or caesarean section), this uncertainty needs to be taken into account.\n\nDiscuss with women in labour whose babies are suspected to be large for gestational age the possible benefits and risks of vaginal birth and caesarean section, including:\n\na higher chance of maternal medical problems such as infection with emergency caesarean section\n\na higher chance of shoulder dystocia and brachial plexus injury with vaginal birth\n\na higher chance of instrumental birth and perineal trauma with vaginal birth.Explain to the woman and her birth companion(s) what it might mean for her and her baby if such problems did occur.\n\nOffer women in labour whose babies are suspected to be large for gestational age a choice between continuing labour, including augmented labour, and caesarean section.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on mode of birth for babies suspected to be large for gestational age\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0Q: large-for-gestational-age baby.\n\nLoading. Please wait.\n\n# No antenatal care\n\n## Risk assessment and management of labour for women with no antenatal care\n\nFor women who have had no antenatal care, be aware of the particular importance of following the recommendations on establishing rapport and treating with respect in the NICE guideline on intrapartum care for healthy women and babies.\n\nProvide obstetric-led intrapartum care for women who have had no antenatal care, and alert the neonatal team and, if relevant, the anaesthetic team. If the woman presents to a midwifery unit, arrange urgent transfer to an obstetric-led unit if appropriate.\n\nFor a woman with no antenatal care who has difficulty understanding, speaking and reading English, provide an interpreter (who may be a link worker or advocate and should not be a member of her family, her legal guardian or her partner), who can communicate with her in her preferred language. [This recommendation is adapted from the NICE guideline on pregnancy and complex social factors.]\n\nIf possible, take a full medical, psychological and social history from women who have had no antenatal care.\n\nTry to find out why there has been no care during pregnancy.\n\nAsk the woman who, if anyone, she would like to support her as her birth companion(s) during labour.\n\nExplore sensitively any possible vulnerability or safeguarding concerns, including:\n\n\n\nyoung maternal age\n\nmaternal mental health\n\nmaternal learning disability\n\nmaternal substance misuse\n\ndomestic or sexual abuse\n\nhomelessness\n\nhuman trafficking\n\nundocumented migrant status\n\nfemale genital mutilation\n\nthe woman or family members being known to children's services or social services.\n\n\n\nCarry out an obstetric and general medical examination of a woman with no antenatal care as soon as possible. This should include the initial assessment described in the NICE guideline on intrapartum care for healthy women and babies.\n\nCarry out an assessment of the unborn baby, including ultrasound if possible, to determine:\n\nviability\n\nthe presentation\n\nan estimate of gestational age\n\nthe possibility of multiple pregnancy\n\nthe placental site.\n\nOffer women who have had no antenatal care, tests for:\n\nanaemia (full blood count)\n\nhaemoglobinopathies\n\nblood group and rhesus\xa0D status\n\natypical red cell alloantibodies\n\nrandom blood glucose\n\nasymptomatic bacteriuria\n\nHIV, hepatitis\xa0B and syphilis.\n\nOffer rapid HIV testing to women thought to be at high risk of infection, which might include:\n\nrecent migrants from countries with high rates of HIV infection\n\nwomen who misuse substances intravenously\n\nsuspected sexual abuse.\n\nExplain to a woman who has had no antenatal care why and when information about her pregnancy may need to be shared with other agencies. [This recommendation is adapted from the NICE guideline on pregnancy and complex social factors.]\n\nContact the woman's GP and, if appropriate, other health or social care professionals for more information about the woman's history and to plan ongoing care.\n\nIf there are safeguarding concerns, refer the woman to safeguarding services, document the referral and inform healthcare professionals such as the GP, health visitor and paediatric teams, and social care professionals (see the NICE guidelines on pregnancy and complex social factors, child maltreatment and child abuse and neglect).\n\nFollow the recommendations in the NICE guideline on intrapartum care for healthy women and babies when no medical conditions or obstetric complications are identified in women who present in labour with no antenatal care.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on risk assessment and management of labour for women with no antenatal care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0R: no antenatal care.\n\nLoading. Please wait.\n\n# Previous caesarean section\n\n## Management of the first and second stages of labour for women with a previous caesarean section\n\nDo not routinely insert an intravenous cannula for women in labour who have had a previous caesarean section.\n\nExplain to women in labour who have had a previous caesarean section that:\n\na vaginal birth is associated with a small chance of uterine rupture\n\nan emergency caesarean section may mean a higher chance of:\n\n\n\nheavy bleeding needing a blood transfusion\n\ninfection, for example, intrauterine infection\n\na longer hospital stay\n\ncomplications in a future pregnancy, for example, placenta praevia and placenta accreta (see the NICE guideline on caesarean birth).\n\n\n\nExplain to women in labour who have had a previous caesarean section that there is little evidence of a difference in outcomes for the baby between a vaginal birth or another caesarean section.\n\nExplain to women who have had a previous caesarean section that they are likely to have a lower chance of complications in labour if they have also had a previous vaginal birth.\n\nWhen discussing oxytocin for delay in the first or second stage of labour, explain to women who have had a previous caesarean section that this:\n\nincreases the chance of uterine rupture\n\nreduces the chance of another caesarean section\n\nincreases the chance of an instrumental birth.\n\nFor guidance on continuous cardiotocography in labour for women with a previous caesarean section, see NICE's guideline on caesarean birth.\n\nSupport informed choice of a full range of options for pain relief for women who have had a previous caesarean section, including labour and birth in water.\n\nExplain to women in labour who have had a previous caesarean section that regional analgesia is associated with:\n\na reduced chance of another caesarean section\n\nan increased chance of an instrumental birth.\n\nDo not routinely offer amniotomy to women in labour who have had a previous caesarean section.\n\nThis recommendation on continuous cardiotocography has been withdrawn (see recommendation 1.19.6).\n\nFor women who have had a previous caesarean section, be aware of the particular importance of following the recommendations from the NICE guideline on intrapartum care for healthy women and babies on:\n\nfood and drink in labour\n\ncontrolling gastric acidity\n\nposition in labour, including the latent first stage, and birth.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on management of the first and second stages of labour for women with a previous caesarean section\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0S: previous caesarean section.\n\nLoading. Please wait.\n\n# Labour after 42\xa0weeks of pregnancy\n\n## Fetal and maternal monitoring for women in labour after 42\xa0weeks of pregnancy\n\nOffer continuous cardiotocography to women in labour after 42\xa0weeks of pregnancy after a full discussion of the benefits and risks to the woman and her baby. Respect the woman's decision if she declines continuous cardiotocography.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on fetal and maternal monitoring for women in labour after 42\xa0weeks of pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0T: labour after 42\xa0weeks of pregnancy.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Chronic kidney disease stages\n\nClassified according to estimated glomerular filtration rate (eGFR) measured before pregnancy. See glomerular filtration rate (GFR) categories in table\xa01 in the NICE guideline on chronic kidney disease in adults.\n\n## Intrapartum period\n\nThe intrapartum period is from the onset of labour (spontaneous or induced) to 24\xa0hours after birth.\n\n## Mechanical heart valves\n\nA mechanical heart valve refers to a prosthetic heart valve that requires long-term anticoagulation to prevent heart valve thrombosis. This is different from a bioprosthetic heart valve, which does not need long-term anticoagulation.\n\n## Regional anaesthesia\n\nRegional anaesthesia includes spinal, epidural and combined spinal–epidural techniques.\n\n## Regional analgesia\n\nRegional analgesia includes spinal, epidural and combined spinal–epidural techniques.", 'Recommendations for research': "The guideline committee has made the following high-priority recommendations for research. For details of all the committee's recommendations for research, see the evidence reviews.\n\n# Subarachnoid haemorrhage or arteriovenous malformation of the brain\n\nDoes caesarean section protect against cerebral haemorrhage in women with a history of subarachnoid haemorrhage or cerebrovascular malformation?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on mode of birth and management of the second stage of labour for women with subarachnoid haemorrhage or arteriovenous malformation of the brain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: subarachnoid haemorrhage or arterio-venous malformation of the brain.\n\nLoading. Please wait.\n\n# Needle siting in pregnant women who are obese\n\nDoes the use of ultrasound of the lumbar spine improve siting of regional anaesthetic needles in pregnant women with a BMI over 30\xa0kg/m2 at the booking appointment?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on anaesthesia and analgesia for women with a BMI over 30\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: obesity.\n\nLoading. Please wait.\n\n# Obesity as a risk factor for perinatal morbidity and mortality\n\nIs obesity an independent risk factor for perinatal morbidity and mortality?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on fetal monitoring for women with a BMI over 30\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: obesity.\n\nLoading. Please wait.\n\n# Risk assessment for women in labour with signs of sepsis\n\nWhat clinical features and laboratory investigations can be used to better stratify risk for women in labour with signs of sepsis (including fever and tachycardia)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on risk assessment for women with obstetric complications or no antenatal care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: risk assessment for women with obstetric complications or no antenatal care.\n\nLoading. Please wait.\n\n# Previous caesarean section\n\nWhat is the clinical and cost effectiveness of intermittent auscultation compared with continuous cardiotocography for women in labour who have had a previous caesarean section?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on previous caesarean section\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0S: previous caesarean section.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Information for women with existing medical conditions\n\nRecommendations 1.1.1 to 1.1.5\n\n## Why the committee made the recommendations\n\nEvidence was very limited, but the committee knew from their experience that providing information is extremely important for pregnant women with medical conditions. They agreed that women would need the general information outlined in the NICE guideline on intrapartum care for healthy women and babies as well as additional information related to the medical condition. Extra time may be needed in a consultation to discuss how the medical condition may affect intrapartum care. It was agreed that information should be delivered by a healthcare professional from the multidisciplinary team who can answer questions the woman may have about the intrapartum period and the medical condition. It is up to the woman to decide whether and how her birth companion(s) are involved in these discussions.\n\n## How the recommendations might affect practice\n\nThe committee did not expect a significant change in practice because the recommendations are in line with what is generally happening in most centres. However, in centres where this is not happening, consultations will take longer.\n\nReturn to recommendations\n\n# Planning for intrapartum care with women with existing medical conditions – involving a multidisciplinary team\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nEvidence did not show a difference in outcomes for women with a BMI over\xa040 or their babies when care was given by a specialist antenatal multidisciplinary team. However, the committee recognised that women with medical conditions have an increased risk of adverse outcomes, and a lack of multidisciplinary working has been repeatedly cited in the Confidential Enquiries into Maternal Deaths and Morbidity as contributing to maternal deaths. To minimise risk, the committee recommended that a standard obstetric team be extended (when appropriate) by involving healthcare professionals with expertise in managing the woman's medical condition, and that teams involved in the woman's care share their intrapartum care plans.\n\n## How the recommendations might affect practice\n\nMultidisciplinary teams are not currently in place in all settings, including settings where care is delivered to women at high risk because of medical conditions. However, multidisciplinary working with other medical or surgical specialties is currently expected within the intermediate and intensive pathways for more complex pregnancies. The recommendations are expected to result in a relatively modest change in practice because most modern multidisciplinary teams are 'virtual' (communicating by telephone or email rather than in person). Obstetric teams and specialists will be seeing the same women that they would see anyway, but multidisciplinary working will give them the opportunity to deliver more holistic care. However, establishing the relationships and ways of working may involve extra organisation and increase the antenatal involvement of obstetric anaesthetists.\n\nReturn to recommendations\n\n# Risk assessment for women with heart disease\n\nRecommendations 1.3.1 to 1.3.5\n\n## Why the committee made the recommendations\n\nThe committee drew on their knowledge and experience to recommend that intrapartum care planning should start early in pregnancy for women with heart disease. Pregnancy and birth are associated with dramatic changes in the performance of the heart and the circulation. Early risk assessment is needed to plan for birth and agree any additional management. Women who present in the intrapartum period with a previously unrecognised heart problem pose a particular challenge. Urgent multidisciplinary discussions are needed to ensure that they are offered comparable intrapartum care to women with an existing diagnosis.\n\nThe committee agreed that multidisciplinary care should include a cardiologist with expertise in managing heart conditions during pregnancy because they were concerned that not all pregnant women with heart disease have appropriate cardiac referrals. Only a few cardiologists in the UK have an interest in managing heart disease in pregnancy and the Confidential Enquiries into Maternal Deaths and Morbidity identified deficient care when non-specialist cardiologists had given inappropriate advice. The benefit of specialist cardiology advice also includes encouraging women with low-risk conditions towards vaginal birth with no medical intervention, in line with the NICE guideline on intrapartum care for healthy women and babies.\n\nBased on the available evidence and their knowledge and experience, the committee agreed that risk assessment should include diagnostic classification, cardiac functional capacity and clinical assessment. For some women, this can mean reassurance that no additional precautions are needed; for others, a full discussion of the risks and a comprehensive plan will be required. The committee recognised the importance of thorough clinical assessment as raised in the confidential enquiries and the need to provide prompt investigation identified in the 2016 MBBRACE‑UK report.\n\nBased on their knowledge and experience, the committee recommended that the woman's clinical condition is reassessed regularly during pregnancy and the intrapartum period. Many changes in performance of the heart and circulation occur gradually during pregnancy, but the intrapartum period and early postpartum period (including the first hours and days after birth) sees changes that can trigger a deterioration in cardiac function and therefore it is vital that investigations are undertaken and acted on promptly.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations will reduce variation in practice and encourage best practice that already exists in many areas of the country. In some areas, there may be more referrals to tertiary level services for specialist advice from a cardiologist with expertise in managing heart conditions during pregnancy. However, specialist advice should better determine which women need additional intervention and provide reassurance for those women whose heart condition would not affect their birth plans.\n\nThe committee believed that cardiac investigations are not rapidly available in all areas of the UK and this is reinforced by delays to investigations being identified by the Confidential Enquiries into Maternal Deaths and Morbidity in some cases of maternal death. There is variation in access to echocardiography, an investigation that can be crucial to making a diagnosis when symptoms of heart disease develop in the intrapartum period. A plan to ensure urgent access to echocardiography (including out of hours) for pregnant women with heart disease should be considered.\n\nThe recommendation that vaginal birth is safe for women with mild heart disease may reduce unnecessary medical intervention.\n\nReturn to recommendations\n\n# Management of anticoagulation for women with mechanical heart valves\n\nRecommendations 1.3.6 to 1.3.13\n\n## Why the committee made the recommendations\n\nThe evidence looked at the effects of different anticoagulants throughout pregnancy on maternal and neonatal outcomes rather than their effects during labour. The evidence was also limited to women with mechanical heart valves. Therefore, the committee based recommendations on their experience and advice from a cardiac specialist.\n\nThey noted that a woman with a mechanical heart valve is prone to thrombosis if she has inadequate anticoagulation, but is vulnerable to excessive bleeding with too much anticoagulation. Either can lead to devastating fatal incidents for the woman and her baby. It is therefore important that planning for the management of anticoagulation during the intrapartum period starts when pregnancy is confirmed. The committee agreed that a woman with a mechanical heart valve should be switched to low-molecular-weight heparin by 36\xa0weeks of pregnancy, or 2\xa0weeks before planned birth, because heparin has a shorter half-life than warfarin and it does not cross the placenta so reducing the risk of bleeding in the baby.\n\nThe committee acknowledged that intravenous unfractionated heparin continues to be used in some centres, although recognised that use of unfractionated heparin has declined in the UK. Recommendations on newer anticoagulants were not made because their use is limited in practice. The committee agreed, based on the once-daily dosing of warfarin, that low-molecular-weight heparin should be started 24\xa0hours after stopping warfarin. Monitoring of anti‑Xa level and dose adjustments are needed to ensure that an appropriate level of anticoagulation is achieved. The committee agreed trough levels might be useful and should be checked.\n\nFor women who have a planned caesarean section, the risk of an epidural haematoma can be reduced by stopping low-molecular-weight heparin 24\xa0hours before. For women having an induction of labour, the decision of when to stop low-molecular-weight heparin should balance the risk of valve thrombosis against the possibility of having regional analgesia. A senior obstetrician should be involved in this decision and review the progress of induction.\n\nFor a woman presenting in labour on warfarin, the committee agreed that anticoagulation be stopped immediately to minimise the risks of excessive bleeding for the woman and baby during labour. The committee recommended that obstetric assessment should occur within 2\xa0hours, recognising that although assessment was urgent, it would not always be possible to do this immediately. The committee agreed that the international normalised ratio (INR) be checked immediately and a haematologist consulted. The INR determines the degree of anticoagulation in the woman and baby and indicates how anticoagulation should be managed. A haematologist would advise how to reverse anticoagulation if this was needed. Senior review, involving a senior obstetrician, haematologist and consultant obstetric anaesthetist, should ensure the safest birth for the woman and baby.\n\nThe committee acknowledged that reintroducing therapeutic anticoagulation 4\xa0to\xa06\xa0hours after birth (rather than 48\xa0hours) increases the risk of uterine haemorrhage. They considered data from the European Registry of Pregnancy and Cardiac Disease (ROPAC) on anticoagulation in pregnancy for women with mechanical heart valves. Although not addressing peripartum anticoagulation, the study confirmed the high risk of haemorrhage with anticoagulation but also indicated a higher risk of mechanical heart valve thrombosis in pregnancy. With limited evidence, the committee, supported by specialist cardiac and haematology input, agreed to follow the European Society of Cardiology (ESC) guidelines and recommend that therapeutic anticoagulation is reintroduced 4\xa0to\xa06\xa0hours after birth. They considered the risk of peripartum mechanical heart valve thrombosis to be higher in pregnancy and to be of greater consequence than the increased risk of uterine haemorrhage with earlier reintroduction of anticoagulation.\n\n## How the recommendations might affect practice\n\nThe committee believed that these recommendations reflect modern UK practice and the growing clinical use of low-molecular-weight heparin, and acknowledge some continued use of unfractionated heparin. Anti‑Xa assays are essential for the monitoring and titration of low-molecular-weight heparin and the committee recognised that access to this test may need to be improved.\n\nReturn to recommendations\n\n# Mode of birth for women with heart disease\n\nRecommendations 1.3.14 to 1.3.18\n\n## Why the committee made the recommendations\n\nEvidence was very limited so the committee drew on their knowledge and experience to make recommendations. They agreed that risk assessment is necessary to understand how well the woman's heart is functioning and is likely to cope with the exertion of labour and the circulatory changes that take place after birth. Women should be involved in formulating an individualised birth plan, with advice from a team with experience of intrapartum care for women with heart conditions. This will usually involve doctors from at least 3\xa0specialties (obstetrics, cardiology and anaesthesia). In this way, the woman's wishes for labour and birth can be discussed in relation to the specific risks of her condition.\n\nIn the UK, the management of pulmonary arterial hypertension is concentrated in a small number of specialist pulmonary hypertension centres. Pulmonary arterial hypertension is a life-threatening condition that requires expert management. The multidisciplinary team planning for a woman with pulmonary hypertension must include a respiratory clinician from 1\xa0of these centres.\n\nIn order to minimise the time without anticoagulation, planned caesarean section or induction of labour should be offered to women with mechanical heart valves. The risks of valve thrombosis cannot be overstated but this needs to be balanced against the risks of bleeding around the time of birth.\n\nPlanned caesarean section should be considered for women with high-risk aortic disease or the most severe cardiac conditions, but the committee recognised that some of these women may prefer to plan for a vaginal birth. When this is the woman's preference, she should be fully informed of the benefits and risks of assisted second stage of labour compared with active pushing alone, in order to reduce the risk of aortic dissection, aortic rupture or acute heart failure.\n\nAlthough the exertion of labour and the fluid shifts at birth may be detrimental to some heart conditions, this is not true for all women. The committee considered that many women with mild heart disease can be reassured that a normal vaginal birth is safe.\n\n## How the recommendations might affect practice\n\nIt is thought that the recommendations largely reflect current UK practice. The committee recognised that most women with more severe heart disease are already managed in large obstetric-led units by clinical teams with experience in this area. By attempting to define the conditions that pose the highest risk, the recommendations may result in further centralisation of specialist services.\n\nWomen with pulmonary hypertension are already offered care in specialist centres. Pregnancy and childbirth hold such serious risks for women with this condition and the committee agreed that liaison with specialist respiratory clinicians was essential.\n\nReturn to recommendations\n\n# Fluid management for women with heart disease\n\nRecommendations 1.3.19 to 1.3.23\n\n## Why the committee made the recommendations\n\nIn the absence of evidence, the committee used their knowledge and experience to make recommendations for haemodynamic monitoring during birth for women with heart disease. Risk assessment and planning of intrapartum monitoring needs specialist multidisciplinary input. Discussions should take place during pregnancy and involve the woman so that she knows how her condition might be affected by changes in blood pressure, blood volume and fluid shifts during labour and birth, and the type of monitoring needed to manage this.\n\nFor women with mild heart disease, management of fluid balance does not mean a change from standard care. For those with more severe conditions, standard care may still be suitable but decisions need to be based on specialist assessment of the type and severity of the condition and the woman's views. There are some heart conditions in which fluid balance is critical to cardiac function, and frequent monitoring and assessment by a clinician with expertise in management of heart disease in pregnancy, such as a consultant anaesthetist, obstetrician, cardiologist or intensivist, are needed as a minimum. For these conditions, more invasive monitoring may also be needed. As part of the clinical review, this should be discussed with the woman, and those who need intensive monitoring should be made aware that they are likely to need to go to an intensive care unit or delivery suite where this expertise exists.\n\n## How the recommendations might affect practice\n\nThe committee agreed that specialist planning for intrapartum monitoring to identify the monitoring needs of women with different heart conditions together with stepped escalation of monitoring intensity, would reduce variation in practice. It would allow NHS resources to be directed more effectively to reduce morbidity and mortality associated with fluid management during the intrapartum period for women with cardiac conditions and their babies. Women's experience of labour and birth would be improved through their involvement in management discussions and because they would receive a level of intervention appropriate to their needs, taking their priorities for birth into account where possible.\n\nReturn to recommendations\n\n# Diagnosis and management of heart failure for all women in the intrapartum period\n\nRecommendations 1.3.24 to 1.3.31\n\n## Why the committee made the recommendations\n\nAlthough most of the recommendations were based on the committee's experience because of the limited evidence, there was some evidence to inform the recommendations on heart rate and using N‑terminal pro‑brain natriuretic peptide (NT‑proBNP) levels. The committee agreed that symptoms and signs suggesting heart failure should be assessed initially by a member of the obstetric team and if present, confirmed by a senior clinician. When clinical examination raises the suspicion of heart failure, imaging and blood tests are needed to assist review by a cardiologist or the most senior available clinician to make a definitive diagnosis. This recommendation arises from evidence from the Confidential Enquiries into Maternal Deaths and Morbidity, that the diagnosis may be missed or delayed.\n\nThe committee made recommendations to support prompt and accurate diagnosis of heart failure because it is difficult to distinguish between the symptoms and signs of the normal physiological changes of late pregnancy and the pathological symptoms and signs of heart failure. A basic but thorough history and examination are key to identifying women who are at risk and the committee wanted to stress the importance of these.\n\nAlthough heart failure in the intrapartum period is rare, it is an important cause of maternal mortality. Prompt medical management is needed to stabilise the woman's immediate condition but a change to the obstetric management may also be necessary to improve or limit worsening of her heart condition.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current best practice. The committee agreed they should reinforce practice as well as improving postnatal prescribing and encouraging these women to breastfeed.\n\nReturn to recommendations\n\n# Anaesthesia and analgesia for women with heart disease\n\nRecommendations 1.3.32 to 1.3.40\n\n## Why the committee made the recommendations\n\nEvidence identified was very limited so the committee made recommendations based on their knowledge and experience. The committee wanted to promote the best medical opinion while also taking into account women's needs and wishes. Regional anaesthesia offers several benefits over general anaesthesia that are still relevant even when a woman has a heart condition.\n\nThe committee was aware that the type of anaesthesia that women with heart conditions receive can vary according to the attending anaesthetist's experience and technical expertise. Enhanced haemodynamic stability can be achieved using low-dose sequential combined spinal–epidural or carefully titrated continuous spinal catheter techniques. Therefore obstetric anaesthetists and cardiac anaesthetists should collaborate to provide the best anaesthetic option for cardiovascular stability for the woman. They agreed that information should be shared with the woman so the best outcomes can be achieved. Women with modified World Health Organization (WHO)\xa01 or modified WHO\xa02 heart disease should be given the same advice as described in the NICE guideline on intrapartum care for healthy women and babies.\n\nBased on knowledge of the physiological consequences of pain and the evidence that regional analgesia provides the most complete pain relief in labour, the committee agreed that to minimise the risks of labour without adversely affecting the woman's heart condition, women with modified WHO\xa03 and modified WHO\xa04 heart disease should be offered regional analgesia for labour. These women have critical heart failure and life-threatening heart disease and need to be carefully monitored to avoid serious mortality and morbidity.\n\nWomen who have not had a prophylactic dose of low-molecular-weight heparin for 12\xa0hours or a therapeutic dose for at least 24\xa0hours could be considered for regional analgesia because, the committee agreed, after this time the risk of bleeding from regional analgesia is considered to be very low.\n\nThe committee also agreed it was important to acknowledge those women who remain on low-molecular-weight heparin, and to provide details regarding the appropriate timing for removal of the epidural catheter.\n\n## How the recommendations might affect practice\n\nMost pregnant women with severe heart disease are already offered care in large obstetric-led units with links to cardiac centres. Therefore, these recommendations reinforce current practice and are unlikely to lead to a change. The recommendation that women with WHO\xa01 and\xa02 heart disease should be treated as healthy women may reduce unnecessary change in routine intrapartum practice.\n\nReturn to recommendations\n\n# Management of the third stage of labour for women with heart disease\n\nRecommendations 1.3.41 to 1.3.44\n\n## Why the committee made the recommendations\n\nThe committee agreed that heart disease covers a spectrum of pathologies, which have different risks associated with management of the third stage of labour. The only evidence was limited, came from a single study and was not helpful in determining management options for women with various heart conditions. Therefore the committee made recommendations based on their knowledge and experience. A management plan developed with multidisciplinary expertise is needed for each woman. Women with less severe heart conditions have similar risks to normal healthy women in the third stage of labour and can be managed accordingly. Because the physiological management of the third stage of labour is associated with a higher risk of postpartum haemorrhage, women with WHO\xa02 heart disease should have the third stage actively managed. Active management is also needed for all women with more severe disease. Oxytocin is the uterotonic of first choice. Second-line options depend on the specific condition. Women with preload-dependent circulation are particularly vulnerable to falls in blood pressure and there is some evidence to suggest that oxytocin should be given as an infusion rather than bolus to avoid this.\n\nErgometrine and oxytocin, 2\xa0of the most commonly administered uterotonic agents, are known to have significant cardiovascular side effects and may be contraindicated in some women with heart disease. However, management of the third stage of labour should not put women with heart disease at increased risk of postpartum haemorrhage because some of these women will tolerate even minor haemorrhage very poorly. The women at potential risk of adverse effects from oxytocin are also those who are at greatest risk if they have a postpartum haemorrhage. The committee took all these factors into account when developing recommendations.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current practice. The committee agreed there should be little change, with the exception of reducing the use of long-acting forms of oxytocin.\n\nReturn to recommendations\n\n# Analgesia for women with asthma\n\nRecommendation 1.4.1\n\n## Why the committee made the recommendation\n\nNo evidence was found on harm from any form of pain relief during labour for women with asthma. In the absence of evidence, the committee drew on their knowledge and experience to agree that the risk of harm was theoretical, and women with asthma should have the same options for pain relief as women without asthma.\n\n## How the recommendation might affect practice\n\nThe recommendation should not significantly alter practice, because many hospitals already offer all types of pain relief to women with asthma. Those that do not will have all the options available for women without asthma and so will be able to quickly implement the recommendation.\n\nReturn to recommendation\n\n# Prostaglandins for women with asthma\n\nRecommendations 1.4.2 to 1.4.4\n\n## Why the committee made the recommendations\n\nVery limited evidence indicated that prostaglandins\xa0E1 and\xa0E2 did not worsen asthma and this was in line with the committee's experience. The committee agreed to recommend prostaglandins\xa0E1 and\xa0E2 as options for inducing labour in women with asthma, and prostaglandin\xa0E1 for postpartum haemorrhage, because these are the options for women without asthma. However, the committee was concerned about a risk of bronchospasm with prostaglandin\xa0F2 alpha and so recommended against it even though it would normally be offered to women without asthma.\n\n## How the recommendations might affect practice\n\nCurrent use of prostaglandins in the intrapartum period is not well documented, but it is thought that practice varies. These recommendations are expected to represent a change in practice, but not a significant resource impact because prostaglandins are already given to women without asthma. Prostaglandin use in women with asthma might increase intensive monitoring of respiratory function during labour or after birth. This would have a resource impact, but would be offset by the reduction in extremely prolonged labour or failed induction, and the impact of postpartum haemorrhage.\n\nReturn to recommendations\n\n# Long-term systemic steroids\n\nRecommendations 1.5.1 to 1.5.4\n\n## Why the committee made the recommendations\n\nNo evidence was found so the committee used their knowledge and experience to make recommendations. They agreed that women who have been taking long-term steroids (equivalent to 5\xa0mg or more prednisolone daily for more than 3\xa0weeks) are at risk of adrenal crisis when under the physiological stress of labour and birth. The committee recommended that these women continued their regular steroid dose during labour and birth, because the effects of stopping are uncertain and there could be problems restarting the dose in the postpartum period.\n\nThey agreed that additional steroids (on top of the normal dose) would be needed to protect against an adrenal crisis. These extra steroids should be given intravenously or intramuscularly because this allows better estimation of the dose absorbed, and avoids the risk of vomiting.\n\nWomen taking inhaled or topical steroids would not normally be at risk of adrenal crisis because of the lower doses. These women should not be offered additional steroids during labour and birth unless a specialist agrees this may be needed.\n\n## How the recommendations might affect practice\n\nThe committee believe that steroids are likely overprescribed for women in labour. Therefore these recommendations might reduce the amount of steroids given, particularly for women taking inhaled or topical steroids. However, because steroids are inexpensive, this is unlikely to have a significant impact on resource use within the NHS in England.\n\nReturn to recommendations\n\n# Regional anaesthesia and analgesia for women with bleeding disorders\n\nRecommendations 1.6.1 and 1.6.2\n\n## Why the committee made the recommendations\n\nThe limited available evidence was not able to show at which level of platelet count or platelet function the risk of complications, such as epidural haematoma, starts to increase. Evidence reported no serious harm (such as epidural haematoma) from regional analgesia or anaesthesia even with a platelet count below 50×109/l. Bleeding complications are more likely with epidural rather than spinal techniques (because smaller needles are used for the latter). The committee agreed that sometimes they would consider regional analgesia and anaesthesia (especially spinal techniques) for women with low platelet counts. Because serious maternal complications are so rare, the evidence did not allow a definite conclusion that there was no significant risk associated with epidural analgesia when platelet count was low. The committee decided not to set a definitive platelet threshold below which epidural or spinal analgesia should not be considered, but agreed that overall bleeding risk (including, but not limited to, platelet count) should be taken into account. Benefits and risks should be discussed with women, because the risk-benefit ratio will be highly individual and could change in the intrapartum period.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current NHS practice.\n\nReturn to recommendations\n\n# Modifying the birth plan according to platelet count or function\n\nRecommendations 1.6.3 to 1.6.6\n\n## Why the committee made the recommendations\n\nNo evidence was identified on platelet count and level of platelet function at which risks for either the woman or her baby would increase. Therefore the committee made recommendations based on their knowledge and expertise. Women with gestational thrombocytopenia are generally considered at low risk of bleeding complications during birth, whereas women with immune thrombocytopenic purpura (ITP) are regarded as high risk. So the committee recommended significant changes to the birth plan only if the woman had ITP, or gestational thrombocytopenia with a low platelet count.\n\nWomen with ITP may have a low platelet count and high risk of bleeding while the baby has a normal platelet count and low risk of bleeding. Conversely, a woman with ITP may have a normal platelet count and a baby with a low platelet count and high risk of bleeding. In other words, for women with ITP, the bleeding risk of the woman does not correspond to the bleeding risk of the baby. Consequently, if the woman has ITP, it is safest to treat the baby as being at high risk of bleeding, and modify the birth plan to reduce the bleeding risk to the baby wherever possible, for example, by not carrying out any fetal blood sampling. The committee thought it important to remind the healthcare professional that, because of the risk of fetal bleeding, procedures using fetal scalp electrodes and mid-cavity or rotational forceps should be carried out with extra care.\n\nWomen with gestational thrombocytopenia do not have an alloantibody that affects the fetal platelet count. Gestational thrombocytopenia therefore only puts the woman at risk of bleeding, and not her baby.\n\n## How the recommendations might affect practice\n\nWomen with ITP are at high risk of bleeding and so should give birth in an obstetric unit with a neonatal unit that routinely provides high-dependency care. However, the committee was aware that this does not always happen in practice, and so the recommendation could create more demand for high-dependency neonatal units. However, this might be offset by women at lower risk (for example, with gestational thrombocytopenia and a high platelet count) not being referred to these units.\n\nReturn to recommendations\n\n# Management of the third stage of labour for women with bleeding disorders\n\nRecommendations 1.6.7 to 1.6.12\n\n## Why the committee made the recommendations\n\nThe committee based the recommendations on their knowledge and experience because the evidence was very limited. A number of bleeding disorders can affect the third stage of labour but evidence was not found for all these conditions. In addition, it was not always possible to tell whether an outcome was linked to a treatment or a specific condition because conditions were sometimes grouped together according to severity.\n\nThe risk to a woman's life from postpartum haemorrhage is greater if she has a bleeding disorder. To reduce postpartum haemorrhage, the committee recommended active management of labour (rather than physiological management), which includes intramuscular oxytocin, clamping of the cord and controlled cord traction, as described in the NICE guideline on intrapartum care for healthy women and babies.\n\nWomen with bleeding disorders may need some adjustments to active management of labour. For example, there may be risks associated with intramuscular injections in these women. These considerations will need oversight from a senior haematologist, more frequent and possibly extended monitoring, and discussion of any changes in clinical condition.\n\n## How the recommendations might affect practice\n\nThese recommendations should lead to fewer attempts at physiological management of the third stage in women with bleeding disorders, with fewer postpartum haemorrhages and reduced maternal morbidity. The recommendations will apply to a small number of women, so implementing them is unlikely to cause staffing or resource issues for hospitals.\n\nReturn to recommendations\n\n# Mode of birth and management of the second stage of labour for women with subarachnoid haemorrhage or arteriovenous malformation of the brain\n\nRecommendations 1.7.1 to 1.7.9\n\n## Why the committee made the recommendations\n\nAlthough the available evidence showed that there were no maternal or neonatal deaths or morbidities related to maternal cerebrovascular malformation or a history of intracranial bleeding, the committee agreed that there was not enough evidence to justify changing practice for women at high risk of an intracranial bleed. Current practice is to manage the bleeding risk as conservatively as possible.\n\nAlthough vaginal birth is an option for women at low risk of intracranial bleeding, the committee acknowledged that some women would choose a caesarean section because of the theoretical risk of a bleed. The committee agreed that mode of birth should be based on the woman's preference as well as obstetric indications.\n\nIn women at high risk, or unknown risk (for example, because they have presented in labour with no antenatal care), the committee decided that in theory a caesarean section reduces the risk of intracranial bleeding because it should reduce the risks of raised intracranial pressure. This theoretical reduction in risk justified caesarean section for this group. The committee added that if a woman at high risk wanted to go into labour, the benefits and risks of an assisted second stage of labour compared with active pushing alone should be explained to the woman to ensure that steps are taken to reduce the risk of intracranial bleeding.\n\nThe committee knew that there was sometimes a reluctance to offer regional analgesia and anaesthesia to women with a history of subarachnoid haemorrhage or arteriovenous malformation of the brain because of the possibility of provoking a bleed. They discussed that this was extremely unlikely unless there was a genetic predisposition to multiple cerebrovascular malformations or unknown genetic history. They agreed that most women should be able to choose regional analgesia if they wished.\n\nThe committee was aware that cerebrovascular malformations affect more than 3% of the population and that women with cerebrovascular malformations or a previous subarachnoid haemorrhage are at risk of a potentially life-threatening cerebral haemorrhage. In current practice, many women with cerebrovascular malformations will be offered a caesarean section. However, it is uncertain whether vaginal birth increases the risk of cerebral haemorrhage in these women and the committee agreed to make a recommendation for research on caesarean section for women with subarachnoid haemorrhage or arteriovenous malformation of the brain to inform future guidance.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current practice for women at high risk, but many healthcare professionals would currently offer an elective caesarean section to women at low risk. So these recommendations could lead to a major change in practice for these women, with fewer caesarean sections. This assumes that their obstetric indications and personal preferences are similar to those of the general population of women.\n\nReturn to recommendations\n\n# Fluid management for women with kidney disease\n\nRecommendations 1.8.1 to 1.8.9\n\n## Why the committee made the recommendations\n\nManaging fluid balance in women with kidney disease during pregnancy is extremely difficult – dehydration can cause acute kidney injury, especially in those with underlying chronic kidney disease, but fluid overload can rapidly lead to pulmonary oedema, especially in women with superimposed pre-eclampsia.\n\nAlthough there was limited evidence on fluid management, its importance has been emphasised by successive confidential enquiries. The committee agreed that fluid management would vary, depending on the clinical condition of the woman and her baby.\n\nThe committee knew from their experience that action could often be taken to improve outcomes if the issue was identified in time. Therefore they recommended regular frequent monitoring every 4\xa0hours during the intrapartum period (in addition to routinely measuring hourly heart rate), including monitoring after birth. Because oliguria is very common in healthy women in the postpartum period, the assessment of urine output more frequently than every 4\xa0hours can be misleading. Exactly what should be monitored would depend on the clinical condition of the woman, but would include observations to assess fluid status, including blood pressure, chest sounds, fluid intake and output, and oxygen saturation.\n\nThe committee agreed that it was important to remind professionals caring for women in labour and during birth that commonly used drugs that are known to be nephrotoxic (for example, non-steroidal anti-inflammatory drugs) should not be offered to women with chronic kidney disease or acute kidney injury.\n\n## How the recommendations might affect practice\n\nCurrent practice is highly variable. The recommendations will mean more observation of women with kidney disease, with increased work for healthcare professionals. But they should lead to significantly fewer instances of morbidity.\n\nThe committee agreed that women with pre-existing chronic kidney disease are particularly vulnerable to both acute kidney injury and pre-eclampsia. By managing fluid balance more effectively, the risk of acute kidney injury in women with chronic kidney disease can be reduced. This will improve short- and longer-term outcomes for women and benefit healthcare systems with reduced length of stay.\n\nReturn to recommendations\n\n# Timing and mode of birth for women with kidney disease\n\nRecommendations 1.8.10 to 1.8.16\n\n## Why the committee made the recommendations\n\nNo evidence was found for timing of birth for women with kidney disease but the committee agreed that this would depend on the extent of the impairment. Longer gestation leads to better outcomes for the baby but may lead to worse outcomes for the woman's kidney function. Therefore, when kidney disease is less severe (chronic kidney disease stage\xa01, or stages\xa02\xa0to\xa04 with stable kidney function), the balance of benefits and harms favours allowing the baby as long as possible to develop without becoming overdue. The committee agreed that when there is a significant risk to the mother's life in allowing the pregnancy to continue, dialysis should be attempted to prolong the pregnancy until at least 34+0\xa0weeks, with a planned birth after this. In the committee's experience, this offers the least risk to mother and baby, and allows as many women as possible to have the birth of their choice.\n\nThere was no evidence that any particular mode of birth was better or worse for women with kidney disease and this was in line with the committee's experience, and so decisions about the mode of birth should be based on the woman's preference and obstetric indications. However, the committee recommended that for women with a kidney transplant, a transplant surgeon should be involved in the intrapartum care planning early on in the antenatal period. This is important particularly if a caesarean section is planned because the transplanted kidney will often be positioned near the usual site of caesarean incision and is therefore at risk of damage. The committee agreed that access to a transplant surgeon, if the caesarean section was complicated, should be recommended.\n\n## How the recommendations might affect practice\n\nThe recommendations are likely to lead to a change in practice in many areas. This is because currently some healthcare professionals only offer early birth to women with the most significant kidney disease. However, others recommend early birth to women who could safely carry the pregnancy a few weeks longer.\n\nReturn to recommendations\n\n# Assessing fetal presentation early in labour for women with a BMI over\xa030\n\nRecommendation 1.9.1\n\n## Why the committee made the recommendation\n\nThe NICE guideline on intrapartum care for healthy women and babies recommends that women with a BMI under 35\xa0kg/m2 can give birth in a midwifery unit or at home. The committee agreed, based on their experience, that identifying the fetal position by palpation can be difficult in women who are obese, particularly when the BMI is over 35\xa0kg/m2. The degree of confidence in palpation often decreases with increasing body weight.\n\nUltrasound scanning at the start of established labour can help with decision making when the baby's presentation is uncertain. The consequences of missing a malpresentation are more serious in women who are obese, who are already at a higher risk of operative interventions in labour. The committee agreed that healthcare professionals should consider ultrasound scanning at the start of established labour when presentation is uncertain and a woman is obese. This should reduce the likelihood of adverse outcomes for the woman and her baby.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nReturn to recommendation\n\n# Anaesthesia and analgesia for women with a BMI over\xa030\n\nRecommendation for research 2\n\n## Why the committee did not make a recommendation and made a research recommendation\n\nThe committee was aware that women who are obese are more likely to need anaesthesia during labour and birth. The rates of operative birth are much higher in this group, particularly in women with a BMI over 40 kg/m2. It's helpful for care planning if an anaesthetist is told when a woman with a BMI over 40 kg/m2 is admitted. Needle siting for anaesthesia is potentially more difficult in women who are obese because the surface landmark anatomy of the lumbar spine can be more difficult to identify. It is thought that there are more unsuccessful attempts to site regional analgesia, and ultrasound might be cost effective for needle siting in this group. The use of ultrasound for needle siting is increasing with resource implications for the NHS. The committee could not make a recommendation on the most appropriate technique for needle siting because the evidence was uncertain, but they agreed to make a recommendation for research on needle siting in pregnant women who are obese to inform future guidance.\n\n# Fetal monitoring for women with a BMI over\xa030\n\nRecommendation 1.9.2\n\n## Why the committee made the recommendation\n\nIt is more difficult to monitor fetal heart rate, uterine contractions and fetal position in women who are obese. These women are likely to have more complications and growth restriction is more likely to have been missed from earlier scans, making accurate fetal monitoring particularly important in the intrapartum period.\n\nHowever, there was no evidence that continuous cardiotocography improves outcomes compared with intermittent auscultation. So the committee agreed to recommend monitoring based on the woman's preference and obstetric indications in line with the NICE guideline on intrapartum care for health women and babies.\n\nThere is variation in management during the intrapartum period for women who are obese. This is because of a lack of agreement on whether women with uncomplicated obesity should be offered continuous fetal monitoring in labour, receive further antenatal ultrasound scanning, including amniotic fluid volume assessment and umbilical artery Doppler scans, or be offered early induction.\n\nResearch to date has not established the effect of stratified BMI on perinatal outcomes. Current research is mainly retrospective, using data dating back to the 1970s and 1980s when BMI was usually self-reported and not stratified according to WHO categorisation. The committee agreed to make a recommendation for research on obesity as a possible independent risk factor for perinatal morbidity and mortality to inform future guidance.\n\n## How the recommendation might affect practice\n\nThere is a wide variation in the use of continuous cardiotocography and intermittent auscultation for women who are obese. However, the recommendation is unlikely to mean a large change in current practice.\n\nReturn to recommendation\n\n# Position in labour for women with a BMI over\xa030\n\nRecommendations 1.9.3 to 1.9.5\n\n## Why the committee made the recommendations\n\nBased on their experience, the committee agreed that there was no reason to alter the advice on the position in the second stage of labour just because a woman is obese. But it is important that she has enough mobility to allow healthcare professionals access in an emergency (for example, the ability to get into the lateral position). For women who have significantly reduced mobility, the committee recommended the lateral position to begin with, because this allows good access and so reduces the risk of adverse events. The committee agreed that these decisions should be made in the third trimester after a risk assessment, to ensure that everyone is aware of the plans for managing the second stage.\n\n## How the recommendations might affect practice\n\nMost midwives know that the lateral position is the safest for women with reduced mobility in labour. Therefore the recommendations are unlikely to lead to a change in practice. The recommendations for women with sufficient mobility are the same as those in the NICE guideline on intrapartum care for healthy women and babies. They should not change practice unless healthcare professionals are unaware that the recommendations in this NICE guideline also apply to women who are obese.\n\nReturn to recommendations\n\n# Equipment needs for women in labour with a BMI over\xa030\n\nRecommendations 1.9.6 to 1.9.8\n\n## Why the committee made the recommendations\n\nThe committee agreed that women who are obese need specialist equipment for a safe birth. They described all the specialist equipment required; not just beds and wheelchairs but specialist surgical tools and monitoring equipment. The committee did not believe that every hospital would have all this equipment, particularly to deal with women with a BMI over 50\xa0kg/m2. They agreed that referral to another obstetric unit should be considered when this is the case to ensure that the needs of the women are adequately met.\n\n## How the recommendations might affect practice\n\nA 2010 report from the Confidential Enquiry into Maternal and Child Health (CMACE) and the Royal College of Obstetrics and Gynaecologists identified major gaps in the provision of hospital equipment for pregnant women who are obese. The committee believed that this has significantly improved and therefore that – for the most part – the recommendations should not affect practice. They should, however, reinforce what hospitals should already be providing.\n\nReturn to recommendations\n\n# Information for women with obstetric complications or no antenatal care\n\nRecommendations 1.10.1 to 1.10.6\n\n## Why the committee made the recommendations\n\nEvidence was limited but the committee agreed that good quality information is important for women who are at increased risk of serious medical problems for themselves or their babies. These women are likely to be more anxious than other women in labour and need information that presents risk in a way that they can understand. The information should be based on local and national data where possible to allow women to make informed choices. Healthcare professionals should recognise that individuals have their own views of risk and they should support women to make informed decisions about their care. The committee recognised that the evidence base was limited but showed that women felt they may be given biased information and that some options were not offered or were actively opposed. Women described having to search out information themselves. The evidence also suggested that there may be inequalities between women when it comes to making an informed decision and being in control of their care. Women who were not able to seek information could be disadvantaged in making informed choices. The committee noted that these themes were reflected by their own experiences and agreed that it is very important that information about all options is offered to women.\n\n## How the recommendations might affect practice\n\nThe committee noted that there was variability in current practice relating to care of women in labour who have a higher chance of serious medical problems. The recommendations may result in a change in practice in some areas, with a change in focus from a risk-based approach to supporting informed decision making for all women.\n\nReturn to recommendations\n\n# Risk assessment for women with obstetric complications or no antenatal care\n\nRecommendations 1.11.1 to 1.11.7\n\n## Why the committee made the recommendations\n\nNo evidence was found on observations for women in labour with obstetric complications so the committee made recommendations based on their expertise and knowledge of good practice. They agreed that in order to understand the whole clinical picture, it is important to listen to the woman's concerns and her own account of her symptoms. The committee acknowledged that women in the following groups would only need routine maternal observations during labour if there were no other concerns:\n\nbreech presentation\n\nsuspected small-for-gestational-age baby\n\nsuspected large-for-gestational-age baby\n\nprevious caesarean section\n\nlabour after 42\xa0weeks of pregnancy\n\nno antenatal care.\n\nThe committee did not want to medicalise care for women with fever in labour and agreed that many of these women do not need additional maternal observations apart from hourly monitoring of temperature and level of consciousness (AVPU [alert, voice, pain, unresponsive]), and 4‑hourly monitoring of respiratory rate and oxygen saturation. However, if other symptoms or signs develop, the possibility of sepsis should be considered.\n\nThe committee did not want to medicalise care for women with slight concerns about possible sepsis, but they agreed that if concerns are enough to warrant antibiotic treatment, more frequent observations are needed because of the risk of sudden deterioration. The committee recommended continuous or half-hourly measurement of pulse, blood pressure and respiratory rate in line with the NICE guideline on sepsis. Hourly monitoring of temperature is sufficient, but AVPU should be monitored every half hour, with continuous or 30‑minute monitoring of oxygen saturation. Hourly recording of urine output should be performed if the woman has a catheter.\n\nThe committee agreed that for women with intrapartum haemorrhage, continuous monitoring of vaginal blood loss is important because this is often underestimated and it can be difficult to decide when more action is needed. Therefore the committee recommended more frequent observations to detect possible changes in a woman's condition. They also recommended other observations such as respiratory rate, volume of urine output, AVPU and oxygen saturation to prompt transfer to an obstetric-led unit and involvement of a senior obstetrician if needed.\n\nBecause of the increased risk of serious medical problems in women with obstetric complications or no antenatal care and the need for timely action when indicated, it is important that the woman's condition is comprehensively reviewed by an experienced healthcare professional who should be responsible for deciding if there is a need to escalate care. The committee was aware that the risk of serious medical problems for the woman or the baby depends on the whole clinical picture. They recommended that this should be taken into account when discussing options for care with the woman during the intrapartum period.\n\nThe lack of evidence on maternal observations for women in labour with suspected sepsis prompted the committee to make a recommendation for research on risk assessment for women in labour with signs of sepsis to inform future guidance.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations reflect current best practice, but this may result in changing practice in some units.\n\nReturn to recommendations\n\n# Use of antipyretics for women in labour with a fever\n\nRecommendations 1.12.1 and 1.12.2\n\n## Why the committee made the recommendations\n\nVery limited evidence showed no difference in the rate of caesarean section or admission to neonatal intensive care when women had paracetamol for fever. However, the committee agreed that paracetamol is safe and can reduce discomfort when a woman has a temperature. They noted that fever can be a sign of sepsis and agreed that recognising and treating sepsis is a clinical priority. Because paracetamol may mask a worsening fever, they recommended that healthcare professionals should remember that paracetamol is not a treatment for sepsis and should not delay investigation and treatment when sepsis is suspected.\n\n## How the recommendations might affect practice\n\nThe recommendations could reduce the inappropriate use of paracetamol and promote the prompt management of sepsis.\n\nReturn to recommendations\n\n# Fetal blood sampling for women in labour with a fever\n\nRecommendation 1.12.3\n\n## Why the committee made the recommendation\n\nNo evidence was found on fetal blood sampling for women in labour with a fever so the committee made a recommendation based on their expertise and knowledge of good practice. Their view was that women with fever in labour should be treated as if they have suspected sepsis for the purpose of fetal blood sampling and so the recommendations in this section mirror those for sepsis and suspected sepsis.\n\n## How the recommendation might affect practice\n\nThe recommendation should harmonise practice, potentially increasing use of fetal blood sampling in areas where healthcare professionals are overly cautious and decreasing use in places where multiple fetal blood samples are taken.\n\nReturn to recommendation\n\n# Mode of birth for women with sepsis or suspected sepsis\n\nRecommendations 1.13.1 to 1.13.10\n\n## Why the committee made the recommendations\n\nNo evidence was found on mode of birth for women in labour with sepsis or suspected sepsis so the committee made recommendations based on their expertise and knowledge of good practice. They recognised that sepsis is an important cause of maternal mortality and that physiological changes during labour may mask the early signs of sepsis. There is no agreed definition of normal physiological adjustments occurring during pregnancy and labour and these can vary as labour progresses.\n\nThe committee agreed that the NICE guideline on sepsis should be followed for the recognition of sepsis in pregnant women and that normal physiological changes in labour (such as increased maternal pulse rate) should also be taken into account.\n\nThe committee agreed that there should be ongoing multidisciplinary review by a senior team with a named lead. Ongoing review means the team is prepared to react to a changing situation, which may alter very quickly. The committee agreed that inadequate or delayed maternal resuscitation may worsen organ dysfunction and have an impact on the safety of anaesthesia, so they recommended that a senior obstetric anaesthetist should be included in the team.\n\nWhen a woman in labour has sepsis (rather than suspected sepsis), the team should be expanded to include a neonatologist and microbiologist, and for women with sepsis and manifestations of organ dysfunction, the team should be further expanded to include a senior intensivist (critical care specialist). The intention is that the multidisciplinary team may not meet face to face but that expert advice can be accessed when needed.\n\nThe committee noted that a clear management plan should be documented and reviewed on a regular basis because it is important not only for the multidisciplinary team but also for the woman to know what is happening.\n\nThe committee emphasised that the woman and her birth companion(s) should be involved in shared decision making about management because they need to be involved in decisions and choices about how to proceed.\n\nAll options for timing and mode of birth should be considered in discussion with the woman and it should not be assumed that caesarean section is the only option for women with sepsis or suspected sepsis. The committee agreed that when the source of sepsis is thought to be the genital tract, healthcare professionals should expedite the birth because there is an increased risk of adverse outcomes for the baby.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations reflect current best practice. This may result in changing practice in some units.\n\nReturn to recommendations\n\n# Anaesthesia for women in labour with sepsis and signs of organ dysfunction\n\nRecommendation 1.13.11\n\n## Why the committee made the recommendation\n\nNo evidence was found on anaesthesia for women in labour with sepsis or suspected sepsis so the committee made recommendations based on their expertise and knowledge of good practice. They wanted to ensure that women in labour with sepsis and signs of organ dysfunction were offered anaesthesia appropriate to their clinical condition and noted that the default practice of using regional anaesthesia may not be appropriate for these women. The committee agreed that regional anaesthesia may be associated with cardiovascular instability when there is sepsis with signs of organ dysfunction. Other adverse outcomes may include epidural abscess and haematoma due to coagulopathy. This led the committee to recommend that regional anaesthesia should be used only with caution and advice from a consultant obstetric anaesthetist and in the presence of a senior anaesthetist.\n\n## How the recommendation might affect practice\n\nThe committee agreed that the recommendation reflects current best practice so there should be no change in practice.\n\nReturn to recommendation\n\n# Analgesia for women in labour with sepsis or suspected sepsis\n\nRecommendations 1.13.12 to 1.13.16\n\n## Why the committee made the recommendations\n\nNo evidence was found to recommend one form of pain relief over another for women in labour with sepsis or suspected sepsis. The committee was aware that women with sepsis and signs of organ dysfunction may have bacteraemia and an increased risk of local infection or meningitis when a needle is inserted for regional analgesia. Therefore they recommended that this should only be used with caution and only with advice from a consultant obstetric anaesthetist. The presence of a senior anaesthetist is not needed because of the lower dose of local anaesthetic used for a woman who is not having surgery.\n\nAlthough there was no evidence that the use of the birthing pool is contraindicated for women in labour with suspected sepsis where concern is insufficient for antibiotic treatment, the committee used their clinical experience and expertise to recommend that for these women, the birthing pool should be considered only after discussion with a senior midwife and a senior obstetrician.\n\nThe committee also made a recommendation that for women needing antibiotics for suspected sepsis, the treatment should begin before inserting the needle for regional analgesia.\n\nA multidisciplinary review of options for pain relief is recommended at least every 4\xa0hours because usually the multidisciplinary team would not be involved this often.\n\n## How the recommendations might affect practice\n\nThe committee was aware that currently the birthing pool would not be considered for some women with suspected sepsis where concern is insufficient for antibiotic treatment. The committee noted that there is variation in practice not only between units but also within obstetric units. Therefore the extent of change in practice will vary according to current practice.\n\nThe committee noted that use of prophylactic antibiotics in women with suspected sepsis before central neuraxial block is not currently universal practice in the UK. The committee's recommendation would reinforce current best practice.\n\nRegular reviews with a minimum 4‑hour frequency are a change to current practice. Currently reviews are performed as and when needed. The committee agreed that recommending a minimum review frequency was a more proactive approach to supporting women's ongoing needs.\n\nThe committee was aware that a discussion with a senior anaesthetist did not always happen in current practice, and their recommendations would reinforce best practice.\n\nReturn to recommendations\n\n# Fetal monitoring for women in labour with sepsis or suspected sepsis\n\nRecommendations 1.13.17 to 1.13.21\n\n## Why the committee made the recommendations\n\nNo evidence was found on fetal monitoring for women in labour with sepsis or suspected sepsis so the committee made recommendations based on their expertise and knowledge of good practice. The committee wanted healthcare professionals to explain to women with sepsis that there is uncertainty about the usefulness of fetal blood sampling so that women have more information when deciding whether to accept or decline testing. The committee also agreed that fetal blood sampling can be falsely reassuring when a woman has sepsis. They wished to emphasise that the whole clinical picture should influence the decision to perform sampling and should be taken into account when interpreting the results.\n\nThere is no evidence to support repeat fetal blood sampling so the committee wanted to highlight the need for caution and consultant obstetric input to guide decision making.\n\n## How the recommendations might affect practice\n\nThe committee hoped the recommendations would harmonise practice, potentially increasing use of fetal blood sampling in areas where clinicians are overly cautious and decreasing use in places where multiple fetal blood samples are taken.\n\nReturn to recommendations\n\n# Antimicrobial treatment for women in labour with sepsis or suspected sepsis\n\nRecommendations 1.13.22 to 1.13.25\n\n## Why the committee made the recommendations\n\nNo evidence was found on when to start antimicrobial treatment for women in labour with sepsis or suspected sepsis so the committee made recommendations based on their expertise and knowledge of good practice. The committee was aware that intrapartum sepsis presents unique diagnostic difficulties, including difficulties identifying the source of the infection, which can lead to under- or over-diagnosis of sepsis. The choice of antibiotics is influenced by concerns about safety for the baby.\n\nNo evidence was found to support the use of specific antimicrobials in labour when the source of infection is clear and therefore the committee decided to follow the NICE guideline on sepsis and recommend referring to local antimicrobial guidance.\n\nWhen the source of infection is unclear, a broad-spectrum intravenous antimicrobial from the local formulary should be offered because intrauterine infection is the most likely source of the infection and is often due to multiple organisms (polymicrobial).\n\nThe committee was aware that local antimicrobial resistance patterns vary and that the choice of antimicrobial would be guided by this. The committee was keen to support shared decision making and to ensure that the woman and her birth companion(s) understood the reasons for the choice of antimicrobial.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current best practice.\n\nReturn to recommendations\n\n# Care for women with sepsis or suspected sepsis immediately after the birth\n\nRecommendation 1.13.26\n\n## Why the committee made the recommendation\n\nNo evidence was found on care for women with sepsis or suspected sepsis in the first 24\xa0hours after the birth so the committee made recommendations based on their expertise and knowledge of good practice. They agreed that a team with a named lead should provide care. The committee felt that determining the need for antibiotics, frequency of monitoring and level of care were important both for the safety of the woman and avoiding separation from her baby. The committee was aware that the woman and baby are often separated if the woman is transferred to a general intensive care unit or high-dependency unit, and this can impact negatively on the developing relationship between the woman and her baby, and consequently on maternal emotional wellbeing and postnatal mental health.\n\nFamilies expect women who have given birth to be discharged home in full health soon after the birth. If the woman develops intrapartum sepsis, additional practical and emotional support will be needed during the recovery from critical illness.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current best practice and should improve practice in some areas, particularly around reducing separation of women and their babies.\n\nReturn to recommendations\n\n# Intrapartum haemorrhage\n\nRecommendations 1.14.1 to 1.14.10\n\n## Why the committee made the recommendations\n\nNo evidence was found on management of intrapartum haemorrhage so the committee based recommendations on their expertise and knowledge of good practice and the recommendations for postpartum haemorrhage in the NICE guideline on intrapartum care for healthy women and babies. They agreed that a large blood loss may result in major shock, and this would be the first priority for treatment. They also agreed that it is good practice that all maternity settings are equipped to manage intrapartum haemorrhage.\n\nThe committee agreed that when vaginal blood loss is more than a show, it is important to transfer the woman to obstetric-led care. They also agreed that it was essential to talk with the woman and her birth companion(s) to explain what is happening, what may happen and understand her preferences. It is also important to determine the likely causes of the blood loss, and how the woman's health may deteriorate or stabilise. The committee agreed that speaking with the woman to gain the history, including any associated events, may help to determine the cause of bleeding.\n\nThe committee agreed that if a woman in labour has vaginal blood loss typical of a 'show', this is not detrimental to the woman or baby and for these women, the NICE guideline on intrapartum care for healthy women and babies should be followed.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current best practice but this may mean a change practice in some units.\n\nReturn to recommendations\n\n# Breech presenting in labour\n\nRecommendations 1.15.1 to 1.15.4\n\n## Why the committee made the recommendations\n\nEvidence showed an increase in maternal infection and other maternal complications during the first 6\xa0weeks after caesarean section in labour for breech presentation compared with vaginal breech birth. This was in line with the committee's experience.\n\nEvidence showed fewer adverse outcomes for the baby after caesarean section in early labour for breech presentation compared with vaginal birth, but the benefit was less clear when caesarean section was performed in the later stages of labour. This was also in line with the committee's experience.\n\nThe committee acknowledged that offering a choice between continuing labour and emergency caesarean section may differ from the advice that women with breech presentation have received during pregnancy. This is because the balance of risks to the woman and baby have changed, with different considerations coming into play when the woman is in labour. For example, considerations will be different when breech presentation is first identified in labour, or when labour is more advanced. The committee wished to ensure that healthcare professionals give women the opportunity to make an informed choice about mode of birth in this situation. They agreed not to recommend one mode of birth over another, but that following discussion of the likely benefits and risks, a woman should be able to decide what is right for her.\n\nBased on their knowledge and experience, the committee agreed that healthcare professionals should follow recommendations on assessing progress in labour in the NICE guideline on intrapartum care for healthy women and babies to avoid unnecessary intervention when there is a delay in labour.\n\n## How the recommendations might affect practice\n\nThere is variation in practice regarding counselling in labour for women with breech presentation, following publication of the Term Breech Trial in 2000, which concluded that vaginal birth was associated with higher risks to the baby. The recommendation to offer women in labour with breech presentation a choice between continuing labour and emergency caesarean section will promote a more consistent approach and improved experience for women and their birth companion(s). Practice previously would frequently have been to recommend caesarean section for these women, whereas the guideline recommendations emphasise choice and informed decision making.\n\nThe committee was aware that training may be needed to fully implement the recommendations supporting vaginal breech birth.\n\nReturn to recommendations\n\n# Small-for-gestational-age baby\n\nRecommendations 1.16.1 to 1.16.3\n\n## Why the committee made the recommendations\n\nNo evidence was found for monitoring in labour for babies suspected to be small for gestational age so the committee used their knowledge and experience to make recommendations. They agreed that babies who are small for gestational age are at risk of adverse outcomes and that this risk is higher when there is growth restriction or problems with birth. However, they acknowledged that it is difficult to be certain about the baby's size before birth. Healthcare professionals should explain the risks and uncertainties to women whose babies are suspected to be small for gestational age and such women should then be offered continuous cardiotocography so that any concerns for the baby can be picked up quickly.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations reflect current best practice so there should be no change. However, they acknowledged that women are currently often not informed about the uncertainty around diagnosis of small-for-gestational-age babies and the effectiveness of cardiotocography in preventing poor outcomes, so this will be a development in practice.\n\nReturn to recommendations\n\n# Large-for-gestational-age baby\n\nRecommendations 1.17.1 to 1.17.3\n\n## Why the committee made the recommendations\n\nThere was no convincing evidence for one mode of birth over another for women in labour whose babies are suspected to be large for gestational age. The committee discussed the difficulty of estimating a baby's size when a woman is in labour. They acknowledged that ultrasound is difficult to perform in labour and is less accurate at estimating a baby's weight than in the antenatal period. They agreed that women should be told about this uncertainty. Evidence showed an increased risk of maternal infection when women in labour had an emergency caesarean section. In the committee's experience, there was a risk of shoulder dystocia and perineal trauma with vaginal birth. The committee agreed that women should be provided with information so that they can make their own decisions about mode of birth when their baby may be large for gestational age.\n\n## How the recommendations might affect practice\n\nThe recommendations ensure that women are offered all the options available to them in labour. It is not anticipated that this will have a large impact on resource use.\n\nReturn to recommendations\n\n# No antenatal care\n\nRecommendations 1.18.1 to 1.18.12\n\n## Why the committee made the recommendations\n\nNo evidence was found on intrapartum care for women who have had no antenatal care so the committee agreed to make recommendations based on their expertise and knowledge of good clinical practice.\n\nBecause of the lack of baseline information and a birth plan, intrapartum care for these women should be led by an obstetrician who will carry out a full assessment of the risks for the woman and her baby. The neonatal team should be alerted because the committee agreed that there is an increased risk of serious medical problems for the baby when a woman has had no antenatal care. Sometimes an anaesthetic team may also be needed.\n\nSensitive enquiry should be made to try to understand the reasons for the lack of antenatal care, as well as to identify any vulnerability and safeguarding issues. It is important to ask the woman who she would like as her birth companion(s) and to identify their relationship with her. If there is a language barrier, an independent interpreter should be used rather than the woman's birth companion(s).\n\nBlood and urine tests normally performed as part of routine antenatal care should be offered to check for markers of anaemia and infection. Therefore, testing for HIV, hepatitis\xa0B and syphilis should be offered. Rapid HIV testing should be offered to women who are thought to be at high risk of HIV because steps can be taken to prevent vertical transmission of known HIV infection during vaginal birth. Evidence suggested that rapid HIV testing would offer a good balance of benefits and costs in women at high risk of infection. The test results would be used to plan care during labour, birth and postnatally.\n\nThe committee agreed that the woman's GP should be contacted to obtain more information about her history and to plan for her own and the baby's ongoing care. Safeguarding concerns should be considered and if necessary referrals made. The woman should be informed when other healthcare professionals, social care professionals, safeguarding teams or the police need to be contacted. It is also important to document and share information with relevant professionals, such as the paediatric team and local health providers, for continuation of care.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect good clinical practice and therefore will not mean a large change. However, rapid HIV testing is not always available. An assessment of local needs for such services should be done.\n\nReturn to recommendations\n\n# Previous caesarean section\n\nRecommendations 1.19.1 to 1.19.11\n\n## Why the committee made the recommendations\n\nNo evidence was found for intravenous cannulation for women in labour with a previous caesarean section. The committee agreed that the chance of needing intravenous access for urgent blood transfusion was unlikely to be higher in these women, and so recommended that cannulation should not be routine.\n\nThe committee noted from the evidence and their expertise that the risk of uterine rupture with vaginal birth was small for women with a previous caesarean section. There was some evidence that performing an emergency caesarean section in labour is associated with an increased risk of heavy bleeding and the need for blood transfusion, infection and a longer hospital stay. The committee recommended that women should be told about this when making decisions about mode of birth.\n\nThe committee felt it was important that women should be made aware that there is no compelling evidence to recommend one mode of birth over another to improve outcomes for the baby.\n\nEvidence indicated that women in labour with a previous caesarean section are likely to be at a lower risk of complications if they have also had a previous vaginal birth.\n\nThere was evidence that augmentation of labour with oxytocin and regional analgesia both reduced the chance of another caesarean section for women in labour who have had a caesarean section in the past. The likelihood of an instrumental vaginal birth (forceps or ventouse) was increased with both. The committee agreed that this should be explained to women so that they can make a fully informed decision.\n\nNo evidence was found to recommend one form of pain relief over another for women with a previous caesarean section. There was also no evidence that the use of the birthing pool for pain relief is contraindicated for these women. Therefore, the committee agreed to recommend that all forms of pain relief, including the birthing pool, should be offered.\n\nNo evidence was found for routine amniotomy in women in labour with previous caesarean section. The committee used their experience and expertise to recommend that this should not be offered.\n\nThe committee was aware that continuous cardiotocography is usually advised for women in labour who have had a previous caesarean section. However, it is uncertain whether continuous cardiotocography in these circumstances allows risk to be identified sooner than if intermittent auscultation is used. The committee made a recommendation for research on monitoring in labour for women with a previous caesarean section to inform future guidance.\n\n## How the recommendations might affect practice\n\nThe committee recognised there was variation in practice and inequity in the choices available to women in labour with a previous caesarean section. The committee wanted to ensure that these women would be offered comprehensive information so that they could make informed decisions about their care and wellbeing, and would not be subjected to unnecessary interventions that may not improve outcomes for the woman or her baby. They noted that the extent of change in practice arising from the recommendations would vary across the UK based on current practice and that the recommendations may result in specific changes in practice around supporting women's choice of place of birth and routine cannulation in labour, which may in turn lead to cost savings for the healthcare system.\n\nReturn to recommendations\n\n# Labour after 42\xa0weeks of pregnancy\n\nRecommendation 1.20.1\n\n## Why the committee made the recommendation\n\nNo evidence was found for monitoring in labour after 42\xa0weeks of pregnancy so the committee made the recommendation based on their knowledge and experience. The committee was aware of some evidence of an increased risk of stillbirth or neonatal death after 42\xa0weeks and this was consistent with their own experience. Because of this, the committee agreed that continuous cardiotocography should be offered for all women in labour after 42\xa0weeks so that any concerns for the baby can be identified quickly. The offer should be preceded by a full discussion of the benefits and risks to the woman and her baby.\n\n## How the recommendation might affect practice\n\nThe recommendation to offer continuous cardiotocography to all women in labour after 42\xa0weeks is in line with current practice.\n\nReturn to recommendation", 'Context': "Risk assessment and planning are key components of individualised care for pregnant women, so that any factors likely to affect the pregnancy or birth can be identified in a timely manner. This guideline deals with care for women at higher risk of complications in labour and birth, either because of an existing medical condition or because obstetric complications develop. With appropriate risk assessment and care planning, care can be delivered to maximise the chances of good outcomes for both the woman and her baby. Assessment and planning start at the antenatal booking appointment and continue throughout pregnancy at each antenatal contact. During labour, routine monitoring of the woman and her unborn baby and of the progress of labour is a continuation of the risk-screening process. Findings from these assessments will affect the plan of care for labour, and may result in changes to the plan being made antenatally or during labour if new complications are identified.\n\nA pregnancy is 'high risk' when the likelihood of an adverse outcome for the woman or the baby is greater than that of the 'normal population'. A labour is 'high risk' when the likelihood of an adverse outcome related to labour (for the woman or the baby) is greater than that of the 'normal population'.\n\nThe level of risk may be determined before pregnancy or arise during pregnancy or during labour, and can affect the woman or the baby:\n\nA woman may have an existing medical condition that can be made worse by physiological changes that occur in labour.\n\nObstetric (pregnancy-related) problems can develop that increase the risk of adverse labour and/or birth outcomes.\n\nA woman can enter labour with no identified complications and be considered at low risk of complications, but problems may arise during labour that can be associated with adverse outcomes."}
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https://www.nice.org.uk/guidance/ng121
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This guideline covers care during labour and birth for women who need extra support because they have a medical condition or complications in their current or previous pregnancy. The guideline also covers women who have had no antenatal care. It aims to improve experiences and outcomes for women and their babies.
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5ea7ebba7e5a642b58819527b77b7ca16828e333
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nice
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Brentuximab vedotin for treating CD30-positive cutaneous T-cell lymphoma
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Brentuximab vedotin for treating CD30-positive cutaneous T-cell lymphoma
Evidence-based recommendations on brentuximab vedotin (Adcetris) for treating CD30-positive cutaneous T-cell lymphoma in adults.
# Recommendations
Brentuximab vedotin is recommended as an option for treating CD30‑positive cutaneous T‑cell lymphoma (CTCL) after at least 1 systemic therapy in adults, only if:
they have mycosis fungoides stage IIB or over, primary cutaneous anaplastic large cell lymphoma or Sézary syndrome and
the company provides brentuximab vedotin according to the commercial arrangement.
These recommendations are not intended to affect treatment with brentuximab vedotin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Brentuximab vedotin is licensed to treat CD30-positive CTCL after at least 1 systemic therapy. It is most likely to be used in the NHS as an alternative to systemic treatments to treat advanced disease. At this point in the pathway, current treatment options include methotrexate, bexarotene and interferon alfa.
Clinical trial evidence shows that brentuximab vedotin is better than methotrexate or bexarotene in terms of response rates and extending how long people live without their disease getting worse. For some people with CTCL, brentuximab vedotin will be used as a bridge to a stem cell transplant.
The most plausible cost-effectiveness estimates for brentuximab vedotin compared with current treatments are less than £30,000 per quality-adjusted life year gained, which is within the range considered to be a cost-effective use of NHS resources. However, these estimates are based on data from people with specific subtypes of advanced disease (mycosis fungoides stage IIB or over, primary cutaneous anaplastic large cell lymphoma and Sézary syndrome), so brentuximab vedotin is only recommended for these subtypes.# Information about brentuximab vedotin
Marketing authorisation indication
Brentuximab vedotin is indicated for the treatment of 'adult patients with CD30-positive cutaneous T-cell lymphoma after at least 1 prior systemic therapy'.
Dosage in the marketing authorisation
The recommended dose is 1.8 mg/kg given as an intravenous infusion over 30 minutes every 3 weeks. People with CTCL should have up to 16 cycles.
Price
The price of brentuximab vedotin is £2,500 for a 50 mg vial (excluding VAT; BNF edition 76). The company has a commercial arrangement. This makes brentuximab vedotin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Takeda and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Potential new treatment option
## Cutaneous T-cell lymphoma significantly affects quality of life
Cutaneous T-cell lymphoma (CTCL) is a form of non-Hodgkin lymphoma that affects the skin. It may start as flat red patches or plaques on the surface of the skin, which progress to skin tumours. People may also have systemic symptoms, such as chronic pain and itching, that can severely limit daily activities. The clinical experts explained that CTCL is a rare disease and people usually live with their condition for many years. The patient experts explained that being diagnosed with CTCL can severely affect a person's physical and psychological wellbeing. It may take several years before CTCL is accurately diagnosed, and symptoms flare up unpredictably. The clinical and patient experts also explained that there is no uniform response to treatment; people with CTCL may be very self-conscious about how their skin looks and uncertain about how the disease will respond to treatment, which has a negative psychological effect. Consultation responses from NHS professionals highlighted the emotional and financial effects on patients and their families and carers. The committee concluded that CTCL significantly reduces patients' quality of life.
## There is an unmet need for more effective treatment options
There is no NICE guidance on treating CTCL. The disease can be divided into a number of subtypes, only some of which express the tumour marker CD30. CD30 is expressed in both primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis, which together form the group of primary cutaneous CD30-positive lymphoproliferative disorders. Mycosis fungoides and Sézary syndrome can also express CD30. CTCL is treated based on the subtype and stage of the disease. Treatments either target the skin (skin-directed) or the entire body (systemic), but there is no standard therapy. The clinical experts highlighted that treatment options are diverse; they aim to relieve symptoms, control local disease and improve quality of life. The committee understood that compared with earlier stages of CTCL, advanced disease is associated with poorer prognosis, lower survival and lower quality of life. Although current treatments are palliative, the clinical experts noted that allogeneic stem cell transplants may consolidate treatment response to achieve durable remission, or possibly cure, and should be considered for certain patients with advanced CTCL. Without a transplant the disease has a cycle of remission and relapse. Because there are limited treatment options available, people with advanced CTCL may live for several years without treatment while having painful, itchy and uncomfortable symptoms on a daily basis. The committee agreed that there is an unmet need for effective treatments that extend the amount of time the disease is in remission and improve quality of life. The committee concluded that both patients and healthcare professionals would welcome potential new treatments.
# Treatment pathway and comparators
## Brentuximab vedotin will be used as an alternative to systemic therapies for specific subtypes of advanced cutaneous T-cell lymphoma
The marketing authorisation does not specify whether brentuximab vedotin may be used for early-stage CTCL or advanced CTCL. The committee noted that the inclusion criteria for ALCANZA (the pivotal trial on which the marketing authorisation was based) included patients with early-stage disease. The committee was also aware that the company's submission focused on a narrower population than the marketing authorisation, including only patients with advanced disease (specifically mycosis fungoides stage IIB or over, primary cutaneous anaplastic large cell lymphoma and Sézary syndrome). The clinical experts explained that skin-directed therapies are often effective for managing early-stage CTCL, but systemic agents (like brentuximab vedotin) are more commonly used for advanced disease. They also highlighted that lymphomatoid papulosis, another subtype of CTCL, is usually treated with skin-directed therapies (because it is less aggressive), so brentuximab vedotin would not be used for this subtype of CTCL. The committee concluded that brentuximab vedotin is most likely to be used in the NHS as an alternative to systemic treatments to treat specific subtypes of advanced CTCL (mycosis fungoides stage IIB or over, primary cutaneous anaplastic large cell lymphoma and Sézary syndrome).
## Methotrexate, bexarotene and interferon alfa are the most appropriate comparators
The committee recalled that systemic agents are most commonly used to treat advanced subtypes of CTCL. The clinical experts explained that patients are first offered retinoids (bexarotene), interferon alpha or single-agent chemotherapy (methotrexate). They highlighted that low-dose methotrexate is not licensed for CTCL but that it has been used in UK clinical practice for over 40 years. Multi-agent chemotherapy regimens are generally not used as standard care and are only considered when first-line systemic therapy options have been exhausted. This is because of their lack of efficacy and associated toxicities, which are especially problematic in people with CTCL who are susceptible to infection. The clinical experts agreed with the company's positioning of brentuximab vedotin as an alternative to bexarotene, interferon alpha and methotrexate, and stated that it would be used after first-line therapy. The committee noted that its marketing authorisation restricted the use of brentuximab vedotin to after at least 1 systemic therapy, and so concluded that it would be used after at least 1 systemic therapy for patients with advanced disease and that, based on current clinical practice, methotrexate, bexarotene and interferon alfa were the most appropriate comparators.
## Current treatment options are considered equally effective
The committee considered the currently available treatment options for people with advanced CTCL. The clinical experts explained that the choice of treatment often depends on the associated adverse events and the patient's needs because all initial therapies are considered equally effective. The committee was aware that evidence for the efficacy of bexarotene monotherapy, low-dose methotrexate monotherapy and interferon alfa for advanced CTCL was from outdated and low-quality studies. The committee concluded that although there was limited evidence, for the purposes of this appraisal it was appropriate to assume that all first-line systemic treatments are equally effective.
## Stem cell transplant is part of the treatment pathway
The clinical experts explained that brentuximab vedotin would be used in 2 ways: either as a bridge to transplant or as a treatment without a future transplant. The committee recalled that allogeneic stem cell transplant may be a potentially curative therapy for certain patients with advanced CTCL (see section 3.2). The clinical experts advised that transplants should only be considered for patients whose disease adequately responds to systemic therapy. This normally means at least a partial response, although they commented that current treatment options produce only short-term responses that are not adequate to allow for a bridge to transplant. The clinical experts explained that everyone who is newly referred to a specialist centre with a diagnosis of advanced CTCL would be assessed for eligibility for a transplant. Consultation responses from NHS professionals supported the view that stem cell transplant gives people with advanced CTCL the best chance of a cure. The clinical experts advised that it is not always possible to identify people for whom transplant is appropriate before starting brentuximab vedotin. However,there are clinical criteria to identify people for whom transplants are not appropriate (for example, people with comorbidities that would compromise their fitness for a transplant). The committee concluded that it would consider the use of brentuximab vedotin as both a treatment without a future transplant and a bridge to transplant for advanced CTCL.
# Clinical evidence
## The clinical-effectiveness evidence is relevant to NHS clinical practice
The main evidence for brentuximab vedotin was from ALCANZA, an international, multicentre, open-label, randomised controlled trial. It included 128 adults (median age 60 years) with CTCL (mycosis fungoides or primary cutaneous anaplastic large cell lymphoma) who had 1 previous systemic therapy and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 and under; 95 patients had advanced CTCL. The trial compared brentuximab vedotin with physician's choice of treatment (either methotrexate or bexarotene). The committee noted that ALCANZA did not assess the comparative effectiveness of brentuximab vedotin and interferon alfa. It noted the company's comment that there was insufficient evidence for an indirect comparison. Having concluded that all first-line systemic treatments are equally effective (see section 3.5), the committee agreed that the lack of a comparison between brentuximab vedotin and interferon alfa was not a major limitation in the evidence. The committee noted that the trial was both international and multicentre, but only 4 centres were in the UK (24 patients). The clinical experts confirmed that patients in the trial were representative of UK patients who would be eligible for brentuximab vedotin. The committee concluded that the clinical-effectiveness evidence from ALCANZA was relevant to clinical practice in the NHS in England.
## Brentuximab vedotin improves progression-free survival and had longer responses compared with current treatment options
The company presented results for all patients in the ALCANZA study and separate results for the advanced disease subgroup. The primary outcome was the rate of objective response that lasted at least 4 months. Secondary outcomes included response rates, length of response, progression-free survival and health-related quality of life. Overall survival was not a prespecified end point, but the company included these data in its submission. The clinical experts stated that the results (see table 1) were clinically meaningful and important to people with advanced CTCL, because current treatments provide only short-term responses. They reiterated that the response rates with brentuximab vedotin meant that more patients could be offered stem cell transplants. The committee concluded that brentuximab vedotin improved progression-free survival and had longer clinical responses compared with methotrexate or bexarotene and accepted that this would also be the case when compared with interferon alfa (see section 3.5).
End point
Brentuximab vedotin (n=49)
Methotrexate or bexarotene (physician's choice; n=46)
P value
Objective response rate lasting for at least 4 months, n (%)
Overall response rate, n (%)
Complete response, n (%)
Partial response, n (%)
Not reported
Progression-free survival, months (95% confidence interval)
(15.5 to 27.5)
(2.4 to 4.9)
Not reported
## The exact proportion of patients who have a stem cell transplant after having brentuximab vedotin is uncertain
The company presented results from a post-hoc analysis of allogeneic stem cell transplants in ALCANZA, which included 7 patients who had a transplant: 5 in the brentuximab vedotin group and 2 in the comparator group. Only 2 of the 5 patients in the brentuximab vedotin treatment group had a transplant directly after treatment; the other 3 had additional systemic therapies before their transplant. Both patients in the comparator group had switched to receive brentuximab vedotin before their transplant. The clinical experts explained that the trial was done in 2013 and although transplants were allowed in ALCANZA, their use was not a prespecified end point. They emphasised that UK clinical practice has evolved since 2013 and transplants are now more common. A clinical expert who had used brentuximab vedotin on the compassionate use programme suggested that around 25% of patients bridged to transplant. The committee understood that the compassionate use programme is highly selective and therefore may not reflect clinical practice in the NHS. In response to consultation, the company presented data on transplant rates from the compassionate use programme (26.3%) and from the UK patients in the ALCANZA trial (16.7%); these were both lower than the transplant rate in the company's base case (27.5%). The committee recalled that not all patients who had a transplant in ALCANZA did so directly after having brentuximab vedotin. The committee concluded that brentuximab vedotin could be used as a bridge to transplant for some patients whose disease adequately responds to treatment, but that there was uncertainty about the exact proportion in clinical practice.
## For patients who cannot have a transplant, it is unclear whether brentuximab vedotin improves overall survival compared with current treatment
The company provided evidence on overall survival from ALCANZA for the advanced disease subgroup. Median overall survival was 43.6 months in the brentuximab vedotin group and 41.6 months in the comparator group. Based on these results, the company considered that it was not possible to assume a difference in overall survival between the 2 groups in patients who were not able to bridge to transplant. They highlighted that the data were immature, based on a relatively small sample size with few events, and may be confounded by treatment switching. Almost half (46%) of patients switched from the comparator group and subsequently had brentuximab vedotin. The company attempted to adjust for this treatment switching, but considered the results to be clinically implausible. The committee acknowledged the company's concerns, such as the limited number of events in each arm, but considered that the adjustment may have been conducted incorrectly. The clinical experts explained that from the available evidence, they had not seen a proven association between progression-free and overall survival in patients with CTCL who were not able to bridge to transplant. However, in the second committee meeting, the clinical lead for the Cancer Drugs Fund explained that it was likely that a substantial gain in progression-free survival (as seen in the ALCANZA trial) would lead to a gain in overall survival. The committee concluded that there was uncertainty about whether brentuximab vedotin increased overall survival compared with current treatments for patients who were not able to bridge to transplant.
## Data from ALCANZA can be generalised to other subgroups of cutaneous T‑cell lymphoma
The committee recalled that the ALCANZA trial included patients with mycosis fungoides or primary cutaneous anaplastic large cell lymphoma, but did not include other subgroups of CTCL. Two phase II trials provided further non-randomised supporting evidence for Sézary syndrome and lymphomatoid papulosis, other subtypes of CTCL which are included in brentuximab vedotin's marketing authorisation. The committee noted that the studies included only a small number of patients with subtypes of CTCL other than mycosis fungoides, but it recalled that CTCL is a rare disease. The clinical experts explained that treatment would be similar for most subtypes of CTCL, but that they would not use brentuximab vedotin for lymphomatoid papulosis (see section 3.3). Having reviewed the supporting data, the committee noted that the findings for response rates and median progression-free survival were generally consistent across the studies and subgroups, and that the European Public Assessment Report for brentuximab vedotin stated that 'the available data appears in support for the extrapolation of efficacy from mycosis fungoides and primary cutaneous anaplastic large cell lymphoma to other subtypes'. The committee concluded that the clinical-effectiveness data from ALCANZA could be generalised to other subtypes of CTCL, such as Sézary syndrome.
## People may have fewer cycles of brentuximab vedotin in clinical practice than in both ALCANZA and the summary of product characteristics
The committee noted that the summary of product characteristics for brentuximab vedotin states that it should be used for up to 16 cycles. The clinical experts explained that the number of cycles used depended on whether brentuximab vedotin was being used to bridge to allogeneic stem cell transplant. They explained that when brentuximab vedotin is used without the intention of bridging to transplant, 16 cycles is common and in some cases patients have retreatment with brentuximab vedotin (that is, they have brentuximab vedotin for a second time after a break from treatment with it). The committee noted that it had not seen evidence of retreatment with brentuximab vedotin and that no evidence on treatment breaks was available from the ALCANZA trial data. The committee was also aware that the summary of product characteristics makes no explicit reference to retreatment. It heard from NHS England's clinical lead for the Cancer Drugs Fund that retreatment with brentuximab vedotin would not be done in clinical practice in the NHS. The clinical experts also advised that, in their experience, treatment with brentuximab vedotin may be stopped after only 2 or 3 cycles if the response is sufficient to allow for a transplant. The committee noted that this was much lower than the maximum number of cycles specified in the summary of product characteristics. It concluded that the number of cycles of brentuximab vedotin used in clinical practice varied, and that this should be factored into its considerations of the cost-effectiveness evidence.
## The size of brentuximab vedotin's effect on health-related quality of life is unclear and the full benefit may not be captured in the trial data
The company provided health-related quality of life and symptom relief data for the advanced disease subgroup using the Skindex‑29 and EQ‑5D‑3L tools. The data showed that patients who had brentuximab vedotin had better symptom relief compared with those who had the comparators. However, the committee noted that there was no statistically significant difference in overall Skindex‑29 score or EQ‑5D‑3L values between the brentuximab vedotin and comparator groups. The clinical experts explained that neither tool fully captures all skin-related and physiological symptoms of CTCL. They further explained that a health-related quality-of-life tool specific to CTCL was being developed but was not yet available. In response to consultation, NHS professionals emphasised the importance of symptom improvement with brentuximab vedotin. The committee acknowledged the limitations of the EQ‑5D‑3L as an assessment tool for advanced CTCL because it may not be sensitive to skin-related diseases, but noted that it should capture depression and pain described by patients in consultation responses. The company explained that the EQ‑5D‑3L data from ALCANZA had a low completion rate in the comparator arm, which also had a high rate of treatment switching, and that it failed to capture nocturnal pruritus, which affects people with advanced CTCL. The committee agreed that further research is needed in this area. It concluded that brentuximab vedotin appears to improve health-related quality of life, but that the size of this effect is unclear. It agreed that this was at least partly because of the health-related quality of life tools available, such that the benefit of brentuximab vedotin may not be fully captured in the trial data. It concluded that this should be factored into its considerations of the cost-effectiveness evidence.
# Adverse effects
## Brentuximab vedotin is generally well tolerated
The committee noted that the adverse effects reported in the ALCANZA study were broadly comparable between the brentuximab vedotin and comparator groups. It noted that there was 1 treatment-related death caused by tumour lysis, but that this was not unique to brentuximab vedotin. A patient expert commented that they had found brentuximab vedotin to be more tolerable than other treatments, but they noted that each patient was likely to react differently. The committee concluded that brentuximab vedotin was generally well tolerated.
# Cost effectiveness
## The company's model structure is appropriate for decision making
The company presented cost-effectiveness analyses comparing brentuximab vedotin with 'physician's choice' of treatment (in clinical practice, either methotrexate or bexarotene) using a partitioned survival model with 5 mutually exclusive health states. The model comprised 2 pathways, 1 that included allogeneic stem cell transplant and 1 that did not. All patients start in the pre-progression health state. Eligibility for a transplant is based on response to treatment in this state. All eligible patients move to the allogeneic stem cell transplant health state at 18 weeks. Patients on either pathway can relapse and move into a post-progression or death state. The clinical experts confirmed that the model reflected the clinical pathway for CTCL. The model was informed by data from the advanced disease subgroup of ALCANZA. This included only patients with the mycosis fungoides and primary cutaneous anaplastic large cell lymphoma subgroups of CTCL, but the committee recalled that the data could be generalised to other subgroups (see section 3.11). The committee concluded that the model's structure was appropriate for decision making.
# Pathway including stem cell transplants
## Rates of stem cell transplant from UK patients in the ALCANZA trial should be used in the cost-effectiveness modelling
The company's base case assumed that 40% of patients whose disease showed at least a partial response to treatment (based on objective response rates) would be eligible for a stem cell transplant. This was based on clinical advice, which accounted for the eligibility of patients for a transplant based on age, comorbidities and likelihood of a matching donor, as well as patient choice. The committee noted that, using the company's base-case assumptions, 27.5% of people who had brentuximab vedotin and 7.1% who had the comparator would go on to have a transplant. The clinical experts confirmed that the assumptions used to inform the 40% proportion of responders reflected clinical practice, but only a small number of patients have had brentuximab vedotin in England. The committee recalled that the company had submitted alternative data from 2 sources in response to consultation, which suggested lower rates of transplant after brentuximab vedotin (16.7% and 26.3%; see section 3.9). The company highlighted that responses to consultation indicated transplant rates after brentuximab vedotin may be as high as 33%. It also presented analyses using a 5% transplant rate in the comparator arm (rather than 7.1% as in the company's base case), reflecting information from the clinical expert submission to NICE. The clinical lead for the Cancer Drugs Fund emphasised that all data sources included small numbers of patients and explained that clinical advice to NHS England suggested that a 20% transplant rate after brentuximab vedotin was high, and that the figure in England is likely to be significantly lower. The committee concluded that the exact transplant rate in each group was uncertain, but that the company's lower rate of 16.7% after brentuximab vedotin and original rate of 7.1% for the comparator arm were acceptable for decision making.
## The company's approach to modelling outcomes after transplant is appropriate for decision making
The committee noted that for people who had a stem cell transplant and moved to the model's transplant pathway, progression-free and overall survival were modelled on real-world evidence presented at the 2018 European Organisation for Research and Treatment of Cancer conference. The company digitised the Kaplan–Meier progression-free survival data and fitted a Gompertz single parametric curve for extrapolation. Overall survival was extrapolated using a log-normal parametric curve. The results are considered academic in confidence and cannot be reported here. The company's model assumed outcomes after disease progression to be substantially worse after a transplant, compared with in people who did not have a transplant. The company explained that people whose disease relapses after transplant are likely to have exhausted all systemic options and have aggressive disease. It also explained that after transplant, many patients remain progression-free for a long time such that many die before their disease progresses. The ERG advised that the short time spent in the post-progression state meant that patients were not entering the resource-intensive 'end-stage care', which may underestimate costs in the brentuximab vedotin arm. The ERG also explained that there was insufficient evidence to support the rate and timing of cure after transplant implied by the progression-free survival curve in the company's model. Responses to consultation from the clinical experts advised that patients whose disease does not relapse within 15 months after transplant are expected to have sustained remission thereafter. The committee noted that there were limited data on transplants in patients who have had brentuximab vedotin. The clinical experts explained that although there had been few stem cell transplants after brentuximab vedotin in clinical practice, there was no reason to expect any differences in outcomes after a transplant in patients after having brentuximab vedotin compared with those after having methotrexate or bexarotene. The committee acknowledged there were limitations in the evidence, including its small sample size and relevance to clinical practice because few patients had a transplant directly after having brentuximab vedotin. However, it was aware that there are limited data on transplants for people with advanced CTCL, and that disease that had not relapsed within 15 months of treatment was likely to remain in long-term remission. The committee concluded that the company's approach to modelling outcomes after transplant was appropriate for decision making.
# Pathway not including stem cell transplants
## The extrapolation of progression-free survival for people not having stem cell transplants is appropriate for decision making
The company explored various parametric survival curves for extrapolating the progression-free survival data. It considered the Weibull models to have the best statistical and visual fit for both the brentuximab vedotin and comparator groups. The committee concluded that the company's approach and its rationale for selecting the Weibull models for its base-case analysis were appropriately justified.
## Assumptions about overall survival with brentuximab vedotin affect the post-progression pathway
The committee recalled that the overall survival data from ALCANZA were immature and confounded by treatment switching (see section 3.10). The company had therefore assumed that the unadjusted survival data for patients in the comparator group could be used to represent overall survival for all patients who did not have a transplant. The committee noted that the company's assumption of equal overall survival for brentuximab vedotin and the comparators alongside a progression-free survival gain for people who had brentuximab vedotin meant that, after disease progression, patients who had brentuximab vedotin died more quickly than patients who had the comparators. The company assumed that patients in both groups spent equal time on subsequent active therapies after disease progression, based on data from the PROCLIPI study. Patients in the brentuximab vedotin group whose disease progressed after subsequent active therapies therefore had a higher risk of death and spent less time in the resource-intensive end-stage care state compared with patients in the comparator group. The committee noted that spending less time in the resource-intensive end-stage care state would reduce overall costs, so this may lead to an overestimation of brentuximab vedotin's cost effectiveness. The committee concluded that assumptions around overall survival in the brentuximab vedotin arm affected the post-progression pathway, and that it should consider this in its decision making.
## The modelling of overall survival for people not having stem cell transplants is uncertain
The company fitted a parametric curve to each treatment group of the trial. It considered the log-logistic parametric model for overall survival in the comparator group to have the best fit, and therefore used it in its base-case analysis to model overall survival for both brentuximab vedotin and the comparators. The company's choice was based on clinical plausibility and on how closely the parametric curves aligned with historical data collected from UK patients with CTCL. The committee recalled that a substantial gain in progression-free survival (as seen in the ALCANZA trial) would also result in a gain in overall survival. It discussed an ERG scenario analysis which examined a potential survival gain with brentuximab vedotin for people who did not have a transplant. The ERG's scenario analysis adjusted the company's base-case overall survival curve for the comparators to generate a 9.5‑month mean gain in overall survival for brentuximab vedotin (equal to the mean gain in progression-free survival for people who don't have a transplant when transplant is included in the treatment pathway). The committee noted that the cost-effectiveness estimates for brentuximab vedotin were much higher in this scenario than in the company's base case. In response to consultation, the company presented scenarios exploring the effect of 2, 4, and 9.5 months' survival benefit after brentuximab vedotin for patients who did not have a transplant. The committee was aware that there was no evidence to show which overall survival gain was most likely to be seen in clinical practice, but recalled that assumptions around overall survival affected the post-progression pathway. It concluded that it should consider this in its decision making.
## An overall survival gain of 9.5 months in the model better reflects the post-progression treatment pathway after brentuximab vedotin in clinical practice
The committee recalled that the company's assumption of equal overall survival with brentuximab vedotin and the comparators alongside a progression-free survival gain with brentuximab vedotin meant that patients having brentuximab vedotin spend less time in the post-progression state than patients having the comparators. The clinical experts explained that the post-progression treatment pathway would be the same for people whose disease relapsed after having brentuximab vedotin (who did not have a transplant) and after having methotrexate or bexarotene. The clinical experts also noted that people having brentuximab vedotin were not expected to have worse outcomes after progression than those having the comparators. The committee therefore agreed that the company's post-progression pathway did not reflect clinical practice. It considered an exploratory analysis by the ERG that assumed equal overall survival and equal time spent in end-stage care for the brentuximab vedotin and comparator arms. The committee understood that this scenario may not accurately represent the current pathway but noted that it was intended to show the model's sensitivity to assumptions about time spent in end-stage care. The committee agreed that both the company's and the ERG's models of the post-progression pathway had limitations, but noted that the scenario analysis assuming a 9.5-month gain in overall survival after brentuximab vedotin (equal to the gain in progression-free survival) made the time spent in end-stage care after brentuximab vedotin similar to the time spent in end-stage care in the comparator arm for patients who did not have a transplant. The committee concluded that although the clinical evidence did not demonstrate a gain in overall survival, based on its effect on the post-progression pathway, a gain in overall survival of 9.5 months with brentuximab vedotin was more likely to reflect clinical practice and should be considered in its decision making.
# Utility values
## The ERG's approach to calculating utility values is more appropriate
To calculate the utility values for the progression-free state in the model, the company used EQ-5D-3L data from the ALCANZA trial but fitted a regression model including Skindex‑29 scores as a covariate. The committee noted that the cost-effectiveness estimates calculated using Skindex‑29 scores would differ to those based on an approach that excluded the scores. It also noted that the utility values in ALCANZA were higher for brentuximab vedotin than for the comparators because of differences at baseline, and that the ERG considered it more appropriate to assume that the utility values for the progression-free state were equal for brentuximab vedotin and the comparators. The ERG's preferred utility value was calculated using an average of the EQ-5D-3L values from the brentuximab vedotin and comparator groups (0.689). The ERG also preferred not to include treatment-related disutilities based on descriptions of side effects in the model: the EQ-5D-3L data from ALCANZA should capture changes in health-related quality of life as a result of adverse events, so further utility decrements would be unnecessary. The committee concluded that the ERG's approach to modelling utility values was more appropriate and suitable for decision making.
# Costs in the model
## The ERG's resource use scenario should be used in the cost-effectiveness modelling
The company's original base case included costs for administering oral chemotherapy. The ERG considered this to be double-counting of costs for the comparator group and the committee agreed that extra costs for oral chemotherapy should not be included. In response to consultation, the company removed extra oral chemotherapy costs from its updated base case but the committee noted that this change had little effect on the cost-effectiveness results. The committee recalled that if there are no treatment options remaining, the only option for patients with advanced CTCL is high-resource care (see section 3.21). End-stage care in the company's model included several outpatient appointments and regular visits from both palliative care and Macmillan nurse teams. The company noted that the resource use data were obtained from semi-structured interviews with clinical experts, with mean values used in its base-case model. The clinical experts reiterated that CTCL is a rare disease; any guidelines would likely recommend that patients have regular hospital admissions and visits from district nurses, but in practice it is likely that some patient care will be managed by families and carers. The committee considered the ERG's scenario analysis which reduced the frequency of outpatient appointments, district and Macmillan nurse visits and palliative support based on its clinical expert advice. In response to consultation the company submitted a scenario analysis using the lower range of resource use from the clinical experts. The clinical lead for the Cancer Drugs Fund explained that the company's estimates for resource use in end-stage care may most closely reflect that for patients with very severe advanced disease, with expert advice to NHS England indicating that such intense care and support would apply to around 25% of patients. The committee concluded that the ERG's scenario analysis may better reflect end-stage care for most patients with advanced CTCL.
## Cost-effectiveness estimates are not sensitive to the length of treatment with brentuximab vedotin before stem cell transplant
Both the company's and ERG's analyses estimated the cost of brentuximab vedotin based on the time-on-treatment data from the ALCANZA study. The company assumed that all patients having a stem cell transplant have the transplant at 18 weeks, after 6 cycles of brentuximab vedotin. The committee recalled the clinical experts' suggestion that if a patient's disease had an adequate response to allow for a transplant, brentuximab vedotin may be stopped after only a few cycles. In response to consultation the company presented scenario analyses in which transplant was done between 12 and 30 weeks of having brentuximab vedotin. The committee concluded that the length of treatment with brentuximab vedotin before transplant has a limited effect on the cost-effectiveness estimates.
# Cost-effectiveness results
## The company's updated analyses include the committee's preferred assumptions but some uncertainty remains
In response to consultation, the company updated its base-case analysis to include the committee's preferred assumptions, using equal utility values for both brentuximab vedotin and the comparators, and excluding extra oral chemotherapy costs. The company also presented a number of scenario analyses that explored uncertainties, including:
the length of treatment before a transplant
the transplant rate in both the brentuximab vedotin and comparator arms
-verall survival in the brentuximab vedotin arm
lower resource use than in the original model. In all updated analyses, brentuximab vedotin was dominant compared with methotrexate or bexarotene (that is, it was more effective and less costly). The committee acknowledged that the company's updated analyses after consultation included all its preferred assumptions, but it recalled that uncertainty remained in terms of the overall survival benefit, resource use and transplant rate.
## The ERG's cost-effectiveness estimates are higher than the company's estimates
The ERG presented exploratory analyses to illustrate the sensitivity of the model to different assumptions, including:
assuming an overall survival gain of 9.5 months with brentuximab vedotin (see section 3.20)
using an alternative progression-free survival curve (changing the proportion and timing of cure) after transplant (see section 3.17)
using lower resource use for end-stage care (see section 3.23)
using the transplant rate from UK patients in the ALCANZA trial (16.7%; see section 3.16).Results from the ERG's sensitivity analyses ranged from an incremental cost-effectiveness ratio (ICER) for brentuximab vedotin compared with methotrexate or bexarotene of £58,516 per quality-adjusted life year (QALY) gained, to brentuximab vedotin being dominant (that is, it was both less costly and more effective). The committee noted the wide range of cost-effectiveness estimates in the ERG's scenario analyses and recognised that this was a result of the model's sensitivity to uncertainties in the evidence base.
## Brentuximab vedotin is a cost-effective use of NHS resources for advanced CD30-positive cutaneous T-cell lymphoma after 1 systemic therapy
The committee recalled that the assumptions which best reflected clinical practice were: a lower transplant rate after brentuximab vedotin (16.7%), overall survival of 9.5 months with brentuximab vedotin, and applying the ERG's lower resource use. Using these assumptions, the ICER for brentuximab vedotin compared with methotrexate or bexarotene was £29,613 per QALY gained. The committee noted that this scenario also included a transplant rate of 7.1% in the comparator arm; it agreed that this rate may be higher than in clinical practice, and so the cost-effectiveness estimate for brentuximab vedotin would be lower (see section 3.16). The committee also recalled that the evidence may not have fully captured the health-related quality of life benefit of brentuximab vedotin, and that doing so would reduce the cost-effectiveness estimate (see section 3.13). It concluded that the most plausible ICER for brentuximab vedotin compared with methotrexate or bexarotene was less than £30,000 per QALY gained, which is within the range normally considered an acceptable use of NHS resources. However, because the clinical and cost-effectiveness data were based on people with specific subtypes of advanced disease (mycosis fungoides stage IIB or over, primary cutaneous anaplastic large cell lymphoma and Sézary syndrome), the committee concluded that brentuximab vedotin was recommended only for these subtypes.
# Other factors
## Brentuximab vedotin is innovative and health-related quality of life benefits not captured in the analyses should be considered
The company considered that brentuximab vedotin was an innovative treatment because it represents a step-change in managing a disease for which there is significant unmet need. Brentuximab vedotin may allow more patients to proceed to a potentially curative transplant. The company also highlighted that brentuximab vedotin is given every 3 weeks in an outpatient setting, which means patients need to spend less time in hospital. The clinical experts agreed that brentuximab vedotin was innovative and that clinical trial results showed longer clinical responses which are rarely achieved with current treatments. The committee agreed that brentuximab vedotin would be beneficial for patients, but that it had not been presented with robust health-related quality of life evidence to show any additional benefits. It agreed that this was at least partly because of the health-related quality of life tools available (see section 3.13). It concluded that this should be factored into its considerations of the cost-effectiveness evidence.
## There are no relevant equality issues
There were no relevant equality issues raised in the company submission or ERG report, or in patient and professional statements. During scoping, stakeholders highlighted that excluding CTCL with less than 5% CD30 expression from the recommendations may deny some patients access to the treatment because of evidence that 1 in 6 cases of CTCL with less than 5% CD30 expression may respond to treatment. However, the marketing authorisation for brentuximab vedotin does not specify a percentage of CD30 expression so this was not considered to be a relevant equality issue.
## Brentuximab vedotin does not meet the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It noted that the company had not provided any evidence to make a case for brentuximab vedotin meeting the criteria to be considered a life-extending treatment at the end of life. It was aware that the clinical experts considered that brentuximab vedotin did not fulfil either criteria for end of life because people with CTCL may survive for several years after treatment (see section 3.2). Based on advice from the clinical experts and data presented by the company and ERG, the committee accepted that brentuximab vedotin did not meet the end-of-life criteria.
|
{'Recommendations': 'Brentuximab vedotin is recommended as an option for treating CD30‑positive cutaneous T‑cell lymphoma (CTCL) after at least 1\xa0systemic therapy in adults, only if:\n\nthey have mycosis fungoides stage\xa0IIB or over, primary cutaneous anaplastic large cell lymphoma or Sézary syndrome and\n\nthe company provides brentuximab vedotin according to the commercial arrangement.\n\nThese recommendations are not intended to affect treatment with brentuximab vedotin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nBrentuximab vedotin is licensed to treat CD30-positive CTCL after at least 1\xa0systemic therapy. It is most likely to be used in the NHS as an alternative to systemic treatments to treat advanced disease. At this point in the pathway, current treatment options include methotrexate, bexarotene and interferon alfa.\n\nClinical trial evidence shows that brentuximab vedotin is better than methotrexate or bexarotene in terms of response rates and extending how long people live without their disease getting worse. For some people with CTCL, brentuximab vedotin will be used as a bridge to a stem cell transplant.\n\nThe most plausible cost-effectiveness estimates for brentuximab vedotin compared with current treatments are less than £30,000 per quality-adjusted life year gained, which is within the range considered to be a cost-effective use of NHS resources. However, these estimates are based on data from people with specific subtypes of advanced disease (mycosis fungoides stage\xa0IIB or over, primary cutaneous anaplastic large cell lymphoma and Sézary syndrome), so brentuximab vedotin is only recommended for these subtypes.', 'Information about brentuximab vedotin': "Marketing authorisation indication\n\nBrentuximab vedotin is indicated for the treatment of 'adult patients with CD30-positive cutaneous T-cell lymphoma after at least 1 prior systemic therapy'.\n\nDosage in the marketing authorisation\n\nThe recommended dose is 1.8\xa0mg/kg given as an intravenous infusion over 30\xa0minutes every 3\xa0weeks. People with CTCL should have up to 16\xa0cycles.\n\nPrice\n\nThe price of brentuximab vedotin is £2,500 for a 50\xa0mg vial (excluding VAT; BNF edition 76). The company has a commercial arrangement. This makes brentuximab vedotin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Takeda and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Potential new treatment option\n\n## Cutaneous T-cell lymphoma significantly affects quality of life\n\nCutaneous T-cell lymphoma (CTCL) is a form of non-Hodgkin lymphoma that affects the skin. It may start as flat red patches or plaques on the surface of the skin, which progress to skin tumours. People may also have systemic symptoms, such as chronic pain and itching, that can severely limit daily activities. The clinical experts explained that CTCL is a rare disease and people usually live with their condition for many years. The patient experts explained that being diagnosed with CTCL can severely affect a person's physical and psychological wellbeing. It may take several\xa0years before CTCL is accurately diagnosed, and symptoms flare up unpredictably. The clinical and patient experts also explained that there is no uniform response to treatment; people with CTCL may be very self-conscious about how their skin looks and uncertain about how the disease will respond to treatment, which has a negative psychological effect. Consultation responses from NHS professionals highlighted the emotional and financial effects on patients and their families and carers. The committee concluded that CTCL significantly reduces patients' quality of life.\n\n## There is an unmet need for more effective treatment options\n\nThere is no NICE guidance on treating CTCL. The disease can be divided into a number of subtypes, only some of which express the tumour marker CD30. CD30 is expressed in both primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis, which together form the group of primary cutaneous CD30-positive lymphoproliferative disorders. Mycosis fungoides and Sézary syndrome can also express CD30. CTCL is treated based on the subtype and stage of the disease. Treatments either target the skin (skin-directed) or the entire body (systemic), but there is no standard therapy. The clinical experts highlighted that treatment options are diverse; they aim to relieve symptoms, control local disease and improve quality of life. The committee understood that compared with earlier stages of CTCL, advanced disease is associated with poorer prognosis, lower survival and lower quality of life. Although current treatments are palliative, the clinical experts noted that allogeneic stem cell transplants may consolidate treatment response to achieve durable remission, or possibly cure, and should be considered for certain patients with advanced CTCL. Without a transplant the disease has a cycle of remission and relapse. Because there are limited treatment options available, people with advanced CTCL may live for several years without treatment while having painful, itchy and uncomfortable symptoms on a daily basis. The committee agreed that there is an unmet need for effective treatments that extend the amount of time the disease is in remission and improve quality of life. The committee concluded that both patients and healthcare professionals would welcome potential new treatments.\n\n# Treatment pathway and comparators\n\n## Brentuximab vedotin will be used as an alternative to systemic therapies for specific subtypes of advanced cutaneous T-cell lymphoma\n\nThe marketing authorisation does not specify whether brentuximab vedotin may be used for early-stage CTCL or advanced CTCL. The committee noted that the inclusion criteria for ALCANZA (the pivotal trial on which the marketing authorisation was based) included patients with early-stage disease. The committee was also aware that the company's submission focused on a narrower population than the marketing authorisation, including only patients with advanced disease (specifically mycosis fungoides stage\xa0IIB or over, primary cutaneous anaplastic large cell lymphoma and Sézary syndrome). The clinical experts explained that skin-directed therapies are often effective for managing early-stage CTCL, but systemic agents (like brentuximab vedotin) are more commonly used for advanced disease. They also highlighted that lymphomatoid papulosis, another subtype of CTCL, is usually treated with skin-directed therapies (because it is less aggressive), so brentuximab vedotin would not be used for this subtype of CTCL. The committee concluded that brentuximab vedotin is most likely to be used in the NHS as an alternative to systemic treatments to treat specific subtypes of advanced CTCL (mycosis fungoides stage\xa0IIB or over, primary cutaneous anaplastic large cell lymphoma and Sézary syndrome).\n\n## Methotrexate, bexarotene and interferon alfa are the most appropriate comparators\n\nThe committee recalled that systemic agents are most commonly used to treat advanced subtypes of CTCL. The clinical experts explained that patients are first offered retinoids (bexarotene), interferon alpha or single-agent chemotherapy (methotrexate). They highlighted that low-dose methotrexate is not licensed for CTCL but that it has been used in UK clinical practice for over 40\xa0years. Multi-agent chemotherapy regimens are generally not used as standard care and are only considered when first-line systemic therapy options have been exhausted. This is because of their lack of efficacy and associated toxicities, which are especially problematic in people with CTCL who are susceptible to infection. The clinical experts agreed with the company's positioning of brentuximab vedotin as an alternative to bexarotene, interferon alpha and methotrexate, and stated that it would be used after first-line therapy. The committee noted that its marketing authorisation restricted the use of brentuximab vedotin to after at least 1\xa0systemic therapy, and so concluded that it would be used after at least 1\xa0systemic therapy for patients with advanced disease and that, based on current clinical practice, methotrexate, bexarotene and interferon alfa were the most appropriate comparators.\n\n## Current treatment options are considered equally effective\n\nThe committee considered the currently available treatment options for people with advanced CTCL. The clinical experts explained that the choice of treatment often depends on the associated adverse events and the patient's needs because all initial therapies are considered equally effective. The committee was aware that evidence for the efficacy of bexarotene monotherapy, low-dose methotrexate monotherapy and interferon alfa for advanced CTCL was from outdated and low-quality studies. The committee concluded that although there was limited evidence, for the purposes of this appraisal it was appropriate to assume that all first-line systemic treatments are equally effective.\n\n## Stem cell transplant is part of the treatment pathway\n\nThe clinical experts explained that brentuximab vedotin would be used in 2\xa0ways: either as a bridge to transplant or as a treatment without a future transplant. The committee recalled that allogeneic stem cell transplant may be a potentially curative therapy for certain patients with advanced CTCL (see section 3.2). The clinical experts advised that transplants should only be considered for patients whose disease adequately responds to systemic therapy. This normally means at least a partial response, although they commented that current treatment options produce only short-term responses that are not adequate to allow for a bridge to transplant. The clinical experts explained that everyone who is newly referred to a specialist centre with a diagnosis of advanced CTCL would be assessed for eligibility for a transplant. Consultation responses from NHS professionals supported the view that stem cell transplant gives people with advanced CTCL the best chance of a cure. The clinical experts advised that it is not always possible to identify people for whom transplant is appropriate before starting brentuximab vedotin. However,there are clinical criteria to identify people for whom transplants are not appropriate (for example, people with comorbidities that would compromise their fitness for a transplant). The committee concluded that it would consider the use of brentuximab vedotin as both a treatment without a future transplant and a bridge to transplant for advanced CTCL.\n\n# Clinical evidence\n\n## The clinical-effectiveness evidence is relevant to NHS clinical practice\n\nThe main evidence for brentuximab vedotin was from ALCANZA, an international, multicentre, open-label, randomised controlled trial. It included 128\xa0adults (median age 60\xa0years) with CTCL (mycosis fungoides or primary cutaneous anaplastic large cell lymphoma) who had 1\xa0previous systemic therapy and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 and under; 95\xa0patients had advanced CTCL. The trial compared brentuximab vedotin with physician's choice of treatment (either methotrexate or bexarotene). The committee noted that ALCANZA did not assess the comparative effectiveness of brentuximab vedotin and interferon alfa. It noted the company's comment that there was insufficient evidence for an indirect comparison. Having concluded that all first-line systemic treatments are equally effective (see section\xa03.5), the committee agreed that the lack of a comparison between brentuximab vedotin and interferon alfa was not a major limitation in the evidence. The committee noted that the trial was both international and multicentre, but only 4\xa0centres were in the UK (24\xa0patients). The clinical experts confirmed that patients in the trial were representative of UK patients who would be eligible for brentuximab vedotin. The committee concluded that the clinical-effectiveness evidence from ALCANZA was relevant to clinical practice in the NHS in England.\n\n## Brentuximab vedotin improves progression-free survival and had longer responses compared with current treatment options\n\nThe company presented results for all patients in the ALCANZA study and separate results for the advanced disease subgroup. The primary outcome was the rate of objective response that lasted at least 4\xa0months. Secondary outcomes included response rates, length of response, progression-free survival and health-related quality of life. Overall survival was not a prespecified end point, but the company included these data in its submission. The clinical experts stated that the results (see table 1) were clinically meaningful and important to people with advanced CTCL, because current treatments provide only short-term responses. They reiterated that the response rates with brentuximab vedotin meant that more patients could be offered stem cell transplants. The committee concluded that brentuximab vedotin improved progression-free survival and had longer clinical responses compared with methotrexate or bexarotene and accepted that this would also be the case when compared with interferon alfa (see section 3.5).\n\nEnd point\n\nBrentuximab vedotin (n=49)\n\nMethotrexate or bexarotene (physician's choice; n=46)\n\nP value\n\nObjective response rate lasting for at least 4\xa0months, n (%)\n\n(59.2)\n\n(8.7)\n\n<0.001\n\nOverall response rate, n (%)\n\n(69.4)\n\n(17.4)\n\n<0.001\n\nComplete response, n (%)\n\n(20.4)\n\n(2.2)\n\n\n\nPartial response, n (%)\n\n(49.0)\n\n(15.2)\n\nNot reported\n\nProgression-free survival,\xa0months (95% confidence interval)\n\n\n\n(15.5 to 27.5)\n\n(2.4 to 4.9)\n\nNot reported\n\n## The exact proportion of patients who have a stem cell transplant after having brentuximab vedotin is uncertain\n\nThe company presented results from a post-hoc analysis of allogeneic stem cell transplants in ALCANZA, which included 7\xa0patients who had a transplant: 5 in the brentuximab vedotin group and 2 in the comparator group. Only 2 of the 5\xa0patients in the brentuximab vedotin treatment group had a transplant directly after treatment; the other 3 had additional systemic therapies before their transplant. Both patients in the comparator group had switched to receive brentuximab vedotin before their transplant. The clinical experts explained that the trial was done in 2013 and although transplants were allowed in ALCANZA, their use was not a prespecified end point. They emphasised that UK clinical practice has evolved since 2013 and transplants are now more common. A clinical expert who had used brentuximab vedotin on the compassionate use programme suggested that around 25% of patients bridged to transplant. The committee understood that the compassionate use programme is highly selective and therefore may not reflect clinical practice in the NHS. In response to consultation, the company presented data on transplant rates from the compassionate use programme (26.3%) and from the UK patients in the ALCANZA trial (16.7%); these were both lower than the transplant rate in the company's base case (27.5%). The committee recalled that not all patients who had a transplant in ALCANZA did so directly after having brentuximab vedotin. The committee concluded that brentuximab vedotin could be used as a bridge to transplant for some patients whose disease adequately responds to treatment, but that there was uncertainty about the exact proportion in clinical practice.\n\n## For patients who cannot have a transplant, it is unclear whether brentuximab vedotin improves overall survival compared with current treatment\n\nThe company provided evidence on overall survival from ALCANZA for the advanced disease subgroup. Median overall survival was 43.6\xa0months in the brentuximab vedotin group and 41.6\xa0months in the comparator group. Based on these results, the company considered that it was not possible to assume a difference in overall survival between the 2\xa0groups in patients who were not able to bridge to transplant. They highlighted that the data were immature, based on a relatively small sample size with few events, and may be confounded by treatment switching. Almost half (46%) of patients switched from the comparator group and subsequently had brentuximab vedotin. The company attempted to adjust for this treatment switching, but considered the results to be clinically implausible. The committee acknowledged the company's concerns, such as the limited number of events in each arm, but considered that the adjustment may have been conducted incorrectly. The clinical experts explained that from the available evidence, they had not seen a proven association between progression-free and overall survival in patients with CTCL who were not able to bridge to transplant. However, in the second committee meeting, the clinical lead for the Cancer Drugs Fund explained that it was likely that a substantial gain in progression-free survival (as seen in the ALCANZA trial) would lead to a gain in overall survival. The committee concluded that there was uncertainty about whether brentuximab vedotin increased overall survival compared with current treatments for patients who were not able to bridge to transplant.\n\n## Data from ALCANZA can be generalised to other subgroups of cutaneous T‑cell lymphoma\n\nThe committee recalled that the ALCANZA trial included patients with mycosis fungoides or primary cutaneous anaplastic large cell lymphoma, but did not include other subgroups of CTCL. Two phase\xa0II trials provided further non-randomised supporting evidence for Sézary syndrome and lymphomatoid papulosis, other subtypes of CTCL which are included in brentuximab vedotin's marketing authorisation. The committee noted that the studies included only a small number of patients with subtypes of CTCL other than mycosis fungoides, but it recalled that CTCL is a rare disease. The clinical experts explained that treatment would be similar for most subtypes of CTCL, but that they would not use brentuximab vedotin for lymphomatoid papulosis (see section 3.3). Having reviewed the supporting data, the committee noted that the findings for response rates and median progression-free survival were generally consistent across the studies and subgroups, and that the European Public Assessment Report for brentuximab vedotin stated that 'the available data appears in support for the extrapolation of efficacy from mycosis fungoides and primary cutaneous anaplastic large cell lymphoma to other subtypes'. The committee concluded that the clinical-effectiveness data from ALCANZA could be generalised to other subtypes of CTCL, such as Sézary syndrome.\n\n## People may have fewer cycles of brentuximab vedotin in clinical practice than in both ALCANZA and the summary of product characteristics\n\nThe committee noted that the summary of product characteristics for brentuximab vedotin states that it should be used for up to 16\xa0cycles. The clinical experts explained that the number of cycles used depended on whether brentuximab vedotin was being used to bridge to allogeneic stem cell transplant. They explained that when brentuximab vedotin is used without the intention of bridging to transplant, 16\xa0cycles is common and in some cases patients have retreatment with brentuximab vedotin (that is, they have brentuximab vedotin for a second time after a break from treatment with it). The committee noted that it had not seen evidence of retreatment with brentuximab vedotin and that no evidence on treatment breaks was available from the ALCANZA trial data. The committee was also aware that the summary of product characteristics makes no explicit reference to retreatment. It heard from NHS England's clinical lead for the Cancer Drugs Fund that retreatment with brentuximab vedotin would not be done in clinical practice in the NHS. The clinical experts also advised that, in their experience, treatment with brentuximab vedotin may be stopped after only 2 or 3\xa0cycles if the response is sufficient to allow for a transplant. The committee noted that this was much lower than the maximum number of cycles specified in the summary of product characteristics. It concluded that the number of cycles of brentuximab vedotin used in clinical practice varied, and that this should be factored into its considerations of the cost-effectiveness evidence.\n\n## The size of brentuximab vedotin's effect on health-related quality of life is unclear and the full benefit may not be captured in the trial data\n\nThe company provided health-related quality of life and symptom relief data for the advanced disease subgroup using the Skindex‑29 and EQ‑5D‑3L tools. The data showed that patients who had brentuximab vedotin had better symptom relief compared with those who had the comparators. However, the committee noted that there was no statistically significant difference in overall Skindex‑29 score or EQ‑5D‑3L values between the brentuximab vedotin and comparator groups. The clinical experts explained that neither tool fully captures all skin-related and physiological symptoms of CTCL. They further explained that a health-related quality-of-life tool specific to CTCL was being developed but was not yet available. In response to consultation, NHS professionals emphasised the importance of symptom improvement with brentuximab vedotin. The committee acknowledged the limitations of the EQ‑5D‑3L as an assessment tool for advanced CTCL because it may not be sensitive to skin-related diseases, but noted that it should capture depression and pain described by patients in consultation responses. The company explained that the EQ‑5D‑3L data from ALCANZA had a low completion rate in the comparator arm, which also had a high rate of treatment switching, and that it failed to capture nocturnal\xa0pruritus, which affects people with advanced CTCL. The committee agreed that further research is needed in this area. It concluded that brentuximab vedotin appears to improve health-related quality of life, but that the size of this effect is unclear. It agreed that this was at least partly because of the health-related quality of life tools available, such that the benefit of brentuximab vedotin may not be fully captured in the trial data. It concluded that this should be factored into its considerations of the cost-effectiveness evidence.\n\n# Adverse effects\n\n## Brentuximab vedotin is generally well tolerated\n\nThe committee noted that the adverse effects reported in the ALCANZA study were broadly comparable between the brentuximab vedotin and comparator groups. It noted that there was 1\xa0treatment-related death caused by tumour lysis, but that this was not unique to brentuximab vedotin. A patient expert commented that they had found brentuximab vedotin to be more tolerable than other treatments, but they noted that each patient was likely to react differently. The committee concluded that brentuximab vedotin was generally well tolerated.\n\n# Cost effectiveness\n\n## The company's model structure is appropriate for decision making\n\nThe company presented cost-effectiveness analyses comparing brentuximab vedotin with 'physician's choice' of treatment (in clinical practice, either methotrexate or bexarotene) using a partitioned survival model with 5\xa0mutually exclusive health states. The model comprised 2\xa0pathways, 1 that included allogeneic stem cell transplant and 1 that did not. All patients start in the pre-progression health state. Eligibility for a transplant is based on response to treatment in this state. All eligible patients move to the allogeneic stem cell transplant health state at 18\xa0weeks. Patients on either pathway can relapse and move into a post-progression or death state. The clinical experts confirmed that the model reflected the clinical pathway for CTCL. The model was informed by data from the advanced disease subgroup of ALCANZA. This included only patients with the mycosis fungoides and primary cutaneous anaplastic large cell lymphoma subgroups of CTCL, but the committee recalled that the data could be generalised to other subgroups (see section 3.11). The committee concluded that the model's structure was appropriate for decision making.\n\n# Pathway including stem cell transplants\n\n## Rates of stem cell transplant from UK patients in the ALCANZA trial should be used in the cost-effectiveness modelling\n\nThe company's base case assumed that 40% of patients whose disease showed at least a partial response to treatment (based on objective response rates) would be eligible for a stem cell transplant. This was based on clinical advice, which accounted for the eligibility of patients for a transplant based on age, comorbidities and likelihood of a matching donor, as well as patient choice. The committee noted that, using the company's base-case assumptions, 27.5% of people who had brentuximab vedotin and 7.1% who had the comparator would go on to have a transplant. The clinical experts confirmed that the assumptions used to inform the 40% proportion of responders reflected clinical practice, but only a small number of patients have had brentuximab vedotin in England. The committee recalled that the company had submitted alternative data from 2\xa0sources in response to consultation, which suggested lower rates of transplant after brentuximab vedotin (16.7% and 26.3%; see section 3.9). The company highlighted that responses to consultation indicated transplant rates after brentuximab vedotin may be as high as 33%. It also presented analyses using a 5% transplant rate in the comparator arm (rather than 7.1% as in the company's base case), reflecting information from the clinical expert submission to NICE. The clinical lead for the Cancer Drugs Fund emphasised that all data sources included small numbers of patients and explained that clinical advice to NHS England suggested that a 20% transplant rate after brentuximab vedotin was high, and that the figure in England is likely to be significantly lower. The committee concluded that the exact transplant rate in each group was uncertain, but that the company's lower rate of 16.7% after brentuximab vedotin and original rate of 7.1% for the comparator arm were acceptable for decision making.\n\n## The company's approach to modelling outcomes after transplant is appropriate for decision making\n\nThe committee noted that for people who had a stem cell transplant and moved to the model's transplant pathway, progression-free and overall survival were modelled on real-world evidence presented at the 2018 European Organisation for Research and Treatment of Cancer conference. The company digitised the Kaplan–Meier progression-free survival data and fitted a Gompertz single parametric curve for extrapolation. Overall survival was extrapolated using a log-normal parametric curve. The results are considered academic in confidence and cannot be reported here. The company's model assumed outcomes after disease progression to be substantially worse after a transplant, compared with in people who did not have a transplant. The company explained that people whose disease relapses after transplant are likely to have exhausted all systemic options and have aggressive disease. It also explained that after transplant, many patients remain progression-free for a long time such that many die before their disease progresses. The ERG advised that the short time spent in the post-progression state meant that patients were not entering the resource-intensive 'end-stage care', which may underestimate costs in the brentuximab vedotin arm. The ERG also explained that there was insufficient evidence to support the rate and timing of cure after transplant implied by the progression-free survival curve in the company's model. Responses to consultation from the clinical experts advised that patients whose disease does not relapse within 15\xa0months after transplant are expected to have sustained remission thereafter. The committee noted that there were limited data on transplants in patients who have had brentuximab vedotin. The clinical experts explained that although there had been few stem cell transplants after brentuximab vedotin in clinical practice, there was no reason to expect any differences in outcomes after a transplant in patients after having brentuximab vedotin compared with those after having methotrexate or bexarotene. The committee acknowledged there were limitations in the evidence, including its small sample size and relevance to clinical practice because few patients had a transplant directly after having brentuximab vedotin. However, it was aware that there are limited data on transplants for people with advanced CTCL, and that disease that had not relapsed within 15\xa0months of treatment was likely to remain in long-term remission. The committee concluded that the company's approach to modelling outcomes after transplant was appropriate for decision making.\n\n# Pathway not including stem cell transplants\n\n## The extrapolation of progression-free survival for people not having stem cell transplants is appropriate for decision making\n\nThe company explored various parametric survival curves for extrapolating the progression-free survival data. It considered the Weibull models to have the best statistical and visual fit for both the brentuximab vedotin and comparator groups. The committee concluded that the company's approach and its rationale for selecting the Weibull models for its base-case analysis were appropriately justified.\n\n## Assumptions about overall survival with brentuximab vedotin affect the post-progression pathway\n\nThe committee recalled that the overall survival data from ALCANZA were immature and confounded by treatment switching (see section 3.10). The company had therefore assumed that the unadjusted survival data for patients in the comparator group could be used to represent overall survival for all patients who did not have a transplant. The committee noted that the company's assumption of equal overall survival for brentuximab vedotin and the comparators alongside a progression-free survival gain for people who had brentuximab vedotin meant that, after disease progression, patients who had brentuximab vedotin died more quickly than patients who had the comparators. The company assumed that patients in both groups spent equal time on subsequent active therapies after disease progression, based on data from the PROCLIPI study. Patients in the brentuximab vedotin group whose disease progressed after subsequent active therapies therefore had a higher risk of death and spent less time in the resource-intensive end-stage care state compared with patients in the comparator group. The committee noted that spending less time in the resource-intensive end-stage care state would reduce overall costs, so this may lead to an overestimation of brentuximab vedotin's cost effectiveness. The committee concluded that assumptions around overall survival in the brentuximab vedotin arm affected the post-progression pathway, and that it should consider this in its decision making.\n\n## The modelling of overall survival for people not having stem cell transplants is uncertain\n\nThe company fitted a parametric curve to each treatment group of the trial. It considered the log-logistic parametric model for overall survival in the comparator group to have the best fit, and therefore used it in its base-case analysis to model overall survival for both brentuximab vedotin and the comparators. The company's choice was based on clinical plausibility and on how closely the parametric curves aligned with historical data collected from UK patients with CTCL. The committee recalled that a substantial gain in progression-free survival (as seen in the ALCANZA trial) would also result in a gain in overall survival. It discussed an ERG scenario analysis which examined a potential survival gain with brentuximab vedotin for people who did not have a transplant. The ERG's scenario analysis adjusted the company's base-case overall survival curve for the comparators to generate a 9.5‑month mean gain in overall survival for brentuximab vedotin (equal to the mean gain in progression-free survival for people who don't have a transplant when transplant is included in the treatment pathway). The committee noted that the cost-effectiveness estimates for brentuximab vedotin were much higher in this scenario than in the company's base case. In response to consultation, the company presented scenarios exploring the effect of 2, 4, and 9.5\xa0months' survival benefit after brentuximab vedotin for patients who did not have a transplant. The committee was aware that there was no evidence to show which overall survival gain was most likely to be seen in clinical practice, but recalled that assumptions around overall survival affected the post-progression pathway. It concluded that it should consider this in its decision making.\n\n## An overall survival gain of 9.5\xa0months in the model better reflects the post-progression treatment pathway after brentuximab vedotin in clinical practice\n\nThe committee recalled that the company's assumption of equal overall survival with brentuximab vedotin and the comparators alongside a progression-free survival gain with brentuximab vedotin meant that patients having brentuximab vedotin spend less time in the post-progression state than patients having the comparators. The clinical experts explained that the post-progression treatment pathway would be the same for people whose disease relapsed after having brentuximab vedotin (who did not have a transplant) and after having methotrexate or bexarotene. The clinical experts also noted that people having brentuximab vedotin were not expected to have worse outcomes after progression than those having the comparators. The committee therefore agreed that the company's post-progression pathway did not reflect clinical practice. It considered an exploratory analysis by the ERG that assumed equal overall survival and equal time spent in end-stage care for the brentuximab vedotin and comparator arms. The committee understood that this scenario may not accurately represent the current pathway but noted that it was intended to show the model's sensitivity to assumptions about time spent in end-stage care. The committee agreed that both the company's and the ERG's models of the post-progression pathway had limitations, but noted that the scenario analysis assuming a 9.5-month gain in overall survival after brentuximab vedotin (equal to the gain in progression-free survival) made the time spent in end-stage care after brentuximab vedotin similar to the time spent in end-stage care in the comparator arm for patients who did not have a transplant. The committee concluded that although the clinical evidence did not demonstrate a gain in overall survival, based on its effect on the post-progression pathway, a gain in overall survival of 9.5\xa0months with brentuximab vedotin was more likely to reflect clinical practice and should be considered in its decision making.\n\n# Utility values\n\n## The ERG's approach to calculating utility values is more appropriate\n\nTo calculate the utility values for the progression-free state in the model, the company used EQ-5D-3L data from the ALCANZA trial but fitted a regression model including Skindex‑29 scores as a covariate. The committee noted that the cost-effectiveness estimates calculated using Skindex‑29 scores would differ to those based on an approach that excluded the scores. It also noted that the utility values in ALCANZA were higher for brentuximab vedotin than for the comparators because of differences at baseline, and that the ERG considered it more appropriate to assume that the utility values for the progression-free state were equal for brentuximab vedotin and the comparators. The ERG's preferred utility value was calculated using an average of the EQ-5D-3L values from the brentuximab vedotin and comparator groups (0.689). The ERG also preferred not to include treatment-related disutilities based on descriptions of side effects in the model: the EQ-5D-3L data from ALCANZA should capture changes in health-related quality of life as a result of adverse events, so further utility decrements would be unnecessary. The committee concluded that the ERG's approach to modelling utility values was more appropriate and suitable for decision making.\n\n# Costs in the model\n\n## The ERG's resource use scenario should be used in the cost-effectiveness modelling\n\nThe company's original base case included costs for administering oral chemotherapy. The ERG considered this to be double-counting of costs for the comparator group and the committee agreed that extra costs for oral chemotherapy should not be included. In response to consultation, the company removed extra oral chemotherapy costs from its updated base case but the committee noted that this change had little effect on the cost-effectiveness results. The committee recalled that if there are no treatment options remaining, the only option for patients with advanced CTCL is high-resource care (see section 3.21). End-stage care in the company's model included several outpatient appointments and regular visits from both palliative care and Macmillan nurse teams. The company noted that the resource use data were obtained from semi-structured interviews with clinical experts, with mean values used in its base-case model. The clinical experts reiterated that CTCL is a rare disease; any guidelines would likely recommend that patients have regular hospital admissions and visits from district nurses, but in practice it is likely that some patient care will be managed by families and carers. The committee considered the ERG's scenario analysis which reduced the frequency of outpatient appointments, district and Macmillan nurse visits and palliative support based on its clinical expert advice. In response to consultation the company submitted a scenario analysis using the lower range of resource use from the clinical experts. The clinical lead for the Cancer Drugs Fund explained that the company's estimates for resource use in end-stage care may most closely reflect that for patients with very severe advanced disease, with expert advice to NHS England indicating that such intense care and support would apply to around 25% of patients. The committee concluded that the ERG's scenario analysis may better reflect end-stage care for most patients with advanced CTCL.\n\n## Cost-effectiveness estimates are not sensitive to the length of treatment with brentuximab vedotin before stem cell transplant\n\nBoth the company's and ERG's analyses estimated the cost of brentuximab vedotin based on the time-on-treatment data from the ALCANZA study. The company assumed that all patients having a stem cell transplant have the transplant at 18\xa0weeks, after 6\xa0cycles of brentuximab vedotin. The committee recalled the clinical experts' suggestion that if a patient's disease had an adequate response to allow for a transplant, brentuximab vedotin may be stopped after only a few\xa0cycles. In response to consultation the company presented scenario analyses in which transplant was done between 12 and 30\xa0weeks of having brentuximab vedotin. The committee concluded that the length of treatment with brentuximab vedotin before transplant has a limited effect on the cost-effectiveness estimates.\n\n# Cost-effectiveness results\n\n## The company's updated analyses include the committee's preferred assumptions but some uncertainty remains\n\nIn response to consultation, the company updated its base-case analysis to include the committee's preferred assumptions, using equal utility values for both brentuximab vedotin and the comparators, and excluding extra oral chemotherapy costs. The company also presented a number of scenario analyses that explored uncertainties, including:\n\nthe length of treatment before a transplant\n\nthe transplant rate in both the brentuximab vedotin and comparator arms\n\noverall survival in the brentuximab vedotin arm\n\nlower resource use than in the original model. In all updated analyses, brentuximab vedotin was dominant compared with methotrexate or bexarotene (that is, it was more effective and less costly). The committee acknowledged that the company's updated analyses after consultation included all its preferred assumptions, but it recalled that uncertainty remained in terms of the\xa0overall survival benefit, resource use and transplant rate.\n\n## The ERG's cost-effectiveness estimates are higher than the company's estimates\n\nThe ERG presented exploratory analyses to illustrate the sensitivity of the model to different assumptions, including:\n\nassuming an overall survival gain of 9.5\xa0months with brentuximab vedotin (see section 3.20)\n\nusing an alternative progression-free survival curve (changing the proportion and timing of cure) after transplant (see section 3.17)\n\nusing lower resource use for end-stage care (see section 3.23)\n\nusing the transplant rate from UK patients in the ALCANZA trial (16.7%; see section 3.16).Results from the ERG's sensitivity analyses ranged from an incremental cost-effectiveness ratio (ICER) for brentuximab vedotin compared with methotrexate or bexarotene of £58,516 per quality-adjusted life year (QALY) gained, to brentuximab vedotin being dominant (that is, it was both less costly and more effective). The committee noted the wide range of cost-effectiveness estimates in the ERG's scenario analyses and recognised that this was a result of the model's sensitivity to uncertainties in the evidence base.\n\n## Brentuximab vedotin is a cost-effective use of NHS resources for advanced CD30-positive cutaneous T-cell lymphoma after 1 systemic therapy\n\nThe committee recalled that the assumptions which best reflected clinical practice were: a lower transplant rate after brentuximab vedotin (16.7%), overall survival of 9.5\xa0months with brentuximab vedotin, and applying the ERG's lower resource use. Using these assumptions, the ICER for brentuximab vedotin compared with methotrexate or bexarotene was £29,613 per QALY gained. The committee noted that this scenario also included a transplant rate of 7.1% in the comparator arm; it agreed that this rate may be higher than in clinical practice, and so the cost-effectiveness estimate for brentuximab vedotin would be lower (see section 3.16). The committee also recalled that the evidence may not have fully captured the health-related quality of life benefit of brentuximab vedotin, and that doing so would reduce the cost-effectiveness estimate (see section 3.13). It concluded that the most plausible ICER for brentuximab vedotin compared with methotrexate or bexarotene was less than £30,000 per QALY gained, which is within the range normally considered an acceptable use of NHS resources. However, because the clinical and cost-effectiveness data were based on people with specific subtypes of advanced disease (mycosis fungoides stage\xa0IIB or over, primary cutaneous anaplastic large cell lymphoma and Sézary syndrome), the committee concluded that brentuximab vedotin was recommended only for these subtypes.\n\n# Other factors\n\n## Brentuximab vedotin is innovative and health-related quality of life benefits not captured in the analyses should be considered\n\nThe company considered that brentuximab vedotin was an innovative treatment because it represents a step-change in managing a disease for which there is significant unmet need. Brentuximab vedotin may allow more patients to proceed to a potentially curative transplant. The company also highlighted that brentuximab vedotin is given every 3\xa0weeks in an outpatient setting, which means patients need to spend less time in hospital. The clinical experts agreed that brentuximab vedotin was innovative and that clinical trial results showed longer clinical responses which are rarely achieved with current treatments. The committee agreed that brentuximab vedotin would be beneficial for patients, but that it had not been presented with robust health-related quality of life evidence to show any additional benefits. It agreed that this was at least partly because of the health-related quality of life tools available (see section 3.13). It concluded that this should be factored into its considerations of the cost-effectiveness evidence.\n\n## There are no relevant equality issues\n\nThere were no relevant equality issues raised in the company submission or ERG report, or in patient and professional statements. During scoping, stakeholders highlighted that excluding CTCL with less than 5% CD30 expression from the recommendations may deny some patients access to the treatment because of evidence that 1 in 6\xa0cases of CTCL with less than 5% CD30 expression may respond to treatment. However, the marketing authorisation for brentuximab vedotin does not specify a percentage of CD30 expression so this was not considered to be a relevant equality issue.\n\n## Brentuximab vedotin does not meet the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It noted that the company had not provided any evidence to make a case for brentuximab vedotin meeting the criteria to be considered a life-extending treatment at the end of life. It was aware that the clinical experts considered that brentuximab vedotin did not fulfil either criteria for end of life because people with CTCL may survive for several\xa0years after treatment (see section 3.2). Based on advice from the clinical experts and data presented by the company and ERG, the committee accepted that brentuximab vedotin did not meet the end-of-life criteria."}
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https://www.nice.org.uk/guidance/ta577
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Evidence-based recommendations on brentuximab vedotin (Adcetris) for treating CD30-positive cutaneous T-cell lymphoma in adults.
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936a5ca418f69947e91cd56c808799329ef528ef
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nice
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Endoscopic ablation for an anal fistula
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Endoscopic ablation for an anal fistula
Evidence-based recommendations on endoscopic ablation for an anal fistula in adults. This involves applying heat to the fistula.
# Recommendations
Current evidence on endoscopic ablation for an anal fistula raises no major safety concerns and the evidence on efficacy is adequate in quality and quantity. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.# The condition, current treatments and procedure
# The condition
An anal fistula is an abnormal tract between the anal canal and the skin around the anus. It may cause symptoms such as pain or discomfort, and leak blood or pus. It usually results from previous anal abscesses (cryptoglandular), and can be associated with other conditions including inflammatory bowel disease (such as Crohn's disease) and cancer.
Anal fistulas can be classified according to their relationship with the external sphincter. A fistula may be complex, with several openings onto the perianal skin. Intersphincteric fistulas are the most common type and cross only the internal anal sphincter. Trans-sphincteric fistulas pass through both the internal and external sphincters.
# Current treatments
Treatment of an anal fistula commonly involves surgery. The type of surgery depends on the medical history, extent, location and complexity of the fistula in relation to surrounding muscles. The aim is to drain infected material and encourage healing. If the fistula does not heal completely, another surgical procedure may be needed. For simple intersphincteric and low trans-sphincteric anal fistulas, the most common treatment is a fistulotomy or laying open of the fistula tract (involving muscle division that may affect continence). For high and complex (deeper) fistulas that involve more muscle, with a high risk of faecal incontinence or recurrence, surgery aims to treat the fistula and preserve sphincter-muscle function. Techniques include a 1‑stage or 2‑stage seton (suture material or rubber sling) either alone or in combination with fistulotomy, ligation of an intersphincteric fistula tract, creating a mucosal advancement flap, injecting glue or paste, or inserting a fistula plug (in line with NICE's interventional procedures guidance on fistula plug).
# The procedure
Endoscopic ablation of an anal fistula is a less invasive procedure than surgery. It aims to preserve sphincter-muscle function and faecal continence. It may be done in combination with surgical techniques such as creating a mucosal advancement flap.
The procedure is usually done as a day case using spinal or general anaesthesia. With the patient in the lithotomy position, a fistuloscope is inserted into the fistula tract from the external opening. A continuous jet of irrigation solution is used, which allows optimal visualisation of the fistula tract, the internal opening and any secondary tracts or abscess cavities. When the fistuloscope exits through the internal opening to the rectal mucosa, 2 or 3 stitches are inserted to isolate the internal opening. Under direct vision, an electrode is passed through the fistuloscope and the material in the fistula tract is cauterised from the external to the internal opening. All necrotic material is removed using a fistula brush and a continuous jet of irrigation solution. The fistuloscope is removed and the internal opening closed by suturing, stapling or by creating a cutaneous mucosal flap.
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{'Recommendations': 'Current evidence on endoscopic ablation for an anal fistula raises no major safety concerns and the evidence on efficacy is adequate in quality and quantity. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.', 'The condition, current treatments and procedure': "# The condition\n\nAn anal fistula is an abnormal tract between the anal canal and the skin around the anus. It may cause symptoms such as pain or discomfort, and leak blood or pus. It usually results from previous anal abscesses (cryptoglandular), and can be associated with other conditions including inflammatory bowel disease (such as Crohn's disease) and cancer.\n\nAnal fistulas can be classified according to their relationship with the external sphincter. A fistula may be complex, with several openings onto the perianal skin. Intersphincteric fistulas are the most common type and cross only the internal anal sphincter. Trans-sphincteric fistulas pass through both the internal and external sphincters.\n\n# Current treatments\n\nTreatment of an anal fistula commonly involves surgery. The type of surgery depends on the medical history, extent, location and complexity of the fistula in relation to surrounding muscles. The aim is to drain infected material and encourage healing. If the fistula does not heal completely, another surgical procedure may be needed. For simple intersphincteric and low trans-sphincteric anal fistulas, the most common treatment is a fistulotomy or laying open of the fistula tract (involving muscle division that may affect continence). For high and complex (deeper) fistulas that involve more muscle, with a high risk of faecal incontinence or recurrence, surgery aims to treat the fistula and preserve sphincter-muscle function. Techniques include a 1‑stage or 2‑stage seton (suture material or rubber sling) either alone or in combination with fistulotomy, ligation of an intersphincteric fistula tract, creating a mucosal advancement flap, injecting glue or paste, or inserting a fistula plug (in line with NICE's interventional procedures guidance on fistula plug).\n\n# The procedure\n\nEndoscopic ablation of an anal fistula is a less invasive procedure than surgery. It aims to preserve sphincter-muscle function and faecal continence. It may be done in combination with surgical techniques such as creating a mucosal advancement flap.\n\nThe procedure is usually done as a day case using spinal or general anaesthesia. With the patient in the lithotomy position, a fistuloscope is inserted into the fistula tract from the external opening. A continuous jet of irrigation solution is used, which allows optimal visualisation of the fistula tract, the internal opening and any secondary tracts or abscess cavities. When the fistuloscope exits through the internal opening to the rectal mucosa, 2\xa0or 3\xa0stitches are inserted to isolate the internal opening. Under direct vision, an electrode is passed through the fistuloscope and the material in the fistula tract is cauterised from the external to the internal opening. All necrotic material is removed using a fistula brush and a continuous jet of irrigation solution. The fistuloscope is removed and the internal opening closed by suturing, stapling or by creating a cutaneous mucosal flap."}
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https://www.nice.org.uk/guidance/ipg645
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Evidence-based recommendations on endoscopic ablation for an anal fistula in adults. This involves applying heat to the fistula.
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603e33122863bcc0961c15c4f2c30ee7f03e07a9
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nice
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Endoscopic ablation for a pilonidal sinus
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Endoscopic ablation for a pilonidal sinus
Evidence-based recommendations on endoscopic ablation for a pilonidal sinus in adults. This involves applying heat to the pilonidal sinus.
# Recommendations
Current evidence on endoscopic ablation for a pilonidal sinus raises no major safety concerns and the evidence on efficacy is adequate in quality and quantity. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.# The condition, current treatments and procedure
# The condition
A pilonidal sinus is a small infected tract or a network of interlinking tracts under the skin between the buttocks. The exact cause is unknown but it may be from loose hairs pushing into the skin, combined with friction from clothes. The risk of developing a pilonidal sinus is increased by spending long periods of time sitting down, being overweight, a persistent irritation or injury to the affected area, having a hairy buttock cleft or a family history of the condition.
A pilonidal sinus does not usually cause symptoms unless it is infected and an abscess develops causing pain, redness, swelling under the skin and leakage of blood and pus.
# Current treatments
Treatments include conservative management with regular bathing and keeping the area dry, and antibiotics if the sinus is infected. However this does not close the sinus tract. Procedures to close the sinus include injecting fibrin glue and surgical excision.
# The procedure
Endoscopic ablation of a pilonidal sinus is less invasive than surgery and is usually done as a day case, using spinal or local anaesthesia. With the patient in the prone position, the external opening of the sinus is incised and a fistuloscope is inserted into the sinus tract. A continuous jet of irrigation solution is used, allowing optimal visualisation and assessment of the inside of the sinus. Under direct vision, forceps are used to remove hairs, infected tissue and any debris. Then an electrode is passed through the fistuloscope to cauterise the main sinus tract and any secondary tracts or abscess cavities. Necrotic material is removed using an endobrush and the sinus tract is cleaned using irrigation solution.
|
{'Recommendations': 'Current evidence on endoscopic ablation for a pilonidal sinus raises no major safety concerns and the evidence on efficacy is adequate in quality and quantity. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.', 'The condition, current treatments and procedure': '# The condition\n\nA pilonidal sinus is a small infected tract or a network of interlinking tracts under the skin between the buttocks. The exact cause is unknown but it may be from loose hairs pushing into the skin, combined with friction from clothes. The risk of developing a pilonidal sinus is increased by spending long periods of time sitting down, being overweight, a persistent irritation or injury to the affected area, having a hairy buttock cleft or a family history of the condition.\n\nA pilonidal sinus does not usually cause symptoms unless it is infected and an abscess develops causing pain, redness, swelling under the skin and leakage of blood and pus.\n\n# Current treatments\n\nTreatments include conservative management with regular bathing and keeping the area dry, and antibiotics if the sinus is infected. However this does not close the sinus tract. Procedures to close the sinus include injecting fibrin glue and surgical excision.\n\n# The procedure\n\nEndoscopic ablation of a pilonidal sinus is less invasive than surgery and is usually done as a day case, using spinal or local anaesthesia. With the patient in the prone position, the external opening of the sinus is incised and a fistuloscope is inserted into the sinus tract. A continuous jet of irrigation solution is used, allowing optimal visualisation and assessment of the inside of the sinus. Under direct vision, forceps are used to remove hairs, infected tissue and any debris. Then an electrode is passed through the fistuloscope to cauterise the main sinus tract and any secondary tracts or abscess cavities. Necrotic material is removed using an endobrush and the sinus tract is cleaned using irrigation solution.'}
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https://www.nice.org.uk/guidance/ipg646
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Evidence-based recommendations on endoscopic ablation for a pilonidal sinus in adults. This involves applying heat to the pilonidal sinus.
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b0cc67b0912cf466c8db7ab9a421f4b89cb542ce
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nice
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Certolizumab pegol for treating moderate to severe plaque psoriasis
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Certolizumab pegol for treating moderate to severe plaque psoriasis
Evidence-based recommendations on certolizumab pegol (Cimzia) for treating moderate to severe plaque psoriasis in adults.
# Recommendations
Certolizumab pegol is recommended as an option for treating plaque psoriasis in adults, only if:
the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 and
the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and
the lowest maintenance dosage of certolizumab pegol is used (200 mg every 2 weeks) after the loading dosage and
the company provides the drug according to the commercial arrangement.
Stop certolizumab pegol at 16 weeks if the psoriasis has not responded adequately. An adequate response is defined as:
a 75% reduction in the PASI score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from when treatment started.
If patients and their clinicians consider certolizumab pegol to be one of a range of suitable treatments, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).
When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with certolizumab pegol that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Certolizumab pegol is proposed as an alternative to other biological treatments already recommended by NICE for treating severe plaque psoriasis in adults. It is also proposed as an alternative to systemic non-biological treatments such as methotrexate, ciclosporin and acitretin in adults who have not had systemic treatment.
Clinical trial results show that certolizumab pegol improves severe plaque psoriasis more than either placebo or etanercept. When compared indirectly, it appears to be as effective as other biological treatments for the condition, and also appears to be more effective than non-biological treatments.
Cost-effectiveness estimates for certolizumab pegol show that:
For people who have not had previous systemic non-biological treatments, the lowest licensed maintenance dose (200 mg) is not cost effective compared with systemic non-biological treatments.
For people who have had systemic non-biological treatments and whose psoriasis has not responded, the lowest licensed maintenance dose (200 mg) has a similar cost effectiveness to other biological treatments.
For people whose psoriasis has partially responded to the lowest licensed maintenance dose, increasing to the highest licensed dose (400 mg) is not cost effective compared with switching to an alternative biological treatment.Therefore, certolizumab pegol at its lowest licensed maintenance dosage (200 mg) is recommended as an option for use in the NHS for severe psoriasis that has not responded to systemic non-biological treatments, or if these are contraindicated or not tolerated.# Information about certolizumab pegol
Marketing authorisation indication
Certolizumab pegol (Cimzia; UCB Pharma) is indicated 'for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.
Dosage in the marketing authorisation
Loading dosage
The recommended starting dosage of certolizumab pegol for adults is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4.
Maintenance dosage
The maintenance dosage of certolizumab pegol for adults is 200 mg every 2 weeks. A dosage of 400 mg every 2 weeks can be considered when there is an insufficient response.
Available data in adults with plaque psoriasis suggest that there is usually a clinical response within 16 weeks of treatment. Continued treatment should be carefully reconsidered in people whose psoriasis shows no evidence of therapeutic benefit within the first 16 weeks of treatment. Sometimes, when there is an initial partial response, it may subsequently improve with continued treatment beyond 16 weeks.
Price
£357.50 per 200 mg pre-filled pen or syringe (excluding VAT, British national formulary online; accessed February 2019).
The company has a commercial arrangement. It is the company's responsibility to let relevant NHS organisations know details of the arrangement.# Committee discussion
The appraisal committee (section 6) considered evidence submitted by UCB Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Experience of people with psoriasis
## Psoriasis is a lifelong condition that affects all aspects of a person's life
Psoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological, social and financial), and it is a lifelong condition. The committee noted that having treatments with few or manageable side effects, and which are effective for psoriasis on the face, hands, feet and genitals, is especially important to people with psoriasis, as is having a choice of treatments.
# Clinical management
## Psoriasis can be treated with topical therapies, phototherapy, and systemic non-biological and biological treatments
People with plaque psoriasis may have topical therapies first line, followed by phototherapy second line. If these do not control the psoriasis, people may have systemic conventional non-biological treatments third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to these, people may have fourth-line treatment including systemic biological treatments (such as adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, infliximab, secukinumab or ustekinumab), or apremilast or dimethyl fumarate. Biosimilar versions of some biological treatments are also available. The drugs are used for as long as they continue to work. If the disease no longer responds to 1 biological treatment, people will be offered another biological treatment. This pattern is likely to be repeated over their lifetime. However, 1 clinical expert explained that switching treatments is likely to affect the effectiveness of subsequent drugs, although there is uncertainty about the degree to which this occurs. For people whose disease does not respond to multiple biological treatments, apremilast or dimethyl fumarate, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging.
# Treatment pathway
## Certolizumab pegol is most likely to be used as an alternative to other systemic biological treatments
The marketing authorisation for certolizumab is for 'adults who are candidates for systemic therapy'. In its submission, the company positioned certolizumab pegol as an alternative to: systemic non-biological treatments such as methotrexate, ciclosporin and acitretin, and following topical therapy and phototherapy; or biological treatments. The committee was aware that, in previous appraisals, biological treatments were only recommended for psoriasis that has not responded to previous systemic non-biological treatments or when these treatments are contraindicated or not tolerated. The clinical experts explained that biological treatments would be unlikely to be considered at the earlier position because of their higher cost compared with the non-biological treatments used in this setting. One clinical expert stated that, if cost was not an issue, some people may prefer a biological treatment at this point in the pathway and that this approach may sometimes be reasonable. The committee agreed that certolizumab pegol is more likely to be used at the same position as alternative biological treatments, but recognised there was some interest in using it earlier. It concluded that it would consider the clinical and cost effectiveness of certolizumab pegol in both positions.
## The most relevant comparators to certolizumab pegol for people who have not had systemic treatments are non-biological systemic treatments
The company identified systemic non-biological treatments, such as methotrexate, ciclosporin and acitretin, as relevant comparators for people with psoriasis who had not had previous systemic treatment. The committee was aware that some other biological treatments had similar marketing authorisations to certolizumab pegol but had not been recommended for use in this population. It recalled that biological treatments are not used in this population because of their higher cost (see section 3.3). It therefore concluded that systemic non‑biological treatments were the most relevant comparators to certolizumab pegol for people who have not had systemic treatments.
## The most relevant comparators to certolizumab pegol for psoriasis that has not responded to systemic non-biological treatments are other biologicals
The company suggested that the systemic non-biological treatments apremilast and dimethyl fumarate, used in NHS clinical practice at the same position as systemic biological treatments, were not relevant comparators for psoriasis that has not responded to previous systemic non-biological treatments, or when these treatments are contraindicated or not tolerated. The clinical expert explained that these options were rarely used in practice because they are perceived to be less effective than biological treatments. They would only be considered for use for people for whom a biological treatment was unsuitable or who were unwilling to have a biological treatment. The committee concluded that although apremilast and dimethyl fumarate are used in the NHS for some people with psoriasis, the most relevant comparators to certolizumab pegol were other biological treatments.
# Clinical evidence
## The CIMPASI and CIMPACT trials provide the key clinical evidence for certolizumab pegol
The main evidence for certolizumab pegol came from the CIMPASI trials 1 and 2, and the CIMPACT trial. These were double-blind randomised controlled trials that included a total of 1,020 patients with plaque psoriasis. They compared 2 doses of certolizumab pegol (200 mg or 400 mg) with placebo (all trials) and etanercept (CIMPACT only). The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the static Physician Global Assessment (sPGA). They were assessed at the end of the induction period (16 weeks in the CIMPASI trials and 12 weeks in CIMPACT) as follows:
In the CIMPASI trials, the co-primary outcomes were the proportion of patients with:
a 75% reduction in the PASI score from when treatment started (PASI 75) and
a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the sPGA.
In the CIMPACT trial, the primary outcome was a PASI 75.Patients in all 3 trials were followed up in open-label extension studies. The company presented open-label follow-up data up to 48 weeks (the trials are scheduled to follow up patients for 144 weeks in total).
## Patients in the certolizumab pegol clinical trials are sufficiently generalisable to those who would have certolizumab pegol in the NHS for decision making
The committee considered whether patients in the CIMPASI trials and in CIMPACT were similar to those in NHS clinical practice for:
Severity of disease: CIMPASI and CIMPACT included patients with 'moderate to severe' psoriasis with a PASI score of 12 or more. No minimum Dermatology Life Quality Index (DLQI) score was specified. Previous NICE technology appraisals defined 'severe' and 'very severe' psoriasis based on the PASI and DLQI; the PASI threshold for 'severe' is 10 or more.
Previous treatment: the committee noted that about 29% of patients in the CIMPASI and CIMPACT trials had not had any previous systemic treatment or phototherapy. This is inconsistent with the current positioning of biological treatments in the NHS (see section 3.3) and may overestimate the clinical effectiveness of certolizumab pegol. One clinical expert explained that international trials may include patients who have not had previous treatment because of different prescribing practices across countries. The committee was aware that only a small number of patients were recruited in the UK, and that these patients were all recruited for the CIMPACT trial.
People who had not had previous systemic therapy: The company stated that, in the CIMPASI and CIMPACT trials, similar PASI 75 response rates were reported in subgroups of patients who had previously had systemic treatment or phototherapy compared with those who had not. The committee noted that the subgroup of patients who had not had systemic non-biological treatment reflected the company's proposed positioning of certolizumab pegol at an earlier setting than that for biological treatments in the NHS. The exception was that none of the patients in this subgroup in the clinical trials had previously had phototherapy.The committee concluded that, while patients in the trials did not fully reflect those who would have certolizumab pegol in NHS practice, they were sufficiently generalisable for decision making.
## Certolizumab pegol is more clinically effective than placebo and etanercept
The committee noted that patients randomised to certolizumab pegol were clinically and statistically significantly more likely to have a PASI 75 and sPGA 0 or 1 response rates at week 16 compared with placebo, and a PASI 75 at week 12 compared with etanercept. The committee concluded that certolizumab pegol was more clinically effective than placebo and etanercept.
## There is no clinical evidence directly comparing certolizumab pegol with the non-biological treatments used earlier in the treatment pathway
The company presented clinical evidence comparing certolizumab pegol with placebo for the subgroup of patients who had not had previous systemic treatment. This showed a statistically significant and clinically meaningful increase in response rates for certolizumab pegol compared with placebo. The clinical experts explained that the relevant comparators in people who have not had previous systemic treatment are systemic non-biological treatments (methotrexate, ciclosporin and acitretin). The committee concluded that there was no clinical trial evidence directly comparing certolizumab pegol with systemic non-biological treatments.
## The company's network meta-analysis suggests that a PASI 75 response is more likely with certolizumab pegol than with non-biological treatments
The company's base-case network meta-analysis compared certolizumab pegol with non-biological treatments (methotrexate, acitretin and ciclosporin). The results showed that treatment with a 200 mg maintenance dose of certolizumab pegol resulted in statistically significantly improved PASI 75 response rates compared with all the non-biological treatments. The committee noted that these results were based on a small number of patients so were highly uncertain. It concluded that a PASI 75 response was more likely with certolizumab pegol than with non-biological treatments, but the extent of this benefit was unclear.
## A PASI 75 response is more likely with certolizumab pegol than with adalimumab or etanercept, and as likely as with other biological treatments
The company's base-case network meta-analysis also compared certolizumab pegol with other biological treatments (adalimumab, brodalumab, etanercept, guselkumab, infliximab, ixekizumab, secukinumab and ustekinumab) using data from 65 trials. It showed that a 200 mg maintenance dose of certolizumab pegol resulted in PASI 75 response rates that were:
statistically significantly higher than the TNF‑alpha inhibitor etanercept
higher (but not statistically significantly so) than the TNF-alpha inhibitor adalimumab
similar to the interleukin inhibitors (brodalumab, guselkumab, ixekizumab, secukinumab and ustekinumab).
## When there is a partial response to the 200 mg certolizumab pegol dose, there may be an improved response to an increased dose
The committee noted that increasing the maintenance dose from 200 mg every 2 weeks to 400 mg every 2 weeks is within certolizumab pegol's marketing authorisation. The company stated that people whose disease had a partial response (defined as a PASI 50 to PASI 74) after 16 weeks of treatment with certolizumab pegol at a maintenance dose of 200 mg were the most likely group for whom this would be considered. It presented evidence from CIMPACT showing that most patients in this group had a PASI 75 response after a further 16 weeks of treatment with certolizumab pegol at the increased maintenance dose of 400 mg. The company stated that there were no prognostic factors identified in the trial that indicated whether a person whose disease had a partial response would be likely to have a PASI 75 response after increasing the dose. The committee noted that the trials did not compare the efficacy of increasing the dose of certolizumab pegol with either placebo or another active treatment. Also, the results for patients whose disease had a partial response were based on a small number of patients. It noted that the company's definition of partial response may have included people with a PASI 50 response and a 5‑point reduction in the DLQI, which is recommended by NICE as an alternative to the PASI 75 to assess response to treatment. The committee would have preferred to see efficacy results that excluded this group, although it recognised that this exclusion would have further reduced the number of patients whose disease was defined as having a partial response and increased the uncertainty of the clinical effectiveness of increasing the dose. The committee noted that people whose disease had a partial response to certolizumab pegol and no, or manageable, adverse events may prefer to continue on a higher dose of certolizumab pegol than to switch to an alternative treatment, which could be less well tolerated. It also noted that psoriasis is a lifelong condition and that people with psoriasis would be likely to try several treatments over their lifetime, so may wish to continue with their current treatment at a higher dose and reserve other biological treatments for future use. The committee concluded that it was appropriate to consider the cost effectiveness of increasing the dosage to 400 mg every 2 weeks in people whose disease had a partial response to certolizumab pegol 200 mg every 2 weeks.
# Company's economic model
## The model has a Markov state transition structure
A Markov state transition model was used to assess the cost effectiveness of certolizumab pegol. The company assumed that treatments improved quality of life but did not extend length of life. The model contained 4 health states: induction treatment, maintenance treatment, best supportive care and death. All patients entered the model in the induction state and had the first treatment in a given sequence. They moved from the induction state to the maintenance state if there was at least a PASI 75 response measured at the end of induction. From there, some patients could stop treatment for any reason and move to the next treatment in the sequence. If there was not a PASI 75 response, patients moved to the induction phase of the next treatment in the sequence. Patients moved to the best supportive care state if their psoriasis did not respond to the last active treatment in a sequence. All patients could move to the death state at any time.
## There are 9 treatment sequences in the company's model when comparing certolizumab pegol with other biological treatments
The company's decision problem compared a sequence of treatments including certolizumab pegol with 8 treatment sequences excluding certolizumab pegol. The treatment sequences chosen by the company were:
The first treatment was either certolizumab pegol or another biological treatment (adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab or ustekinumab ).
The second treatment was ustekinumab (90 mg), except in the sequences in which ustekinumab was used as the first treatment; in these sequences, adalimumab was used as the second treatment.
The third treatment was infliximab.
After that, treatment in all sequences was best supportive care.The company chose these sequences based on expert advice. The committee was aware that, over time, a sequence of biological treatments will be used to treat severe psoriasis in current NHS practice as people switch from 1 option to another. It was also aware that additional factors should be considered when comparing treatment sequences, such as the best ordering of treatments and the effect of including treatments that may not be cost effective. The committee agreed that, in principle, it was appropriate to compare treatment sequences in this appraisal.
# Assumptions in the economic model
## Key assumptions in the economic model are acceptable for decision making
The company made several assumptions in the economic model that were consistent with the approach taken in previous appraisals for psoriasis, including:
a common stopping rate of 20% for all treatments during maintenance treatment
an equal treatment effect regardless of the position of a treatment in a sequence
a treatment effect that is sustained throughout the entire treatment period.The committee was aware that there was limited evidence to support or dispute these assumptions, but concluded that they were consistent with previous appraisals so were acceptable for decision making.
## Several of the ERG's preferred assumptions are incorporated into the company's base case
In response to clarification, the company updated its base-case analysis to incorporate several of the ERG's preferred base-case assumptions, including:
basing utility values only on patients with a DLQI score of greater than 10 to reflect patients who would have biological treatment in the NHS
assuming that utility values for patients who had treatment with biological treatments and best supportive care were equal
using the drug acquisition costs of the biosimilars of etanercept and infliximab in place of costs for the reference product.The committee concluded that including these assumptions was appropriate.
# Costs in the economic model
## The cost of best supportive care for moderate to severe psoriasis is uncertain
The company calculated the cost of best supportive care based on:
drug acquisition costs from the British national formulary, with proportions of patients on each treatment based on clinical expert opinion and mean treatment duration from Fonia et al. (2010)
secondary care costs from Fonia et al. inflated to 2017 values.The committee was aware that previous appraisals used drug acquisition costs from either NICE's guideline on psoriasis (based on Fonia et al.) or Fonia et al. itself. This company's alternative approach resulted in a lower cost for best supportive care because of a fall in the price of ciclosporin and because fumaric acid esters were excluded from best supportive care. The committee was also aware that secondary care costs from Fonia et al. did not reflect clinical practice and were likely to have overestimated the costs of secondary care. It concluded that the cost of best supportive care for moderate to severe psoriasis was uncertain. The committee further concluded that defining costs associated with psoriasis that reflect current clinical practice was an important area for research.
## The ERG's analysis using alternative best supportive care costs is useful for decision making
The lower cost of best supportive care used in the company's base case (see section 3.17) had important implications for the cost-effectiveness results from the economic model. Firstly, compared with best supportive care, no treatment in the company's model had an incremental cost-effectiveness ratio (ICER) lower than £30,000 per quality-adjusted life year (QALY) gained. Secondly, treatments with a lower efficacy could appear to be more cost effective than treatments with a higher efficacy and a similar cost. This was because treatments with lower response rates led to patients in the model advancing to best supportive care more quickly, and therefore incurring lower costs. The ERG also did an exploratory analysis incorporating assumptions from NICE's technology appraisal guidance on brodalumab, which included higher costs for best supportive care than in the company's analysis. The ERG noted that these assumptions were not necessarily superior to those in the company's base case but were presented for illustrative purposes. In this analysis, several biological treatments were cost effective compared with best supportive care. The committee concluded that it was appropriate to consider the ERG's analysis using alternative best supportive care costs in its decision making.
# Cost-effectiveness estimates
## Treatment sequences may result in misleading cost-effectiveness estimates
The committee was aware that treatment sequences, although more likely to reflect the treatment switching seen in clinical practice, may have provided misleading cost-effectiveness estimates for certolizumab pegol. It noted that some of the treatments were not cost effective in the model. Therefore, the cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding potentially cost-ineffective subsequent treatments, or by choosing treatments with lower response rates, resulting in an earlier transition to best supportive care (see section 3.18). The committee was also aware that the company's model compared a limited number of all potential treatment sequences. The ERG set subsequent options in all sequences to best supportive care, so that the only difference between sequences was the first treatment used. The committee concluded that it would consider these comparisons of individual treatments with best supportive care in its decision making.
## Certolizumab pegol is not cost effective earlier in the treatment pathway compared with non‑biological treatments for severe psoriasis
The committee considered whether certolizumab pegol would be a cost‑effective use of NHS resources for people with severe psoriasis who have not had systemic treatment, that is, when the disease has not responded to topical treatments and phototherapy, or they are contraindicated or not tolerated (earlier than the current position for biological treatments in NHS practice). It recalled that there was no clinical evidence directly comparing certolizumab pegol with standard care in this population; evidence for the clinical efficacy of certolizumab pegol relative to methotrexate, ciclosporin and acitretin was based on the company's network meta-analysis (see section 3.10):
The company's base-case cost-effectiveness analysis used efficacy data from the placebo arms of the CIMPASI and CIMPACT trials as a proxy for standard care. The committee agreed that this was inappropriate because standard care (systemic non-biological treatment) is an active comparator. The committee considered an alternative analysis presented by the company, which used efficacy data for methotrexate from the subgroup of patients who had not had systemic treatment in the company's network meta‑analysis. The committee was aware that these data were based on a small number of patients, so the indirect comparison was subject to a high degree of uncertainty. It noted that, in the company's scenario analysis, certolizumab pegol had an ICER of £18,145 per QALY gained compared with methotrexate.
The committee noted that the company's scenario analysis compared the following 2 sequences:
methotrexate, followed by adalimumab, ustekinumab, infliximab and best supportive care
certolizumab pegol 200 mg, followed by ustekinumab, infliximab and best supportive care.The committee agreed that the treatment sequences compared by the company were selective. It would have preferred to have seen standard care (methotrexate) sequences that included alternative biological treatments as the second treatment in the sequence, including certolizumab pegol. The ERG presented a scenario analysis comparing the following 2 sequences:
methotrexate, followed by certolizumab pegol 200 mg, ustekinumab, infliximab and best supportive care
certolizumab pegol 200 mg, followed by ustekinumab, infliximab and best supportive care.This comparison resulted in an ICER of over £400,000 per QALY gained. The committee recalled its previous conclusion that it was appropriate to consider sequences in which subsequent biological therapies in the treatment sequence were replaced by best supportive care (see section 3.19). Modifying the ERG's scenario analysis in this way resulted in 2 sequences:
methotrexate, followed by certolizumab pegol 200 mg and best supportive care
certolizumab pegol 200 mg, followed by best supportive care.The committee noted that, in this analysis, certolizumab pegol had a similar QALY gain to methotrexate at a much higher cost. The committee considered the ERG's analysis to be more appropriate than the company's. It therefore concluded that certolizumab pegol was not a cost-effective use of NHS resources, and that it could not recommend certolizumab pegol as an option for treating severe chronic plaque psoriasis that has not been treated with non-biological systemic treatments.
## Certolizumab pegol is cost effective compared with other biological treatments for severe psoriasis
The committee considered whether certolizumab pegol would be a cost‑effective use of NHS resources for people with severe psoriasis for whom non-biological treatment has failed or is contraindicated or not tolerated. To do this, it took into account the patient access schemes for brodalumab, guselkumab, ixekizumab and secukinumab. The committee noted that several treatments had only small differences in total costs and QALY gains, and that these small differences could be difficult to see using ICERs from fully incremental or pairwise analyses. The ERG therefore presented the cost-effectiveness results in a net monetary benefit framework. The committee agreed that this analysis was useful to support decision making. It noted that certolizumab pegol was similarly or more cost effective than alternative biological treatments in both the company's and ERG's base cases, but recalled that these analyses may have disadvantaged treatments with higher response rates (see section 3.18). It therefore considered the ERG's alternative base case (using best supportive care costs from previous guidance) and noted that, in this analysis, compared with best supportive care, certolizumab pegol had:
a lower pairwise ICER than the interleukin inhibitor ustekinumab and the TNF‑alpha inhibitor etanercept
a similar pairwise ICER (range about £19,500 to £21,500 per QALY gained) to the interleukin inhibitors brodalumab, ixekizumab, guselkumab and secukinumab
a higher pairwise ICER than the TNF-alpha inhibitor adalimumab.The committee agreed that people with psoriasis would value the option of an alternative TNF‑alpha inhibitor that was more effective than etanercept and could be used during pregnancy (see section 3.25). It therefore concluded that it could recommend certolizumab pegol as an option for treating severe chronic plaque psoriasis that has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or if these options are contraindicated or not tolerated.
## The cost effectiveness of increasing the maintenance dose of certolizumab pegol should be assessed by comparing it with switching to another biological
The committee recalled its previous conclusion that the cost effectiveness of increasing the maintenance dose of certolizumab pegol in people whose disease partially responded should be considered (see section 3.12). It noted that the company's base case compared 2 sequences:
certolizumab pegol 200 mg increased to certolizumab pegol 400 mg (when there is a partial response, defined as a PASI 50 to 74) or ustekinumab (when there is no response, defined as a PASI less than 50), followed by ustekinumab, infliximab and best supportive care
adalimumab 40 mg increased to adalimumab 80 mg (for partial and no response), followed by ustekinumab, infliximab and best supportive care.The company and the ERG also presented several scenario analyses in which increasing the dose of certolizumab pegol was compared with switching to ixekizumab, secukinumab and ustekinumab. The committee recalled that, in the CIMPACT trial, there were no prognostic factors identifying people who were likely to benefit from increasing the dose of certolizumab pegol (see section 3.12). It also noted that clinicians would be unlikely to make treatment decisions based on people needing a future dose increase because it would not be known whose disease would have a partial response and need an increased dose. Therefore, it concluded that a comparison between increasing the maintenance dose of certolizumab pegol from 200 mg to 400 mg and increasing the maintenance dose of adalimumab from 40 mg to 80 mg was not clinically relevant. It also concluded that the most relevant comparison would be between increasing the maintenance dose of certolizumab pegol from 200 mg to 400 mg and switching from certolizumab pegol to another biological treatment.
## It is not cost effective to increase the dose of certolizumab pegol to 400 mg if response to the 200 mg dose is inadequate
The company noted in its response to the appraisal consultation document that the ERG scenarios switching to alternative biological treatments (see section 3.22) used efficacy data from the CIMPACT trial for certolizumab pegol (see section 3.12) and the network meta-analysis (see section 3.11) for comparators. It was concerned that this may bias results against certolizumab pegol because this approach assumed that the comparator (used second line in the sequence) is as clinically effective as if it had been used first line. The company therefore provided additional scenario analyses which used the network meta-analysis results for both certolizumab pegol and the comparator, or (in the absence of clinical trial data for the comparator) assumed that the comparator had equivalent efficacy to certolizumab pegol in CIMPACT. The committee concluded that although this was a source of uncertainty, the scenario analyses exploring alternative assumptions had only a small effect on the cost‑effectiveness results and did not affect decision making. The company also explained that the cost of increasing the maintenance dose of certolizumab pegol may have been overestimated by a small amount because, in the model, patients who stopped certolizumab pegol 200 mg because of adverse events then had certolizumab pegol 400 mg, which would not occur in clinical practice. The committee concluded that, although this was a limitation in the model structure, the resulting overestimation in costs was likely to have a minimal effect on the cost-effectiveness results because it only applied to a small number of patients. After taking into account all confidential commercial arrangements for comparator treatments, the ICERs for certolizumab pegol were considerably above the range usually considered cost effective by NICE. The committee therefore concluded that increasing the maintenance dose was not cost effective.
## Certolizumab pegol should be stopped if there is an inadequate response at 16 weeks
Previous NICE technology appraisals for treating psoriasis have recommended stopping treatment if there is an inadequate response. An adequate response is defined as either a 75% reduction in the PASI score from when treatment started, or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. The committee agreed that, if there was an inadequate response to certolizumab pegol, treatment should be stopped. It noted that PASI 75, assessed 16 weeks after starting treatment, was recommended as appropriate to assess response in the summary of product characteristics. It also recalled its previous conclusion that increasing the dose of certolizumab pegol when psoriasis has responded inadequately was not a cost-effective strategy (see section 3.23). The committee therefore concluded that certolizumab pegol should be stopped if there is an inadequate response at 16 weeks using the same definition of an adequate response as in previous NICE technology appraisals.
# Equality issues
## Certolizumab pegol can be used before and during pregnancy if clinically needed and while breastfeeding
The summary of product characteristics for certolizumab pegol states that it can be used during pregnancy if clinically needed and while breastfeeding. The clinical experts considered this to be reasonable. The patient experts explained that people who are pregnant or who are considering pregnancy would welcome further effective treatment options for plaque psoriasis that do not need to be stopped before and during pregnancy (if clinically needed), or while breastfeeding. The committee concluded that these patients would value an additional treatment option.
## The PASI and DLQI may not be appropriate for all people with psoriasis
The committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:
the PASI might underestimate disease severity in people with darker skin
the DLQI has limited validity in some people, and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.# Recommendations for research
The committee noted that the costs of best supportive care are derived from a study published in 2010 and that clinical practice has changed substantially since then. It therefore considered that it would be valuable to have studies investigating:
the costs associated with best supportive care
resource use, including frequency and length of hospitalisation, and associated costs.
|
{'Recommendations': 'Certolizumab pegol is recommended as an option for treating plaque psoriasis in adults, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of\xa010 or more and a Dermatology Life Quality Index (DLQI) of more than\xa010 and\n\nthe disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and\n\nthe lowest maintenance dosage of certolizumab pegol is used (200\xa0mg every 2\xa0weeks) after the loading dosage and\n\nthe company provides the drug according to the commercial arrangement.\n\nStop certolizumab pegol at 16\xa0weeks if the psoriasis has not responded adequately. An adequate response is defined as:\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from when treatment started.\n\nIf patients and their clinicians consider certolizumab pegol to be one of a range of suitable treatments, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with certolizumab pegol that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCertolizumab pegol is proposed as an alternative to other biological treatments already recommended by NICE for treating severe plaque psoriasis in adults. It is also proposed as an alternative to systemic non-biological treatments such as methotrexate, ciclosporin and acitretin in adults who have not had systemic treatment.\n\nClinical trial results show that certolizumab pegol improves severe plaque psoriasis more than either placebo or etanercept. When compared indirectly, it appears to be as effective as other biological treatments for the condition, and also appears to be more effective than non-biological treatments.\n\nCost-effectiveness estimates for certolizumab pegol show that:\n\nFor people who have not had previous systemic non-biological treatments, the lowest licensed maintenance dose (200\xa0mg) is not cost effective compared with systemic non-biological treatments.\n\nFor people who have had systemic non-biological treatments and whose psoriasis has not responded, the lowest licensed maintenance dose (200\xa0mg) has a similar cost effectiveness to other biological treatments.\n\nFor people whose psoriasis has partially responded to the lowest licensed maintenance dose, increasing to the highest licensed dose (400\xa0mg) is not cost effective compared with switching to an alternative biological treatment.Therefore, certolizumab pegol at its lowest licensed maintenance dosage (200\xa0mg) is recommended as an option for use in the NHS for severe psoriasis that has not responded to systemic non-biological treatments, or if these are contraindicated or not tolerated.', 'Information about certolizumab pegol': "Marketing authorisation indication\n\nCertolizumab pegol (Cimzia; UCB Pharma) is indicated 'for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.\n\nDosage in the marketing authorisation\n\nLoading dosage\n\nThe recommended starting dosage of certolizumab pegol for adults is 400\xa0mg (given as 2\xa0subcutaneous injections of 200\xa0mg each) at weeks\xa00, 2\xa0and\xa04.\n\nMaintenance dosage\n\nThe maintenance dosage of certolizumab pegol for adults is 200\xa0mg every 2\xa0weeks. A dosage of 400\xa0mg every 2\xa0weeks can be considered when there is an insufficient response.\n\nAvailable data in adults with plaque psoriasis suggest that there is usually a clinical response within 16\xa0weeks of treatment. Continued treatment should be carefully reconsidered in people whose psoriasis shows no evidence of therapeutic benefit within the first 16\xa0weeks of treatment. Sometimes, when there is an initial partial response, it may subsequently improve with continued treatment beyond 16\xa0weeks.\n\nPrice\n\n£357.50 per 200\xa0mg pre-filled pen or syringe (excluding VAT, British national formulary online; accessed February 2019).\n\nThe company has a commercial arrangement. It is the company's responsibility to let relevant NHS organisations know details of the arrangement.", 'Committee discussion': "The appraisal committee (section\xa06) considered evidence submitted by UCB Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Experience of people with psoriasis\n\n## Psoriasis is a lifelong condition that affects all aspects of a person's life\n\nPsoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological, social and financial), and it is a lifelong condition. The committee noted that having treatments with few or manageable side effects, and which are effective for psoriasis on the face, hands, feet and genitals, is especially important to people with psoriasis, as is having a choice of treatments.\n\n# Clinical management\n\n## Psoriasis can be treated with topical therapies, phototherapy, and systemic non-biological and biological treatments\n\nPeople with plaque psoriasis may have topical therapies first line, followed by phototherapy second line. If these do not control the psoriasis, people may have systemic conventional non-biological treatments third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to these, people may have fourth-line treatment including systemic biological treatments (such as adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, infliximab, secukinumab or ustekinumab), or apremilast or dimethyl fumarate. Biosimilar versions of some biological treatments are also available. The drugs are used for as long as they continue to work. If the disease no longer responds to 1\xa0biological treatment, people will be offered another biological treatment. This pattern is likely to be repeated over their lifetime. However, 1\xa0clinical expert explained that switching treatments is likely to affect the effectiveness of subsequent drugs, although there is uncertainty about the degree to which this occurs. For people whose disease does not respond to multiple biological treatments, apremilast or dimethyl fumarate, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging.\n\n# Treatment pathway\n\n## Certolizumab pegol is most likely to be used as an alternative to other systemic biological treatments\n\nThe marketing authorisation for certolizumab is for 'adults who are candidates for systemic therapy'. In its submission, the company positioned certolizumab pegol as an alternative to: systemic non-biological treatments such as methotrexate, ciclosporin and acitretin, and following topical therapy and phototherapy; or biological treatments. The committee was aware that, in previous appraisals, biological treatments were only recommended for psoriasis that has not responded to previous systemic non-biological treatments or when these treatments are contraindicated or not tolerated. The clinical experts explained that biological treatments would be unlikely to be considered at the earlier position because of their higher cost compared with the non-biological treatments used in this setting. One clinical expert stated that, if cost was not an issue, some people may prefer a biological treatment at this point in the pathway and that this approach may sometimes be reasonable. The committee agreed that certolizumab pegol is more likely to be used at the same position as alternative biological treatments, but recognised there was some interest in using it earlier. It concluded that it would consider the clinical and cost effectiveness of certolizumab pegol in both positions.\n\n## The most relevant comparators to certolizumab pegol for people who have not had systemic treatments are non-biological systemic treatments\n\nThe company identified systemic non-biological treatments, such as methotrexate, ciclosporin and acitretin, as relevant comparators for people with psoriasis who had not had previous systemic treatment. The committee was aware that some other biological treatments had similar marketing authorisations to certolizumab pegol but had not been recommended for use in this population. It recalled that biological treatments are not used in this population because of their higher cost (see section\xa03.3). It therefore concluded that systemic non‑biological treatments were the most relevant comparators to certolizumab pegol for people who have not had systemic treatments.\n\n## The most relevant comparators to certolizumab pegol for psoriasis that has not responded to systemic non-biological treatments are other biologicals\n\nThe company suggested that the systemic non-biological treatments apremilast and dimethyl fumarate, used in NHS clinical practice at the same position as systemic biological treatments, were not relevant comparators for psoriasis that has not responded to previous systemic non-biological treatments, or when these treatments are contraindicated or not tolerated. The clinical expert explained that these options were rarely used in practice because they are perceived to be less effective than biological treatments. They would only be considered for use for people for whom a biological treatment was unsuitable or who were unwilling to have a biological treatment. The committee concluded that although apremilast and dimethyl fumarate are used in the NHS for some people with psoriasis, the most relevant comparators to certolizumab pegol were other biological treatments.\n\n# Clinical evidence\n\n## The CIMPASI and CIMPACT trials provide the key clinical evidence for certolizumab pegol\n\nThe main evidence for certolizumab pegol came from the CIMPASI trials 1\xa0and\xa02, and the CIMPACT trial. These were double-blind randomised controlled trials that included a total of 1,020\xa0patients with plaque psoriasis. They compared 2\xa0doses of certolizumab pegol (200\xa0mg or 400\xa0mg) with placebo (all trials) and etanercept (CIMPACT only). The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the static Physician Global Assessment (sPGA). They were assessed at the end of the induction period (16\xa0weeks in the CIMPASI trials and 12\xa0weeks in CIMPACT) as follows:\n\nIn the CIMPASI trials, the co-primary outcomes were the proportion of patients with:\n\n\n\na 75% reduction in the PASI score from when treatment started (PASI\xa075) and\n\na rating of 'clear' (score of\xa00) or 'almost clear' (score of\xa01) on the sPGA.\n\n\n\nIn the CIMPACT trial, the primary outcome was a PASI\xa075.Patients in all 3\xa0trials were followed up in open-label extension studies. The company presented open-label follow-up data up to 48\xa0weeks (the trials are scheduled to follow up patients for 144\xa0weeks in total).\n\n## Patients in the certolizumab pegol clinical trials are sufficiently generalisable to those who would have certolizumab pegol in the NHS for decision making\n\nThe committee considered whether patients in the CIMPASI trials and in CIMPACT were similar to those in NHS clinical practice for:\n\nSeverity of disease: CIMPASI and CIMPACT included patients with 'moderate to severe' psoriasis with a PASI score of 12\xa0or more. No minimum Dermatology Life Quality Index (DLQI) score was specified. Previous NICE technology appraisals defined 'severe' and 'very severe' psoriasis based on the PASI and DLQI; the PASI threshold for 'severe' is 10\xa0or more.\n\nPrevious treatment: the committee noted that about 29% of patients in the CIMPASI and CIMPACT trials had not had any previous systemic treatment or phototherapy. This is inconsistent with the current positioning of biological treatments in the NHS (see section\xa03.3) and may overestimate the clinical effectiveness of certolizumab pegol. One clinical expert explained that international trials may include patients who have not had previous treatment because of different prescribing practices across countries. The committee was aware that only a small number of\xa0patients were recruited in the UK, and that these patients were all recruited for the CIMPACT trial.\n\nPeople who had not had previous systemic therapy: The company stated that, in the CIMPASI and CIMPACT trials, similar PASI\xa075 response rates were reported in subgroups of patients who had previously had systemic treatment or phototherapy compared with those who had not. The committee noted that the subgroup of patients who had not had systemic non-biological treatment reflected the company's proposed positioning of certolizumab pegol at an earlier setting than that for biological treatments in the NHS. The exception was that none of the patients in this subgroup in the clinical trials had previously had phototherapy.The committee concluded that, while patients in the trials did not fully reflect those who would have certolizumab pegol in NHS practice, they were sufficiently generalisable for decision making.\n\n## Certolizumab pegol is more clinically effective than placebo and etanercept\n\nThe committee noted that patients randomised to certolizumab pegol were clinically and statistically significantly more likely to have a PASI\xa075 and sPGA\xa00 or 1\xa0response rates at week\xa016 compared with placebo, and a PASI\xa075 at week\xa012 compared with etanercept. The committee concluded that certolizumab pegol was more clinically effective than placebo and etanercept.\n\n## There is no clinical evidence directly comparing certolizumab pegol with the non-biological treatments used earlier in the treatment pathway\n\nThe company presented clinical evidence comparing certolizumab pegol with placebo for the subgroup of patients who had not had previous systemic treatment. This showed a statistically significant and clinically meaningful increase in response rates for certolizumab pegol compared with placebo. The clinical experts explained that the relevant comparators in people who have not had previous systemic treatment are systemic non-biological treatments (methotrexate, ciclosporin and acitretin). The committee concluded that there was no clinical trial evidence directly comparing certolizumab pegol with systemic non-biological treatments.\n\n## The company's network meta-analysis suggests that a PASI\xa075 response is more likely with certolizumab pegol than with non-biological treatments\n\nThe company's base-case network meta-analysis compared certolizumab pegol with non-biological treatments (methotrexate, acitretin and ciclosporin). The results showed that treatment with a 200\xa0mg maintenance dose of certolizumab pegol resulted in statistically significantly improved PASI\xa075 response rates compared with all the non-biological treatments. The committee noted that these results were based on a small number of patients so were highly uncertain. It concluded that a PASI\xa075 response was more likely with certolizumab pegol than with non-biological treatments, but the extent of this benefit was unclear.\n\n## A PASI\xa075 response is more likely with certolizumab pegol than with adalimumab or etanercept, and as likely as with other biological treatments\n\nThe company's base-case network meta-analysis also compared certolizumab pegol with other biological treatments (adalimumab, brodalumab, etanercept, guselkumab, infliximab, ixekizumab, secukinumab and ustekinumab) using data from 65\xa0trials. It showed that a 200\xa0mg maintenance dose of certolizumab pegol resulted in PASI\xa075 response rates that were:\n\nstatistically significantly higher than the TNF‑alpha inhibitor etanercept\n\nhigher (but not statistically significantly so) than the TNF-alpha inhibitor adalimumab\n\nsimilar to the interleukin inhibitors (brodalumab, guselkumab, ixekizumab, secukinumab and ustekinumab).\n\n## When there is a partial response to the 200\xa0mg certolizumab pegol dose, there may be an improved response to an increased dose\n\nThe committee noted that increasing the maintenance dose from 200\xa0mg every 2\xa0weeks to 400\xa0mg every 2\xa0weeks is within certolizumab pegol's marketing authorisation. The company stated that people whose disease had a partial response (defined as a PASI\xa050 to PASI\xa074) after 16\xa0weeks of treatment with certolizumab pegol at a maintenance dose of 200\xa0mg were the most likely group for whom this would be considered. It presented evidence from CIMPACT showing that most patients in this group had a PASI\xa075 response after a further 16\xa0weeks of treatment with certolizumab pegol at the increased maintenance dose of 400\xa0mg. The company stated that there were no prognostic factors identified in the trial that indicated whether a person whose disease had a partial response would be likely to have a PASI\xa075 response after increasing the dose. The committee noted that the trials did not compare the efficacy of increasing the dose of certolizumab pegol with either placebo or another active treatment. Also, the results for patients whose disease had a partial response were based on a small number of patients. It noted that the company's definition of partial response may have included people with a PASI\xa050 response and a 5‑point reduction in the DLQI, which is recommended by NICE as an alternative to the PASI\xa075 to assess response to treatment. The committee would have preferred to see efficacy results that excluded this group, although it recognised that this exclusion would have further reduced the number of patients whose disease was defined as having a partial response and increased the uncertainty of the clinical effectiveness of increasing the dose. The committee noted that people whose disease had a partial response to certolizumab pegol and no, or manageable, adverse events may prefer to continue on a higher dose of certolizumab pegol than to switch to an alternative treatment, which could be less well tolerated. It also noted that psoriasis is a lifelong condition and that people with psoriasis would be likely to try several treatments over their lifetime, so may wish to continue with their current treatment at a higher dose and reserve other biological treatments for future use. The committee concluded that it was appropriate to consider the cost effectiveness of increasing the dosage to 400\xa0mg every 2\xa0weeks in people whose disease had a partial response to certolizumab pegol 200\xa0mg every 2\xa0weeks.\n\n# Company's economic model\n\n## The model has a Markov state transition structure\n\nA Markov state transition model was used to assess the cost effectiveness of certolizumab pegol. The company assumed that treatments improved quality of life but did not extend length of life. The model contained 4\xa0health states: induction treatment, maintenance treatment, best supportive care and death. All patients entered the model in the induction state and had the first treatment in a given sequence. They moved from the induction state to the maintenance state if there was at least a PASI\xa075 response measured at the end of induction. From there, some patients could stop treatment for any reason and move to the next treatment in the sequence. If there was not a PASI\xa075 response, patients moved to the induction phase of the next treatment in the sequence. Patients moved to the best supportive care state if their psoriasis did not respond to the last active treatment in a sequence. All patients could move to the death state at any time.\n\n## There are 9\xa0treatment sequences in the company's model when comparing certolizumab pegol with other biological treatments\n\nThe company's decision problem compared a sequence of treatments including certolizumab pegol with 8\xa0treatment sequences excluding certolizumab pegol. The treatment sequences chosen by the company were:\n\nThe first treatment was either certolizumab pegol or another biological treatment (adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab or ustekinumab [45\xa0mg or 90\xa0mg dose]).\n\nThe second treatment was ustekinumab (90\xa0mg), except in the sequences in which ustekinumab was used as the first treatment; in these sequences, adalimumab was used as the second treatment.\n\nThe third treatment was infliximab.\n\nAfter that, treatment in all sequences was best supportive care.The company chose these sequences based on expert advice. The committee was aware that, over time, a sequence of biological treatments will be used to treat severe psoriasis in current NHS practice as people switch from 1\xa0option to another. It was also aware that additional factors should be considered when comparing treatment sequences, such as the best ordering of treatments and the effect of including treatments that may not be cost effective. The committee agreed that, in principle, it was appropriate to compare treatment sequences in this appraisal.\n\n# Assumptions in the economic model\n\n## Key assumptions in the economic model are acceptable for decision making\n\nThe company made several assumptions in the economic model that were consistent with the approach taken in previous appraisals for psoriasis, including:\n\na common stopping rate of 20% for all treatments during maintenance treatment\n\nan equal treatment effect regardless of the position of a treatment in a sequence\n\na treatment effect that is sustained throughout the entire treatment period.The committee was aware that there was limited evidence to support or dispute these assumptions, but concluded that they were consistent with previous appraisals so were acceptable for decision making.\n\n## Several of the ERG's preferred assumptions are incorporated into the company's base case\n\nIn response to clarification, the company updated its base-case analysis to incorporate several of the ERG's preferred base-case assumptions, including:\n\nbasing utility values only on patients with a DLQI score of greater than\xa010 to reflect patients who would have biological treatment in the NHS\n\nassuming that utility values for patients who had treatment with biological treatments and best supportive care were equal\n\nusing the drug acquisition costs of the biosimilars of etanercept and infliximab in place of costs for the reference product.The committee concluded that including these assumptions was appropriate.\n\n# Costs in the economic model\n\n## The cost of best supportive care for moderate to severe psoriasis is uncertain\n\nThe company calculated the cost of best supportive care based on:\n\ndrug acquisition costs from the British national formulary, with proportions of patients on each treatment based on clinical expert opinion and mean treatment duration from Fonia et al. (2010)\n\nsecondary care costs from Fonia et al. inflated to 2017 values.The committee was aware that previous appraisals used drug acquisition costs from either NICE's guideline on psoriasis (based on Fonia et al.) or Fonia et al. itself. This company's alternative approach resulted in a lower cost for best supportive care because of a fall in the price of ciclosporin and because fumaric acid esters were excluded from best supportive care. The committee was also aware that secondary care costs from Fonia et al. did not reflect clinical practice and were likely to have overestimated the costs of secondary care. It concluded that the cost of best supportive care for moderate to severe psoriasis was uncertain. The committee further concluded that defining costs associated with psoriasis that reflect current clinical practice was an important area for research.\n\n## The ERG's analysis using alternative best supportive care costs is useful for decision making\n\nThe lower cost of best supportive care used in the company's base case (see section\xa03.17) had important implications for the cost-effectiveness results from the economic model. Firstly, compared with best supportive care, no treatment in the company's model had an incremental cost-effectiveness ratio (ICER) lower than £30,000 per quality-adjusted life year (QALY) gained. Secondly, treatments with a lower efficacy could appear to be more cost effective than treatments with a higher efficacy and a similar cost. This was because treatments with lower response rates led to patients in the model advancing to best supportive care more quickly, and therefore incurring lower costs. The ERG also did an exploratory analysis incorporating assumptions from NICE's technology appraisal guidance on brodalumab, which included higher costs for best supportive care than in the company's analysis. The ERG noted that these assumptions were not necessarily superior to those in the company's base case but were presented for illustrative purposes. In this analysis, several biological treatments were cost effective compared with best supportive care. The committee concluded that it was appropriate to consider the ERG's analysis using alternative best supportive care costs in its decision making.\n\n# Cost-effectiveness estimates\n\n## Treatment sequences may result in misleading cost-effectiveness estimates\n\nThe committee was aware that treatment sequences, although more likely to reflect the treatment switching seen in clinical practice, may have provided misleading cost-effectiveness estimates for certolizumab pegol. It noted that some of the treatments were not cost effective in the model. Therefore, the cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding potentially cost-ineffective subsequent treatments, or by choosing treatments with lower response rates, resulting in an earlier transition to best supportive care (see section\xa03.18). The committee was also aware that the company's model compared a limited number of all potential treatment sequences. The ERG set subsequent options in all sequences to best supportive care, so that the only difference between sequences was the first treatment used. The committee concluded that it would consider these comparisons of individual treatments with best supportive care in its decision making.\n\n## Certolizumab pegol is not cost effective earlier in the treatment pathway compared with non‑biological treatments for severe psoriasis\n\nThe committee considered whether certolizumab pegol would be a cost‑effective use of NHS resources for people with severe psoriasis who have not had systemic treatment, that is, when the disease has not responded to topical treatments and phototherapy, or they are contraindicated or not tolerated (earlier than the current position for biological treatments in NHS practice). It recalled that there was no clinical evidence directly comparing certolizumab pegol with standard care in this population; evidence for the clinical efficacy of certolizumab pegol relative to methotrexate, ciclosporin and acitretin was based on the company's network meta-analysis (see section\xa03.10):\n\nThe company's base-case cost-effectiveness analysis used efficacy data from the placebo arms of the CIMPASI and CIMPACT trials as a proxy for standard care. The committee agreed that this was inappropriate because standard care (systemic non-biological treatment) is an active comparator. The committee considered an alternative analysis presented by the company, which used efficacy data for methotrexate from the subgroup of patients who had not had systemic treatment in the company's network meta‑analysis. The committee was aware that these data were based on a small number of patients, so the indirect comparison was subject to a high degree of uncertainty. It noted that, in the company's scenario analysis, certolizumab pegol had an ICER of £18,145 per QALY gained compared with methotrexate.\n\nThe committee noted that the company's scenario analysis compared the following 2\xa0sequences:\n\n\n\nmethotrexate, followed by adalimumab, ustekinumab, infliximab and best supportive care\n\ncertolizumab pegol 200\xa0mg, followed by ustekinumab, infliximab and best supportive care.The committee agreed that the treatment sequences compared by the company were selective. It would have preferred to have seen standard care (methotrexate) sequences that included alternative biological treatments as the second treatment in the sequence, including certolizumab pegol. The ERG presented a scenario analysis comparing the following 2\xa0sequences:\n\nmethotrexate, followed by certolizumab pegol 200\xa0mg, ustekinumab, infliximab and best supportive care\n\ncertolizumab pegol 200\xa0mg, followed by ustekinumab, infliximab and best supportive care.This comparison resulted in an ICER of over £400,000 per QALY gained. The committee recalled its previous conclusion that it was appropriate to consider sequences in which subsequent biological therapies in the treatment sequence were replaced by best supportive care (see section\xa03.19). Modifying the ERG's scenario analysis in this way resulted in 2\xa0sequences:\n\nmethotrexate, followed by certolizumab pegol 200\xa0mg and best supportive care\n\ncertolizumab pegol 200\xa0mg, followed by best supportive care.The committee noted that, in this analysis, certolizumab pegol had a similar QALY gain to methotrexate at a much higher cost. The committee considered the ERG's analysis to be more appropriate than the company's. It therefore concluded that certolizumab pegol was not a cost-effective use of NHS resources, and that it could not recommend certolizumab pegol as an option for treating severe chronic plaque psoriasis that has not been treated with non-biological systemic treatments.\n\n\n\n## Certolizumab pegol is cost effective compared with other biological treatments for severe psoriasis\n\nThe committee considered whether certolizumab pegol would be a cost‑effective use of NHS resources for people with severe psoriasis for whom non-biological treatment has failed or is contraindicated or not tolerated. To do this, it took into account the patient access schemes for brodalumab, guselkumab, ixekizumab and secukinumab. The committee noted that several treatments had only small differences in total costs and QALY gains, and that these small differences could be difficult to see using ICERs from fully incremental or pairwise analyses. The ERG therefore presented the cost-effectiveness results in a net monetary benefit framework. The committee agreed that this analysis was useful to support decision making. It noted that certolizumab pegol was similarly or more cost effective than alternative biological treatments in both the company's and ERG's base cases, but recalled that these analyses may have disadvantaged treatments with higher response rates (see section\xa03.18). It therefore considered the ERG's alternative base case (using best supportive care costs from previous guidance) and noted that, in this analysis, compared with best supportive care, certolizumab pegol had:\n\na lower pairwise ICER than the interleukin inhibitor ustekinumab and the TNF‑alpha inhibitor etanercept\n\na similar pairwise ICER (range about £19,500 to £21,500 per QALY gained) to the interleukin inhibitors brodalumab, ixekizumab, guselkumab and secukinumab\n\na higher pairwise ICER than the TNF-alpha inhibitor adalimumab.The committee agreed that people with psoriasis would value the option of an alternative TNF‑alpha inhibitor that was more effective than etanercept and could be used during pregnancy (see section\xa03.25). It therefore concluded that it could recommend certolizumab pegol as an option for treating severe chronic plaque psoriasis that has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or if these options are contraindicated or not tolerated.\n\n## The cost effectiveness of increasing the maintenance dose of certolizumab pegol should be assessed by comparing it with switching to another biological\n\nThe committee recalled its previous conclusion that the cost effectiveness of increasing the maintenance dose of certolizumab pegol in people whose disease partially responded should be considered (see section\xa03.12). It noted that the company's base case compared 2\xa0sequences:\n\ncertolizumab pegol 200\xa0mg increased to certolizumab pegol 400\xa0mg (when there is a partial response, defined as a PASI 50\xa0to\xa074) or ustekinumab (when there is no response, defined as a PASI less than\xa050), followed by ustekinumab, infliximab and best supportive care\n\nadalimumab 40\xa0mg increased to adalimumab 80\xa0mg (for partial and no response), followed by ustekinumab, infliximab and best supportive care.The company and the ERG also presented several scenario analyses in which increasing the dose of certolizumab pegol was compared with switching to ixekizumab, secukinumab and ustekinumab. The committee recalled that, in the CIMPACT trial, there were no prognostic factors identifying people who were likely to benefit from increasing the dose of certolizumab pegol (see section\xa03.12). It also noted that clinicians would be unlikely to make treatment decisions based on people needing a future dose increase because it would not be known whose disease would have a partial response and need an increased dose. Therefore, it concluded that a comparison between increasing the maintenance dose of certolizumab pegol from 200\xa0mg to 400\xa0mg and increasing the maintenance dose of adalimumab from 40\xa0mg to 80\xa0mg was not clinically relevant. It also concluded that the most relevant comparison would be between increasing the maintenance dose of certolizumab pegol from 200\xa0mg to 400\xa0mg and switching from certolizumab pegol to another biological treatment.\n\n## It is not cost effective to increase the dose of certolizumab pegol to 400\xa0mg if response to the 200\xa0mg dose is inadequate\n\nThe company noted in its response to the appraisal consultation document that the ERG scenarios switching to alternative biological treatments (see section\xa03.22) used efficacy data from the CIMPACT trial for certolizumab pegol (see section\xa03.12) and the network meta-analysis (see section\xa03.11) for comparators. It was concerned that this may bias results against certolizumab pegol because this approach assumed that the comparator (used second line in the sequence) is as clinically effective as if it had been used first line. The company therefore provided additional scenario analyses which used the network meta-analysis results for both certolizumab pegol and the comparator, or (in the absence of clinical trial data for the comparator) assumed that the comparator had equivalent efficacy to certolizumab pegol in CIMPACT. The committee concluded that although this was a source of uncertainty, the scenario analyses exploring alternative assumptions had only a small effect on the cost‑effectiveness results and did not affect decision making. The company also explained that the cost of increasing the maintenance dose of certolizumab pegol may have been overestimated by a small amount because, in the model, patients who stopped certolizumab pegol 200\xa0mg because of adverse events then had certolizumab pegol 400\xa0mg, which would not occur in clinical practice. The committee concluded that, although this was a limitation in the model structure, the resulting overestimation in costs was likely to have a minimal effect on the cost-effectiveness results because it only applied to a small number of patients. After taking into account all confidential commercial arrangements for comparator treatments, the ICERs for certolizumab pegol were considerably above the range usually considered cost effective by NICE. The committee therefore concluded that increasing the maintenance dose was not cost effective.\n\n## Certolizumab pegol should be stopped if there is an inadequate response at 16\xa0weeks\n\nPrevious NICE technology appraisals for treating psoriasis have recommended stopping treatment if there is an inadequate response. An adequate response is defined as either a 75% reduction in the PASI score from when treatment started, or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. The committee agreed that, if there was an inadequate response to certolizumab pegol, treatment should be stopped. It noted that PASI\xa075, assessed 16\xa0weeks after starting treatment, was recommended as appropriate to assess response in the summary of product characteristics. It also recalled its previous conclusion that increasing the dose of certolizumab pegol when psoriasis has responded inadequately was not a cost-effective strategy (see section\xa03.23). The committee therefore concluded that certolizumab pegol should be stopped if there is an inadequate response at 16\xa0weeks using the same definition of an adequate response as in previous NICE technology appraisals.\n\n# Equality issues\n\n## Certolizumab pegol can be used before and during pregnancy if clinically needed and while breastfeeding\n\nThe summary of product characteristics for certolizumab pegol states that it can be used during pregnancy if clinically needed and while breastfeeding. The clinical experts considered this to be reasonable. The patient experts explained that people who are pregnant or who are considering pregnancy would welcome further effective treatment options for plaque psoriasis that do not need to be stopped before and during pregnancy (if clinically needed), or while breastfeeding. The committee concluded that these patients would value an additional treatment option.\n\n## The PASI and DLQI may not be appropriate for all people with psoriasis\n\nThe committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:\n\nthe PASI might underestimate disease severity in people with darker skin\n\nthe DLQI has limited validity in some people, and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.", 'Recommendations for research': 'The committee noted that the costs of best supportive care are derived from a study published in 2010 and that clinical practice has changed substantially since then. It therefore considered that it would be valuable to have studies investigating:\n\nthe costs associated with best supportive care\n\nresource use, including frequency and length of hospitalisation, and associated costs.'}
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https://www.nice.org.uk/guidance/ta574
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Evidence-based recommendations on certolizumab pegol (Cimzia) for treating moderate to severe plaque psoriasis in adults.
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Tildrakizumab for treating moderate to severe plaque psoriasis
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Tildrakizumab for treating moderate to severe plaque psoriasis
Evidence-based recommendations on tildrakizumab (Ilumetri) for treating moderate to severe plaque psoriasis in adults.
# Recommendations
Tildrakizumab is recommended as an option for treating plaque psoriasis in adults, only if:
the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 and
the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and
the company provides the drug according to the commercial arrangement.
Consider stopping tildrakizumab between 12 weeks and 28 weeks if there has not been at least a 50% reduction in the PASI score from when treatment started.
Stop tildrakizumab at 28 weeks if the psoriasis has not responded adequately. An adequate response is defined as:
a 75% reduction in the PASI score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from when treatment started.
If patients and their clinicians consider tildrakizumab to be one of a range of suitable treatments, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).
When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with tildrakizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment for moderate to severe plaque psoriasis includes systemic biological treatments for disease that does not respond to systemic non-biological treatments. Tildrakizumab is proposed as an alternative to other systemic biological treatments already recommended by NICE.
Clinical trial results show that tildrakizumab improves severe plaque psoriasis compared with placebo or etanercept. More improvement is usually seen at 28 weeks compared with 12 weeks of treatment. When compared indirectly, tildrakizumab appears to be as effective as adalimumab and ustekinumab but not as effective as other biological treatments.
The most plausible cost-effectiveness estimates for tildrakizumab compared with most other available biological treatments show that it is generally cost effective. Therefore, tildrakizumab is recommended as an option for use in the NHS for severe psoriasis that has not responded to systemic non-biological treatments, or if these are contraindicated or not tolerated.# Information about tildrakizumab
Marketing authorisation indication
Tildrakizumab (Ilumetri, Almirall) has a marketing authorisation 'for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy.'
Dosage in the marketing authorisation
Tildrakizumab is administered by subcutaneous injection at a dose of 100 mg at weeks 0 and 4 and every 12 weeks thereafter. In patients with certain characteristics (for example, high disease burden, body weight of 90 kg or more), a 200 mg dose may provide greater efficacy.
Consideration should be given to stopping treatment in patients whose psoriasis has shown no response after 28 weeks of treatment. An initial partial response may subsequently improve with continued treatment beyond 28 weeks.
Price
The list price of tildrakizumab is £3,241 for both the 100 mg (single-dose pack of 1 prefilled syringe) and the 200 mg (single-dose pack of 2×100 mg prefilled syringes) doses (excluding VAT; price as quoted in company's submission).
The company has a commercial arrangement. This makes tildrakizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 6) considered evidence submitted by Almirall and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Experience of people with psoriasis
## Psoriasis is a lifelong condition that affects all aspects of a person's life
Psoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological, social and financial), and it is a lifelong condition. The committee noted that having treatments with few or manageable side effects, and which are effective for psoriasis on the face, hands, feet and genitals, is especially important to people with psoriasis, as is having a choice of treatments.
# Clinical management
## Psoriasis can be treated with topical therapies, phototherapy, and systemic non-biological and biological treatments
People with plaque psoriasis may have topical therapies first line, followed by phototherapy second line. If these do not control the psoriasis, people may have systemic conventional non-biological treatments third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to these, people may have fourth-line treatment including systemic biological treatments (such as adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, infliximab, secukinumab or ustekinumab), or apremilast or dimethyl fumarate. Biosimilar versions of some biologicals are also available. The drugs are used for as long as they continue to work. If the disease no longer responds to 1 biological, people will be offered another biological. This pattern is likely to be repeated over their lifetime. However, 1 clinical expert explained that previous biological treatments may affect the effectiveness of subsequent treatments, although there is uncertainty about the degree to which this occurs. Also, switching treatments can have a negative psychological effect on people with psoriasis. The clinical expert also stated that a variety of treatments are needed because patients can respond very differently to treatments with the same biological method of action. For people whose disease does not respond to multiple biological treatments, apremilast or dimethyl fumarate, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging.
# Treatment pathway
## Tildrakizumab is most likely to be used as an alternative to other systemic biological treatments
The marketing authorisation for tildrakizumab is for 'adults who are candidates for systemic therapy'. However, in the company submission, tildrakizumab was positioned as an alternative only to systemic biological treatments, which are used after systemic non-biological treatments in current NHS practice. The positioning therefore captures a narrower population than the marketing authorisation. However, the clinical expert confirmed that this is the most likely stage in the treatment pathway at which NHS clinicians would consider using tildrakizumab. The committee concluded that this position in the treatment pathway was appropriate and that it would appraise tildrakizumab compared with other biological treatments.
## Infliximab is a relevant comparator to tildrakizumab
The company suggested that infliximab was not a relevant comparator because it was recommended only for people with very severe plaque psoriasis. The ERG explained that a large proportion of the population in the tildrakizumab trials (see section 3.7) had very severe plaque psoriasis. Also, infliximab was included as a comparator in previous appraisals at the same position in the treatment pathway as tildrakizumab. The committee concluded that infliximab was a relevant comparator to tildrakizumab.
## The most relevant comparators to tildrakizumab are other biological treatments
The company suggested that the systemic non-biological treatments apremilast and dimethyl fumarate, used in NHS clinical practice at the same position as systemic biological treatments, were not relevant comparators. The clinical expert explained that these options were rarely used in practice because they are perceived to be less effective than biological treatments. They would only be considered for use for people for whom a biological treatment was unsuitable or who were unwilling to have a biological treatment. The committee concluded that although apremilast and dimethyl fumarate were used in the NHS for some people with psoriasis, the most relevant comparators to tildrakizumab were other biological treatments.
# Clinical evidence
## The reSURFACE trials provide the key clinical evidence for tildrakizumab
The main evidence for tildrakizumab came from the reSURFACE trials (reSURFACE 1 and reSURFACE 2). These were double-blind randomised controlled trials that included a total of 1,862 patients with plaque psoriasis. They compared 2 doses of tildrakizumab (100 mg and 200 mg) with placebo, and reSURFACE 2 also included an etanercept arm. The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the Physician Global Assessment (PGA). Both PASI and PGA were assessed at 12 weeks and 28 weeks, as follows:
PASI 75: a 75% reduction in the PASI score from when treatment started and
PGA: a PGA rating of 'clear' (score of 0) or 'almost clear' (score of 1).Patients in reSURFACE 1 and reSURFACE 2 were followed up for longer-term outcomes, for 64 weeks and 52 weeks respectively.
## The populations in the reSURFACE trials are similar to patients in the NHS who may have tildrakizumab
The committee considered whether patients in the reSURFACE trials were similar to those in NHS clinical practice for:
Severity of disease: the reSURFACE trials included patients with moderate to severe psoriasis with a PASI score of 12 or more. No minimum Dermatology Life Quality Index (DLQI) score was included. Previous NICE technology appraisals have defined severe and very severe psoriasis based on the PASI and DLQI; the PASI threshold for severe psoriasis is 10 or more.
Previous systemic non-biological treatment: the committee noted that 24% of patients in reSURFACE 1 and 40% of patients in reSURFACE 2 had previous systemic non-biological treatment. The clinical expert stated that these proportions were lower than in the relevant population in NHS clinical practice. The committee was aware that subgroup analyses did not provide any evidence of a clinically relevant effect of previous systemic non-biological treatments on subsequent response to tildrakizumab.
Previous systemic biologicals: the committee noted that 23% of patients in reSURFACE 1 and 13% of patients in reSURFACE 2 had previous systemic biological treatment. The ERG suggested that this might not represent NHS clinical practice at the proposed positioning of tildrakizumab. The committee recalled the clinical expert's advice that previous biological treatments may influence the effectiveness of subsequent treatments (see section 3.2). However, the committee was also aware that there was uncertainty as to the extent that this may occur, and that subgroup analyses did not provide any evidence of a clinically relevant effect of previous biological treatments on subsequent response to tildrakizumab.The committee noted that the results of the reSURFACE trials may have overestimated the clinical effectiveness of tildrakizumab because of the proportions of patients who had not had previous non-biological and biological systemic treatment. The clinical expert advised that this would not be expected to have a large effect on the relative efficacy results. The committee concluded that the patients in the trials generally reflected those who would have treatment with tildrakizumab in NHS clinical practice.
## Both 100 mg and 200 mg doses of tildrakizumab are appropriate
The company presented results for both licensed doses of tildrakizumab (100 mg and 200 mg). The company representative explained that the higher dose is intended for use from treatment induction in people with a higher body weight or disease burden, determined by the clinician. The committee noted that there was no difference in efficacy between the 2 doses in the reSURFACE trials. The clinical expert explained that clinicians would welcome flexibility in available doses of the same treatment. The committee concluded that it was appropriate to consider both licensed doses in its decision making.
## Clinical outcomes assessed at 12 weeks and 28 weeks should be considered
The committee was aware that tildrakizumab's marketing authorisation states that, if there is no response after 28 weeks of treatment, stopping tildrakizumab should be considered. It recalled that the PASI 75 response rate for tildrakizumab at 28 weeks was statistically significantly higher than at 12 weeks in the reSURFACE trials, and other biological treatments also had higher response rates at later assessments. The committee considered that tildrakizumab's less frequent dosing schedule meant that this late treatment effect was more noticeable because only 2 doses had been given before assessment of response at 12 weeks. The clinical expert advised that assessment at 12 weeks would be premature, and they would prefer to minimise the risk of a patient switching from a potentially effective treatment (see section 3.2). The committee concluded that the clinical outcomes from the reSURFACE trials at weeks 12 and 28 should be considered in its decision making.
## Tildrakizumab is more clinically effective than placebo or etanercept
The committee noted that:
At week 12, patients randomised to tildrakizumab were more likely to have a PASI 75 and PGA clear or minimal response than patients randomised to placebo or etanercept.
At week 28, patients randomised to tildrakizumab were more likely to have a PASI 75 and PGA clear or minimal response than those randomised to etanercept, but no information compared with placebo was available.The committee concluded that tildrakizumab was more clinically effective than placebo and etanercept.
## Assess response to tildrakizumab before and at 28 weeks, and consider stopping treatment if there is no response
Based on consultation comments, the committee understood that clinicians may find it unreasonable to continue tildrakizumab for 28 weeks for patients whose psoriasis is not responding to treatment. The committee recalled that, in the reSURFACE trials, patients whose disease had not had at least a 50% reduction in the PASI score at 12 weeks were less likely to have a PASI 75 response at 28 weeks than patients whose disease had partially responded at 12 weeks (PASI 50). The committee also recalled that most patients whose psoriasis had a PASI 75 response reached this outcome by week 22, after taking the third dose in week 16. It was aware that no similar data were presented for other outcomes such as DLQI. The committee considered that although stopping treatment from 14 weeks was considered in the economic modelling (see section 3.17), it was more appropriate to consider stopping treatment from 12 weeks. This was because this reflected the trial data and was in line with previous NICE technology appraisal guidance, such as NICE's technology appraisal guidance for etanercept efalizumab for the treatment of adults with psoriasis, brodalumab for treating moderate to severe plaque psoriasis, ixekizumab for treating moderate to severe plaque psoriasis and secukinumab for treating moderate to severe plaque psoriasis. The committee concluded that if there was no adequate response at 28 weeks (either a PASI 75 response, or a PASI 50 response and a 5‑point reduction in DLQI), tildrakizumab should be stopped (see section 3.9). Also, if there has not been at least a 50% reduction in the PASI score from when treatment started to between 12 weeks and 28 weeks, stopping tildrakizumab should be considered.
# Network meta-analysis
## The network meta-analysis including infliximab is appropriate for decision making
The company did a network meta-analysis to indirectly compare tildrakizumab with other biological treatments (adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab and ustekinumab) using data from 45 trials. The included trials assessed PASI 75 response at various time points, which the company grouped into separate stages for its analysis:
Response measured at 12 weeks to 16 weeks (stage I).
Response measured at 16 weeks to 24 weeks (stage II). Stage II was a separate planned analysis that excluded the placebo arms, resulting in an incomplete network, therefore it was not considered in this appraisal.
Response measured at 24 weeks to 28 weeks (stage III).No trials reported placebo outcomes at stage III. To include placebo in its stage III network, the company used placebo response rates from the same trials at stage I. The ERG noted that this made the stage III analysis weaker than the stage I analysis. This was because there were no direct placebo data at 24 weeks to 28 weeks, and because most trials were open label at this point, although a stage III etanercept control group was included. The ERG also advised that excluding infliximab from the network was inconsistent with previous appraisals, and that including it would strengthen the network. The ERG therefore included 6 additional trials in an exploratory analysis. The committee concluded that the network meta-analysis, including infliximab, was appropriate for decision making. The company accepted the committee's preference and the ERG's exploratory analysis.
## Tildrakizumab is more effective at 28 weeks than at 12 weeks
For the stage I (12 weeks to 16 weeks) analysis, the committee noted that the PASI 75 response rates for tildrakizumab were higher than those for etanercept, similar to adalimumab and ustekinumab, and lower than for other targeted biological treatments, including guselkumab (an interleukin‑23 inhibitor, as is tildrakizumab). For the stage III (24 weeks to 28 weeks) analysis the committee noted that the network meta-analysis suggested that the PASI 75 response rates for tildrakizumab were statistically significantly higher than at stage I. It also noted that tildrakizumab at stage III had a higher PASI 75 response rate than etanercept and adalimumab at stage III, and similar efficacy to other targeted biological treatments at stage I, which reflected the stopping rules used in NHS practice for those treatments. The committee concluded that tildrakizumab was more effective at stage III than at stage I. It also concluded that the efficacy of tildrakizumab at stage I was closest to adalimumab at stage I, and the efficacy of tildrakizumab at stage III was closest to guselkumab at stage I.
# Company's economic model
## The model has a Markov state transition structure
A Markov state transition model was used to assess the cost effectiveness of tildrakizumab. It assumed that treatments improved quality of life but did not extend length of life. The model contained 4 health states: induction treatment, maintenance treatment, best supportive care and death. All patients entered the model in the induction state and had the first treatment in a given sequence (see section 3.15). They moved from the induction state to the maintenance state if there was at least a PASI 75 response measured at the end of induction. From there, some patients could stop treatment for any reason and move to the next treatment in the sequence. If there was not a PASI 75 response, patients moved to the induction phase of the next treatment in the sequence. Patients moved to the best supportive care state if their psoriasis did not respond to the last active treatment in a sequence. All patients could move to the death state at any time.
## The company's model compares treatment sequences
The company's decision problem compared a sequence of treatments including tildrakizumab with 7 other sequences excluding tildrakizumab. Each sequence comprised 4 treatments:
The first treatment was either tildrakizumab or another biological treatment (adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab or ustekinumab).
The second treatment was ustekinumab, except in the sequence in which ustekinumab was used as the first treatment; in that sequence, adalimumab was used as the second treatment.
The third treatment was secukinumab, except in the sequence in which secukinumab was used as the first treatment; in that sequence, adalimumab was used as the third treatment.
The fourth treatment in all sequences was best supportive care.The company chose these sequences based on expert advice. The committee was aware that, over time, a sequence of biologicals would be used to treat severe psoriasis in current NHS practice because people switch from 1 option to another. It was also aware that additional factors should be considered when comparing treatment sequences, such as the best ordering of treatments and the effect of including treatments that may not be cost effective. The committee agreed that, in principle, it was appropriate to compare treatment sequences in this appraisal.
# Assumptions in the economic model
## A common 14‑week induction period is inappropriate
The company included a common 14‑week induction period for tildrakizumab and all comparators in its economic model. The company explained that this was to simplify the model, and that a 14‑week induction period was chosen to represent the midpoint of the range of typical induction periods (stage I from the network meta-analysis; 12 weeks to 16 weeks). The ERG explained that this method would create bias in the costs of the induction period. So, it explored a scenario of modelling treatment-specific induction period costs to reflect the recommended induction duration of each one. The committee recognised that a common 14‑week induction period was particularly inconsistent with a potential 28‑week induction period for tildrakizumab (see section 3.11). The committee concluded that assuming a common induction period could apply to treatments with different induction durations was inappropriate. It therefore preferred the ERG's modelling of treatment-specific induction period costs. The company subsequently provided a revised base case in which treatment-specific induction costs were used.
## Tildrakizumab is compared with the induction periods used in current practice for other biological treatments
The company included a scenario analysis in its submission comparing the cost effectiveness of tildrakizumab with a 28‑week induction period with all other treatments at 28 weeks. The ERG noted that no other treatments had a recommended assessment time in the stage III time range, and so the appropriate comparison would be with treatments at their recommended assessment times. The ERG therefore included tildrakizumab with 14‑week and 28‑week induction periods as separate interventions in its exploratory analysis. The committee recalled that the network meta-analyses showed a statistically significant improvement in the PASI 75 response rate for tildrakizumab between the 2 assessment points (see section 3.13). The committee concluded that it preferred the ERG's approach; namely, that tildrakizumab with a 14‑week and a 28‑week induction period should be compared with other biological treatments at their recommended 12‑week to 16‑week induction periods, to reflect the stopping rules used in NHS practice for those treatments. The company subsequently provided a revised base case in which tildrakizumab with a 14‑week and a 28‑week induction period was compared with other biological treatments at their recommended 12‑week to 16‑week induction periods.
# Utility values in the economic model
## The company's utility values are appropriate, without adjustment for age
The company used EQ‑5D data collected in the reSURFACE 1 trial to inform utility values in its economic model. Utility values were stratified by the level of PASI response. The company implemented its utility values in the economic model by assuming a percentage change from general age-related population values. The ERG suggested that adjusting utility values for age in this way may be inappropriate because it assumes a constant relationship between age and PASI score. It also noted that, because no extension of life for any treatment had been modelled, adjusting for age added a complexity to the model that was not needed. The committee concluded that the ERG's scenario analysis using the company's absolute utility values without adjusting for age was more appropriate. The company subsequently provided a revised base case in which absolute utility values without adjusting for age were used.
## Best supportive care utility values should return to baseline
The company assumed, in its model, that the utility value for patients having best supportive care was equal to the utility value associated with the lowest PASI reduction (less than 50%). The clinical expert considered this to be inappropriate, advising that a patient who switched from an active treatment to best supportive care would revert to their baseline quality of life shortly after switching. The ERG noted limitations in stratifying utility value by PASI response; namely, a person with a PASI response below 50% might still have some improvement in their PASI that has a positive effect on quality of life, and that PASI response may not fully capture improvements in the psoriasis from treatment. This may explain why the utility value for the 'PASI response less than 50%' group was notably higher than the baseline value. The ERG did an exploratory analysis using the baseline utility value for those having best supportive care. The committee concluded that the baseline utility value was more appropriate for representing health-related quality of life than the utility value for patients whose psoriasis had the lowest response to treatment. The company subsequently provided a revised base case in which baseline utility values were used for patients having best supportive care.
# Costs in the economic model
## The ERG's drug costs and resource use estimates are appropriate for decision making
The company presented drug costs adjusted for a 14‑week induction period and annual maintenance costs adjusted for a 14‑week cycle length. The ERG revised these costs for each treatment-specific induction period (see section 3.16) and corrected maintenance costs. Biosimilar price reductions for etanercept were considered by the company. The ERG included additional healthcare costs for those whose psoriasis did not respond to biological treatments, increasing the company's one-off switching costs to reflect a 14‑week cycle cost. The committee concluded that the ERG's amendments to costs and resource use were appropriate for decision making. The company subsequently provided a revised base case using the ERG's amendments to costs and resource use.
## The costs of best supportive care are uncertain
In its model, the company included the costs of best supportive care from NICE's guideline on psoriasis: assessment and management, which includes drug treatment, day centre care and inpatient care. Previous psoriasis appraisals obtained direct costs from an observational study (Fonia et al. 2010). The ERG advised that the costs of best supportive care from this source, used in previous appraisals, were considerably lower than the company's estimate from the psoriasis guideline. The ERG advised that, despite being lower than the company's estimates, the costs in Fonia et al. may still have overestimated the true costs of best supportive care in NHS practice because the secondary care resource use in the study appeared to be high. The committee concluded that the costs of best supportive care for people whose psoriasis does not respond to treatment is uncertain because of a lack of recent studies to quantify the true costs in clinical practice. It concluded that, for this appraisal, the Fonia et al. costs should be used because they are more likely to reflect current clinical practice than the costs used in the company's model, and this is consistent with previous appraisals. The company subsequently provided a revised base case using the Fonia et al. best supportive care costs. The committee further concluded that defining costs associated with psoriasis that reflect current clinical practice was an important area for research.
# Cost-effectiveness estimates
## Treatment sequences may result in misleading cost-effectiveness estimates
The committee was aware that treatment sequences, although more likely to reflect the treatment switching seen in clinical practice, may have provided misleading cost-effectiveness estimates for tildrakizumab. It noted that some of the treatments were not cost effective in the model. Therefore, the cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding potentially cost-ineffective subsequent treatments or by choosing treatments with lower response rates, resulting in an earlier transition to best supportive care. The committee was also aware that the company's model compared a limited number of all potential treatment sequences. The ERG compared individual treatments with best supportive care in its own base case, setting the second and third options in all sequences to best supportive care. The committee concluded that it would consider these comparisons of individual treatments with best supportive care in its decision making to account for potential bias caused by analysing treatment sequences. The company subsequently provided a revised base case with pairwise comparisons of individual treatments with best supportive care.
## Considering incremental net monetary benefit in addition to ICERs is appropriate for decision making
The company did a fully incremental analysis of treatment sequences, using the cheapest biological treatment (etanercept) as a baseline. The committee noted that several treatments had only small differences in total costs and quality-adjusted life year (QALY) gains, and that these small differences could be difficult to see using incremental cost-effectiveness ratios (ICERs) from fully incremental or pairwise analyses. The ERG therefore presented the cost-effectiveness results in a net monetary benefit framework. The incremental net monetary benefit of each comparator was compared with best supportive care at opportunity costs of £20,000 and £30,000 per QALY gained. The committee concluded that incremental net monetary benefit was useful in determining the relative cost effectiveness of the interventions with similar costs and QALYs, and that it should be considered alongside the company's and the ERG's ICERs. The company subsequently provided a revised base case, which included results presented in a net monetary benefit framework.
## Tildrakizumab is more cost effective than other biological treatments
The committee considered whether tildrakizumab would be a cost-effective use of NHS resources for people with severe psoriasis for whom biological treatments are an option, taking into account a revised patient access scheme for tildrakizumab and the patient access schemes for the other biological treatments. The committee considered deterministic results from the company's revised analyses as adjusted by the ERG to take into account the patient access schemes for brodalumab, guselkumab, ixekizumab and secukinumab. The revised analyses included results of comparisons between treatment sequences (see section 3.15) as well as results of pairwise comparisons of individual treatments with best supportive care (see section 3.22). The revised analyses used the committee's preferred utility values (see section 3.18 and section 3.19), cost estimates (see section 3.20 and section 3.21) and induction period durations (see section 3.16 and section 3.17).
For tildrakizumab assessed at 28 weeks, its QALY gain compared with best supportive care was closer to the QALY gains of other targeted treatments that are usually assessed between 12 weeks to 16 weeks (such as brodalumab, guselkumab, ixekizumab, infliximab and secukinumab). The committee agreed that this meant that tildrakizumab, when assessed at 28 weeks, could potentially displace these treatments. The committee therefore considered the cost-effectiveness estimates for tildrakizumab assessed at 28 weeks compared with these comparators. It noted that, although other biological treatments were more expensive and more effective, tildrakizumab provided one of the highest net benefits compared with best supportive care (more than £7,000 at an opportunity cost of £20,000 per QALY gained, compared with less than £6,000 for the comparators) and was therefore considered cost effective. The committee concluded that tildrakizumab assessed at 28 weeks was likely to be a cost-effective use of NHS resources.
The committee then considered whether tildrakizumab would be cost effective with a shorter induction period (14 weeks). The QALY gain compared with best supportive care was lower than when assessed at 28 weeks and lower than the QALY gain of most other biological treatments. However, tildrakizumab had a higher net benefit compared with best supportive care (around £7,000) than many other NICE approved biological treatments, such as ixekizumab, guselkumab and secukinumab compared with best supportive care (less than £6,000). The committee, therefore, concluded that tildrakizumab assessed at 14 weeks was likely to be a cost-effective use of NHS resources.The committee concluded that tildrakizumab was likely to be a cost-effective use of NHS resources when response was assessed either at 14 or 28 weeks. However, tildrakizumab with a 28‑week stopping rule produced a higher QALY gain than with a 14‑week stopping rule and had a higher net benefit. The committee, taking into account the considerations mentioned in section 3.9, concluded that if there was no adequate response at 28 weeks (either a PASI 75 response, or a PASI 50 response and a 5‑point reduction in DLQI) tildrakizumab should be stopped. The committee also concluded that, if there had not been at least a 50% reduction in the PASI score from when treatment started to between 12 and 28 weeks, stopping tildrakizumab should be considered (see section 3.11).
# Other factors
## The PASI and DLQI may not be appropriate for all people with psoriasis
The committee noted, as in previous NICE technology appraisal guidance on psoriasis, potential equality issues:
the PASI might underestimate disease severity in people with darker skin
the DLQI has limited validity in some people, and may miss anxiety and depressionThe committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.
## Tildrakizumab is not innovative
The committee understood that tildrakizumab is an interleukin‑23 inhibitor with a 12‑week dosing schedule. The committee was aware that the 12‑week interval between doses is longer than for most other biological treatments currently available in NHS practice. The clinical expert advised that this would be welcomed by patients as a less burdensome treatment option. The committee concluded that, although less frequent dosing may reduce the burden to people with psoriasis, it was unlikely that there were additional gains in health-related quality of life over those already included in the QALY calculations.# Recommendations for research
The committee noted that the costs of best supportive care are derived from a study published in 2010 and that clinical practice has changed substantially since then. It therefore considered that it would be valuable to have studies investigating:
the costs associated with best supportive care
resource use, including frequency and length of hospitalisation, and associated costs.
|
{'Recommendations': 'Tildrakizumab is recommended as an option for treating plaque psoriasis in adults, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of\xa010 or more and a Dermatology Life Quality Index (DLQI) of more than\xa010 and\n\nthe disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and\n\nthe company provides the drug according to the commercial arrangement.\n\nConsider stopping tildrakizumab between 12\xa0weeks and 28\xa0weeks if there has not been at least a 50% reduction in the PASI score from when treatment started.\n\nStop tildrakizumab at 28\xa0weeks if the psoriasis has not responded adequately. An adequate response is defined as:\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from when treatment started.\n\nIf patients and their clinicians consider tildrakizumab to be one of a range of suitable treatments, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with tildrakizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment for moderate to severe plaque psoriasis includes systemic biological treatments for disease that does not respond to systemic non-biological treatments. Tildrakizumab is proposed as an alternative to other systemic biological treatments already recommended by NICE.\n\nClinical trial results show that tildrakizumab improves severe plaque psoriasis compared with placebo or etanercept. More improvement is usually seen at 28\xa0weeks compared with 12\xa0weeks of treatment. When compared indirectly, tildrakizumab appears to be as effective as adalimumab and ustekinumab but not as effective as other biological treatments.\n\nThe most plausible cost-effectiveness estimates for tildrakizumab compared with most other available biological treatments show that it is generally cost effective. Therefore, tildrakizumab is recommended as an option for use in the NHS for severe psoriasis that has not responded to systemic non-biological treatments, or if these are contraindicated or not tolerated.', 'Information about tildrakizumab': "Marketing authorisation indication\n\nTildrakizumab (Ilumetri, Almirall) has a marketing authorisation 'for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy.'\n\nDosage in the marketing authorisation\n\nTildrakizumab is administered by subcutaneous injection at a dose of 100\xa0mg at weeks\xa00 and\xa04 and every 12\xa0weeks thereafter. In patients with certain characteristics (for example, high disease burden, body weight of 90\xa0kg or more), a 200\xa0mg dose may provide greater efficacy.\n\nConsideration should be given to stopping treatment in patients whose psoriasis has shown no response after 28\xa0weeks of treatment. An initial partial response may subsequently improve with continued treatment beyond 28\xa0weeks.\n\nPrice\n\nThe list price of tildrakizumab is £3,241 for both the 100\xa0mg (single-dose pack of 1\xa0prefilled syringe) and the 200\xa0mg (single-dose pack of 2×100\xa0mg prefilled syringes) doses (excluding VAT; price as quoted in company's submission).\n\nThe company has a commercial arrangement. This makes tildrakizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa06) considered evidence submitted by Almirall and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Experience of people with psoriasis\n\n## Psoriasis is a lifelong condition that affects all aspects of a person's life\n\nPsoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological, social and financial), and it is a lifelong condition. The committee noted that having treatments with few or manageable side effects, and which are effective for psoriasis on the face, hands, feet and genitals, is especially important to people with psoriasis, as is having a choice of treatments.\n\n# Clinical management\n\n## Psoriasis can be treated with topical therapies, phototherapy, and systemic non-biological and biological treatments\n\nPeople with plaque psoriasis may have topical therapies first line, followed by phototherapy second line. If these do not control the psoriasis, people may have systemic conventional non-biological treatments third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to these, people may have fourth-line treatment including systemic biological treatments (such as adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, infliximab, secukinumab or ustekinumab), or apremilast or dimethyl fumarate. Biosimilar versions of some biologicals are also available. The drugs are used for as long as they continue to work. If the disease no longer responds to 1\xa0biological, people will be offered another biological. This pattern is likely to be repeated over their lifetime. However, 1\xa0clinical expert explained that previous biological treatments may affect the effectiveness of subsequent treatments, although there is uncertainty about the degree to which this occurs. Also, switching treatments can have a negative psychological effect on people with psoriasis. The clinical expert also stated that a variety of treatments are needed because patients can respond very differently to treatments with the same biological method of action. For people whose disease does not respond to multiple biological treatments, apremilast or dimethyl fumarate, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging.\n\n# Treatment pathway\n\n## Tildrakizumab is most likely to be used as an alternative to other systemic biological treatments\n\nThe marketing authorisation for tildrakizumab is for 'adults who are candidates for systemic therapy'. However, in the company submission, tildrakizumab was positioned as an alternative only to systemic biological treatments, which are used after systemic non-biological treatments in current NHS practice. The positioning therefore captures a narrower population than the marketing authorisation. However, the clinical expert confirmed that this is the most likely stage in the treatment pathway at which NHS clinicians would consider using tildrakizumab. The committee concluded that this position in the treatment pathway was appropriate and that it would appraise tildrakizumab compared with other biological treatments.\n\n## Infliximab is a relevant comparator to tildrakizumab\n\nThe company suggested that infliximab was not a relevant comparator because it was recommended only for people with very severe plaque psoriasis. The ERG explained that a large proportion of the population in the tildrakizumab trials (see section\xa03.7) had very severe plaque psoriasis. Also, infliximab was included as a comparator in previous appraisals at the same position in the treatment pathway as tildrakizumab. The committee concluded that infliximab was a relevant comparator to tildrakizumab.\n\n## The most relevant comparators to tildrakizumab are other biological treatments\n\nThe company suggested that the systemic non-biological treatments apremilast and dimethyl fumarate, used in NHS clinical practice at the same position as systemic biological treatments, were not relevant comparators. The clinical expert explained that these options were rarely used in practice because they are perceived to be less effective than biological treatments. They would only be considered for use for people for whom a biological treatment was unsuitable or who were unwilling to have a biological treatment. The committee concluded that although apremilast and dimethyl fumarate were used in the NHS for some people with psoriasis, the most relevant comparators to tildrakizumab were other biological treatments.\n\n# Clinical evidence\n\n## The reSURFACE trials provide the key clinical evidence for tildrakizumab\n\nThe main evidence for tildrakizumab came from the reSURFACE trials (reSURFACE\xa01 and reSURFACE\xa02). These were double-blind randomised controlled trials that included a total of 1,862\xa0patients with plaque psoriasis. They compared 2\xa0doses of tildrakizumab (100\xa0mg and 200\xa0mg) with placebo, and reSURFACE\xa02 also included an etanercept arm. The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the Physician Global Assessment (PGA). Both PASI and PGA were assessed at 12\xa0weeks and 28\xa0weeks, as follows:\n\nPASI\xa075: a 75% reduction in the PASI score from when treatment started and\n\nPGA: a PGA rating of 'clear' (score of\xa00) or 'almost clear' (score of\xa01).Patients in reSURFACE\xa01 and reSURFACE\xa02 were followed up for longer-term outcomes, for 64\xa0weeks and 52\xa0weeks respectively.\n\n## The populations in the reSURFACE trials are similar to patients in the NHS who may have tildrakizumab\n\nThe committee considered whether patients in the reSURFACE trials were similar to those in NHS clinical practice for:\n\nSeverity of disease: the reSURFACE trials included patients with moderate to severe psoriasis with a PASI score of 12\xa0or more. No minimum Dermatology Life Quality Index (DLQI) score was included. Previous NICE technology appraisals have defined severe and very severe psoriasis based on the PASI and DLQI; the PASI threshold for severe psoriasis is 10\xa0or more.\n\nPrevious systemic non-biological treatment: the committee noted that 24% of patients in reSURFACE\xa01 and 40% of patients in reSURFACE\xa02 had previous systemic non-biological treatment. The clinical expert stated that these proportions were lower than in the relevant population in NHS clinical practice. The committee was aware that subgroup analyses did not provide any evidence of a clinically relevant effect of previous systemic non-biological treatments on subsequent response to tildrakizumab.\n\nPrevious systemic biologicals: the committee noted that 23% of patients in reSURFACE\xa01 and 13% of patients in reSURFACE\xa02 had previous systemic biological treatment. The ERG suggested that this might not represent NHS clinical practice at the proposed positioning of tildrakizumab. The committee recalled the clinical expert's advice that previous biological treatments may influence the effectiveness of subsequent treatments (see section\xa03.2). However, the committee was also aware that there was uncertainty as to the extent that this may occur, and that subgroup analyses did not provide any evidence of a clinically relevant effect of previous biological treatments on subsequent response to tildrakizumab.The committee noted that the results of the reSURFACE trials may have overestimated the clinical effectiveness of tildrakizumab because of the proportions of patients who had not had previous non-biological and biological systemic treatment. The clinical expert advised that this would not be expected to have a large effect on the relative efficacy results. The committee concluded that the patients in the trials generally reflected those who would have treatment with tildrakizumab in NHS clinical practice.\n\n## Both 100\xa0mg and 200\xa0mg doses of tildrakizumab are appropriate\n\nThe company presented results for both licensed doses of tildrakizumab (100\xa0mg and 200\xa0mg). The company representative explained that the higher dose is intended for use from treatment induction in people with a higher body weight or disease burden, determined by the clinician. The committee noted that there was no difference in efficacy between the 2\xa0doses in the reSURFACE trials. The clinical expert explained that clinicians would welcome flexibility in available doses of the same treatment. The committee concluded that it was appropriate to consider both licensed doses in its decision making.\n\n## Clinical outcomes assessed at 12\xa0weeks and 28\xa0weeks should be considered\n\nThe committee was aware that tildrakizumab's marketing authorisation states that, if there is no response after 28\xa0weeks of treatment, stopping tildrakizumab should be considered. It recalled that the PASI\xa075 response rate for tildrakizumab at 28\xa0weeks was statistically significantly higher than at 12\xa0weeks in the reSURFACE trials, and other biological treatments also had higher response rates at later assessments. The committee considered that tildrakizumab's less frequent dosing schedule meant that this late treatment effect was more noticeable because only 2\xa0doses had been given before assessment of response at 12\xa0weeks. The clinical expert advised that assessment at 12\xa0weeks would be premature, and they would prefer to minimise the risk of a patient switching from a potentially effective treatment (see section\xa03.2). The committee concluded that the clinical outcomes from the reSURFACE trials at weeks 12\xa0and 28\xa0should be considered in its decision making.\n\n## Tildrakizumab is more clinically effective than placebo or etanercept\n\nThe committee noted that:\n\nAt week\xa012, patients randomised to tildrakizumab were more likely to have a PASI\xa075 and PGA clear or minimal response than patients randomised to placebo or etanercept.\n\nAt week\xa028, patients randomised to tildrakizumab were more likely to have a PASI\xa075 and PGA clear or minimal response than those randomised to etanercept, but no information compared with placebo was available.The committee concluded that tildrakizumab was more clinically effective than placebo and etanercept.\n\n## Assess response to tildrakizumab before and at 28\xa0weeks, and consider stopping treatment if there is no response\n\nBased on consultation comments, the committee understood that clinicians may find it unreasonable to continue tildrakizumab for 28\xa0weeks for patients whose psoriasis is not responding to treatment. The committee recalled that, in the reSURFACE trials, patients whose disease had not had at least a 50% reduction in the PASI score at 12\xa0weeks were less likely to have a PASI\xa075 response at 28\xa0weeks than patients whose disease had partially responded at 12\xa0weeks (PASI\xa050). The committee also recalled that most patients whose psoriasis had a PASI\xa075 response reached this outcome by week\xa022, after taking the third dose in week\xa016. It was aware that no similar data were presented for other outcomes such as DLQI. The committee considered that although stopping treatment from 14\xa0weeks was considered in the economic modelling (see section\xa03.17), it was more appropriate to consider stopping treatment from 12\xa0weeks. This was because this reflected the trial data and was in line with previous NICE technology appraisal guidance, such as NICE's technology appraisal guidance for etanercept efalizumab for the treatment of adults with psoriasis, brodalumab for treating moderate to severe plaque psoriasis, ixekizumab for treating moderate to severe plaque psoriasis and secukinumab for treating moderate to severe plaque psoriasis. The committee concluded that if there was no adequate response at 28\xa0weeks (either a PASI\xa075 response, or a PASI\xa050 response and a 5‑point reduction in DLQI), tildrakizumab should be stopped (see section\xa03.9). Also, if there has not been at least a 50% reduction in the PASI score from when treatment started to between 12\xa0weeks and 28\xa0weeks, stopping tildrakizumab should be considered.\n\n# Network meta-analysis\n\n## The network meta-analysis including infliximab is appropriate for decision making\n\nThe company did a network meta-analysis to indirectly compare tildrakizumab with other biological treatments (adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab and ustekinumab) using data from 45\xa0trials. The included trials assessed PASI\xa075 response at various time points, which the company grouped into separate stages for its analysis:\n\nResponse measured at 12\xa0weeks to 16\xa0weeks (stage\xa0I).\n\nResponse measured at 16\xa0weeks to 24\xa0weeks (stage\xa0II). Stage\xa0II was a separate planned analysis that excluded the placebo arms, resulting in an incomplete network, therefore it was not considered in this appraisal.\n\nResponse measured at 24\xa0weeks to 28\xa0weeks (stage\xa0III).No trials reported placebo outcomes at stage\xa0III. To include placebo in its stage\xa0III network, the company used placebo response rates from the same trials at stage\xa0I. The ERG noted that this made the stage\xa0III analysis weaker than the stage\xa0I analysis. This was because there were no direct placebo data at 24\xa0weeks to 28\xa0weeks, and because most trials were open label at this point, although a stage\xa0III etanercept control group was included. The ERG also advised that excluding infliximab from the network was inconsistent with previous appraisals, and that including it would strengthen the network. The ERG therefore included 6\xa0additional trials in an exploratory analysis. The committee concluded that the network meta-analysis, including infliximab, was appropriate for decision making. The company accepted the committee's preference and the ERG's exploratory analysis.\n\n## Tildrakizumab is more effective at 28\xa0weeks than at 12\xa0weeks\n\nFor the stage\xa0I (12\xa0weeks to 16\xa0weeks) analysis, the committee noted that the PASI\xa075 response rates for tildrakizumab were higher than those for etanercept, similar to adalimumab and ustekinumab, and lower than for other targeted biological treatments, including guselkumab (an interleukin‑23 inhibitor, as is tildrakizumab). For the stage\xa0III (24\xa0weeks to 28\xa0weeks) analysis the committee noted that the network meta-analysis suggested that the PASI\xa075 response rates for tildrakizumab were statistically significantly higher than at stage\xa0I. It also noted that tildrakizumab at stage\xa0III had a higher PASI\xa075 response rate than etanercept and adalimumab at stage\xa0III, and similar efficacy to other targeted biological treatments at stage\xa0I, which reflected the stopping rules used in NHS practice for those treatments. The committee concluded that tildrakizumab was more effective at stage\xa0III than at stage\xa0I. It also concluded that the efficacy of tildrakizumab at stage\xa0I was closest to adalimumab at stage\xa0I, and the efficacy of tildrakizumab at stage\xa0III was closest to guselkumab at stage\xa0I.\n\n# Company's economic model\n\n## The model has a Markov state transition structure\n\nA Markov state transition model was used to assess the cost effectiveness of tildrakizumab. It assumed that treatments improved quality of life but did not extend length of life. The model contained 4\xa0health states: induction treatment, maintenance treatment, best supportive care and death. All patients entered the model in the induction state and had the first treatment in a given sequence (see section\xa03.15). They moved from the induction state to the maintenance state if there was at least a PASI\xa075 response measured at the end of induction. From there, some patients could stop treatment for any reason and move to the next treatment in the sequence. If there was not a PASI\xa075 response, patients moved to the induction phase of the next treatment in the sequence. Patients moved to the best supportive care state if their psoriasis did not respond to the last active treatment in a sequence. All patients could move to the death state at any time.\n\n## The company's model compares treatment sequences\n\nThe company's decision problem compared a sequence of treatments including tildrakizumab with 7\xa0other sequences excluding tildrakizumab. Each sequence comprised 4\xa0treatments:\n\nThe first treatment was either tildrakizumab or another biological treatment (adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab or ustekinumab).\n\nThe second treatment was ustekinumab, except in the sequence in which ustekinumab was used as the first treatment; in that sequence, adalimumab was used as the second treatment.\n\nThe third treatment was secukinumab, except in the sequence in which secukinumab was used as the first treatment; in that sequence, adalimumab was used as the third treatment.\n\nThe fourth treatment in all sequences was best supportive care.The company chose these sequences based on expert advice. The committee was aware that, over time, a sequence of biologicals would be used to treat severe psoriasis in current NHS practice because people switch from 1\xa0option to another. It was also aware that additional factors should be considered when comparing treatment sequences, such as the best ordering of treatments and the effect of including treatments that may not be cost effective. The committee agreed that, in principle, it was appropriate to compare treatment sequences in this appraisal.\n\n# Assumptions in the economic model\n\n## A common 14‑week induction period is inappropriate\n\nThe company included a common 14‑week induction period for tildrakizumab and all comparators in its economic model. The company explained that this was to simplify the model, and that a 14‑week induction period was chosen to represent the midpoint of the range of typical induction periods (stage\xa0I from the network meta-analysis; 12\xa0weeks to 16\xa0weeks). The ERG explained that this method would create bias in the costs of the induction period. So, it explored a scenario of modelling treatment-specific induction period costs to reflect the recommended induction duration of each one. The committee recognised that a common 14‑week induction period was particularly inconsistent with a potential 28‑week induction period for tildrakizumab (see section\xa03.11). The committee concluded that assuming a common induction period could apply to treatments with different induction durations was inappropriate. It therefore preferred the ERG's modelling of treatment-specific induction period costs. The company subsequently provided a revised base case in which treatment-specific induction costs were used.\n\n## Tildrakizumab is compared with the induction periods used in current practice for other biological treatments\n\nThe company included a scenario analysis in its submission comparing the cost effectiveness of tildrakizumab with a 28‑week induction period with all other treatments at 28\xa0weeks. The ERG noted that no other treatments had a recommended assessment time in the stage\xa0III time range, and so the appropriate comparison would be with treatments at their recommended assessment times. The ERG therefore included tildrakizumab with 14‑week and 28‑week induction periods as separate interventions in its exploratory analysis. The committee recalled that the network meta-analyses showed a statistically significant improvement in the PASI\xa075 response rate for tildrakizumab between the 2\xa0assessment points (see section\xa03.13). The committee concluded that it preferred the ERG's approach; namely, that tildrakizumab with a 14‑week and a 28‑week induction period should be compared with other biological treatments at their recommended 12‑week to 16‑week induction periods, to reflect the stopping rules used in NHS practice for those treatments. The company subsequently provided a revised base case in which tildrakizumab with a 14‑week and a 28‑week induction period was compared with other biological treatments at their recommended 12‑week to 16‑week induction periods.\n\n# Utility values in the economic model\n\n## The company's utility values are appropriate, without adjustment for age\n\nThe company used EQ‑5D data collected in the reSURFACE\xa01 trial to inform utility values in its economic model. Utility values were stratified by the level of PASI response. The company implemented its utility values in the economic model by assuming a percentage change from general age-related population values. The ERG suggested that adjusting utility values for age in this way may be inappropriate because it assumes a constant relationship between age and PASI score. It also noted that, because no extension of life for any treatment had been modelled, adjusting for age added a complexity to the model that was not needed. The committee concluded that the ERG's scenario analysis using the company's absolute utility values without adjusting for age was more appropriate. The company subsequently provided a revised base case in which absolute utility values without adjusting for age were used.\n\n## Best supportive care utility values should return to baseline\n\nThe company assumed, in its model, that the utility value for patients having best supportive care was equal to the utility value associated with the lowest PASI reduction (less than 50%). The clinical expert considered this to be inappropriate, advising that a patient who switched from an active treatment to best supportive care would revert to their baseline quality of life shortly after switching. The ERG noted limitations in stratifying utility value by PASI response; namely, a person with a PASI response below 50% might still have some improvement in their PASI that has a positive effect on quality of life, and that PASI response may not fully capture improvements in the psoriasis from treatment. This may explain why the utility value for the 'PASI response less than 50%' group was notably higher than the baseline value. The ERG did an exploratory analysis using the baseline utility value for those having best supportive care. The committee concluded that the baseline utility value was more appropriate for representing health-related quality of life than the utility value for patients whose psoriasis had the lowest response to treatment. The company subsequently provided a revised base case in which baseline utility values were used for patients having best supportive care.\n\n# Costs in the economic model\n\n## The ERG's drug costs and resource use estimates are appropriate for decision making\n\nThe company presented drug costs adjusted for a 14‑week induction period and annual maintenance costs adjusted for a 14‑week cycle length. The ERG revised these costs for each treatment-specific induction period (see section\xa03.16) and corrected maintenance costs. Biosimilar price reductions for etanercept were considered by the company. The ERG included additional healthcare costs for those whose psoriasis did not respond to biological treatments, increasing the company's one-off switching costs to reflect a 14‑week cycle cost. The committee concluded that the ERG's amendments to costs and resource use were appropriate for decision making. The company subsequently provided a revised base case using the ERG's amendments to costs and resource use.\n\n## The costs of best supportive care are uncertain\n\nIn its model, the company included the costs of best supportive care from NICE's guideline on psoriasis: assessment and management, which includes drug treatment, day centre care and inpatient care. Previous psoriasis appraisals obtained direct costs from an observational study (Fonia et al. 2010). The ERG advised that the costs of best supportive care from this source, used in previous appraisals, were considerably lower than the company's estimate from the psoriasis guideline. The ERG advised that, despite being lower than the company's estimates, the costs in Fonia et al. may still have overestimated the true costs of best supportive care in NHS practice because the secondary care resource use in the study appeared to be high. The committee concluded that the costs of best supportive care for people whose psoriasis does not respond to treatment is uncertain because of a lack of recent studies to quantify the true costs in clinical practice. It concluded that, for this appraisal, the Fonia et al. costs should be used because they are more likely to reflect current clinical practice than the costs used in the company's model, and this is consistent with previous appraisals. The company subsequently provided a revised base case using the Fonia et al. best supportive care costs. The committee further concluded that defining costs associated with psoriasis that reflect current clinical practice was an important area for research.\n\n# Cost-effectiveness estimates\n\n## Treatment sequences may result in misleading cost-effectiveness estimates\n\nThe committee was aware that treatment sequences, although more likely to reflect the treatment switching seen in clinical practice, may have provided misleading cost-effectiveness estimates for tildrakizumab. It noted that some of the treatments were not cost effective in the model. Therefore, the cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding potentially cost-ineffective subsequent treatments or by choosing treatments with lower response rates, resulting in an earlier transition to best supportive care. The committee was also aware that the company's model compared a limited number of all potential treatment sequences. The ERG compared individual treatments with best supportive care in its own base case, setting the second and third options in all sequences to best supportive care. The committee concluded that it would consider these comparisons of individual treatments with best supportive care in its decision making to account for potential bias caused by analysing treatment sequences. The company subsequently provided a revised base case with pairwise comparisons of individual treatments with best supportive care.\n\n## Considering incremental net monetary benefit in addition to ICERs is appropriate for decision making\n\nThe company did a fully incremental analysis of treatment sequences, using the cheapest biological treatment (etanercept) as a baseline. The committee noted that several treatments had only small differences in total costs and quality-adjusted life year (QALY) gains, and that these small differences could be difficult to see using incremental cost-effectiveness ratios (ICERs) from fully incremental or pairwise analyses. The ERG therefore presented the cost-effectiveness results in a net monetary benefit framework. The incremental net monetary benefit of each comparator was compared with best supportive care at opportunity costs of £20,000 and £30,000 per QALY gained. The committee concluded that incremental net monetary benefit was useful in determining the relative cost effectiveness of the interventions with similar costs and QALYs, and that it should be considered alongside the company's and the ERG's ICERs. The company subsequently provided a revised base case, which included results presented in a net monetary benefit framework.\n\n## Tildrakizumab is more cost effective than other biological treatments\n\nThe committee considered whether tildrakizumab would be a cost-effective use of NHS resources for people with severe psoriasis for whom biological treatments are an option, taking into account a revised patient access scheme for tildrakizumab and the patient access schemes for the other biological treatments. The committee considered deterministic results from the company's revised analyses as adjusted by the ERG to take into account the patient access schemes for brodalumab, guselkumab, ixekizumab and secukinumab. The revised analyses included results of comparisons between treatment sequences (see section\xa03.15) as well as results of pairwise comparisons of individual treatments with best supportive care (see section\xa03.22). The revised analyses used the committee's preferred utility values (see section\xa03.18 and section\xa03.19), cost estimates (see section\xa03.20 and section\xa03.21) and induction period durations (see section\xa03.16 and section\xa03.17).\n\nFor tildrakizumab assessed at 28\xa0weeks, its QALY gain compared with best supportive care was closer to the QALY gains of other targeted treatments that are usually assessed between 12\xa0weeks to 16\xa0weeks (such as brodalumab, guselkumab, ixekizumab, infliximab and secukinumab). The committee agreed that this meant that tildrakizumab, when assessed at 28\xa0weeks, could potentially displace these treatments. The committee therefore considered the cost-effectiveness estimates for tildrakizumab assessed at 28\xa0weeks compared with these comparators. It noted that, although other biological treatments were more expensive and more effective, tildrakizumab provided one of the highest net benefits compared with best supportive care (more than £7,000 at an opportunity cost of £20,000 per QALY gained, compared with less than £6,000 for the comparators) and was therefore considered cost effective. The committee concluded that tildrakizumab assessed at 28\xa0weeks was likely to be a cost-effective use of NHS resources.\n\nThe committee then considered whether tildrakizumab would be cost effective with a shorter induction period (14\xa0weeks). The QALY gain compared with best supportive care was lower than when assessed at 28\xa0weeks and lower than the QALY gain of most other biological treatments. However, tildrakizumab had a higher net benefit compared with best supportive care (around £7,000) than many other NICE approved biological treatments, such as ixekizumab, guselkumab and secukinumab compared with best supportive care (less than £6,000). The committee, therefore, concluded that tildrakizumab assessed at 14\xa0weeks was likely to be a cost-effective use of NHS resources.The committee concluded that tildrakizumab was likely to be a cost-effective use of NHS resources when response was assessed either at 14\xa0or 28\xa0weeks. However, tildrakizumab with a 28‑week stopping rule produced a higher QALY gain than with a 14‑week stopping rule and had a higher net benefit. The committee, taking into account the considerations mentioned in section\xa03.9, concluded that if there was no adequate response at 28\xa0weeks (either a PASI\xa075 response, or a PASI\xa050 response and a 5‑point reduction in DLQI) tildrakizumab should be stopped. The committee also concluded that, if there had not been at least a 50% reduction in the PASI score from when treatment started to between 12\xa0and\xa028 weeks, stopping tildrakizumab should be considered (see section\xa03.11).\n\n# Other factors\n\n## The PASI and DLQI may not be appropriate for all people with psoriasis\n\nThe committee noted, as in previous NICE technology appraisal guidance on psoriasis, potential equality issues:\n\nthe PASI might underestimate disease severity in people with darker skin\n\nthe DLQI has limited validity in some people, and may miss anxiety and depressionThe committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\n## Tildrakizumab is not innovative\n\nThe committee understood that tildrakizumab is an interleukin‑23 inhibitor with a 12‑week dosing schedule. The committee was aware that the 12‑week interval between doses is longer than for most other biological treatments currently available in NHS practice. The clinical expert advised that this would be welcomed by patients as a less burdensome treatment option. The committee concluded that, although less frequent dosing may reduce the burden to people with psoriasis, it was unlikely that there were additional gains in health-related quality of life over those already included in the QALY calculations.", 'Recommendations for research': 'The committee noted that the costs of best supportive care are derived from a study published in 2010 and that clinical practice has changed substantially since then. It therefore considered that it would be valuable to have studies investigating:\n\nthe costs associated with best supportive care\n\nresource use, including frequency and length of hospitalisation, and associated costs.'}
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https://www.nice.org.uk/guidance/ta575
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Evidence-based recommendations on tildrakizumab (Ilumetri) for treating moderate to severe plaque psoriasis in adults.
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23e6b75585742f48bc6f27026d1b6ccc910cbe28
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nice
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Specialist neonatal respiratory care for babies born preterm
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Specialist neonatal respiratory care for babies born preterm
This guideline covers specific aspects of respiratory support (for example, oxygen supplementation, assisted ventilation, treatment of some respiratory disorders, and aspects of monitoring) for preterm babies in hospital.
# Recommendations
Parents and carers have the right to be involved in planning and making decisions about their baby's health and care, and to be given information and support to enable them to do this, as set out in the NHS constitution and summarised in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Risk factors for bronchopulmonary dysplasia
Be aware that the risk factors for bronchopulmonary dysplasia (BPD) include those in table 1. Note that the risk factors 'treated with surfactant' and 'treated for a patent ductus arteriosus (PDA)' are likely to reflect the severity of the baby's condition. Surfactant should be used, and a PDA should be treated, where clinically appropriate.
The risk factors in table 1 (below) have been identified in large prospective cohort studies, but other gestational ages and other risk factors not listed here might also be associated with an increased risk of bronchopulmonary dysplasia.
In babies born before 32 weeks
Lower gestational age
Lower birthweight
Small for gestational age
Male sex
Core body temperature of less than 35°C on admission to neonatal unit
Invasive ventilation begun within 24 hours of birth
Clinical sepsis with or without positive blood cultures
Feeding with formula milk (exclusively or in addition to breast milk)
Treated with surfactant
Treated for a patent ductus arteriosus (PDA)
The risk factors of being treated with surfactant and treated for a PDA are likely to reflect the severity of the baby's condition. Surfactant should be used, and a PDA should be treated, where clinically appropriate.
In babies born before 30 weeks
Cardiopulmonary resuscitation performed at birth
For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on risk factors for BPD .
Full details of the evidence and the committee's discussion are in evidence review A: diagnosing respiratory disorders.
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# Respiratory support for preterm babies
## Respiratory support before admission to the neonatal unit
When stabilising preterm babies who need respiratory support soon after birth and before admission to the neonatal unit, use continuous positive airways pressure (CPAP) where clinically appropriate, rather than invasive ventilation.
For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on respiratory support before admission to the neonatal unit .
Full details of the evidence and the committee's discussion are in evidence review B: respiratory support.
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## Surfactant
Give surfactant to preterm babies who need invasive ventilation for stabilisation in the early postnatal period.
When giving surfactant to a preterm baby who does not need invasive ventilation, use a minimally invasive administration technique. If this is not possible, for example, in units without the facilities or trained staff to carry out these techniques, use endotracheal intubation to give surfactant, with early extubation afterwards.In April 2019, this was an off-label use for some brands of surfactant. See NICE's information on prescribing medicines.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on giving surfactant .
Full details of the evidence and the committee's discussion are in evidence review B: respiratory support.
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## Oxygen
Use nasal cannula or incubator oxygen for preterm babies who need supplemental oxygen.
Humidify oxygen when giving oxygen at higher flow rates, such as 2 litres per minute or more.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on oxygen .
Full details of the evidence and the committee's discussion are in evidence review B: respiratory support.
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## Non-invasive ventilation techniques in the neonatal unit
For preterm babies who need non-invasive ventilation, consider nasal CPAP or nasal high-flow therapy as the primary mode of respiratory support.
## Invasive ventilation techniques in the neonatal unit
For preterm babies who need invasive ventilation, use volume-targeted ventilation (VTV) in combination with synchronised ventilation as the primary mode of respiratory support. If this is not effective, consider high-frequency oscillatory ventilation (HFOV).
For preterm babies who need invasive ventilation but VTV and HFOV are not available or not suitable, consider synchronised intermittent mandatory ventilation (SIMV).
Do not use synchronised pressure-limited ventilation such as assist control (AC), synchronised intermittent positive pressure ventilation (SIPPV), patient-triggered ventilation (PTV), pressure support ventilation (PSV) or synchronised time-cycled pressure-limited ventilation (STCPLV).
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on ventilation techniques .
Full details of the evidence and the committee's discussion are in evidence review B: respiratory support.
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## Nitric oxide
Do not routinely use inhaled nitric oxide for preterm babies who need respiratory support for respiratory distress syndrome (RDS), unless there are other indications such as pulmonary hypoplasia or pulmonary hypertension.In April 2019, the following uses were off-label: inhaled nitric oxide for pulmonary hypoplasia and inhaled nitric oxide for pulmonary hypertension in babies less than 34 weeks' gestation. See NICE's information on prescribing medicines.
For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on nitric oxide .
Full details of the evidence and the committee's discussion are in evidence review B: respiratory support.
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# Managing respiratory disorders
## Corticosteroids
Consider dexamethasone to reduce the risk of BPD for preterm babies who are 8 days or older and still need invasive ventilation for respiratory disease. When considering whether to use dexamethasone in these babies:
take into account the risk factors for BPD in table 1 and
discuss the possible benefits and harms with the parents or carers. Topics to discuss include those in table 2. In April 2019, this was an off-label use of dexamethasone. See NICE's information on prescribing medicines.
For preterm babies who are younger than 8 days old, be aware that dexamethasone increases the risk of gastrointestinal perforation.
Do not use dexamethasone with non-steroidal anti-inflammatory drugs (NSAIDs).
Monitor the blood pressure of babies who receive dexamethasone, because of the risk of hypertension.
Outcome
Benefit or harm for preterm babies 8 days or older
Notes
Mortality before discharge
There is no difference in mortality before discharge in babies who receive dexamethasone compared with babies who do not receive dexamethasone.
There was evidence demonstrating this lack of difference.
BPD at 36 weeks' postmenstrual age
Babies who receive dexamethasone are less likely to develop BPD compared with babies who do not receive dexamethasone.
On average:
without dexamethasone treatment, 63 babies per 100 would develop BPD (and 37 would not)
with dexamethasone treatment, 47 babies per 100 would develop BPD (and 53 would not).
There was evidence demonstrating this difference.
Cerebral palsy
There is no difference in the incidence of cerebral palsy in babies who receive dexamethasone compared with babies who do not receive dexamethasone.
Although there was evidence demonstrating this lack of difference, there is uncertainty about the risk, so the possibility of cerebral palsy occurring cannot be excluded.
Other neurodevelopmental outcomes (neurodevelopmental delay and neurosensory impairment)
There is no difference in neurodevelopmental outcomes in babies who receive dexamethasone compared with babies who do not receive dexamethasone.
Although there was evidence demonstrating this lack of difference, there is uncertainty about the risk of neurodevelopmental delay and neurosensory impairment because the studies reported neurodevelopmental assessments at different timepoints.
Days on invasive ventilation
Babies who receive dexamethasone have fewer days on invasive ventilation compared with babies who do not receive dexamethasone.
Although there was evidence demonstrating this difference, there is uncertainty about the difference in the number of days on invasive ventilation because of the different ways the studies reported it.
Gastrointestinal perforation
There is no difference in gastrointestinal perforation in babies who receive dexamethasone compared with babies who do not receive dexamethasone.
Although there was evidence demonstrating this lack of difference, there is uncertainty about the risk, so the possibility of gastrointestinal perforation occurring cannot be excluded.
Hypertension
Babies who receive dexamethasone are more likely to develop hypertension compared with babies who do not receive dexamethasone.
On average:
without dexamethasone treatment, 3 preterm babies per 100 would develop hypertension (and 97 would not)
with dexamethasone treatment, 11 babies per 100 would develop hypertension (and 89 would not).
There was evidence demonstrating this difference.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on dexamethasone .
Full details of the evidence and the committee's discussion are in evidence review C: managing respiratory disorders.
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## Diuretics
For a short explanation of why the committee did not make a recommendation, see the rationale on diuretics .
Full details of the evidence and the committee's discussion are in evidence review C: managing respiratory disorders.
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## Caffeine citrate
Use caffeine citrate routinely in preterm babies born at or before 30 weeks, starting it as early as possible and ideally before 3 days of age.
Consider stopping caffeine citrate at 33 to 35 weeks' corrected gestational age if the baby is clinically stable.
Consider caffeine citrate for any preterm baby with apnoea.Give a loading dose of 20 mg/kg of caffeine citrate, followed 24 hours later by a maintenance dosage of 5 mg/kg once daily, increasing up to 20 mg/kg daily if episodes of apnoea persist.In April 2019, this dosage was an off-label use of caffeine citrate. See NICE's information on prescribing medicines.
Consider a maintenance dosage higher than 20 mg/kg daily if therapeutic efficacy is not achieved, while ensuring that a safe plasma level is maintained.In April 2019, this dosage was an off-label use of caffeine citrate. See NICE's information on prescribing medicines.When measuring plasma levels, prescribers should use the local laboratory's reference ranges. See the BNF for Children for further information about caffeine citrate.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on caffeine citrate .
Full details of the evidence and the committee's discussion are in evidence review C: managing respiratory disorders.
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## Patent ductus arteriosus
Do not treat a PDA in a preterm baby unless the PDA causes a significant clinical problem, for example, difficulty weaning the baby from a ventilator.
For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on PDA .
Full details of the evidence and the committee's discussion are in evidence review C: managing respiratory disorders.
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# Monitoring
## Oxygen
Use continuous pulse oximetry to measure oxygen saturation in preterm babies, supplemented by arterial sampling if clinically indicated.
After initial stabilisation, aim for an oxygen saturation of 91% to 95% in preterm babies.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
For preterm babies on invasive ventilation who are clinically unstable, consider transcutaneous oxygen monitoring.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on oxygen monitoring .
Full details of the evidence and the committee's discussion are in evidence review D: monitoring.
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## Carbon dioxide
For preterm babies on invasive ventilation, aim for a carbon dioxide partial pressure (PCO2) of:
kPa to 8.5 kPa on days 1 to 3 and
kPa to 10 kPa from day 4 onwards.
Reduce minute ventilation without delay in preterm babies with a low PCO2, and check the PCO2 within an hour of the low measurement being identified.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on carbon dioxide monitoring .
Full details of the evidence and the committee's discussion are in evidence review D: monitoring.
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## Blood pressure
Do not treat preterm babies for hypotension based solely on specific blood pressure thresholds, but take into account other factors, such as evidence of poor tissue perfusion. The aim of treatment should be to improve perfusion.
For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on blood pressure .
Full details of the evidence and the committee's discussion are in evidence review D: monitoring.
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# Sedation and analgesia
## Morphine
Do not routinely use morphine for preterm babies on respiratory support.
Consider morphine if the baby is in pain. Assess the baby's pain using locally agreed protocols or guidelines.In April 2019, the following uses were off-label: intravenous morphine for children under 12 years and oral morphine for children under 1 year. See NICE's information on prescribing medicines.
Regularly reassess babies on morphine to ensure that it is stopped as soon as possible.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on morphine .
Full details of the evidence and the committee's discussion are in evidence review E: sedation and analgesia.
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## Premedication before intubation
Consider premedication before elective non-urgent intubation in preterm babies.
If giving premedication, consider either:
an opioid analgesic (for example, morphine or fentanyl), combined with a neuromuscular blocking agent (for example, suxamethonium) or
propofol alone.In April 2019, the following uses were off-label: intravenous morphine for children under 12 years, oral morphine for children under 1 year, fentanyl for children under 2 years, and propofol for children under 1 month. See NICE's information on prescribing medicines.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on premedication for intubation .
Full details of the evidence and the committee's discussion are in evidence review E: sedation and analgesia.
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# Involving, supporting and informing parents and carers
NICE has produced a guideline on babies, children and young people's experience of healthcare.
## Involving parents and carers while their preterm baby is on respiratory support
Explain to the parents and carers of preterm babies on respiratory support that non-nutritive sucking (using a dummy) during periods when the baby is awake is beneficial because:
it can help soothe the baby between feeds and
in babies fed by a nasogastric tube, dummy use can reduce the length of the baby's hospital stay.
Tell parents and carers about the benefits of using touch, for example, through skin-to-skin contact, to communicate with their baby.
Consider providing the Newborn individualized developmental care and assessment program (NIDCAP®) to improve cognitive development in babies born at less than 27 weeks.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on involving parents and carers .
Full details of the evidence and the committee's discussion are in evidence review F: involving and supporting parents and carers.
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## Supporting parents and carers while their preterm baby is on respiratory support
Recognise parents and carers as partners in their baby's care, and support them in this role.
Encourage and support parents and carers to:
be involved in planning and providing their baby's day-to-day care, for example, feeding and nappy changing
participate in discussions and decisions about their baby during ward rounds, providing input into planning and providing care.
Provide regular opportunities and time for parents and carers to discuss their baby's care, ask questions about the information they have been given, and discuss concerns.
Give parents and carers the time, support and encouragement they need to become confident in caring effectively for their baby.
Offer parents and carers psychological support from a professional who is trained to deliver this type of help and advice.
## Providing information to parents and carers while their preterm baby is on respiratory support
Ask parents and carers about how and when they would like to receive information about their baby's treatment and progress, and how they would prefer to be contacted when they are away from the neonatal unit.
Support discussions with parents and carers using written information. Ensure that information is up to date, relevant, appropriate to the parents' and carers' needs and preferences, and consistent between healthcare professionals. For more guidance on communication (including different formats and languages), providing information, and shared decision making, see the NICE guidelines on patient experience in adult NHS services and shared decision making.
Ensure that information for parents and carers is delivered by an appropriate healthcare professional, and information for hospitalised mothers who cannot visit their baby is delivered by a senior healthcare professional, for example, a neonatologist or specialist registrar, face-to-face whenever possible.
Be sensitive about the timing of discussions with parents and carers. In particular, discuss significant perinatal events without delay, providing the mother has sufficiently recovered from the birth.
Provide information for parents and carers that includes:
explanations and regular updates about their baby's condition and treatment, especially if there are any changes
what happens in the neonatal unit, and the equipment being used to support their baby
what respiratory support is being provided for their baby
how to get involved in their baby's day-to-day care, interact with their baby and interpret the baby's neurobehavioural cues
the roles and responsibilities of different members of their baby's healthcare team, and key contacts
information about caring for a premature baby to share with family and friends, and practical suggestions about how to get help and support from family and friends
-pportunities for peer support from neonatal unit graduate parents or parent buddies
details of local support groups, online forums and national charities, and how to get in touch with them.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on supporting and providing information to parents and carers .
Full details of the evidence and the committee's discussion are in evidence review F: involving and supporting parents and carers.
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## Neonatal services for preterm babies on respiratory support
Those responsible for planning and delivering neonatal services should ensure that neonatal units:
are welcoming and friendly
foster positive and supportive relationships by providing parents and carers with 24‑hour access to their baby
provide privacy for skin-to-skin contact and feeding
have private areas for difficult conversations
have comfortable furniture and provide a relaxing environment for families.
Ensure that healthcare professionals in neonatal units can support parents and carers by being competent in:
communicating complex and sensitive information clearly
tailoring information and support to the person's individual needs and circumstances.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on neonatal services .
Full details of the evidence and the committee's discussion are in evidence review F: involving and supporting parents and carers.
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# Discharge planning
## Planning safe discharge from the neonatal unit for preterm babies on respiratory support
Neonatal units should consider appointing a member of staff as a designated neonatal discharge coordinator to discuss the following with parents and carers:
-ngoing support and follow‑up after discharge (also see the NICE guideline on developmental follow-up of children and young people born preterm)
how to care for their baby at home
how to use specialist equipment safely
how to travel with their baby and specialist equipment.
When planning to discharge a preterm baby on respiratory support from the neonatal unit:
follow the principles in the NICE guideline on postnatal care
consider early referral to, and regular contact with, community and continuing healthcare teams
consider an interim discharge placement to, for example, a hospice, alternative family member's home, step-down unit, transitional care unit, or alternative suitable accommodation, where appropriate.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on planning safe discharge .
Full details of the evidence and the committee's discussion are in evidence review G: discharge planning.
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## Supporting and providing information to parents and carers of preterm babies on respiratory support – preparing for discharge
Recognise parents and carers as partners in the discharge planning process. Answer their questions and concerns as they arise, and support them in making joint decisions with the discharge team.
Throughout the baby's neonatal admission, provide support and guidance for parents and carers with constructive and supportive feedback about how to care for their baby and how to use specialist equipment. Use a formal competency-based assessment tool to evaluate the safe use of specialist equipment.
Discuss any modifications that parents and carers might need to make to their home as soon as possible.
Educate parents and carers about possible emergencies that may arise, how to deal with them and who to contact for help and advice. This should include how to carry out cardiopulmonary resuscitation, and what to do if there are problems with any specialist equipment.
Provide parents and carers with opportunities to care for their baby overnight.
Provide information for parents and carers to help them care for their baby safely and confidently after discharge. Follow the principles in the section on communication and information-giving in this guideline, and also see the NICE guideline on postnatal care. Information should include:
how to recognise signs of illness in their baby, and what to do
how to adapt routines such as feeding and sleeping after discharge, and information about safe sleep guidance
how to make follow‑up appointments and timing of immunisations
who to contact after discharge, as well as a list of useful medical contacts.
Tell parents and carers about sources of support after discharge, for example:
-pportunities for peer support
help and support for their own needs, for example, postnatal depression (also see the NICE guideline on antenatal and postnatal mental health).
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on supporting and providing information to parents as part of discharge planning .
Full details of the evidence and the committee's discussion are in evidence review G: discharge planning.
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# Terms used in this guideline
## Automated oxygen titration
A control system that measures the oxygen saturation and automatically adjusts the oxygen flow to maintain oxygen saturation within a predefined target range.
## Invasive ventilation
Administration of respiratory support via an endotracheal tube or tracheostomy, using a mechanical ventilator. The definitions of invasive ventilation modes are summarised in table 3.
Volume-targeted ventilation (VTV)
Volume guarantee ventilation (VGV)
Target tidal volume (TTV)
Pressure regulated volume control (PRVC) ventilation (PRVCV)
Volume-limited ventilation (VLV)
Volume assured pressure support (VAPS)
Any synchronised pressure-limited ventilation (SPLV) plus VTV
Synchronised intermittent mandatory ventilation (SIMV) plus VTV
Synchronised pressure-limited ventilation (SPLV)
Assist control ventilation (AC)
Synchronised intermittent positive pressure ventilation (SIPPV)
Patient-triggered ventilation (PTV)
Pressure support ventilation (PSV)
Synchronised time-cycled pressure-limited ventilation (STCPL)
Synchronised Intermittent Mandatory Ventilation (SIMV)
Non-synchronised pressure-limited ventilation (NSPLV)
Conventional mandatory ventilation (CMV)
Non-triggered/unsynchronised time-cycled pressure-limited ventilation (TCPL)
Intermittent mandatory ventilation (IMV)
High-frequency ventilation (HFV)
High-frequency oscillatory ventilation (HFOV)
High-frequency flow interruption (HFFI)
## Minimally invasive administration technique
Administration of surfactant through a thin endotracheal catheter without insertion of an endotracheal tube or invasive ventilation.
## Minute ventilation
The tidal volume of each breath in millilitres (ml) multiplied by the number of breaths per minute gives the minute ventilation in ml/minute (usually expressed as ml/kg/minute, which is achieved by dividing by the baby's weight in kg).
## Neurobehavioural cues
Sounds, characteristics of movements including facial expressions and physiological parameters such as heart rate, breathing patterns and skin tone that reflect the baby's current level of sensitivity or wellbeing, and reveal their current developmental stage.
## Neurodevelopmental outcomes
In this guideline, neurodevelopmental outcomes at 18 months or older have been defined as:
cerebral palsy (reported as presence or absence of condition, not severity)
neurodevelopmental delay (reported as dichotomous outcomes, not continuous outcomes such as mean change in score):
severe (score of more than 2 standard deviations below normal on validated assessment scales, or a score of less than 70 on the Bayley II scale of infant development mental developmental index or psychomotor developmental index , or complete inability to assign score because of cerebral palsy or severe cognitive delay)
moderate (score of 1 to 2 SD below normal on validated assessment scales, or a score of 70 to 84 on the Bayley II scale of infant development MDI or PDI)
neurosensory impairment (reported as presence or absence of condition, not severity):
severe hearing impairment (for example, deaf)
severe visual impairment (for example, blind).
## Non-invasive ventilation
Administration of respiratory support using a ventilator or flow driver, but not via an endotracheal tube or tracheostomy.
## Perinatal
In this guideline, the perinatal period is defined as the period of time from 48 hours before birth up until 7 completed days after birth.
## Preterm
A baby born before 37 weeks. This can be subdivided further:
extremely preterm: babies born at less than 28 weeks
very preterm: babies born at between 28 and 31+6 weeks
moderate to late preterm: babies born at between 32 and 36+6 weeks.
## Skin-to-skin contact
Holding a naked baby, or a baby wearing only a nappy, on the skin of a parent or carer, usually on the chest.
## Stabilisation
Facilitating and supporting a smooth transition from fetal to neonatal life. The process involves careful assessment of heart rate, colour (oxygenation) and breathing, with provision of appropriate interventions where indicated.# Recommendations for research
# Key recommendations for research
## Non-invasive ventilation techniques
What is the effectiveness of high-pressure non-invasive positive pressure ventilation (NIPPV) compared with continuous positive airways pressure (CPAP) flow driver as the primary mode of ventilation?
For a short explanation of why the committee made the recommendation for research, see the rationale section on non-invasive ventilation techniques .
Full details of the evidence and the committee's discussion are in evidence review B: respiratory support.
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## Surfactant
What is the best technique for delivering surfactant in a minimally invasive manner?
For a short explanation of why the committee made the recommendation for research, see the rationale section on surfactant .
Full details of the evidence and the committee's discussion are in evidence review B: respiratory support.
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## Diuretics
What is the effectiveness of diuretics compared with placebo in preventing bronchopulmonary dysplasia (BPD) in preterm babies on respiratory support?
For a short explanation of why the committee made the recommendation for research, see the rationale section on diuretics .
Full details of the evidence and the committee's discussion are in evidence review C: managing respiratory disorders.
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## Oxygen monitoring
Does targeting higher oxygen saturations of 92% to 97% in preterm babies lead to improved survival without significant complications?
For a short explanation of why the committee made the recommendation for research, see the rationale section on oxygen monitoring .
Full details of the evidence and the committee's discussion are in evidence review D: monitoring.
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## Premedication before intubation
What is the most effective combination of an analgesic with a neuromuscular blocker, or an analgesic with an anaesthetic agent, for premedication in preterm babies requiring elective or semi-elective intubation?
For a short explanation of why the committee made the recommendation for research, see the rationale section on premedication before intubation .
Full details of the evidence and the committee's discussion are in evidence review E: sedation and analgesia.
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# Other recommendations for research
## Respiratory support before admission to the neonatal unit
Does CPAP plus prophylactic surfactant, administered by a non-invasive technique in the delivery room, improve outcomes compared with CPAP alone in preterm babies?
## Surfactant
What is the optimal dosing regimen of surfactant when delivered in a minimally invasive manner?
## Oxygen administration
What is the effectiveness of humidified and non-humidified supplemental low-flow oxygen in preterm babies?
What should be the target oxygen saturation range for preterm babies when using an automated oxygen titration system that creates a normal frequency-saturation curve?
## Invasive ventilation techniques
Are there differences in the long-term neurodevelopmental outcomes for preterm babies receiving volume-targeted ventilation (VTV) compared with high-frequency oscillatory ventilation (HFOV) as their primary mode of ventilation?
## Corticosteroids
What is the comparative efficacy of hydrocortisone compared with dexamethasone for preventing BPD in preterm babies requiring respiratory support?
Is nebulised budesonide effective compared with placebo in preventing BPD in preterm babies requiring respiratory support?
## Diuretics
What is the effectiveness of diuretics compared with placebo in the treatment of BPD in preterm babies on respiratory support?
## Caffeine citrate
What is the optimal maintenance dose of caffeine citrate in order to optimise neurodevelopmental outcomes in preterm babies?
## Oxygen monitoring
What is the accuracy of pulse oximetry and transcutaneous measurement of partial pressure of oxygen compared with arterial oxygen levels for detecting hyperoxia and hypoxia in preterm babies?
## Carbon dioxide monitoring
What is the optimal carbon dioxide target range in preterm babies on non-invasive ventilation at different gestational ages?
## Blood pressure
What is the optimal method and frequency of measuring blood pressure for preterm babies requiring respiratory support?
What is the optimal target blood pressure range for preterm babies requiring respiratory support?
## Morphine
What is the effectiveness of morphine compared with containment holding for preterm babies receiving respiratory support?
## Involving parents and carers
What is the impact of parental involvement as part of Family integrated care (FIC) or the Newborn individualised developmental care and assessment programme (NIDCAP®) on the incidence of BPD and length of hospital stay in preterm babies?
## Discharge planning
What is best practice around discharge planning for preterm babies on respiratory support?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect services. They link to details of the evidence and a full description of the committee's discussion.
# Risk factors for bronchopulmonary dysplasia
Recommendation 1.1.1
## Why the committee made the recommendation
There was evidence that lower gestational age, lower birth weight, being small for gestational age, male sex, lower body temperature, sepsis, any formula feeding, surfactant use, treatment for a patent ductus arteriosus (PDA), cardiopulmonary resuscitation and mechanical ventilation, are all independent risk factors for bronchopulmonary dysplasia (BPD) in preterm babies.
No evidence was found to link antenatal steroids, chorioamnionitis, intrauterine growth restriction, ethnicity or race, or postnatal steroid use, and BPD. However, the committee did not prioritise these areas for further research.
The committee was concerned that including surfactant use and treatment for PDA as risk factors for BPD could lead to a reduction in surfactant use and PDA treatment. They agreed that there was unlikely to be a causal link – rather, the increased risk of BPD associated with these factors is more likely to reflect the severity of the baby's condition, and that surfactant should be used, and a PDA should be treated, where clinically appropriate.
The committee noted that there was an absence of evidence for certain risk factors for BPD; some evidence was for specific gestational ages at birth from which the committee was unable to extrapolate to other gestational ages, and for some risk factors, the evidence was underpowered to detect an effect. The committee therefore concluded that other gestational ages and other risk factors not listed here might also be associated with increased risk of BPD.
No evidence was found for some of the potential risk factors that had been suggested by the committee (such as necrotising enterocolitis and supplementary oxygen), but these were not prioritised by the committee for further research.
## How the recommendation might affect services
Knowledge of BPD risk factors means healthcare professionals can identify preterm babies who are more likely to develop BPD, and prioritise treatment regimens accordingly. This may reduce the incidence of BPD, which will lead to long-term savings for the NHS.
Return to recommendation
# Respiratory support before admission to the neonatal unit
Recommendation 1.2.1
## Why the committee made the recommendation
The evidence did not show a clear difference between continuous positive airways pressure (CPAP) alone and invasive ventilation with surfactant when used in preterm babies in the delivery room, for any of the outcomes that the committee had prioritised (mortality, BPD and neurodevelopmental outcomes). However, the evidence showed a possible reduction in mortality before discharge, and a possible reduction in the incidence of BPD at 36 weeks' postmenstrual age with CPAP.
One large study found that just over half of the babies who received CPAP instead of intubation did need to be intubated at some point during their hospitalisation. However, the committee agreed that this was a very positive result, because around half of babies avoided all the risks of invasive intervention.
The committee agreed that it is preferable to avoid invasive ventilation wherever possible and agreed that when stabilising a preterm baby in the delivery room, the non-invasive ventilation technique of CPAP should be used rather than invasive ventilation. The committee agreed that this approach may not be suitable for some babies, for example, if the baby is not breathing and needs invasive ventilation. In addition, the committee agreed that this approach would probably not be suitable for preterm babies born very early, for example at less than 25 weeks, because these babies may not have the necessary respiratory drive, and because the failure rate of non-invasive ventilation is high in babies of this age. The committee agreed that for these very preterm babies, it may be more practical to use invasive ventilation with surfactant in the delivery room, but because this would be a clinical decision, it was not appropriate to set a particular age cut‑off.
Because there was not enough evidence to make recommendations on the use of CPAP with surfactant compared with CPAP without surfactant in the delivery room, the committee recommended that further research be done in this area.
## How the recommendation might affect services
Current practice in most units is to routinely intubate preterm babies (below a certain gestation, often 27 to 28 weeks, but specific cut‑offs will vary) and give surfactant, so this will be a change in practice for these units. Because CPAP is associated with lower costs than invasive ventilation, this change is likely to lead to cost savings.
Return to recommendation
# Surfactant
Recommendations 1.2.2 and 1.2.3
## Why the committee made the recommendations
It is established clinical practice in the UK to give surfactant to preterm babies needing invasive ventilation in the early postnatal period, based on good evidence and extensive clinical experience, so the committee agreed to make a recommendation that reinforces this.
In preterm babies who do not require invasive ventilation, there was evidence that minimally invasive surfactant administration techniques reduce the incidence of BPD, the number of days on invasive ventilation, and the incidence of pneumothorax, compared with endotracheal administration.
However, not all neonatal units have the facilities to carry out minimally invasive surfactant administration techniques, and not all healthcare professionals have been trained to use them. The committee agreed that in these circumstances, endotracheal surfactant administration followed by early extubation should be used, because there was evidence that it reduces the incidence of BPD compared with conventional administration of surfactant with continued ventilation.
Because there was not enough good evidence to make recommendations on which minimally invasive administration technique leads to the best outcomes, or on different surfactant dosing regimens, the committee recommended that further research be done in these areas.
## How the recommendations might affect services
Current practice for giving surfactant to preterm babies varies among neonatal units because of differences in available facilities and training. The recommendations may increase the trend towards using less invasive techniques of surfactant administration. Neonatal units that currently use conventional endotracheal administration of surfactant may therefore change practice to use minimally invasive techniques or to extubate earlier.
Return to recommendations
# Oxygen
Recommendations 1.2.4 and 1.2.5
## Why the committee made the recommendations
There was a small amount of evidence suggesting there is no difference in the effectiveness or safety of oxygen delivered by nasal cannula compared with oxygen delivered in the incubator. However, because the evidence was limited, the committee made a recommendation based on consensus that nasal cannula or incubator oxygen could be used. They noted that incubator oxygen may be preferred for short-term use and assessment, whereas nasal cannula oxygen is preferable for longer-term use because it allows the baby to be touched and cuddled, and provides a stable concentration of oxygen.
There was evidence that automated oxygen titration reduces the number of days on oxygen, reduces the number of manual adjustments for titration, and increases the time that preterm babies spend in the optimal target oxygen saturation range. However, the committee were concerned, based on their clinical knowledge, that the cumulative frequency oxygen curves for oxygen saturation achieved by automated titration may lead to the mean saturation level achieved by babies being reduced (because of the normal distribution of the frequency-saturation curve) compared with manual adjustments (where the frequency-saturation curve is skewed to the higher end of the target saturation range). The committee therefore made a recommendation for research to determine the optimal target oxygen saturation range for use in conjunction with an automated oxygen titration system.
There was no evidence comparing humidified to non-humidified oxygen, but the committee agreed that this is standard clinical practice at higher flow rates and made a consensus recommendation for the use of humidified oxygen. The committee also made a recommendation for research to assess the effectiveness of humidified and non-humidified supplemental low-flow oxygen.
## How the recommendations might affect services
The recommendations reflect current clinical practice.
Return to recommendations
# Ventilation techniques
Recommendations 1.2.6 to 1.2.9
## Why the committee made the recommendations
The available evidence made it difficult to differentiate between the various non-invasive ventilation techniques. The evidence showed that nasal high-flow therapy had the highest probability of being the best technique for reducing mortality before discharge, compared with other non-invasive ventilation techniques. However, the committee agreed that babies born extremely preterm are less likely to manage successfully on nasal high-flow therapy as the primary mode of ventilation when compared with babies born less preterm.
The evidence showed a reduction in the failure of non-invasive ventilation with CPAP compared with nasal high-flow therapy. Using their clinical experience, the committee agreed that CPAP would be a more suitable option for use in babies born more preterm.
Because of the lack of good evidence, the committee agreed that CPAP or nasal high-flow therapy should be used as a primary mode of ventilation in preterm babies who need non-invasive ventilation, with the decision on which option to use being made for individual babies.
There was evidence that nasal intermittent positive pressure ventilation (NIPPV) had lower rates of failed non-invasive ventilation and fewer days on invasive ventilation than CPAP, but the delivery of NIPPV in the studies was significantly different to routine clinical practice in the UK, so the committee recommended that further research should be carried out comparing NIPPV and CPAP.
There was evidence from the network meta-analysis that volume-targeted ventilation (VTV) has the highest probability of being the best technique as the primary mode of ventilation, both for mortality before discharge and BPD at 36 weeks.
The committee agreed that VTV may not be appropriate for all preterm babies, for example, if there is an air leak. There was evidence that if VTV is not effective, high-frequency oscillatory ventilation (HFOV) should be considered as an alternative. The committee acknowledged that the flow sensors required for VTV are expensive, but the committee agreed that most units already have flow sensors for triggered ventilation and the same sensor could be used for VTV. In units or situations where neither VTV nor HFOV are available or suitable, the evidence showed that synchronised intermittent mandatory ventilation (SIMV) was the next most effective mode of ventilation.
The committee agreed that synchronised pressure-limited ventilation should be avoided because the evidence showed an increase in the incidence of mortality before discharge, compared with non-synchronised pressure-limited ventilation, HFOV and VTV. The evidence also showed an increase in days on invasive ventilation and pneumothorax, compared with VTV.
The evidence from the pair-wise analysis showed no significant difference between HFOV and VTV, and there was no evidence on neurodevelopmental outcomes at 18 months or older, so the committee recommended that further research should be carried out.
## How the recommendations might affect services
The recommendations should reinforce current clinical practice and lead to greater consistency.
Return to recommendations
# Nitric oxide
Recommendation 1.2.10
## Why the committee made the recommendation
There was no evidence of benefit for inhaled nitric oxide in preterm babies who need respiratory support for respiratory distress syndrome (RDS). There was some evidence of adverse effects, and the treatment is unlikely to be cost effective. The committee agreed that there may be exceptions for preterm babies who have other conditions such as pulmonary hypoplasia and pulmonary hypertension, for whom there may be some survival benefits.
## How the recommendation might affect services
The recommendation will reduce the use of inhaled nitric oxide for preterm babies who need respiratory support, which may lead to cost savings to the NHS given the high acquisition cost of inhaled nitric oxide.
Return to recommendation
# Corticosteroids
Recommendations 1.3.1 to 1.3.4
## Why the committee made the recommendations on dexamethasone
There was evidence that in babies 8 days or older, dexamethasone reduces the incidence of BPD, but dexamethasone is associated with an increased risk of hypertension. There were no clinically important differences in mortality before discharge between babies who received dexamethasone and those who did not.
There was some evidence suggesting that dexamethasone reduces the number of days on invasive ventilation, but this was difficult to interpret because of the different ways the studies reported the time on ventilation.
In babies 8 days or older, there was evidence that dexamethasone is not associated with an increased risk of cerebral palsy, neurodevelopmental delay, neurosensory impairment or gastrointestinal perforation. However, the committee emphasised that there was some uncertainty about the evidence for these outcomes.
In babies younger than 8 days, there was evidence that dexamethasone reduces the incidence of BPD but is associated with an increased risk of gastrointestinal perforation.
The committee therefore recommended that dexamethasone be considered for babies 8 days or older who still need ventilation for respiratory disease, after taking into account risk factors for BPD. This is in line with current practice, which is to use corticosteroids to assist weaning from ventilatory support when a baby is 8 days or older, rather than using corticosteroids as 'prophylaxis' for babies younger than 8 days old.
The committee agreed the importance of discussing the risks of gastrointestinal perforation, hypertension and cerebral palsy with parents and carers before starting dexamethasone therapy, because there may be lifelong implications for the baby and their family.
Although the combination of dexamethasone and non-steroidal anti-inflammatory drugs (NSAIDs) was not reviewed, the committee confirmed that they should not be used together because this increases the risk of gastrointestinal bleeding and perforation. The committee agreed that although this risk is widely recognised, it should be reinforced in the guideline to ensure that dexamethasone and NSAIDs are not used together in clinical practice.
Because of the increased risk of hypertension with dexamethasone, the committee recommended that babies' blood pressure should be monitored. There was no evidence about when or for how long to monitor blood pressure, so the committee agreed that this should be decided by the neonatologist responsible for the baby's care.
The evidence did not show any differences between different dosing strategies, and so the committee did not make any specific dosing recommendations.
## Why the committee didn't make any recommendations on hydrocortisone and nebulised budesonide
Evidence comparing hydrocortisone and placebo was inconclusive, so the committee did not make any recommendations. The committee was aware that there is an ongoing, large multicentre randomised controlled trial investigating hydrocortisone compared with placebo in preterm babies who need respiratory support, so did not make a recommendation for research that would replicate this study. However, they agreed that a comparison of dexamethasone and hydrocortisone could provide useful guidance and so made a recommendation for research for this comparison.
There was very little evidence for the use of nebulised budesonide and therefore the committee made a recommendation for research.
## How the recommendations might affect services
Current practice is to use corticosteroids in preterm babies to assist weaning or removal from ventilatory support, but they are not routinely used to prevent BPD in all preterm babies. The choice of dexamethasone or hydrocortisone varies among neonatal units. These recommendations are unlikely to affect how often corticosteroids are used, but they might prompt units who currently use hydrocortisone to consider dexamethasone as an alternative.
Return to recommendations
# Diuretics
## Why the committee did not make any recommendations
The evidence on the use of diuretics in preterm babies on respiratory support was very limited. None of the studies identified assessed critical outcomes such as mortality before discharge, BPD or neurodevelopmental outcomes. Although the studies looked at short-term adverse effects associated with diuretics, it was not clear whether there was an increased risk of adverse effects because of the small sample size of the studies.
Because of the limited evidence and lack of clinical consensus, the committee could not make any recommendations for or against diuretic use in preterm babies on respiratory support. Instead, the committee recommended that further research be done in this area.
## How the recommendations might affect services
Although they did not make any recommendations, some of the committee members thought that the lack of evidence identified may lead to healthcare professionals reviewing their use of diuretics. This may lead to a reduction in the use of diuretics in preterm babies on respiratory support, at least until further evidence is available.
Return to recommendation
# Caffeine citrate
Recommendations 1.3.5 to 1.3.8
## Why the committee made the recommendations
There was evidence that in preterm babies born before 31 weeks, caffeine citrate reduces the incidence of BPD, cerebral palsy (at 18 to 21 months' follow‑up) and blindness (at 11‑year follow‑up) compared with placebo. However, from their clinical experience, and based on the inclusion criteria of the CAP study, the committee agreed that it was appropriate to start babies, born at or before 30 weeks (equivalent to babies born at or below 1.25 kg), on caffeine citrate on admission to the neonatal unit, so they recommended earlier initiation. Based on their clinical experience, the committee agreed that administering caffeine citrate would also reduce apnoea in older preterm babies.
There was evidence that, compared with lower doses, higher doses of caffeine citrate reduce the incidence of BPD, continued apnoea and extubation failure.
Evidence showed that the treatment with caffeine citrate before 3 days of age may lead to a reduction in BPD. There was also evidence that treatment with caffeine citrate for 15 to 30 days reduces the incidence of BPD compared with a shorter duration, and that treatment for longer than 30 days reduces the incidence of necrotising enterocolitis compared with treatment for less than 15 days.
To determine when caffeine citrate should be stopped, the committee referred back to the studies and identified the age at which caffeine citrate was started, the duration of caffeine citrate, and hence the age at which it had been stopped. The committee noted that caffeine citrate had been stopped in the studies at between 33 and 35 weeks. This reflected the clinical experience of the committee as the age at which preterm babies were no longer expected to have apnoea, and so this figure was used by the committee to develop their recommendations.
The committee made their dosing recommendations based on evidence that a higher dose is more effective than a lower dose, and on currently recommended doses used in clinical practice. However, the variation in loading and maintenance doses used across different clinical trials made selecting an optimal dose difficult, and although higher doses appeared to improve early outcomes, there were few data on long-term outcomes. For this reason, the committee recommended further research to identify the maintenance dose of caffeine citrate needed to optimise neurodevelopmental outcomes.
The committee also discussed whether monitoring caffeine citrate levels was necessary and noted that the Evelina London Paediatric Formulary advises that babies can receive 10 mg/kg of caffeine citrate twice daily without monitoring blood plasma levels (Evelina London 2015). The committee noted that there are units that do not currently monitor blood levels, and increasing doses to higher than 20 mg/kg daily may be a concern if units did not test blood levels at these higher doses. Therefore, the committee made an additional recommendation that if apnoea persists and a baby receives more than 20 mg/kg daily, caffeine citrate levels should be tested.
## How the recommendations might affect services
The recommendations will have a minimal impact on current practice. The committee noted that there is some variation in dosage regimens across the NHS, so these recommendations should lead to greater consistency in the choice of dosage regimens. The committee agreed that oral caffeine citrate is used in most cases, and has a low acquisition cost. The committee acknowledged that intravenous caffeine citrate has a substantially higher acquisition cost. However, because of the single-use vial sizes available, irrespective of dose, a single vial will be required for administration of each dose, so increasing the dose would not increase the costs. In addition, only a small number of babies would need the intravenous solution. Furthermore, there may be a small increase in the number of blood tests performed to assess caffeine citrate levels if higher doses are used, but again the number of babies who will require high doses is small. Overall, the recommendations may result in a slight increase in drug and monitoring costs, but this is not anticipated to be substantial.
Return to recommendations
# Patent ductus arteriosus
Recommendation 1.3.9
## Why the committee made the recommendation
There was no evidence of benefit from treating a PDA, and there was evidence for potential harms from treating it, with either medicines or surgery. However, the committee agreed that for some babies, treatment might be appropriate, for example, if there is difficulty weaning the baby from a ventilator.
## How the recommendation might affect services
The recommendation will reduce the unnecessary treatment of PDA and the number of babies exposed to potential harms from its treatment. The recommendations may result in cost savings because fewer procedures will be carried out.
Return to recommendation
# Oxygen monitoring
Recommendations 1.4.1 to 1.4.3
## Why the committee made the recommendations
The evidence on the best method for measuring oxygen levels in diagnosing hyperoxia or hypoxia in preterm babies was very limited. There were no studies assessing the diagnostic accuracy of SpO2 (peripheral capillary oxygen saturation) compared with the standard PaO2 (partial pressure of arterial oxygen) that met the review's inclusion criteria. The committee agreed, based on clinical consensus and their experience of clinical practice, that SpO2 should remain the first-line method for continuous monitoring of oxygen saturation levels in preterm babies because of its widespread availability and non-invasive nature. The committee agreed that arterial sampling of partial pressure of oxygen remained the 'gold standard', but is not always possible and can never be continuous.
The only evidence on tcPO2 (transcutaneous oxygen) was 1 study from the 1970s, and the way this procedure is performed has changed substantially since then. However, tcPO2 is currently used in clinical practice, and in the committee's experience it can provide useful information. This is particularly the case for preterm babies on invasive ventilation who are clinically unstable and need continuous monitoring to guide management, and in whom SpO2 may not be accurate.
Because of the lack of good evidence, the committee agreed that further research needs to be conducted looking at the diagnostic accuracy of tcPO2 and SpO2 against the gold standard arterial oxygen saturation in diagnosing hyperoxia and hypoxia in a preterm baby population.
There was evidence that higher target oxygen saturation levels reduce mortality. Although a higher target is associated with an increase in retinopathy of prematurity and an increased risk of BPD, the evidence suggested no increase in severe visual impairment at 18 months, and the reduction in mortality was considered to offset the increased risk of BPD. The committee were aware that target oxygen levels (up to 97%) may be more beneficial but there was no evidence to support this, so they made a recommendation for research.
## How the recommendation might affect services
The recommendations reflect current practice, where SpO2 is generally used as routine continuous oxygen monitoring in preterm babies, and tcPO2 is reserved for the more clinically unstable preterm babies as a continuous monitoring tool.
Many units already use 91% to 95% as their target saturation level for preterm babies, but for those that do not, this will be a change in practice. This will reduce the variation in clinical practice.
Return to recommendations
# Carbon dioxide monitoring
Recommendations 1.4.4 and 1.4.5
## Why the committee made the recommendations
The evidence showed no differences in the outcomes measured between higher and lower target ranges for the partial pressure of carbon dioxide in preterm babies on invasive ventilation. The committee recognised that the higher target ranges specified in the studies were in line with the definition of permissive hypercapnia and would probably not have any detrimental effects on clinical outcomes and long-term neurodevelopmental outcomes. In view of this, the committee agreed that when healthcare professionals are monitoring carbon dioxide levels in preterm babies on invasive ventilation, a higher target range would be acceptable. This avoids the need for frequent adjustment of the ventilators to reach an extremely tight target range.
There was variation in the target ranges of carbon dioxide used by different studies, and the range of days at which at different permissive hypercapnia levels were tolerated. The committee agreed to make a recommendation in line with the largest and most recent study that looked at clinical and long-term neurodevelopmental outcomes, but simplified the 3-stage ranges (days 1 to 3, days 4 to 6 and day 7 onwards) used in this study, to a 2-stage range based on their clinical experience that the difference in upper limits tolerated would be negligible and would have minimal detrimental effects on a preterm baby on invasive ventilation.
There was no evidence on the action to be taken when a low carbon dioxide level was detected, but the committee were aware that this was a dangerous situation, so agreed the action to be taken based on their clinical knowledge and experience.
All the evidence for the optimal target range of carbon dioxide was in preterm babies on invasive ventilation. The committee recognised the lack of evidence in preterm babies on non-invasive ventilation, so they recommended further research in this area.
## How the recommendations might affect services
The recommendations reflect current practice, both where permissive hypercapnia is accepted in the monitoring of carbon dioxide levels in preterm babies on invasive ventilation, and for the action to be taken if hypocapnia is detected.
Return to recommendations
# Blood pressure
Recommendation 1.4.6
## Why the committee made the recommendation
There was no good evidence to define the normal range of blood pressure in preterm babies, or how blood pressure should be measured. The committee wanted to make healthcare professionals aware of this lack of evidence to prevent unnecessary treatment based on the level of blood pressure only. The committee advised, based on their clinical experience, that inadequate perfusion should be treated with the aim of increasing perfusion, and not to aim for a particular blood pressure target.
Because there was no good evidence, the committee made recommendations for research to determine both the optimal blood pressure target and method of measuring blood pressure in preterm babies.
## How the recommendation might affect services
For units that routinely monitor blood pressure in preterm babies and treat when blood pressure falls outside certain limits, this will be a change in practice. The recommendation will lead to less unnecessary monitoring and treatment of blood pressure.
Return to recommendation
# Morphine
Recommendations 1.5.1 to 1.5.3
## Why the committee made the recommendations
The evidence showed that there was no difference in mortality before discharge in babies who received morphine compared with placebo. Babies receiving morphine took longer to achieve full enteral feeding, and babies born at 27 to 29 weeks' gestation had an increased risk of severe intraventricular haemorrhage (IVH). There was some evidence that, when compared with placebo, morphine improves sedation and pain scores in preterm babies who need invasive respiratory support during infusion. However, moderate quality evidence from a larger study showed no difference in pain scores during endotracheal suctioning between babies who received morphine compared with placebo.
The only evidence available comparing morphine with fentanyl showed no clinically significant difference in rates of severe IVH.
There was some evidence that, when compared with midazolam, babies receiving morphine may have decreased rates of severe IVH.
Babies receiving morphine experienced less pain during infusion, but less sedation after infusion.
Because of the mixed evidence regarding the effectiveness of morphine and taking into account the risks, the committee agreed that morphine should not be used routinely, but may be considered when it is clear the baby is in pain, and that neonatal units would have their own guidelines or preferred scales to determine pain in preterm babies.
The committee discussed other concerns about using morphine, such as suppressed respiratory drive and opioid dependency. They agreed that regular reassessments are important to ensure that morphine is stopped as soon as appropriate.
The committee did not make any recommendations for paracetamol or non-pharmacological interventions because there was no evidence available. Instead, the committee recommended that further research be done to compare morphine with containment holding during respiratory support, because the committee agreed that containment holding may improve outcomes in preterm babies, with a reduced risk of adverse events compared with pharmacological therapy.
## How the recommendations might affect services
Use of sedation and analgesia currently varies among units. The recommendations will have little impact in units that do not routinely use morphine, but other units may need to change practice and this may lead to a reduction in the use of morphine. The recommendations will make practice more consistent across the NHS.
Return to recommendations
# Premedication before intubation
Recommendations 1.5.4 and 1.5.5
## Why the committee made the recommendations
There was some evidence from small, single studies that using an analgesic with a neuromuscular blocker, or an anaesthetic such as propofol used alone, is an effective regimen to achieve successful intubation in preterm babies, while avoiding adverse effects.
However, there was a lack of evidence to show exactly which medicines or classes of medicines form the best combination, so the committee recommended that healthcare professionals should consider premedication before elective intubation and recommended that further research be done in this area.
## How the recommendations might affect services
Current practice of using premedication for elective intubation in preterm babies varies among units. Units that currently use single medicines (such as morphine or fentanyl) may need to change practice to follow the recommendation. The recommendation will make practice more consistent across the NHS.
Return to recommendations
# Involving parents and carers while their preterm baby is on respiratory support
Recommendations 1.6.1 to 1.6.3
## Why the committee made the recommendations
There was good evidence that using a dummy (non-nutritive sucking) during nasogastric feeds reduces the length of the baby's hospital stay. In addition, there was some evidence that the Newborn individualized developmental care and assessment program (NIDCAP®) improved neurodevelopmental outcomes relating to cognitive development and was a cost-effective intervention in babies born at less than 27 weeks. Although the evidence for skin-to-skin contact did not show any benefit, there was no evidence of harm. There was no evidence that Family integrated care (FIC) provided any additional benefits compared with standard care.
Based on their experience and the clinical evidence, the committee recommended explaining to parents and carers about the potential benefits of interacting with their baby because early social development and relationship-forming are key to successful emotional and behavioural development.
Because of the limited evidence available on FIC and NIDCAP®, the committee made it a priority to recommend that further research be done to investigate the potential impact of NIDCAP® and FIC on length of stay and BPD.
## How the recommendations might affect services
The committee agreed that the recommendations on non-nutritive sucking and using positive touch (such as skin-to-skin contact) would not result in a major change in practice, but will help improve consistency in best practice.
Although there are cost implications for units to train professionals in NIDCAP®, the recommendation to consider NIDCAP® would lead to a more consistent approach across neonatal care networks to practice linked with neurodevelopmental care. It would also improve babies' access to this type of neurodevelopmental care and allow greater involvement of parents and carers in the care of their baby.
Return to recommendations
# Supporting and informing parents and carers while their preterm baby is on respiratory support
Recommendations 1.6.4 to 1.6.13
## Why the committee made the recommendations
There was good evidence that parents value emotional, psychological and practical support from staff, friends and family, peers (such as other parents of preterm babies) and employers when caring for a preterm baby receiving respiratory support. Parents also value professional support and counselling.
There was also evidence that parents value being partners in their baby's care, want to be supported by staff in caring for their baby, and need to be able to develop good communication and relationships with the staff caring for their baby.
There was evidence that parents value a comfortable, homely environment on the neonatal unit that is conducive to being involved in planning and providing care for their baby. Parents also value having 24‑hour access to the neonatal unit, with private areas and privacy when needed.
There was good evidence that parents and carers value high-quality, relevant, consistent information about their baby's health and care, including regular updates on their baby's progress. Parents and carers value information that is appropriate for their needs and explained clearly to them, and value the opportunity to ask questions. There was evidence that the appropriate timing of information is important to parents. The evidence also showed that parents and carers prefer information to be provided by an appropriate healthcare professional, and for it to be backed up by written information.
Parents value information on a range of topics, including how to interpret their baby's neurobehavioural cues, breastfeeding, skin-to-skin contact, the medical equipment used, who to contact, and other sources of information they could access themselves.
## How the recommendations might affect services
The committee agreed that the recommendations would not result in a major change in practice, but will help improve consistency in best practice.
Return to recommendations
# Neonatal unit services
Recommendations 1.6.14 and 1.6.15
## Why the committee made the recommendations
There was evidence that parents and carers value having 24‑hour access to the neonatal unit, which should be a homely environment with comfortable furniture and private areas. In a number of the support and information themes, parents and carers agreed that healthcare professionals who provide information and support should be trained and competent in this, so the committee made an overarching recommendation.
## How the recommendations might affect services
The committee agreed that the recommendations would not result in a major change in practice, but will help improve consistency in best practice.
Return to recommendations
# Discharge planning – planning safe discharge
Recommendations 1.7.1 and 1.7.2
## Why the committee made the recommendations
There was evidence about the importance of good communication with parents about their baby's discharge. The committee agreed that a designated neonatal discharge coordinator, as a single point-of-contact, would facilitate the communication of key information with parents and carers. The committee also agreed that early referral to community and continuing healthcare teams would also help parents prepare for their baby's discharge. Having the option to discharge to an alternative location, such as to another relative's home or a hospice, would enable parents and carers whose homes are not suitable for their preterm baby to be able to care for their baby outside the hospital.
The committee also recognised that some of the advice in the NICE guideline on postnatal care was also relevant to babies born preterm and so made a cross reference to this guideline.
However, because there were only 2 studies, and no evidence for a number of themes identified by the committee, the committee agreed that more research could better define best practice, and so made a recommendation for research.
## How the recommendations might affect services
The committee agreed that the recommendations would not result in a major change in practice, but will help improve consistency in delivering best practice.
Return to recommendations
# Discharge planning – preparing for discharge
Recommendations 1.7.3 to 1.7.9
## Why the committee made the recommendations
There was evidence that parents and carers value having support and information about their baby's routine care, being involved in preparing for the baby's discharge, and having information on equipment, identifying illness in their baby, and dealing with emergencies. Parents and carers also value information about future care, such as contact details, follow‑up appointments and immunisations, ongoing peer support and self-care for problems such as postnatal depression.
## How the recommendations might affect services
The committee agreed that the recommendations would not result in a major change in practice, but will help improve consistency in delivering best practice.
Return to recommendations# Context
In 2016, a national neonatal audit found that approximately 13% of babies in the UK need specialist neonatal care, either because they are born preterm (at less than 37 weeks) or because of an illness or condition.
A comparison of the EPICure studies published in 2012 found that, between 1995 and 2006, the number of babies born at less than 26 weeks and admitted to neonatal units increased by 30% in England. Over the same period, survival rates for babies born at 22 to 25 weeks and admitted for intensive care increased by 13%. In addition, a higher proportion of these babies survived without disability (particularly babies born at 24 to 25 weeks). International comparisons show that the neonatal mortality rate varies significantly by country.
Preterm babies are at risk of respiratory disorders, including respiratory distress syndrome and bronchopulmonary dysplasia (BPD). High-quality respiratory care can reduce the length of hospital stay and risk of long-term disability. BPD is particularly common in preterm babies who require assisted ventilation. Babies with BPD need prolonged specialist care and respiratory support.
Respiratory support is used in different ways in different units, and it is unclear what the best method is for providing ventilation and preventing BPD. There are many other areas of uncertainty and variation in how respiratory support is provided. There is also variation in other areas of respiratory management, including how corticosteroids are used to prevent and manage BPD.
Since 2013, neonatal critical care services have been managed within Operational Delivery Networks. For healthy babies and babies with minor problems, most care is provided by the hospital they are born in. Neonatal intensive care units are responsible for babies who have more complex problems. Neonatal intensive care, and the service specifications for Neonatal Critical Care and Neonatal Intensive Care Transport, are within the scope of the neonatal critical care Clinical Reference Group.
This guideline is for:
healthcare professionals in primary, secondary and tertiary care
parents and carers of babies born preterm who need respiratory support
commissioners and providers of specialist neonatal care services.
Babies born preterm who need respiratory support (for example, oxygen supplementation or assisted ventilation) in hospital, beginning in the neonatal period.
Babies born at term.
Babies who need respiratory support because of congenital disorders, for example, congenital diaphragmatic hernia.
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{'Recommendations': "Parents and carers have the right to be involved in planning and making decisions about their baby's health and care, and to be given information and support to enable them to do this, as set out in the NHS constitution and summarised in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Risk factors for bronchopulmonary dysplasia\n\nBe aware that the risk factors for bronchopulmonary dysplasia (BPD) include those in table\xa01. Note that the risk factors 'treated with surfactant' and 'treated for a patent ductus arteriosus (PDA)' are likely to reflect the severity of the baby's condition. Surfactant should be used, and a PDA should be treated, where clinically appropriate.\n\nThe risk factors in table 1 (below) have been identified in large prospective cohort studies, but other gestational ages and other risk factors not listed here might also be associated with an increased risk of bronchopulmonary dysplasia.\n\n\n\nIn babies born before 32\xa0weeks\n\nLower gestational age\n\nLower birthweight\n\nSmall for gestational age\n\nMale sex\n\nCore body temperature of less than 35°C on admission to neonatal unit\n\nInvasive ventilation begun within 24 hours of birth\n\nClinical sepsis with or without positive blood cultures\n\nFeeding with formula milk (exclusively or in addition to breast milk)\n\nTreated with surfactant\n\nTreated for a patent ductus arteriosus (PDA)\n\nThe risk factors of being treated with surfactant and treated for a PDA are likely to reflect the severity of the baby's condition. Surfactant should be used, and a PDA should be treated, where clinically appropriate.\n\nIn babies born before 30\xa0weeks\n\nCardiopulmonary resuscitation performed at birth\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on risk factors for BPD\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: diagnosing respiratory disorders.\n\nLoading. Please wait.\n\n# Respiratory support for preterm babies\n\n## Respiratory support before admission to the neonatal unit\n\nWhen stabilising preterm babies who need respiratory support soon after birth and before admission to the neonatal unit, use continuous positive airways pressure (CPAP) where clinically appropriate, rather than invasive ventilation.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on respiratory support before admission to the neonatal unit\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: respiratory support.\n\nLoading. Please wait.\n\n## Surfactant\n\nGive surfactant to preterm babies who need invasive ventilation for stabilisation in the early postnatal period.\n\nWhen giving surfactant to a preterm baby who does not need invasive ventilation, use a minimally invasive administration technique. If this is not possible, for example, in units without the facilities or trained staff to carry out these techniques, use endotracheal intubation to give surfactant, with early extubation afterwards.In April 2019, this was an off-label use for some brands of surfactant. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on giving surfactant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: respiratory support.\n\nLoading. Please wait.\n\n## Oxygen\n\nUse nasal cannula or incubator oxygen for preterm babies who need supplemental oxygen.\n\nHumidify oxygen when giving oxygen at higher flow rates, such as 2\xa0litres per minute or more.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on oxygen\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: respiratory support.\n\nLoading. Please wait.\n\n## Non-invasive ventilation techniques in the neonatal unit\n\nFor preterm babies who need non-invasive ventilation, consider nasal CPAP or nasal high-flow therapy as the primary mode of respiratory support.\n\n## Invasive ventilation techniques in the neonatal unit\n\nFor preterm babies who need invasive ventilation, use volume-targeted ventilation (VTV) in combination with synchronised ventilation as the primary mode of respiratory support. If this is not effective, consider high-frequency oscillatory ventilation (HFOV).\n\nFor preterm babies who need invasive ventilation but VTV and HFOV are not available or not suitable, consider synchronised intermittent mandatory ventilation (SIMV).\n\nDo not use synchronised pressure-limited ventilation such as assist control (AC), synchronised intermittent positive pressure ventilation (SIPPV), patient-triggered ventilation (PTV), pressure support ventilation (PSV) or synchronised time-cycled pressure-limited ventilation (STCPLV).\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on ventilation techniques\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: respiratory support.\n\nLoading. Please wait.\n\n## Nitric oxide\n\nDo not routinely use inhaled nitric oxide for preterm babies who need respiratory support for respiratory distress syndrome (RDS), unless there are other indications such as pulmonary hypoplasia or pulmonary hypertension.In April 2019, the following uses were off-label: inhaled nitric oxide for pulmonary hypoplasia and inhaled nitric oxide for pulmonary hypertension in babies less than 34\xa0weeks' gestation. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on nitric oxide\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: respiratory support.\n\nLoading. Please wait.\n\n# Managing respiratory disorders\n\n## Corticosteroids\n\nConsider dexamethasone to reduce the risk of BPD for preterm babies who are 8\xa0days or older and still need invasive ventilation for respiratory disease. When considering whether to use dexamethasone in these babies:\n\ntake into account the risk factors for BPD in table\xa01 and\n\ndiscuss the possible benefits and harms with the parents or carers. Topics to discuss include those in table\xa02. In April 2019, this was an off-label use of dexamethasone. See NICE's information on prescribing medicines.\n\nFor preterm babies who are younger than 8\xa0days old, be aware that dexamethasone increases the risk of gastrointestinal perforation.\n\nDo not use dexamethasone with non-steroidal anti-inflammatory drugs (NSAIDs).\n\nMonitor the blood pressure of babies who receive dexamethasone, because of the risk of hypertension.\n\nOutcome\n\nBenefit or harm for preterm babies 8\xa0days or older\n\nNotes\n\nMortality before discharge\n\nThere is no difference in mortality before discharge in babies who receive dexamethasone compared with babies who do not receive dexamethasone.\n\nThere was evidence demonstrating this lack of difference.\n\nBPD at 36\xa0weeks' postmenstrual age\n\nBabies who receive dexamethasone are less likely to develop BPD compared with babies who do not receive dexamethasone.\n\nOn average:\n\nwithout dexamethasone treatment, 63\xa0babies per\xa0100 would develop BPD (and 37\xa0would not)\n\nwith dexamethasone treatment, 47\xa0babies per\xa0100 would develop BPD (and 53\xa0would not).\n\nThere was evidence demonstrating this difference.\n\nCerebral palsy\n\nThere is no difference in the incidence of cerebral palsy in babies who receive dexamethasone compared with babies who do not receive dexamethasone.\n\nAlthough there was evidence demonstrating this lack of difference, there is uncertainty about the risk, so the possibility of cerebral palsy occurring cannot be excluded.\n\nOther neurodevelopmental outcomes (neurodevelopmental delay and neurosensory impairment)\n\nThere is no difference in neurodevelopmental outcomes in babies who receive dexamethasone compared with babies who do not receive dexamethasone.\n\nAlthough there was evidence demonstrating this lack of difference, there is uncertainty about the risk of neurodevelopmental delay and neurosensory impairment because the studies reported neurodevelopmental assessments at different timepoints.\n\nDays on invasive ventilation\n\nBabies who receive dexamethasone have fewer days on invasive ventilation compared with babies who do not receive dexamethasone.\n\nAlthough there was evidence demonstrating this difference, there is uncertainty about the difference in the number of days on invasive ventilation because of the different ways the studies reported it.\n\nGastrointestinal perforation\n\nThere is no difference in gastrointestinal perforation in babies who receive dexamethasone compared with babies who do not receive dexamethasone.\n\nAlthough there was evidence demonstrating this lack of difference, there is uncertainty about the risk, so the possibility of gastrointestinal perforation occurring cannot be excluded.\n\nHypertension\n\nBabies who receive dexamethasone are more likely to develop hypertension compared with babies who do not receive dexamethasone.\n\nOn average:\n\nwithout dexamethasone treatment, 3\xa0preterm babies per\xa0100 would develop hypertension (and 97\xa0would not)\n\nwith dexamethasone treatment, 11\xa0babies per\xa0100 would develop hypertension (and 89\xa0would not).\n\nThere was evidence demonstrating this difference.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on dexamethasone\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: managing respiratory disorders.\n\nLoading. Please wait.\n\n## Diuretics\n\nFor a short explanation of why the committee did not make a recommendation, see the rationale on diuretics\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: managing respiratory disorders.\n\nLoading. Please wait.\n\n## Caffeine citrate\n\nUse caffeine citrate routinely in preterm babies born at or before 30\xa0weeks, starting it as early as possible and ideally before 3\xa0days of age.\n\nConsider stopping caffeine citrate at 33\xa0to 35\xa0weeks' corrected gestational age if the baby is clinically stable.\n\nConsider caffeine citrate for any preterm baby with apnoea.Give a loading dose of 20\xa0mg/kg of caffeine citrate, followed 24\xa0hours later by a maintenance dosage of 5\xa0mg/kg once daily, increasing up to 20\xa0mg/kg daily if episodes of apnoea persist.In April 2019, this dosage was an off-label use of caffeine citrate. See NICE's information on prescribing medicines.\n\nConsider a maintenance dosage higher than 20\xa0mg/kg daily if therapeutic efficacy is not achieved, while ensuring that a safe plasma level is maintained.In April 2019, this dosage was an off-label use of caffeine citrate. See NICE's information on prescribing medicines.When measuring plasma levels, prescribers should use the local laboratory's reference ranges. See the BNF for Children for further information about caffeine citrate.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on caffeine citrate\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: managing respiratory disorders.\n\nLoading. Please wait.\n\n## Patent ductus arteriosus\n\nDo not treat a PDA in a preterm baby unless the PDA causes a significant clinical problem, for example, difficulty weaning the baby from a ventilator.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on PDA\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: managing respiratory disorders.\n\nLoading. Please wait.\n\n# Monitoring\n\n## Oxygen\n\nUse continuous pulse oximetry to measure oxygen saturation in preterm babies, supplemented by arterial sampling if clinically indicated.\n\nAfter initial stabilisation, aim for an oxygen saturation of 91% to 95% in preterm babies.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nFor preterm babies on invasive ventilation who are clinically unstable, consider transcutaneous oxygen monitoring.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on oxygen monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: monitoring.\n\nLoading. Please wait.\n\n## Carbon dioxide\n\nFor preterm babies on invasive ventilation, aim for a carbon dioxide partial pressure (PCO2) of:\n\nkPa to 8.5\xa0kPa on days\xa01\xa0to\xa03 and\n\nkPa to 10\xa0kPa from day\xa04 onwards.\n\nReduce minute ventilation without delay in preterm babies with a low PCO2, and check the PCO2 within an hour of the low measurement being identified.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on carbon dioxide monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: monitoring.\n\nLoading. Please wait.\n\n## Blood pressure\n\nDo not treat preterm babies for hypotension based solely on specific blood pressure thresholds, but take into account other factors, such as evidence of poor tissue perfusion. The aim of treatment should be to improve perfusion.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on blood pressure\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: monitoring.\n\nLoading. Please wait.\n\n# Sedation and analgesia\n\n## Morphine\n\nDo not routinely use morphine for preterm babies on respiratory support.\n\nConsider morphine if the baby is in pain. Assess the baby's pain using locally agreed protocols or guidelines.In April 2019, the following uses were off-label: intravenous morphine for children under 12\xa0years and oral morphine for children under 1\xa0year. See NICE's information on prescribing medicines.\n\nRegularly reassess babies on morphine to ensure that it is stopped as soon as possible.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on morphine\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: sedation and analgesia.\n\nLoading. Please wait.\n\n## Premedication before intubation\n\nConsider premedication before elective non-urgent intubation in preterm babies.\n\nIf giving premedication, consider either:\n\nan opioid analgesic (for example, morphine or fentanyl), combined with a neuromuscular blocking agent (for example, suxamethonium) or\n\npropofol alone.In April 2019, the following uses were off-label: intravenous morphine for children under 12\xa0years, oral morphine for children under 1\xa0year, fentanyl for children under 2\xa0years, and propofol for children under 1\xa0month. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on premedication for intubation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: sedation and analgesia.\n\nLoading. Please wait.\n\n# Involving, supporting and informing parents and carers\n\nNICE has produced a guideline on babies, children and young people's experience of healthcare.\n\n## Involving parents and carers while their preterm baby is on respiratory support\n\nExplain to the parents and carers of preterm babies on respiratory support that non-nutritive sucking (using a dummy) during periods when the baby is awake is beneficial because:\n\nit can help soothe the baby between feeds and\n\nin babies fed by a nasogastric tube, dummy use can reduce the length of the baby's hospital stay.\n\nTell parents and carers about the benefits of using touch, for example, through skin-to-skin contact, to communicate with their baby.\n\nConsider providing the Newborn individualized developmental care and assessment program (NIDCAP®) to improve cognitive development in babies born at less than 27\xa0weeks.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on involving parents and carers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: involving and supporting parents and carers.\n\nLoading. Please wait.\n\n## Supporting parents and carers while their preterm baby is on respiratory support\n\nRecognise parents and carers as partners in their baby's care, and support them in this role.\n\nEncourage and support parents and carers to:\n\nbe involved in planning and providing their baby's day-to-day care, for example, feeding and nappy changing\n\nparticipate in discussions and decisions about their baby during ward rounds, providing input into planning and providing care.\n\nProvide regular opportunities and time for parents and carers to discuss their baby's care, ask questions about the information they have been given, and discuss concerns.\n\nGive parents and carers the time, support and encouragement they need to become confident in caring effectively for their baby.\n\nOffer parents and carers psychological support from a professional who is trained to deliver this type of help and advice.\n\n## Providing information to parents and carers while their preterm baby is on respiratory support\n\nAsk parents and carers about how and when they would like to receive information about their baby's treatment and progress, and how they would prefer to be contacted when they are away from the neonatal unit.\n\nSupport discussions with parents and carers using written information. Ensure that information is up to date, relevant, appropriate to the parents' and carers' needs and preferences, and consistent between healthcare professionals. For more guidance on communication (including different formats and languages), providing information, and shared decision making, see the NICE guidelines on patient experience in adult NHS services and shared decision making.\n\nEnsure that information for parents and carers is delivered by an appropriate healthcare professional, and information for hospitalised mothers who cannot visit their baby is delivered by a senior healthcare professional, for example, a neonatologist or specialist registrar, face-to-face whenever possible.\n\nBe sensitive about the timing of discussions with parents and carers. In particular, discuss significant perinatal events without delay, providing the mother has sufficiently recovered from the birth.\n\nProvide information for parents and carers that includes:\n\nexplanations and regular updates about their baby's condition and treatment, especially if there are any changes\n\nwhat happens in the neonatal unit, and the equipment being used to support their baby\n\nwhat respiratory support is being provided for their baby\n\nhow to get involved in their baby's day-to-day care, interact with their baby and interpret the baby's neurobehavioural cues\n\nthe roles and responsibilities of different members of their baby's healthcare team, and key contacts\n\ninformation about caring for a premature baby to share with family and friends, and practical suggestions about how to get help and support from family and friends\n\nopportunities for peer support from neonatal unit graduate parents or parent buddies\n\ndetails of local support groups, online forums and national charities, and how to get in touch with them.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on supporting and providing information to parents and carers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: involving and supporting parents and carers.\n\nLoading. Please wait.\n\n## Neonatal services for preterm babies on respiratory support\n\nThose responsible for planning and delivering neonatal services should ensure that neonatal units:\n\nare welcoming and friendly\n\nfoster positive and supportive relationships by providing parents and carers with 24‑hour access to their baby\n\nprovide privacy for skin-to-skin contact and feeding\n\nhave private areas for difficult conversations\n\nhave comfortable furniture and provide a relaxing environment for families.\n\nEnsure that healthcare professionals in neonatal units can support parents and carers by being competent in:\n\ncommunicating complex and sensitive information clearly\n\ntailoring information and support to the person's individual needs and circumstances.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on neonatal services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: involving and supporting parents and carers.\n\nLoading. Please wait.\n\n# Discharge planning\n\n## Planning safe discharge from the neonatal unit for preterm babies on respiratory support\n\nNeonatal units should consider appointing a member of staff as a designated neonatal discharge coordinator to discuss the following with parents and carers:\n\nongoing support and follow‑up after discharge (also see the NICE guideline on developmental follow-up of children and young people born preterm)\n\nhow to care for their baby at home\n\nhow to use specialist equipment safely\n\nhow to travel with their baby and specialist equipment.\n\nWhen planning to discharge a preterm baby on respiratory support from the neonatal unit:\n\nfollow the principles in the NICE guideline on postnatal care\n\nconsider early referral to, and regular contact with, community and continuing healthcare teams\n\nconsider an interim discharge placement to, for example, a hospice, alternative family member's home, step-down unit, transitional care unit, or alternative suitable accommodation, where appropriate.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on planning safe discharge\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: discharge planning.\n\nLoading. Please wait.\n\n## Supporting and providing information to parents and carers of preterm babies on respiratory support – preparing for discharge\n\nRecognise parents and carers as partners in the discharge planning process. Answer their questions and concerns as they arise, and support them in making joint decisions with the discharge team.\n\nThroughout the baby's neonatal admission, provide support and guidance for parents and carers with constructive and supportive feedback about how to care for their baby and how to use specialist equipment. Use a formal competency-based assessment tool to evaluate the safe use of specialist equipment.\n\nDiscuss any modifications that parents and carers might need to make to their home as soon as possible.\n\nEducate parents and carers about possible emergencies that may arise, how to deal with them and who to contact for help and advice. This should include how to carry out cardiopulmonary resuscitation, and what to do if there are problems with any specialist equipment.\n\nProvide parents and carers with opportunities to care for their baby overnight.\n\nProvide information for parents and carers to help them care for their baby safely and confidently after discharge. Follow the principles in the section on communication and information-giving in this guideline, and also see the NICE guideline on postnatal care. Information should include:\n\nhow to recognise signs of illness in their baby, and what to do\n\nhow to adapt routines such as feeding and sleeping after discharge, and information about safe sleep guidance\n\nhow to make follow‑up appointments and timing of immunisations\n\nwho to contact after discharge, as well as a list of useful medical contacts.\n\nTell parents and carers about sources of support after discharge, for example:\n\nopportunities for peer support\n\nhelp and support for their own needs, for example, postnatal depression (also see the NICE guideline on antenatal and postnatal mental health).\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on supporting and providing information to parents as part of discharge planning\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: discharge planning.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Automated oxygen titration\n\nA control system that measures the oxygen saturation and automatically adjusts the oxygen flow to maintain oxygen saturation within a predefined target range.\n\n## Invasive ventilation\n\nAdministration of respiratory support via an endotracheal tube or tracheostomy, using a mechanical ventilator. The definitions of invasive ventilation modes are summarised in table\xa03.\n\n\n\nVolume-targeted ventilation (VTV)\n\nVolume guarantee ventilation (VGV)\n\nTarget tidal volume (TTV)\n\nPressure regulated volume control (PRVC) ventilation (PRVCV)\n\nVolume-limited ventilation (VLV)\n\nVolume assured pressure support (VAPS)\n\nAny synchronised pressure-limited ventilation (SPLV) plus VTV\n\nSynchronised intermittent mandatory ventilation (SIMV) plus VTV\n\nSynchronised pressure-limited ventilation (SPLV)\n\nAssist control ventilation (AC)\n\nSynchronised intermittent positive pressure ventilation (SIPPV)\n\nPatient-triggered ventilation (PTV)\n\nPressure support ventilation (PSV)\n\nSynchronised time-cycled pressure-limited ventilation (STCPL)\n\nSynchronised Intermittent Mandatory Ventilation (SIMV)\n\n–\n\nNon-synchronised pressure-limited ventilation (NSPLV)\n\nConventional mandatory ventilation (CMV)\n\nNon-triggered/unsynchronised time-cycled pressure-limited ventilation (TCPL)\n\nIntermittent mandatory ventilation (IMV)\n\nHigh-frequency ventilation (HFV)\n\nHigh-frequency oscillatory ventilation (HFOV)\n\nHigh-frequency flow interruption (HFFI)\n\n## Minimally invasive administration technique\n\nAdministration of surfactant through a thin endotracheal catheter without insertion of an endotracheal tube or invasive ventilation.\n\n## Minute ventilation\n\nThe tidal volume of each breath in millilitres (ml) multiplied by the number of breaths per minute gives the minute ventilation in ml/minute (usually expressed as ml/kg/minute, which is achieved by dividing by the baby's weight in kg).\n\n## Neurobehavioural cues\n\nSounds, characteristics of movements including facial expressions and physiological parameters such as heart rate, breathing patterns and skin tone that reflect the baby's current level of sensitivity or wellbeing, and reveal their current developmental stage.\n\n## Neurodevelopmental outcomes\n\nIn this guideline, neurodevelopmental outcomes at 18\xa0months or older have been defined as:\n\ncerebral palsy (reported as presence or absence of condition, not severity)\n\nneurodevelopmental delay (reported as dichotomous outcomes, not continuous outcomes such as mean change in score):\n\n\n\nsevere (score of more than 2\xa0standard deviations [SD] below normal on validated assessment scales, or a score of less than\xa070 on the Bayley\xa0II scale of infant development mental developmental index [MDI] or psychomotor developmental index [PDI], or complete inability to assign score because of cerebral palsy or severe cognitive delay)\n\nmoderate (score of 1\xa0to\xa02\xa0SD below normal on validated assessment scales, or a score of 70\xa0to\xa084 on the Bayley\xa0II scale of infant development MDI or PDI)\n\n\n\nneurosensory impairment (reported as presence or absence of condition, not severity):\n\n\n\nsevere hearing impairment (for example, deaf)\n\nsevere visual impairment (for example, blind).\n\n\n\n## Non-invasive ventilation\n\nAdministration of respiratory support using a ventilator or flow driver, but not via an endotracheal tube or tracheostomy.\n\n## Perinatal\n\nIn this guideline, the perinatal period is defined as the period of time from 48\xa0hours before birth up until 7\xa0completed days after birth.\n\n## Preterm\n\nA baby born before 37\xa0weeks. This can be subdivided further:\n\nextremely preterm: babies born at less than 28\xa0weeks\n\nvery preterm: babies born at between 28\xa0and 31+6\xa0weeks\n\nmoderate to late preterm: babies born at between 32\xa0and 36+6\xa0weeks.\n\n## Skin-to-skin contact\n\nHolding a naked baby, or a baby wearing only a nappy, on the skin of a parent or carer, usually on the chest.\n\n## Stabilisation\n\nFacilitating and supporting a smooth transition from fetal to neonatal life. The process involves careful assessment of heart rate, colour (oxygenation) and breathing, with provision of appropriate interventions where indicated.", 'Recommendations for research': "# Key recommendations for research\n\n## Non-invasive ventilation techniques\n\nWhat is the effectiveness of high-pressure non-invasive positive pressure ventilation (NIPPV) compared with continuous positive airways pressure (CPAP) flow driver as the primary mode of ventilation?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on non-invasive ventilation techniques\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: respiratory support.\n\nLoading. Please wait.\n\n## Surfactant\n\nWhat is the best technique for delivering surfactant in a minimally invasive manner?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on surfactant\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: respiratory support.\n\nLoading. Please wait.\n\n## Diuretics\n\nWhat is the effectiveness of diuretics compared with placebo in preventing bronchopulmonary dysplasia (BPD) in preterm babies on respiratory support?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on diuretics\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: managing respiratory disorders.\n\nLoading. Please wait.\n\n## Oxygen monitoring\n\nDoes targeting higher oxygen saturations of\xa092% to 97%\xa0in preterm babies lead to improved survival without\xa0significant complications?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on oxygen monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: monitoring.\n\nLoading. Please wait.\n\n## Premedication before intubation\n\nWhat is the most effective combination of an analgesic with a neuromuscular blocker, or an analgesic with an anaesthetic agent, for premedication in preterm babies requiring elective or semi-elective intubation?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on premedication before intubation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: sedation and analgesia.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Respiratory support before admission to the neonatal unit\n\nDoes CPAP plus prophylactic surfactant, administered by a non-invasive technique in the delivery room, improve outcomes compared with CPAP alone in preterm babies?\n\n## Surfactant\n\nWhat is the optimal dosing regimen of surfactant when delivered in a minimally invasive manner?\n\n## Oxygen administration\n\nWhat is the effectiveness of humidified and non-humidified supplemental low-flow oxygen in preterm babies?\n\nWhat should be the target oxygen saturation range for preterm babies when using an automated oxygen titration system that creates a normal frequency-saturation curve?\n\n## Invasive ventilation techniques\n\nAre there differences in the long-term neurodevelopmental outcomes for preterm babies receiving volume-targeted ventilation (VTV) compared with high-frequency oscillatory ventilation (HFOV) as their primary mode of ventilation?\n\n## Corticosteroids\n\nWhat is the comparative efficacy of hydrocortisone compared with dexamethasone for preventing BPD in preterm babies requiring respiratory support?\n\nIs nebulised budesonide effective compared with placebo in preventing BPD in preterm babies requiring respiratory support?\n\n## Diuretics\n\nWhat is the effectiveness of diuretics compared with placebo in the treatment of BPD in preterm babies on respiratory support?\n\n## Caffeine citrate\n\nWhat is the optimal maintenance dose of caffeine citrate in order to optimise neurodevelopmental outcomes in preterm babies?\n\n## Oxygen monitoring\n\nWhat is the accuracy of pulse oximetry and transcutaneous measurement of partial pressure of oxygen compared with arterial oxygen levels for detecting hyperoxia and hypoxia in preterm babies?\n\n## Carbon dioxide monitoring\n\nWhat is the optimal carbon dioxide target range in preterm babies on non-invasive ventilation at different gestational ages?\n\n## Blood pressure\n\nWhat is the optimal method and frequency of measuring blood pressure for preterm babies requiring respiratory support?\n\nWhat is the optimal target blood pressure range for preterm babies requiring respiratory support?\n\n## Morphine\n\nWhat is the effectiveness of morphine compared with containment holding for preterm babies receiving respiratory support?\n\n## Involving parents and carers\n\nWhat is the impact of parental involvement as part of Family integrated care (FIC) or the Newborn individualised developmental care and assessment programme (NIDCAP®) on the incidence of BPD and length of hospital stay in preterm babies?\n\n## Discharge planning\n\nWhat is best practice around discharge planning for preterm babies on respiratory support?", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect services. They link to details of the evidence and a full description of the committee's discussion.\n\n# Risk factors for bronchopulmonary dysplasia\n\nRecommendation 1.1.1\n\n## Why the committee made the recommendation\n\nThere was evidence that lower gestational age, lower birth weight, being small for gestational age, male sex, lower body temperature, sepsis, any formula feeding, surfactant use, treatment for a patent ductus arteriosus (PDA), cardiopulmonary resuscitation and mechanical ventilation, are all independent risk factors for bronchopulmonary dysplasia (BPD) in preterm babies.\n\nNo evidence was found to link antenatal steroids, chorioamnionitis, intrauterine growth restriction, ethnicity or race, or postnatal steroid use, and BPD. However, the committee did not prioritise these areas for further research.\n\nThe committee was concerned that including surfactant use and treatment for PDA as risk factors for BPD could lead to a reduction in surfactant use and PDA treatment. They agreed that there was unlikely to be a causal link – rather, the increased risk of BPD associated with these factors is more likely to reflect the severity of the baby's condition, and that surfactant should be used, and a PDA should be treated, where clinically appropriate.\n\nThe committee noted that there was an absence of evidence for certain risk factors for BPD; some evidence was for specific gestational ages at birth from which the committee was unable to extrapolate to other gestational ages, and for some risk factors, the evidence was underpowered to detect an effect. The committee therefore concluded that other gestational ages and other risk factors not listed here might also be associated with increased risk of BPD.\n\nNo evidence was found for some of the potential risk factors that had been suggested by the committee (such as necrotising enterocolitis and supplementary oxygen), but these were not prioritised by the committee for further research.\n\n## How the recommendation might affect services\n\nKnowledge of BPD risk factors means healthcare professionals can identify preterm babies who are more likely to develop BPD, and prioritise treatment regimens accordingly. This may reduce the incidence of BPD, which will lead to long-term savings for the NHS.\n\nReturn to recommendation\n\n# Respiratory support before admission to the neonatal unit\n\nRecommendation 1.2.1\n\n## Why the committee made the recommendation\n\nThe evidence did not show a clear difference between continuous positive airways pressure (CPAP) alone and invasive ventilation with surfactant when used in preterm babies in the delivery room, for any of the outcomes that the committee had prioritised (mortality, BPD and neurodevelopmental outcomes). However, the evidence showed a possible reduction in mortality before discharge, and a possible reduction in the incidence of BPD at 36\xa0weeks' postmenstrual age with CPAP.\n\nOne large study found that just over half of the babies who received CPAP instead of intubation did need to be intubated at some point during their hospitalisation. However, the committee agreed that this was a very positive result, because around half of babies avoided all the risks of invasive intervention.\n\nThe committee agreed that it is preferable to avoid invasive ventilation wherever possible and agreed that when stabilising a preterm baby in the delivery room, the non-invasive ventilation technique of CPAP should be used rather than invasive ventilation. The committee agreed that this approach may not be suitable for some babies, for example, if the baby is not breathing and needs invasive ventilation. In addition, the committee agreed that this approach would probably not be suitable for preterm babies born very early, for example at less than 25\xa0weeks, because these babies may not have the necessary respiratory drive, and because the failure rate of non-invasive ventilation is high in babies of this age. The committee agreed that for these very preterm babies, it may be more practical to use invasive ventilation with surfactant in the delivery room, but because this would be a clinical decision, it was not appropriate to set a particular age cut‑off.\n\nBecause there was not enough evidence to make recommendations on the use of CPAP with surfactant compared with CPAP without surfactant in the delivery room, the committee recommended that further research be done in this area.\n\n## How the recommendation might affect services\n\nCurrent practice in most units is to routinely intubate preterm babies (below a certain gestation, often 27 to 28\xa0weeks, but specific cut‑offs will vary) and give surfactant, so this will be a change in practice for these units. Because CPAP is associated with lower costs than invasive ventilation, this change is likely to lead to cost savings.\n\nReturn to recommendation\n\n# Surfactant\n\nRecommendations 1.2.2 and 1.2.3\n\n## Why the committee made the recommendations\n\nIt is established clinical practice in the UK to give surfactant to preterm babies needing invasive ventilation in the early postnatal period, based on good evidence and extensive clinical experience, so the committee agreed to make a recommendation that reinforces this.\n\nIn preterm babies who do not require invasive ventilation, there was evidence that minimally invasive surfactant administration techniques reduce the incidence of BPD, the number of days on invasive ventilation, and the incidence of pneumothorax, compared with endotracheal administration.\n\nHowever, not all neonatal units have the facilities to carry out minimally invasive surfactant administration techniques, and not all healthcare professionals have been trained to use them. The committee agreed that in these circumstances, endotracheal surfactant administration followed by early extubation should be used, because there was evidence that it reduces the incidence of BPD compared with conventional administration of surfactant with continued ventilation.\n\nBecause there was not enough good evidence to make recommendations on which minimally invasive administration technique leads to the best outcomes, or on different surfactant dosing regimens, the committee recommended that further research be done in these areas.\n\n## How the recommendations might affect services\n\nCurrent practice for giving surfactant to preterm babies varies among neonatal units because of differences in available facilities and training. The recommendations may increase the trend towards using less invasive techniques of surfactant administration. Neonatal units that currently use conventional endotracheal administration of surfactant may therefore change practice to use minimally invasive techniques or to extubate earlier.\n\nReturn to recommendations\n\n# Oxygen\n\nRecommendations 1.2.4 and 1.2.5\n\n## Why the committee made the recommendations\n\nThere was a small amount of evidence suggesting there is no difference in the effectiveness or safety of oxygen delivered by nasal cannula compared with oxygen delivered in the incubator. However, because the evidence was limited, the committee made a recommendation based on consensus that nasal cannula or incubator oxygen could be used. They noted that incubator oxygen may be preferred for short-term use and assessment, whereas nasal cannula oxygen is preferable for longer-term use because it allows the baby to be touched and cuddled, and provides a stable concentration of oxygen.\n\nThere was evidence that automated oxygen titration reduces the number of days on oxygen, reduces the number of manual adjustments for titration, and increases the time that preterm babies spend in the optimal target oxygen saturation range. However, the committee were concerned, based on their clinical knowledge, that the cumulative frequency oxygen curves for oxygen saturation achieved by automated titration may lead to the mean saturation level achieved by babies being reduced (because of the normal distribution of the frequency-saturation curve) compared with manual adjustments (where the frequency-saturation curve is skewed to the higher end of the target saturation range). The committee therefore made a recommendation for research to determine the optimal target oxygen saturation range for use in conjunction with an automated oxygen titration system.\n\nThere was no evidence comparing humidified to non-humidified oxygen, but the committee agreed that this is standard clinical practice at higher flow rates and made a consensus recommendation for the use of humidified oxygen. The committee also made a recommendation for research to assess the effectiveness of humidified and non-humidified supplemental low-flow oxygen.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current clinical practice.\n\nReturn to recommendations\n\n# Ventilation techniques\n\nRecommendations 1.2.6 to 1.2.9\n\n## Why the committee made the recommendations\n\nThe available evidence made it difficult to differentiate between the various non-invasive ventilation techniques. The evidence showed that nasal high-flow therapy had the highest probability of being the best technique for reducing mortality before discharge, compared with other non-invasive ventilation techniques. However, the committee agreed that babies born extremely preterm are less likely to manage successfully on nasal high-flow therapy as the primary mode of ventilation when compared with babies born less preterm.\n\nThe evidence showed a reduction in the failure of non-invasive ventilation with CPAP compared with nasal high-flow therapy. Using their clinical experience, the committee agreed that CPAP would be a more suitable option for use in babies born more preterm.\n\nBecause of the lack of good evidence, the committee agreed that CPAP or nasal high-flow therapy should be used as a primary mode of ventilation in preterm babies who need non-invasive ventilation, with the decision on which option to use being made for individual babies.\n\nThere was evidence that nasal intermittent positive pressure ventilation (NIPPV) had lower rates of failed non-invasive ventilation and fewer days on invasive ventilation than CPAP, but the delivery of NIPPV in the studies was significantly different to routine clinical practice in the UK, so the committee recommended that further research should be carried out comparing NIPPV and CPAP.\n\nThere was evidence from the network meta-analysis that volume-targeted ventilation (VTV) has the highest probability of being the best technique as the primary mode of ventilation, both for mortality before discharge and BPD at 36\xa0weeks.\n\nThe committee agreed that VTV may not be appropriate for all preterm babies, for example, if there is an air leak. There was evidence that if VTV is not effective, high-frequency oscillatory ventilation (HFOV) should be considered as an alternative. The committee acknowledged that the flow sensors required for VTV are expensive, but the committee agreed that most units already have flow sensors for triggered ventilation and the same sensor could be used for VTV. In units or situations where neither VTV nor HFOV are available or suitable, the evidence showed that synchronised intermittent mandatory ventilation (SIMV) was the next most effective mode of ventilation.\n\nThe committee agreed that synchronised pressure-limited ventilation should be avoided because the evidence showed an increase in the incidence of mortality before discharge, compared with non-synchronised pressure-limited ventilation, HFOV and VTV. The evidence also showed an increase in days on invasive ventilation and pneumothorax, compared with VTV.\n\nThe evidence from the pair-wise analysis showed no significant difference between HFOV and VTV, and there was no evidence on neurodevelopmental outcomes at 18\xa0months or older, so the committee recommended that further research should be carried out.\n\n## How the recommendations might affect services\n\nThe recommendations should reinforce current clinical practice and lead to greater consistency.\n\nReturn to recommendations\n\n# Nitric oxide\n\nRecommendation 1.2.10\n\n## Why the committee made the recommendation\n\nThere was no evidence of benefit for inhaled nitric oxide in preterm babies who need respiratory support for respiratory distress syndrome (RDS). There was some evidence of adverse effects, and the treatment is unlikely to be cost effective. The committee agreed that there may be exceptions for preterm babies who have other conditions such as pulmonary hypoplasia and pulmonary hypertension, for whom there may be some survival benefits.\n\n## How the recommendation might affect services\n\nThe recommendation will reduce the use of inhaled nitric oxide for preterm babies who need respiratory support, which may lead to cost savings to the NHS given the high acquisition cost of inhaled nitric oxide.\n\nReturn to recommendation\n\n# Corticosteroids\n\nRecommendations 1.3.1 to 1.3.4\n\n## Why the committee made the recommendations on dexamethasone\n\nThere was evidence that in babies 8\xa0days or older, dexamethasone reduces the incidence of BPD, but dexamethasone is associated with an increased risk of hypertension. There were no clinically important differences in mortality before discharge between babies who received dexamethasone and those who did not.\n\nThere was some evidence suggesting that dexamethasone reduces the number of days on invasive ventilation, but this was difficult to interpret because of the different ways the studies reported the time on ventilation.\n\nIn babies 8\xa0days or older, there was evidence that dexamethasone is not associated with an increased risk of cerebral palsy, neurodevelopmental delay, neurosensory impairment or gastrointestinal perforation. However, the committee emphasised that there was some uncertainty about the evidence for these outcomes.\n\nIn babies younger than 8\xa0days, there was evidence that dexamethasone reduces the incidence of BPD but is associated with an increased risk of gastrointestinal perforation.\n\nThe committee therefore recommended that dexamethasone be considered for babies 8\xa0days or older who still need ventilation for respiratory disease, after taking into account risk factors for BPD. This is in line with current practice, which is to use corticosteroids to assist weaning from ventilatory support when a baby is 8\xa0days or older, rather than using corticosteroids as 'prophylaxis' for babies younger than 8\xa0days old.\n\nThe committee agreed the importance of discussing the risks of gastrointestinal perforation, hypertension and cerebral palsy with parents and carers before starting dexamethasone therapy, because there may be lifelong implications for the baby and their family.\n\nAlthough the combination of dexamethasone and non-steroidal anti-inflammatory drugs (NSAIDs) was not reviewed, the committee confirmed that they should not be used together because this increases the risk of gastrointestinal bleeding and perforation. The committee agreed that although this risk is widely recognised, it should be reinforced in the guideline to ensure that dexamethasone and NSAIDs are not used together in clinical practice.\n\nBecause of the increased risk of hypertension with dexamethasone, the committee recommended that babies' blood pressure should be monitored. There was no evidence about when or for how long to monitor blood pressure, so the committee agreed that this should be decided by the neonatologist responsible for the baby's care.\n\nThe evidence did not show any differences between different dosing strategies, and so the committee did not make any specific dosing recommendations.\n\n## Why the committee didn't make any recommendations on hydrocortisone and nebulised budesonide\n\nEvidence comparing hydrocortisone and placebo was inconclusive, so the committee did not make any recommendations. The committee was aware that there is an ongoing, large multicentre randomised controlled trial investigating hydrocortisone compared with placebo in preterm babies who need respiratory support, so did not make a recommendation for research that would replicate this study. However, they agreed that a comparison of dexamethasone and hydrocortisone could provide useful guidance and so made a recommendation for research for this comparison.\n\nThere was very little evidence for the use of nebulised budesonide and therefore the committee made a recommendation for research.\n\n## How the recommendations might affect services\n\nCurrent practice is to use corticosteroids in preterm babies to assist weaning or removal from ventilatory support, but they are not routinely used to prevent BPD in all preterm babies. The choice of dexamethasone or hydrocortisone varies among neonatal units. These recommendations are unlikely to affect how often corticosteroids are used, but they might prompt units who currently use hydrocortisone to consider dexamethasone as an alternative.\n\nReturn to recommendations\n\n# Diuretics\n\n## Why the committee did not make any recommendations\n\nThe evidence on the use of diuretics in preterm babies on respiratory support was very limited. None of the studies identified assessed critical outcomes such as mortality before discharge, BPD or neurodevelopmental outcomes. Although the studies looked at short-term adverse effects associated with diuretics, it was not clear whether there was an increased risk of adverse effects because of the small sample size of the studies.\n\nBecause of the limited evidence and lack of clinical consensus, the committee could not make any recommendations for or against diuretic use in preterm babies on respiratory support. Instead, the committee recommended that further research be done in this area.\n\n## How the recommendations might affect services\n\nAlthough they did not make any recommendations, some of the committee members thought that the lack of evidence identified may lead to healthcare professionals reviewing their use of diuretics. This may lead to a reduction in the use of diuretics in preterm babies on respiratory support, at least until further evidence is available.\n\nReturn to recommendation\n\n# Caffeine citrate\n\nRecommendations 1.3.5 to 1.3.8\n\n## Why the committee made the recommendations\n\nThere was evidence that in preterm babies born before 31\xa0weeks, caffeine citrate reduces the incidence of BPD, cerebral palsy (at 18\xa0to 21\xa0months' follow‑up) and blindness (at 11‑year follow‑up) compared with placebo. However, from their clinical experience, and based on the inclusion criteria of the CAP study, the committee agreed that it was appropriate to start babies, born at or before 30\xa0weeks (equivalent to babies born at or below 1.25\xa0kg), on caffeine citrate on admission to the neonatal unit, so they recommended earlier initiation. Based on their clinical experience, the committee agreed that administering caffeine citrate would also reduce apnoea in older preterm babies.\n\nThere was evidence that, compared with lower doses, higher doses of caffeine citrate reduce the incidence of BPD, continued apnoea and extubation failure.\n\nEvidence showed that the treatment with caffeine citrate before 3\xa0days of age may lead to a reduction in BPD. There was also evidence that treatment with caffeine citrate for 15\xa0to 30\xa0days reduces the incidence of BPD compared with a shorter duration, and that treatment for longer than 30\xa0days reduces the incidence of necrotising enterocolitis compared with treatment for less than 15\xa0days.\n\nTo determine when caffeine citrate should be stopped, the committee referred back to the studies and identified the age at which caffeine citrate was started, the duration of caffeine citrate, and hence the age at which it had been stopped. The committee noted that caffeine citrate had been stopped in the studies at between 33\xa0and 35\xa0weeks. This reflected the clinical experience of the committee as the age at which preterm babies were no longer expected to have apnoea, and so this figure was used by the committee to develop their recommendations.\n\nThe committee made their dosing recommendations based on evidence that a higher dose is more effective than a lower dose, and on currently recommended doses used in clinical practice. However, the variation in loading and maintenance doses used across different clinical trials made selecting an optimal dose difficult, and although higher doses appeared to improve early outcomes, there were few data on long-term outcomes. For this reason, the committee recommended further research to identify the maintenance dose of caffeine citrate needed to optimise neurodevelopmental outcomes.\n\nThe committee also discussed whether monitoring caffeine citrate levels was necessary and noted that the Evelina London Paediatric Formulary advises that babies can receive 10\xa0mg/kg of caffeine citrate twice daily without monitoring blood plasma levels (Evelina London 2015). The committee noted that there are units that do not currently monitor blood levels, and increasing doses to higher than 20\xa0mg/kg daily may be a concern if units did not test blood levels at these higher doses. Therefore, the committee made an additional recommendation that if apnoea persists and a baby receives more than 20\xa0mg/kg daily, caffeine citrate levels should be tested.\n\n## How the recommendations might affect services\n\nThe recommendations will have a minimal impact on current practice. The committee noted that there is some variation in dosage regimens across the NHS, so these recommendations should lead to greater consistency in the choice of dosage regimens. The committee agreed that oral caffeine citrate is used in most cases, and has a low acquisition cost. The committee acknowledged that intravenous caffeine citrate has a substantially higher acquisition cost. However, because of the single-use vial sizes available, irrespective of dose, a single vial will be required for administration of each dose, so increasing the dose would not increase the costs. In addition, only a small number of babies would need the intravenous solution. Furthermore, there may be a small increase in the number of blood tests performed to assess caffeine citrate levels if higher doses are used, but again the number of babies who will require high doses is small. Overall, the recommendations may result in a slight increase in drug and monitoring costs, but this is not anticipated to be substantial.\n\nReturn to recommendations\n\n# Patent ductus arteriosus\n\nRecommendation 1.3.9\n\n## Why the committee made the recommendation\n\nThere was no evidence of benefit from treating a PDA, and there was evidence for potential harms from treating it, with either medicines or surgery. However, the committee agreed that for some babies, treatment might be appropriate, for example, if there is difficulty weaning the baby from a ventilator.\n\n## How the recommendation might affect services\n\nThe recommendation will reduce the unnecessary treatment of PDA and the number of babies exposed to potential harms from its treatment. The recommendations may result in cost savings because fewer procedures will be carried out.\n\nReturn to recommendation\n\n# Oxygen monitoring\n\nRecommendations 1.4.1 to 1.4.3\n\n## Why the committee made the recommendations\n\nThe evidence on the best method for measuring oxygen levels in diagnosing hyperoxia or hypoxia in preterm babies was very limited. There were no studies assessing the diagnostic accuracy of SpO2 (peripheral capillary oxygen saturation) compared with the standard PaO2 (partial pressure of arterial oxygen) that met the review's inclusion criteria. The committee agreed, based on clinical consensus and their experience of clinical practice, that SpO2 should remain the first-line method for continuous monitoring of oxygen saturation levels in preterm babies because of its widespread availability and non-invasive nature. The committee agreed that arterial sampling of partial pressure of oxygen remained the 'gold standard', but is not always possible and can never be continuous.\n\nThe only evidence on tcPO2 (transcutaneous oxygen) was 1 study from the 1970s, and the way this procedure is performed has changed substantially since then. However, tcPO2 is currently used in clinical practice, and in the committee's experience it can provide useful information. This is particularly the case for preterm babies on invasive ventilation who are clinically unstable and need continuous monitoring to guide management, and in whom SpO2 may not be accurate.\n\nBecause of the lack of good evidence, the committee agreed that further research needs to be conducted looking at the diagnostic accuracy of tcPO2 and SpO2 against the gold standard arterial oxygen saturation in diagnosing hyperoxia and hypoxia in a preterm baby population.\n\nThere was evidence that higher target oxygen saturation levels reduce mortality. Although a higher target is associated with an increase in retinopathy of prematurity and an increased risk of BPD, the evidence suggested no increase in severe visual impairment at 18\xa0months, and the reduction in mortality was considered to offset the increased risk of BPD. The committee were aware that target oxygen levels (up to\xa097%) may be more beneficial but there was no evidence to support this, so they made a recommendation for research.\n\n## How the recommendation might affect services\n\nThe recommendations reflect current practice, where SpO2 is generally used as routine continuous oxygen monitoring in preterm babies, and tcPO2 is reserved for the more clinically unstable preterm babies as a continuous monitoring tool.\n\nMany units already use 91% to 95% as their target saturation level for preterm babies, but for those that do not, this will be a change in practice. This will reduce the variation in clinical practice.\n\nReturn to recommendations\n\n# Carbon dioxide monitoring\n\nRecommendations 1.4.4 and 1.4.5\n\n## Why the committee made the recommendations\n\nThe evidence showed no differences in the outcomes measured between higher and lower target ranges for the partial pressure of carbon dioxide in preterm babies on invasive ventilation. The committee recognised that the higher target ranges specified in the studies were in line with the definition of permissive hypercapnia and would probably not have any detrimental effects on clinical outcomes and long-term neurodevelopmental outcomes. In view of this, the committee agreed that when healthcare professionals are monitoring carbon dioxide levels in preterm babies on invasive ventilation, a higher target range would be acceptable. This avoids the need for frequent adjustment of the ventilators to reach an extremely tight target range.\n\nThere was variation in the target ranges of carbon dioxide used by different studies, and the range of days at which at different permissive hypercapnia levels were tolerated. The committee agreed to make a recommendation in line with the largest and most recent study that looked at clinical and long-term neurodevelopmental outcomes, but simplified the 3-stage ranges (days\xa01 to 3, days\xa04 to 6 and day\xa07 onwards) used in this study, to a 2-stage range based on their clinical experience that the difference in upper limits tolerated would be negligible and would have minimal detrimental effects on a preterm baby on invasive ventilation.\n\nThere was no evidence on the action to be taken when a low carbon dioxide level was detected, but the committee were aware that this was a dangerous situation, so agreed the action to be taken based on their clinical knowledge and experience.\n\nAll the evidence for the optimal target range of carbon dioxide was in preterm babies on invasive ventilation. The committee recognised the lack of evidence in preterm babies on non-invasive ventilation, so they recommended further research in this area.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, both where permissive hypercapnia is accepted in the monitoring of carbon dioxide levels in preterm babies on invasive ventilation, and for the action to be taken if hypocapnia is detected.\n\nReturn to recommendations\n\n# Blood pressure\n\nRecommendation 1.4.6\n\n## Why the committee made the recommendation\n\nThere was no good evidence to define the normal range of blood pressure in preterm babies, or how blood pressure should be measured. The committee wanted to make healthcare professionals aware of this lack of evidence to prevent unnecessary treatment based on the level of blood pressure only. The committee advised, based on their clinical experience, that inadequate perfusion should be treated with the aim of increasing perfusion, and not to aim for a particular blood pressure target.\n\nBecause there was no good evidence, the committee made recommendations for research to determine both the optimal blood pressure target and method of measuring blood pressure in preterm babies.\n\n## How the recommendation might affect services\n\nFor units that routinely monitor blood pressure in preterm babies and treat when blood pressure falls outside certain limits, this will be a change in practice. The recommendation will lead to less unnecessary monitoring and treatment of blood pressure.\n\nReturn to recommendation\n\n# Morphine\n\nRecommendations 1.5.1 to 1.5.3\n\n## Why the committee made the recommendations\n\nThe evidence showed that there was no difference in mortality before discharge in babies who received morphine compared with placebo. Babies receiving morphine took longer to achieve full enteral feeding, and babies born at 27 to 29 weeks' gestation had an increased risk of severe intraventricular haemorrhage (IVH). There was some evidence that, when compared with placebo, morphine improves sedation and pain scores in preterm babies who need invasive respiratory support during infusion. However, moderate quality evidence from a larger study showed no difference in pain scores during endotracheal suctioning between babies who received morphine compared with placebo.\n\nThe only evidence available comparing morphine with fentanyl showed no clinically significant difference in rates of severe IVH.\n\nThere was some evidence that, when compared with midazolam, babies receiving morphine may have decreased rates of severe IVH.\n\nBabies receiving morphine experienced less pain during infusion, but less sedation after infusion.\n\nBecause of the mixed evidence regarding the effectiveness of morphine and taking into account the risks, the committee agreed that morphine should not be used routinely, but may be considered when it is clear the baby is in pain, and that neonatal units would have their own guidelines or preferred scales to determine pain in preterm babies.\n\nThe committee discussed other concerns about using morphine, such as suppressed respiratory drive and opioid dependency. They agreed that regular reassessments are important to ensure that morphine is stopped as soon as appropriate.\n\nThe committee did not make any recommendations for paracetamol or non-pharmacological interventions because there was no evidence available. Instead, the committee recommended that further research be done to compare morphine with containment holding during respiratory support, because the committee agreed that containment holding may improve outcomes in preterm babies, with a reduced risk of adverse events compared with pharmacological therapy.\n\n## How the recommendations might affect services\n\nUse of sedation and analgesia currently varies among units. The recommendations will have little impact in units that do not routinely use morphine, but other units may need to change practice and this may lead to a reduction in the use of morphine. The recommendations will make practice more consistent across the NHS.\n\nReturn to recommendations\n\n# Premedication before intubation\n\nRecommendations 1.5.4 and 1.5.5\n\n## Why the committee made the recommendations\n\nThere was some evidence from small, single studies that using an analgesic with a neuromuscular blocker, or an anaesthetic such as propofol used alone, is an effective regimen to achieve successful intubation in preterm babies, while avoiding adverse effects.\n\nHowever, there was a lack of evidence to show exactly which medicines or classes of medicines form the best combination, so the committee recommended that healthcare professionals should consider premedication before elective intubation and recommended that further research be done in this area.\n\n## How the recommendations might affect services\n\nCurrent practice of using premedication for elective intubation in preterm babies varies among units. Units that currently use single medicines (such as morphine or fentanyl) may need to change practice to follow the recommendation. The recommendation will make practice more consistent across the NHS.\n\nReturn to recommendations\n\n# Involving parents and carers while their preterm baby is on respiratory support\n\nRecommendations 1.6.1 to 1.6.3\n\n## Why the committee made the recommendations\n\nThere was good evidence that using a dummy (non-nutritive sucking) during nasogastric feeds reduces the length of the baby's hospital stay. In addition, there was some evidence that the Newborn individualized developmental care and assessment program (NIDCAP®) improved neurodevelopmental outcomes relating to cognitive development and was a cost-effective intervention in babies born at less than 27\xa0weeks. Although the evidence for skin-to-skin contact did not show any benefit, there was no evidence of harm. There was no evidence that Family integrated care (FIC) provided any additional benefits compared with standard care.\n\nBased on their experience and the clinical evidence, the committee recommended explaining to parents and carers about the potential benefits of interacting with their baby because early social development and relationship-forming are key to successful emotional and behavioural development.\n\nBecause of the limited evidence available on FIC and NIDCAP®, the committee made it a priority to recommend that further research be done to investigate the potential impact of NIDCAP® and FIC on length of stay and BPD.\n\n## How the recommendations might affect services\n\nThe committee agreed that the recommendations on non-nutritive sucking and using positive touch (such as skin-to-skin contact) would not result in a major change in practice, but will help improve consistency in best practice.\n\nAlthough there are cost implications for units to train professionals in NIDCAP®, the recommendation to consider NIDCAP® would lead to a more consistent approach across neonatal care networks to practice linked with neurodevelopmental care. It would also improve babies' access to this type of neurodevelopmental care and allow greater involvement of parents and carers in the care of their baby.\n\nReturn to recommendations\n\n# Supporting and informing parents and carers while their preterm baby is on respiratory support\n\nRecommendations 1.6.4 to 1.6.13\n\n## Why the committee made the recommendations\n\nThere was good evidence that parents value emotional, psychological and practical support from staff, friends and family, peers (such as other parents of preterm babies) and employers when caring for a preterm baby receiving respiratory support. Parents also value professional support and counselling.\n\nThere was also evidence that parents value being partners in their baby's care, want to be supported by staff in caring for their baby, and need to be able to develop good communication and relationships with the staff caring for their baby.\n\nThere was evidence that parents value a comfortable, homely environment on the neonatal unit that is conducive to being involved in planning and providing care for their baby. Parents also value having 24‑hour access to the neonatal unit, with private areas and privacy when needed.\n\nThere was good evidence that parents and carers value high-quality, relevant, consistent information about their baby's health and care, including regular updates on their baby's progress. Parents and carers value information that is appropriate for their needs and explained clearly to them, and value the opportunity to ask questions. There was evidence that the appropriate timing of information is important to parents. The evidence also showed that parents and carers prefer information to be provided by an appropriate healthcare professional, and for it to be backed up by written information.\n\nParents value information on a range of topics, including how to interpret their baby's neurobehavioural cues, breastfeeding, skin-to-skin contact, the medical equipment used, who to contact, and other sources of information they could access themselves.\n\n## How the recommendations might affect services\n\nThe committee agreed that the recommendations would not result in a major change in practice, but will help improve consistency in best practice.\n\nReturn to recommendations\n\n# Neonatal unit services\n\nRecommendations 1.6.14 and 1.6.15\n\n## Why the committee made the recommendations\n\nThere was evidence that parents and carers value having 24‑hour access to the neonatal unit, which should be a homely environment with comfortable furniture and private areas. In a number of the support and information themes, parents and carers agreed that healthcare professionals who provide information and support should be trained and competent in this, so the committee made an overarching recommendation.\n\n## How the recommendations might affect services\n\nThe committee agreed that the recommendations would not result in a major change in practice, but will help improve consistency in best practice.\n\nReturn to recommendations\n\n# Discharge planning – planning safe discharge\n\nRecommendations 1.7.1 and 1.7.2\n\n## Why the committee made the recommendations\n\nThere was evidence about the importance of good communication with parents about their baby's discharge. The committee agreed that a designated neonatal discharge coordinator, as a single point-of-contact, would facilitate the communication of key information with parents and carers. The committee also agreed that early referral to community and continuing healthcare teams would also help parents prepare for their baby's discharge. Having the option to discharge to an alternative location, such as to another relative's home or a hospice, would enable parents and carers whose homes are not suitable for their preterm baby to be able to care for their baby outside the hospital.\n\nThe committee also recognised that some of the advice in the NICE guideline on postnatal care was also relevant to babies born preterm and so made a cross reference to this guideline.\n\nHowever, because there were only 2\xa0studies, and no evidence for a number of themes identified by the committee, the committee agreed that more research could better define best practice, and so made a recommendation for research.\n\n## How the recommendations might affect services\n\nThe committee agreed that the recommendations would not result in a major change in practice, but will help improve consistency in delivering best practice.\n\nReturn to recommendations\n\n# Discharge planning – preparing for discharge\n\nRecommendations 1.7.3 to 1.7.9\n\n## Why the committee made the recommendations\n\nThere was evidence that parents and carers value having support and information about their baby's routine care, being involved in preparing for the baby's discharge, and having information on equipment, identifying illness in their baby, and dealing with emergencies. Parents and carers also value information about future care, such as contact details, follow‑up appointments and immunisations, ongoing peer support and self-care for problems such as postnatal depression.\n\n## How the recommendations might affect services\n\nThe committee agreed that the recommendations would not result in a major change in practice, but will help improve consistency in delivering best practice.\n\nReturn to recommendations", 'Context': 'In 2016, a national neonatal audit found that approximately 13% of babies in the UK need specialist neonatal care, either because they are born preterm (at less than 37\xa0weeks) or because of an illness or condition.\n\nA comparison of the EPICure studies published in 2012 found that, between 1995 and 2006, the number of babies born at less than 26\xa0weeks and admitted to neonatal units increased by 30% in England. Over the same period, survival rates for babies born at 22\xa0to 25\xa0weeks and admitted for intensive care increased by 13%. In addition, a higher proportion of these babies survived without disability (particularly babies born at 24\xa0to 25\xa0weeks). International comparisons show that the neonatal mortality rate varies significantly by country.\n\nPreterm babies are at risk of respiratory disorders, including respiratory distress syndrome and bronchopulmonary dysplasia (BPD). High-quality respiratory care can reduce the length of hospital stay and risk of long-term disability. BPD is particularly common in preterm babies who require assisted ventilation. Babies with BPD need prolonged specialist care and respiratory support.\n\nRespiratory support is used in different ways in different units, and it is unclear what the best method is for providing ventilation and preventing BPD. There are many other areas of uncertainty and variation in how respiratory support is provided. There is also variation in other areas of respiratory management, including how corticosteroids are used to prevent and manage BPD.\n\nSince 2013, neonatal critical care services have been managed within Operational Delivery Networks. For healthy babies and babies with minor problems, most care is provided by the hospital they are born in. Neonatal intensive care units are responsible for babies who have more complex problems. Neonatal intensive care, and the service specifications for Neonatal Critical Care and Neonatal Intensive Care Transport, are within the scope of the neonatal critical care Clinical Reference Group.\n\nThis guideline is for:\n\nhealthcare professionals in primary, secondary and tertiary care\n\nparents and carers of babies born preterm who need respiratory support\n\ncommissioners and providers of specialist neonatal care services.\n\nBabies born preterm who need respiratory support (for example, oxygen supplementation or assisted ventilation) in hospital, beginning in the neonatal period.\n\nBabies born at term.\n\nBabies who need respiratory support because of congenital disorders, for example, congenital diaphragmatic hernia.'}
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https://www.nice.org.uk/guidance/ng124
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This guideline covers specific aspects of respiratory support (for example, oxygen supplementation, assisted ventilation, treatment of some respiratory disorders, and aspects of monitoring) for preterm babies in hospital.
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b94efa903b3e635587810679789d56412de0278a
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nice
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Ertugliflozin as monotherapy or with metformin for treating type 2 diabetes
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Ertugliflozin as monotherapy or with metformin for treating type 2 diabetes
Evidence-based recommendations on ertugliflozin (Steglatro) as monotherapy or with metformin for treating type 2 diabetes in adults.
# Recommendations
Ertugliflozin as monotherapy is recommended as an option for treating type 2 diabetes in adults for whom metformin is contraindicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control, only if:
a dipeptidyl peptidase 4 (DPP‑4) inhibitor would otherwise be prescribed and
a sulfonylurea or pioglitazone is not appropriate.
Ertugliflozin in a dual-therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if:
a sulfonylurea is contraindicated or not tolerated or
the person is at significant risk of hypoglycaemia or its consequences.
If patients and their clinicians consider ertugliflozin to be 1 of a range of suitable treatments including canagliflozin, dapagliflozin and empagliflozin, the least expensive should be chosen.
These recommendations are not intended to affect treatment with ertugliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Canagliflozin, dapagliflozin and empagliflozin are options for treating type 2 diabetes in adults. They are taken with metformin or on their own (that is, as monotherapy) if metformin is not appropriate. They are sodium-glucose cotransporter 2 (SGLT‑2) inhibitors, as is ertugliflozin.
Indirect comparisons show that ertugliflozin has similar overall health benefits to canagliflozin, dapagliflozin and empagliflozin. The acquisition cost of ertugliflozin is lower than the acquisition costs of these other drugs. Ertugliflozin is therefore recommended as an option for treating type 2 diabetes as monotherapy or with metformin in line with the previous recommendations for SGLT‑2 inhibitors.# Information about ertugliflozin
Marketing authorisation
Ertugliflozin (Steglatro, Merck Sharp & Dohme) is indicated 'in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
as monotherapy in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications
in addition to other medicinal products for the treatment of diabetes'.
Dosage in the marketing authorisation
'The recommended starting dose of ertugliflozin is 5 mg once daily. In patients tolerating ertugliflozin 5 mg once daily, the dose can be increased to 15 mg once daily if additional glycaemic control is needed.'
Price
mg (28 tablets) or 15 mg (28 tablets): £29.40 per pack (excluding VAT; company submission). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Comparators
## Canagliflozin, dapagliflozin or empagliflozin are appropriate comparators
Ertugliflozin is a sodium-glucose cotransporter 2 (SGLT‑2) inhibitor. NICE has already produced technology appraisal guidance on 3 other SGLT‑2 inhibitors for treating type 2 diabetes (canagliflozin, dapagliflozin and empagliflozin). These treatments are recommended:
as monotherapy when metformin is contraindicated or not tolerated, diet and exercise alone do not provide adequate glycaemic control, a dipeptidyl peptidase 4 (DPP‑4) inhibitor would otherwise be prescribed, and a sulfonylurea or pioglitazone is not appropriate
with metformin (dual therapy) when a sulfonylurea is contraindicated or not tolerated, or the person is at significant risk of hypoglycaemia or its consequences.The company presented a cost-comparison case in which it proposed that:
the overall health benefits associated with ertugliflozin are similar to or greater than those associated with canagliflozin, dapagliflozin and empagliflozin for monotherapy and dual therapy
the acquisition cost of ertugliflozin is similar to or lower than the costs associated with canagliflozin, dapagliflozin and empagliflozin.The committee understood that canagliflozin, dapagliflozin and empagliflozin are standard treatments for type 2 diabetes in the NHS. It concluded that canagliflozin, dapagliflozin and empagliflozin are appropriate comparators for this appraisal.
# Clinical effectiveness
## Ertugliflozin monotherapy is clinically effective compared with placebo
The company presented the results of the VERTIS‑MONO trial. This compared ertugliflozin monotherapy at the licensed dosages (5 mg and 15 mg) against placebo in 461 people aged 18 years or older with inadequate glycaemic control (defined as HbA1c 7.0% to 10.5% ) despite diet and exercise. The primary outcome was change in HbA1c (measured as change in least-squared means from baseline to week 26). Both doses of ertugliflozin showed a statistically significant improvement compared with placebo in the full analysis set, which included all randomised patients who took at least 1 dose of study medication and had at least 1 measurement of the outcome variable (at baseline or after baseline). The results for secondary outcomes (percentage of patients with HbA1c less than 7% at week 26, and changes in body weight and systolic and diastolic blood pressure from baseline to week 26) were favourable for both doses, although not all findings were statistically significant. The committee concluded that ertugliflozin monotherapy is a clinically effective treatment compared with placebo.
## Ertugliflozin in a dual-therapy regimen with metformin is clinically effective compared with placebo
The company presented the results of 2 clinical trials that provided evidence on the efficacy of ertugliflozin as dual therapy with metformin:
VERTIS‑MET, which compared ertugliflozin 5 mg and 15 mg with placebo in 621 people aged 18 years or older with inadequate glycaemic control (defined as HbA1c 7.0% to 10.5% ) despite diet and exercise.
VERTIS‑FACTORIAL, which was a 5‑arm study of 1,232 people aged 18 years or older with inadequate glycaemic control (defined as HbA1c 7.5% to 11.0% ). The study had 2 arms with ertugliflozin in dual therapy, and 3 arms that looked at its use in combination with 2 other glucose-lowering medicinal products (triple therapy). Only the evidence from the dual-therapy arms was considered relevant by the company and presented in the submission.In both studies, the primary outcome was change in HbA1c (measured as change in least-squared means from baseline to week 26). Both doses of ertugliflozin showed a statistically significant improvement compared with placebo for all outcomes in VERTIS‑MET. The results for VERTIS‑FACTORIAL showed that patients having ertugliflozin had lower mean HbA1c, body weight and blood pressure at week 26 compared with baseline. The committee concluded that ertugliflozin with metformin is a clinically effective treatment compared with placebo.
## Ertugliflozin has similar clinical effectiveness to canagliflozin, dapagliflozin and empagliflozin in both monotherapy and dual therapy
The company presented 2 network meta-analyses (NMAs) comparing the clinical effectiveness of ertugliflozin as monotherapy and dual therapy against canagliflozin, dapagliflozin and empagliflozin (all outcomes were assessed at 24 to 26 weeks). The NMAs included the pivotal trials for ertugliflozin (VERTIS‑MONO, VERTIS‑MET and VERTIS‑FACTORIAL). The results showed that ertugliflozin, canagliflozin, dapagliflozin and empagliflozin had similar efficacy and safety. The trials included in the NMAs were generally the same as the trials that were assessed for the previous NICE technology appraisals of canagliflozin, dapagliflozin and empagliflozin. The ERG commented that differences between the studies included in the company's NMAs and the NMAs in the previous appraisals were either well-justified by the company or had little impact on the overall results of the analyses. However, the ERG also took the view that it was unnecessary, under the fast track appraisal cost-comparison process, for the company to have conducted the NMAs at all because they only needed to show that ertugliflozin has similar health benefits compared with 1 previously recommended product. In its own analysis, the ERG compared the results from each of the placebo-controlled trials for ertugliflozin against the results of another well-matched study; VERTIS‑MONO was compared with the CANTATA‑M trial of canagliflozin by Stenlof et al. 2013 and VERTIS‑MET was compared with a dapagliflozin trial by Bailey et al. 2010. The ERG did not do any statistical analysis but presented the results of the selected trials alongside the results of the VERTIS studies for the committee to compare visually. The ERG's interpretation of its additional analysis aligned with the company's conclusion that ertugliflozin and its comparators have similar efficacy and safety. The committee concluded that the clinical effectiveness of ertugliflozin, both as monotherapy and in dual therapy, is likely to be similar to that of the comparator treatments.
## Adverse events with ertugliflozin are likely to be similar to those with canagliflozin, dapagliflozin and empagliflozin in monotherapy and dual therapy
The company's NMAs showed no statistically significant differences in adverse-event rates between ertugliflozin and its comparators (canagliflozin, dapagliflozin and empagliflozin). The committee noted that women taking ertugliflozin monotherapy (5 mg and 15 mg) in VERTIS‑MONO had a statistically significantly higher rate of genital mycotic infections than women in the placebo group. Similarly, women taking the 15‑mg dose in VERTIS‑MET had a statistically significantly higher rate of genital mycotic infections than women in the placebo group. However, the committee noted the ERG's comment that the event rate observed in VERTIS‑MONO seemed high compared with the rates observed in other ertugliflozin trials, and it considered this to be reassuring. The committee concluded that the adverse events associated with ertugliflozin are likely to be similar to those for canagliflozin, dapagliflozin or empagliflozin.
# Resource use
## It is appropriate to assume that all resource use and costs, other than drug acquisition costs, are identical for ertugliflozin and its comparators
The company assumed that, apart from direct drug acquisition costs, resource use and costs would be identical for ertugliflozin and its comparators. These costs included starting and administering treatment, treatment monitoring, managing adverse events and long-term disease management. The committee agreed with this assumption.
# Cost-comparison results
## Ertugliflozin meets the criteria for recommendation on the basis of similar health benefits and similar or lower cost
The company presented the results of a cost-comparison analysis for 1 year of treatment. It showed that, at list price, the acquisition cost of ertugliflozin is lower than that of canagliflozin, dapagliflozin and empagliflozin. The committee concluded that ertugliflozin, both as monotherapy and in dual therapy, meets the criteria for recommendation on the basis of a cost comparison, because:
the overall health benefits are similar to those of its comparators
the acquisition costs are similar to or lower than those of its comparators.Ertugliflozin is therefore recommended as monotherapy or dual therapy with metformin, as an option for treating type 2 diabetes in adults.
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{'Recommendations': 'Ertugliflozin as monotherapy is recommended as an option for treating type\xa02 diabetes in adults for whom metformin is contraindicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control, only if:\n\na dipeptidyl peptidase\xa04 (DPP‑4) inhibitor would otherwise be prescribed and\n\na sulfonylurea or pioglitazone is not appropriate.\n\nErtugliflozin in a dual-therapy regimen in combination with metformin is recommended as an option for treating type\xa02 diabetes, only if:\n\na sulfonylurea is contraindicated or not tolerated or\n\nthe person is at significant risk of hypoglycaemia or its consequences.\n\nIf patients and their clinicians consider ertugliflozin to be 1\xa0of a range of suitable treatments including canagliflozin, dapagliflozin and empagliflozin, the least expensive should be chosen.\n\nThese recommendations are not intended to affect treatment with ertugliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCanagliflozin, dapagliflozin and empagliflozin are options for treating type\xa02 diabetes in adults. They are taken with metformin or on their own (that is, as monotherapy) if metformin is not appropriate. They are sodium-glucose cotransporter\xa02 (SGLT‑2) inhibitors, as is ertugliflozin.\n\nIndirect comparisons show that ertugliflozin has similar overall health benefits to canagliflozin, dapagliflozin and empagliflozin. The acquisition cost of ertugliflozin is lower than the acquisition costs of these other drugs. Ertugliflozin is therefore recommended as an option for treating type\xa02 diabetes as monotherapy or with metformin in line with the previous recommendations for SGLT‑2 inhibitors.', 'Information about ertugliflozin': "Marketing authorisation\n\nErtugliflozin (Steglatro, Merck Sharp & Dohme) is indicated 'in adults aged 18\xa0years and older with type\xa02 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:\n\nas monotherapy in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications\n\nin addition to other medicinal products for the treatment of diabetes'.\n\nDosage in the marketing authorisation\n\n'The recommended starting dose of ertugliflozin is 5\xa0mg once daily. In patients tolerating ertugliflozin 5\xa0mg once daily, the dose can be increased to 15\xa0mg once daily if additional glycaemic control is needed.'\n\nPrice\n\nmg (28 tablets) or 15\xa0mg (28 tablets): £29.40 per pack (excluding VAT; company submission). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Comparators\n\n## Canagliflozin, dapagliflozin or empagliflozin are appropriate comparators\n\nErtugliflozin is a sodium-glucose cotransporter 2 (SGLT‑2) inhibitor. NICE has already produced technology appraisal guidance on 3\xa0other SGLT‑2 inhibitors for treating type\xa02 diabetes (canagliflozin, dapagliflozin and empagliflozin). These treatments are recommended:\n\nas monotherapy when metformin is contraindicated or not tolerated, diet and exercise alone do not provide adequate glycaemic control, a dipeptidyl peptidase\xa04 (DPP‑4) inhibitor would otherwise be prescribed, and a sulfonylurea or pioglitazone is not appropriate\n\nwith metformin (dual therapy) when a sulfonylurea is contraindicated or not tolerated, or the person is at significant risk of hypoglycaemia or its consequences.The company presented a cost-comparison case in which it proposed that:\n\nthe overall health benefits associated with ertugliflozin are similar to or greater than those associated with canagliflozin, dapagliflozin and empagliflozin for monotherapy and dual therapy\n\nthe acquisition cost of ertugliflozin is similar to or lower than the costs associated with canagliflozin, dapagliflozin and empagliflozin.The committee understood that canagliflozin, dapagliflozin and empagliflozin are standard treatments for type\xa02 diabetes in the NHS. It concluded that canagliflozin, dapagliflozin and empagliflozin are appropriate comparators for this appraisal.\n\n# Clinical effectiveness\n\n## Ertugliflozin monotherapy is clinically effective compared with placebo\n\nThe company presented the results of the VERTIS‑MONO trial. This compared ertugliflozin monotherapy at the licensed dosages (5\xa0mg and 15\xa0mg) against placebo in 461\xa0people aged 18\xa0years or older with inadequate glycaemic control (defined as HbA1c 7.0%\xa0to\xa010.5% [53\xa0to 91\xa0mmol/mol]) despite diet and exercise. The primary outcome was change in HbA1c (measured as change in least-squared means from baseline to week\xa026). Both doses of ertugliflozin showed a statistically significant improvement compared with placebo in the full analysis set, which included all randomised patients who took at least 1\xa0dose of study medication and had at least 1\xa0measurement of the outcome variable (at baseline or after baseline). The results for secondary outcomes (percentage of patients with HbA1c less than 7% [less than 53\xa0mmol/mol] at week\xa026, and changes in body weight and systolic and diastolic blood pressure from baseline to week\xa026) were favourable for both doses, although not all findings were statistically significant. The committee concluded that ertugliflozin monotherapy is a clinically effective treatment compared with placebo.\n\n## Ertugliflozin in a dual-therapy regimen with metformin is clinically effective compared with placebo\n\nThe company presented the results of 2\xa0clinical trials that provided evidence on the efficacy of ertugliflozin as dual therapy with metformin:\n\nVERTIS‑MET, which compared ertugliflozin 5\xa0mg and 15\xa0mg with placebo in 621\xa0people aged 18\xa0years or older with inadequate glycaemic control (defined as HbA1c 7.0%\xa0to\xa010.5% [53\xa0to 91\xa0mmol/mol]) despite diet and exercise.\n\nVERTIS‑FACTORIAL, which was a 5‑arm study of 1,232\xa0people aged 18\xa0years or older with inadequate glycaemic control (defined as HbA1c 7.5%\xa0to\xa011.0% [58\xa0to 97\xa0mmol/mol]). The study had 2\xa0arms with ertugliflozin in dual therapy, and 3 arms that looked at its use in combination with 2\xa0other glucose-lowering medicinal products (triple therapy). Only the evidence from the dual-therapy arms was considered relevant by the company and presented in the submission.In both studies, the primary outcome was change in HbA1c (measured as change in least-squared means from baseline to week\xa026). Both doses of ertugliflozin showed a statistically significant improvement compared with placebo for all outcomes in VERTIS‑MET. The results for VERTIS‑FACTORIAL showed that patients having ertugliflozin had lower mean HbA1c, body weight and blood pressure at week\xa026 compared with baseline. The committee concluded that ertugliflozin with metformin is a clinically effective treatment compared with placebo.\n\n## Ertugliflozin has similar clinical effectiveness to canagliflozin, dapagliflozin and empagliflozin in both monotherapy and dual therapy\n\nThe company presented 2\xa0network meta-analyses (NMAs) comparing the clinical effectiveness of ertugliflozin as monotherapy and dual therapy against canagliflozin, dapagliflozin and empagliflozin (all outcomes were assessed at 24\xa0to 26\xa0weeks). The NMAs included the pivotal trials for ertugliflozin (VERTIS‑MONO, VERTIS‑MET and VERTIS‑FACTORIAL). The results showed that ertugliflozin, canagliflozin, dapagliflozin and empagliflozin had similar efficacy and safety. The trials included in the NMAs were generally the same as the trials that were assessed for the previous NICE technology appraisals of canagliflozin, dapagliflozin and empagliflozin. The ERG commented that differences between the studies included in the company's NMAs and the NMAs in the previous appraisals were either well-justified by the company or had little impact on the overall results of the analyses. However, the ERG also took the view that it was unnecessary, under the fast track appraisal cost-comparison process, for the company to have conducted the NMAs at all because they only needed to show that ertugliflozin has similar health benefits compared with 1\xa0previously recommended product. In its own analysis, the ERG compared the results from each of the placebo-controlled trials for ertugliflozin against the results of another well-matched study; VERTIS‑MONO was compared with the CANTATA‑M trial of canagliflozin by Stenlof et al. 2013 and VERTIS‑MET was compared with a dapagliflozin trial by Bailey et al. 2010. The ERG did not do any statistical analysis but presented the results of the selected trials alongside the results of the VERTIS studies for the committee to compare visually. The ERG's interpretation of its additional analysis aligned with the company's conclusion that ertugliflozin and its comparators have similar efficacy and safety. The committee concluded that the clinical effectiveness of ertugliflozin, both as monotherapy and in dual therapy, is likely to be similar to that of the comparator treatments.\n\n## Adverse events with ertugliflozin are likely to be similar to those with canagliflozin, dapagliflozin and empagliflozin in monotherapy and dual therapy\n\nThe company's NMAs showed no statistically significant differences in adverse-event rates between ertugliflozin and its comparators (canagliflozin, dapagliflozin and empagliflozin). The committee noted that women taking ertugliflozin monotherapy (5\xa0mg and 15\xa0mg) in VERTIS‑MONO had a statistically significantly higher rate of genital mycotic infections than women in the placebo group. Similarly, women taking the 15‑mg dose in VERTIS‑MET had a statistically significantly higher rate of genital mycotic infections than women in the placebo group. However, the committee noted the ERG's comment that the event rate observed in VERTIS‑MONO seemed high compared with the rates observed in other ertugliflozin trials, and it considered this to be reassuring. The committee concluded that the adverse events associated with ertugliflozin are likely to be similar to those for canagliflozin, dapagliflozin or empagliflozin.\n\n# Resource use\n\n## It is appropriate to assume that all resource use and costs, other than drug acquisition costs, are identical for ertugliflozin and its comparators\n\nThe company assumed that, apart from direct drug acquisition costs, resource use and costs would be identical for ertugliflozin and its comparators. These costs included starting and administering treatment, treatment monitoring, managing adverse events and long-term disease management. The committee agreed with this assumption.\n\n# Cost-comparison results\n\n## Ertugliflozin meets the criteria for recommendation on the basis of similar health benefits and similar or lower cost\n\nThe company presented the results of a cost-comparison analysis for 1\xa0year of treatment. It showed that, at list price, the acquisition cost of ertugliflozin is lower than that of canagliflozin, dapagliflozin and empagliflozin. The committee concluded that ertugliflozin, both as monotherapy and in dual therapy, meets the criteria for recommendation on the basis of a cost comparison, because:\n\nthe overall health benefits are similar to those of its comparators\n\nthe acquisition costs are similar to or lower than those of its comparators.Ertugliflozin is therefore recommended as monotherapy or dual therapy with metformin, as an option for treating type\xa02 diabetes in adults."}
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https://www.nice.org.uk/guidance/ta572
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Evidence-based recommendations on ertugliflozin (Steglatro) as monotherapy or with metformin for treating type 2 diabetes in adults.
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e36cd5c55e11c4227d9d539435e6e4918ae91777
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nice
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The Debrisoft monofilament debridement pad for use in acute or chronic wounds
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The Debrisoft monofilament debridement pad for use in acute or chronic wounds
Evidence-based recommendations on the Debrisoft monofilament debridement pad for use in acute or chronic wounds.
# Recommendations
The case for adopting the Debrisoft monofilament debridement pad as part of the management of acute or chronic wounds in the community is supported by the evidence. The available evidence is limited, but the likely benefits of using the Debrisoft pad on appropriate wounds are that they will be fully debrided more quickly, with fewer nurse visits needed, compared with other debridement methods. In addition, the Debrisoft pad is convenient and easy to use, and is well tolerated by patients. Debridement is an important component of standard woundcare management as described in the NICE guidelines on pressure ulcers and diabetic foot problems.
The Debrisoft pad is indicated for adults and children with acute or chronic wounds. The available evidence is mainly in adults with chronic wounds needing debridement in the community. The data show that the device is particularly effective for chronic sloughy wounds and hyperkeratotic skin around acute or chronic wounds.
The Debrisoft pad is estimated to be cost saving for complete debridement compared with other debridement methods. When compared with hydrogel, gauze and bagged larvae, cost savings per patient (per complete debridement) are estimated to be £99, £154 and £373 respectively in a community clinic, and £213, £292 and £277 respectively in the home. # The technology
# Description of the technology
The Debrisoft range (L&R Medical UK) are sterile and single-use monofilament debridement devices intended for nurses and other healthcare professionals to use on adults and children to remove devitalised tissue, debris, and hyperkeratotic skin around acute or chronic wounds. They are made of monofilament polyester fibres with a reverse side of polyacrylate. The monofilament fibres are cut with angled tips designed to penetrate irregularly shaped areas and remove devitalised skin and wound debris. There are 2 sizes of pad (10 cm × 10 cm and 13 cm × 20 cm, both with a hand pocket to facilitate handling) and a version with a handle (Debrisoft Lolly).
The Debrisoft pad is moistened with tap water, sterile water or saline, folded and then, using the soft fleecy side, wiped across the wound with gentle pressure. Cellular debris, slough tissue, exudate and hyperkeratotic tissues become integrated into the monofilaments and are removed from the wound site. The Debrisoft pad is intended for use without analgesia, and the process takes, on average, 2 to 4 minutes. A new pad is normally needed for each separate wound being treated. For large areas, more than 1 pad may be needed.
The cost of 1 Debrisoft monofilament debridement pad stated in the sponsor's submission in August 2013 was £6.19 and is currently £6.27 (both excluding VAT).
The claimed benefits of the Debrisoft pad in the case for adoption presented by the sponsor are:
reduction in pain associated with debridement with no analgesia required in most cases
improved acceptability to patients with reduced fear and anxiety associated with treatment
faster treatment and healing with reduced frequency and total episodes of care
reduced risks of trauma to healthy tissue, and of bleeding
reduced time and resources associated with debridement and reduced overall time to healing
use by nurses and other healthcare professionals in the community leading to lower costs and shorter waiting times for treatment
more effective debridement facilitating initial assessment with the possibility of reduced referrals, hospital administration and inappropriate treatment through misdiagnosis
improved patient concordance with reduced costs of analgesia often required with other forms of debridement
avoidance of ongoing costs relating to specialist methods of debridement and treatment that require additional consumables.
# Current management
Debridement is the removal of dead, damaged tissue or haematoma from a wound. Several techniques are used for debridement, depending on the nature of the wound. In the community these are likely to include mechanical, autolytic and biosurgical techniques. Debridement can be carried out with or without analgesia depending on the degree of wound pain, the site, size and severity of the wound as well as the patient's preference.
The NICE guideline on pressure ulcers states that standard practice in the management of chronic wounds includes wound debridement to remove dead tissue, and that clinicians should recognise the potential benefit of debridement in the management of pressure ulcers. NICE includes the technique of debridement in the NICE Pathway on pressure ulcers.
The NICE guideline on diabetic foot problems recommends that diabetic foot ulcers can be managed using debridement. The guideline states that debridement should be performed only by healthcare professionals from a multidisciplinary foot care team, using the technique that best matches their specialist expertise, clinical experience, patient preference, and the site of the ulcer.
The clinical pathway for people with burns or with surgical wounds that have ruptured (dehisced) is not well defined and varies by wound type. Treatment for dehisced wounds may include antibiotics, wound packing, and negative pressure wound therapy. Haematomas with overlying necrotic skin can be treated conservatively using autolytic, larvae or honey debridement. If the haematoma is very large, surgical debridement and treatment may be needed dependent on depth, severity, size, position and patient-related factors.# Clinical evidence
# Summary of clinical evidence
Full details of all clinical outcomes considered by the Committee are available in the assessment report overview.
The key clinical outcomes for the Debrisoft monofilament debridement pad presented in the decision problem were:
pain and discomfort for the patient when debriding the wound
wound malodour
time to complete debridement
time to healing
wound infection/cellulitis
the number, frequency and duration of healthcare professional (nurse) visits for each patient
the number of debridements needed
device-related adverse events, including non-selective trauma to healthy surrounding tissue or bleeding.
The clinical evidence for the Debrisoft pad was based on 15 multiple-patient case-series reports (5 peer-reviewed papers and 10 posters), some of which included retrospective comparators. There were no randomised controlled trials. The External Assessment Centre considered that 7 studies (Bahr et al. 2011; Callaghan and Stephen-Haynes, 2012; Collarte et al. 2011; Johnson et al. 2012a; Mustafi et al. 2011; Pietroletti et al. 2012; Wiser et al. 2012) were directly relevant to the scope because they included appropriate comparators and outcomes. Two of the papers (Bahr et al. 2011; Mustafi et al. 2011) presented results from the same study.
## Multiple patient case-series: peer-reviewed papers
Bahr et al. (2011) and Mustafi et al. (2011) compared the overall mean time of each debridement session, using the Debrisoft pad, with hydrogel, gauze and surgical debridement in 60 patients. In minutes, this was 2.51 (SD±0.57) for Debrisoft, 7 (±2.08) for hydrogel, 5 (±1.60) for gauze and 9 (±2.64) for surgical debridement. Complete debridement was achieved in 77% (n=44) of patients using the Debrisoft pad in 12 days compared with an estimate taken from the literature of approximately 20 days for enzymes or hydrogel. Using a 6-point scale (1=excellent to 6=inadequate), Debrisoft users rated its debridement efficacy as 'very good', giving a mean score of 1.98 (±0.68) compared with hydrogel, which scored 2.54 (±0.72). The convenience and ease of use of the Debrisoft pad was rated 'very good' by its users, with a mean score of 2.29 (±0.57) on the 6-point scale. Wet gauze was rated similarly with a mean score of 2.49 (±0.67). When using the Debrisoft pad, there was a significant improvement in wound bed condition after 3 debridement sessions. After 1 session, 60% of wounds (n=34) were categorised as covered in slough with some necrotic tissue, after 3 sessions this was 47% (n=27). After 1 session 28% of wounds (n=16) were categorised as covered in slough with no necrotic tissue, after 3 sessions this was 25% (n=14). After 1 session 12% of wounds (n=7) were clean with less than 20% slough, after 3 sessions this was 7% (n=4). Twenty-one per cent (n=12) of wounds had re-epithelialised. Debridement was effective in 93.4% (142/152) of the sessions. During the debridement procedure 45% (n=26) of patients reported that they experienced no pain, 50.4% (n=29) reported slight discomfort of short duration (mean 2 minutes) and 4.6% (n=2) reported moderate pain of short duration (mean 2.4 minutes). No side effects after the procedure were reported by 56 out of 57 patients. No serious adverse events or adverse events were reported. Clinicians reported that the Debrisoft pad removed debris, slough, dried exudate and crusts efficiently, without damaging the fragile skin surrounding the wound. Photographic analysis confirmed this.
Gray et al. (2011) described a case series of 18 patients that evaluated which types of slough and necrotic tissue benefit most from debridement with the Debrisoft pad. One patient was unable to tolerate the use of the pad. Results were reported for 10 patients only. Two patients had hyperkeratotic skin removed on their lower limb in less than 2 minutes. One patient's hyperkeratotic skin was not removed by the Debrisoft pad, but it was thought that this was because an emollient was applied before the treatment. Two patients had their wound beds cleared of any haematoma after it had been debrided for less than 5 minutes. One patient had most (not specified how much) of their haematoma cleared from the wound bed. Two patients with pressure wounds on the heel were reported as having partially successful debridement (not clear how successful). Sloughy leg ulcers in 2 patients were fully debrided. The authors noted that when dry, black necrosis or slough had adhered to the wound bed, the Debrisoft pad did not remove the devitalised tissue.
Hammerle et al. (2011) described a case series of 11 patients with chronic wounds from 2 hospitals. The Debrisoft pad was able to remove most of the coatings in exudating, seropurulent wounds with highly viscous yellow slough (indicating local infection) after a single use. Most of the material removed by debridement became attached to the pad. In dry wounds with serocrusts between the new vital granulation and epithelial tissue, the Debrisoft pad was able to remove the crusts without affecting the new healthy tissue. In wounds with necrotic layers, hyperkeratotic debris and crusts of dried exudate, the Debrisoft pad removed the necrotic layers after a single use and revealed the skin of the lower extremity, showing an almost normal epidermis. For both types of wound, the Debrisoft pad was able to debride without affecting the new healthy tissue, which was undisturbed by the debridement process.
Johnson et al. (2012a) described a 2-centre observational study that compared the effectiveness of the Debrisoft pad with other non-specified debridement methods. Ten patients were recruited from each centre. Although it was not stated explicitly, it appears from the results that each wound was treated once using the Debrisoft pad. Patients found the treatment very acceptable with minimal pain reported in 95% of cases. The reported time to debridement was 2–4 minutes for 10 patients, 5–7 minutes for 5 patients and more than 7 minutes for 5 patients. Skin condition after Debrisoft pad use compared with a previous hyperkeratosis method was rated for 8 patients and was 'much better' for 6 patients, 'good' for 1 patient and 'very good' for 1 patient. Debridement performance compared with a previous method was rated for 16 patients by the clinician and was 'much better' for 8 patients, 'good' for 5 and 'very good' for 3.
Stephen-Haynes and Callaghan (2012) evaluated the use of the Debrisoft pad by 40 tissue viability nurses, over a 12-week period, on a wound or hyperkeratosis. The Debrisoft pad was used for wound debridement by 25 nurses (62.5%), for hyperkeratosis by 4 nurses (10%), and for both by 11 nurses (27.5%). Thirty-eight of the nurses (95%) said that patients' skin condition improved, whereas 2 (5%) said that it remained the same. Thirty-two of the nurses (80%) reported a positive impact on the wound bed using visual assessment. Thirty-four nurses (85%) reported that after debridement, there was clearer visibility of the wound bed and surrounding skin because of the removal of debris, slough or hyperkeratosis, so they were able to identify clearer wound management objectives. Six out of 40 nurses (15%) said there was no improvement. The time taken to carry out debridement using the Debrisoft pad was 0–2 minutes in 8 patients (20%); 3–5 minutes in 21 patients (52.5%) and 6–10 minutes in 9 patients (22.5%). The overall performance of the Debrisoft pad was rated as 'very good' by 24 nurses (60%), 'good' by 10 nurses (25%), 'fairly good' by 5 nurses (12.5%) and 'poor' by 1 nurse (2.5%).
## Multiple patient case-series: posters
Albas (2012) evaluated the Debrisoft pad for 10 patients with trauma wounds and bites. Debridement was considered effective in all patients because visible debris and slough were successfully removed. A mean of 2.1 sessions (SD±0.83; range: 1–3) was needed to obtain a clean wound bed. In all sessions, the product remained intact. The mean time for the debridement sessions was 2.57 minutes (SD±0.04; range 2–4). Patients reported slight discomfort for a short duration (2 minutes on average) in 35% of cases and no discomfort in 65% of cases. No secondary infections were reported.
Callaghan and Stephen-Haynes (2012) described a case series of 12 patients with pressure ulcers. The time to achieve debridement was 0–5 minutes in all 12 patients. Four patients had pain during the procedure (visual analogue scale : 1, 1, 6, 4) but the first 3 of these patients had pain before treatment started (VAS: 1, 1, 7). No patients reported pain after treatment. There was improved visualisation of the wound bed in 92% (11/12) of the patients. Treatment using the Debrisoft pad reduced wound care visits in 92% (11/12) of the patients. The treatment helped assess the category of pressure ulcer in all 12 patients.
Collarte et al. (2011) evaluated the use of the Debrisoft pad in 10 patients and reported that it was easy to use and removed devitalised tissue and hyperkeratosis more quickly compared with standard treatment. The time to treat was decreased and patients found the treatment to be comfortable. One patient had a venous leg ulcer debrided in 4 minutes using the Debrisoft pad, with no reported pain or discomfort. Previously nurses had attempted to debride the wound with autolytic therapy and larvae, but with limited success.
Dam (2012) evaluated the Debrisoft pad in 29 patients with chronic wounds. On average, fibrin was reduced by 30%. It was reported that thin and soft layers of fibrin were easier to remove than thick fibrin and necrotic tissue. The Debrisoft pad was not able to remove fibrin that had firmly adhered to the wound bed. Topical analgesia was used in 11 patients; 8 patients reported no change in pain level and 10 patients reported increased pain during debridement. Keratosis was present in 21 patients and this was removed by the Debrisoft pad in all 21 patients.
Johnson (2012b) described a case series in which the Debrisoft pad facilitated healing in all 10 patients. It was stated that pain scores remained low during debridement, with most patients scoring the same before, during and after the procedure. The average debridement time was 4 minutes (range 2–10). The time to complete healing was recorded as between 2 weeks for 2 patients with venous leg ulcers and 6 weeks for 2 patients with mixed aetiology. The wound of 1 patient treated before a below knee amputation healed with no complications but it was not stated how long this took. The wounds of 2 other patients did not heal before the end of the 12 weeks and 1 patient was lost to follow-up.
Pietroletti et al. (2012) assessed the efficacy of the Debrisoft pad in a case series of 27 patients. The data were retrospectively compared with a group of 25 patients who had used an autolytic debridement method of either hydrogel or enzymes. The wound condition in both groups was wound bed coated with fibrin and slough or skin around the wound with keratosis and/or exudate. The maximum area of the wounds was 60 cm2. Results showed that 92% of patients had their wound debrided after 1 application of the Debrisoft pad. This involved 1 visit, whereas 38.4% of patients had debrided wounds after 1 application of the autolytic or enzymatic debridement, which involved 2 visits. The author concluded that based on these results, autolytic debridement would need to be used 8 to 10 times to achieve the same results as the Debrisoft pad.
Rieke (2012) reported the results of an observational study of 25 patients in which the Debrisoft pad was used on diabetic foot ulcers. Debridement was effective in all of the sessions and visible debris, slough, hyperkeratosis and scabs were successfully removed. In 8 cases additional surgical debridement was performed to remove the thick callus at the edges. The mean time for each debridement session was 2.59 minutes (±SD 0.06). Eighteen of the 25 ulcers healed within 16 weeks (study end point), 2 needed surgery and 5 did not heal.
Skovgaard-Holm and Simonsens (2012) described a study of 10 patients that was completed by homecare nurses. Debridement using the Debrisoft pad was performed 3 times a week over a 2-week period. The efficacy rate of the Debrisoft pad was found to depend on the thickness and adherence of the slough and the thickness of the hyperkeratotic layer. Debridement reduced the area of thin slough by an average of 24% in 3 patients. In 6 patients, an adherence layer of slough was reduced by an average of 7%. The Debrisoft pad reduced a thick soft layer of slough by 10% in 1 patient. Three patients did not feel increased pain during treatment, but 3 experienced severe pain (VAS scores of 8, 7 and 6). The pain level decreased immediately after treatment to the level at the starting point. The nurses felt that 4 patients would have benefitted from local anaesthesia before treatment.
Wiser et al. (2012) retrospectively compared the debridement results using the Debrisoft pad in 15 patients with venous leg ulcers or diabetic foot ulcers with a sloughy wound bed with the results obtained with saline soaks used in a similar patient group. No quantitative results were reported. The Debrisoft pad was shown to deliver effective and fast debridement, but it was reported to be somewhat rigid when used on toes or cavity wounds. Patient-reported pain during the procedure was less than for those treated with saline soaks, especially for the patients with arterial ulcers. The slight discomfort reported with the Debrisoft pad seemed to be better tolerated than debridement using saline soaks. Use of the product did not cause damage to the fragile skin surrounding the wound.
## Adverse events
No adverse event reports relating to the Debrisoft pad were reported in a search of the US Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. The Medicines and Healthcare products Regulatory Agency (MHRA) has not received any reports of adverse events relating to the Debrisoft pad.
## Committee considerations
The Committee noted that the clinical evidence base for the Debrisoft pad was limited to 15 studies with 10 of these coming from poster presentations. The Committee agreed with the External Assessment Centre's conclusions that there was a lack of good quality comparative evidence. The Committee recognised that the lack of this type of evidence is common in woundcare management, and it would encourage the collection of better quality comparative evidence to improve decision-making in the debridement of acute or chronic wounds.
The Committee considered that the studies provided evidence that the Debrisoft pad was safe to use for wound debridement and in some cases had equal or greater efficacy than the comparators. Using expert advice and the available evidence the Committee judged that the Debrisoft pad was likely to completely debride appropriate wounds more quickly than gauze and hydrogel. The Committee accepted that quicker debridement may give earlier visibility of the wound bed and therefore enable better management of the wound. In addition, the Committee considered that the Debrisoft pad was convenient and easy to use, and was well tolerated by patients.
The Committee considered that there was evidence of efficacy for the use of the Debrisoft pad on sloughy wounds with exudate and hyperkeratotic skin. It noted from the clinical evidence and expert advice that the Debrisoft pad may not be as effective on wounds in which black necrosis or slough had adhered to the wound bed. The Committee considered that little evidence was presented that was specific to use on acute wounds or to the treatment of children. The Committee concluded that appropriate wound selection is important for the use of the Debrisoft pad.
The Committee noted that NICE clinical guidelines support wound debridement, but that the clinical pathway may vary for different types of wounds. The Committee accepted expert advice that hydrogel and larvae are the most appropriate comparators currently used in the community for the same type of wounds as the Debrisoft pad. The Committee considered that the role of gauze in clinical practice is particularly unclear, but it received expert advice that gauze is unlikely to be used to debride a wound in UK clinical practice, because its use is painful for the patient.
The Committee received expert clinical advice that the use of larvae is a valid comparator because they are now provided in bags and are regularly used in community wound management.# NHS considerations
# System impact
The claimed system benefits in the case for adoption presented by the sponsor are that the Debrisoft pad may:
reduce the time and resources associated with debridement, leading to a reduction in the time to healing
achieve more effective debridement facilitating initial assessment, which may result in less frequent and fewer overall care visits
reduce the amount of community care needed, leading to reduced overall costs, shorter waiting times for treatment and reduced referrals to hospital.
## Committee considerations
The Committee considered that an improvement in clinical outcomes may result from faster treatment and healing of wounds. However, the Committee noted that evidence for the Debrisoft pad was presented as time to complete debridement rather than time to healing.
The Committee received expert advice that the Debrisoft pad would improve debridement and help further assessment and treatment of the wound. The Committee heard that it is plausible that the Debrisoft pad would debride a wound with 1 application. This may also be the same for larvae. Expert opinion was that it is likely that hydrogel and gauze would each take up to 10 applications to debride a wound. The Committee considered that using the Debrisoft pad instead of the comparators may reduce the number, length and frequency of nurse visits.
The Committee considered that the Debrisoft pad can be easily included as an option for debridement in wound management in the community. The Debrisoft pads are portable and readily available. No special arrangements are needed for disposal of the used dressings. No evidence was presented by the sponsor to suggest that using the Debrisoft pad would reduce referrals for specialist debridement methods.
The Committee was advised that nurses and other healthcare professionals should only use the Debrisoft pad after appropriate training in how and when to use it.# Cost considerations
# Cost evidence
## Published evidence
None of the identified published studies contained cost information relating to the Debrisoft pad. The Soares (2009) study, which reported results from the VenUS II trial, was used to provide clinical effectiveness information for the comparators in the cost analysis.
## Sponsor cost model
The sponsor submitted a de novo cost analysis that estimated the costs and resource consequences of using the Debrisoft pad in a community setting compared with hydrogel, gauze and larvae. Full details of all cost evidence and modelling considered by the Committee are available in the assessment report overview.
The sponsor submitted a base-case analysis for 2 community settings: a community-based clinic and home (including a residential or nursing home). The population was adults and children needing debridement of an acute or chronic wound. A single cost analysis was provided in the sponsor's submission to account for all debridement; no distinction was made between adults and children, or between acute or chronic wounds.
Clinical effectiveness information for each product was used to inform the 'number of applications to complete debridement' parameter in the cost analysis. Data from the VenUS II trial (Soares et al. 2009) were used to represent the effectiveness of larvae and hydrogel. The effectiveness of gauze was based on clinical opinion obtained by the sponsor. The effectiveness estimate for the Debrisoft pad was obtained from the Bahr et al. (2011) study. The design of this study limited the number of applications of the Debrisoft pad to 3. Results from this study showed that 77% of wounds were completely debrided after 3 applications. In the cost analysis the remaining 23% of patients were assumed to switch to hydrogel after the 3 Debrisoft pad applications.
The sponsor's base case included several key assumptions:
the time horizon of the analysis was the time to complete debridement of the wound
all treatments were provided by a district nurse and were based on a wound size of 10 cm × 10 cm
each nurse visit took 15 minutes
the number of nurse visits per application depended on the product and its availability
wound was treated per patient.
The following parameters were based on clinical opinion:
The Debrisoft pad and hydrogel were pre-ordered for use in a home setting but were available immediately in a clinic setting. Larvae needed pre-ordering in both settings.
Following treatment with hydrogel, gauze and larvae, an additional nurse appointment was needed to remove them.
The External Assessment Centre corrected an error in the implementation of the sponsor's model in which 23% of Debrisoft patients switched to hydrogel (see section 5.4) but the Debrisoft costs for these patients were omitted in the original modelling. Results from the corrected model showed that:
For the clinic setting, the total cost of complete debridement per patient was £97 for the Debrisoft pad, £165 for hydrogel, £180 for gauze, and £306 for larvae, a cost saving per patient of £68, £83, and £209 respectively.
For the home setting, the total cost of complete debridement per patient was £189 for Debrisoft, £308 for hydrogel, £330 for gauze and £351 for larvae, a cost saving per patient of £119, £141, and £162 respectively.
The sponsor explored the uncertainty around the model parameters and the effect this had on the incremental cost of the Debrisoft pad using deterministic sensitivity analysis. The results of the corrected sensitivity analyses showed that the Debrisoft pad remained cost saving for clinic and home visits in all scenarios tested. The key drivers of the cost savings associated with the Debrisoft pad were the fewer nurse visits needed compared with hydrogel and gauze and the cheaper product costs compared with larvae.
## External Assessment Centre cost model
The External Assessment Centre did not consider that all of the assumptions in the sponsor's cost model were appropriate and presented a revised cost model. Key changes were:
the use of bagged, rather than loose larvae
changing the cost of a district nurse to a more accurate hourly rate
increasing the length of a district nurse visit to 22 minutes in the clinic setting and to 40 minutes in the home setting
the cost of wound dressings was removed from visits when the debridement products had to be ordered
using the cheapest option for the cost of hydrogel, gauze and dressings.
Results from the External Assessment Centre's revised analysis showed increased incremental cost savings for the Debrisoft pad compared with the sponsor's model. In a community clinic setting, cost savings per patient for the Debrisoft pad of £99, £152 and £375 compared with hydrogel, gauze and larvae respectively, were obtained. In a home setting, cost savings per patient for the Debrisoft pad of £211, £288 and £280 compared with hydrogel, gauze and larvae respectively, were obtained. The External Assessment Centre re-ran the sponsor's sensitivity analyses using the revised cost model and the Debrisoft pad remained cost saving in almost all scenarios. The External Assessment Centre noted that the increased cost savings were mainly a result of the longer length of nurse visits and the higher cost of bagged larvae.
The External Assessment Centre also conducted a threshold analysis to identify the number of Debrisoft pad applications needed to make it more expensive than hydrogel in 2 different scenarios:
switching to hydrogel after a given number of Debrisoft pad applications (applying the stopping rule)
applying the Debrisoft pad until the wound was completely debrided.In the first scenario, the Debrisoft pad was no longer cost saving in both the home and clinic settings if the wound was not completely debrided after 7 applications and the patient had to be switched to hydrogel. In the second scenario, when the Debrisoft pad alone was used, it was no longer cost saving in the clinic setting if more than 9 applications were needed per patient and in the home setting if more than 10 applications were needed per patient.
## Additional External Assessment Centre analysis
An additional base-case analysis was calculated by the External Assessment Centre based on assumptions that more closely reflect current practice in NHS community settings according to expert advice to the Committee:
For every larvae application, 5 additional nurse visits were included to allow daily visits to assess and redress the wound.
For home visits, the Debrisoft pad and hydrogel would be carried by the nurse and so would be available at the first visit if needed.
Results from the additional cost modelling indicated that the costs of complete debridement using the Debrisoft pad were estimated to be even more cost saving per patient compared with the use of hydrogel, gauze and bagged larvae in both community clinic and home settings. When used by a nurse in a community clinic, there were cost savings per patient of £99 for the Debrisoft pad compared with hydrogel, £152 compared with gauze and £484 compared with bagged larvae. When used by a nurse in the home, there were cost savings per patient of £222 for the Debrisoft pad compared with hydrogel, £347 compared with gauze and £469 compared with bagged larvae.
## Committee considerations
The Committee identified uncertainties in a number of the parameters in the cost analyses presented by the sponsor. The clinical effectiveness data for the products were obtained from 2 clinical trials with different methodologies and in particular the data available for the Debrisoft pad were limited. Many of the key parameters in the model were based on clinical opinion and the Committee was aware of the large variation in practice in wound care. The Committee recognised that the sponsor had tried to address the uncertainties by conducting deterministic sensitivity analyses to explore the robustness of the cost saving.
The Committee considered the additional analyses carried out by the External Assessment Centre. The Committee heard advice from clinical experts about the scenarios most likely to reflect routine clinical practice in woundcare management in the community. It agreed that the additional cost analysis (see section 5.12) was the most plausible. This model demonstrated cost savings per patient, when complete debridement was achieved, ranging from £99 to £484, depending on the comparator, in a community clinic and from £222 to £469, in the home setting. The Committee noted that although this indicates considerable cost saving for the use of the Debrisoft pad, there are also considerable uncertainties in the model because of the limited data available and the variation in clinical practice. Results from the sensitivity analyses indicated that the cost savings were robust when key parameters were varied. The Committee was also informed by the External Assessment Centre that it had re-run the cost analyses at the increased cost for the Debrisoft pad and that the results did not change substantially.
The Committee discussed the 'stopping rule' used in the model, which assumes the Debrisoft pad is used for a maximum of 3 applications and then patients are switched to hydrogel. The Committee understood this assumption was based on the limited data available from Bahr et al. (2011) and does not reflect routine clinical practice. It noted that no other switching sequences were considered in the model. Expert advice to the Committee was that for most appropriate wounds the Debrisoft pad would complete debridement in 1 or 2 applications. The Committee noted the results of the threshold analysis conducted by the External Assessment Centre which showed that the Debrisoft pad was no longer cost saving if a wound needed more than 9 applications in the clinic setting or more than 10 applications in a home setting. Based on the clinical evidence and on expert advice, it considered these scenarios to be very unlikely.
The Committee considered that it was important to note that the cost savings demonstrated in the model do not take into account the type of treated wound. The Committee understood that there is a large variation in wound types, some of which are more suited to different debridement techniques. Expert advice to the Committee was that the Debrisoft pad was not suitable for wounds with black necrotic tissue or hard eschar. The Committee agreed that selection of an appropriate wound was important if the cost savings demonstrated in the model were to be realised.
The Committee would like to have seen a cost analysis based on time to wound healing, which could have analysed situations that routinely occur in practice when chronic wounds recur and need debriding again. However, it recognised that data were not available to inform such an analysis.
## Revisions to cost model for 2019 guidance review
For the guidance review, the External Assessment Centre revised the cost model parameters to reflect 2018 values (original guidance values given in brackets). Nurse costs were inflated using the 2015/16 pay and price series. The main parameter changes were the unit costs of Debrisoft at £6.55 (£6.19, 10 cm × 10 cm), Hydrogel at £1.41 (£1.02), gauze at £0.42 (£0.39) and bagged larvae at £319 (£295). In addition, analysis was done with the larger Debrisoft pad at £16.38 (13 cm × 20 cm) and Debrisoft Lolly at £5.88. Use of the Debrisoft pad remains cost saving compared with saline and gauze (£292), hydrogel (£213) and larvae (£277) for a 10 cm × 10 cm wound area in the home setting. Larger Debrisoft pads (13 cm × 20 cm) and the Debrisoft Lolly are also cost saving in the home setting compared with saline and gauze, hydrogel and larvae. In the clinic setting, use of Debrisoft is cost saving for all 3 Debrisoft pads when compared with saline and gauze (£154 for 10 cm × 10 cm), hydrogel (£99 for 10 cm × 10 cm) and larvae (£373 for 10 cm × 10 cm). Full details are in the External Assessment Centre cost model update report. # Conclusions
The Committee concluded that there is sufficient evidence to support the use of the Debrisoft pad in the debridement of wounds in a community setting. The Committee noted that the available evidence is mainly in adults with chronic wounds and accepted that there is little evidence specific to children or the debridement of acute wounds. The Committee also noted, from the limited available evidence, that the Debrisoft pad is particularly suited to the debridement of sloughy wounds with exudate and hyperkeratotic skin. There was some evidence that suggested that the Debrisoft pad is less successful in debriding wounds with black necrotic tissue and hard eschar. It concluded that the use of the Debrisoft pad in community clinic or home settings could lead to quicker debridement, fewer nurse visits and possibly less discomfort for the patient compared with other debridement methods.
The Committee considered that, although there is uncertainty in the cost model, the use of the Debrisoft pad could generate cost savings compared with hydrogel, gauze and larvae when used for debridement of appropriate wounds in both community clinic and home settings. The Committee concluded that overall, the case for adoption of the Debrisoft pad in the debridement of appropriate acute or chronic wounds in adults and children in a community setting was found to be supported by the evidence.Peter GrovesVice Chair, Medical Technologies Advisory CommitteeMarch 2014
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{'Recommendations': 'The case for adopting the Debrisoft monofilament debridement pad as part of the management of acute or chronic wounds in the community is supported by the evidence. The available evidence is limited, but the likely benefits of using the Debrisoft pad on appropriate wounds are that they will be fully debrided more quickly, with fewer nurse visits needed, compared with other debridement methods. In addition, the Debrisoft pad is convenient and easy to use, and is well tolerated by patients. Debridement is an important component of standard woundcare management as described in the NICE guidelines on pressure ulcers and diabetic foot problems. \n\nThe Debrisoft pad is indicated for adults and children with acute or chronic wounds. The available evidence is mainly in adults with chronic wounds needing debridement in the community. The data show that the device is particularly effective for chronic sloughy wounds and hyperkeratotic skin around acute or chronic wounds.\n\nThe Debrisoft pad is estimated to be cost saving for complete debridement compared with other debridement methods. When compared with hydrogel, gauze and bagged larvae, cost savings per patient (per complete debridement) are estimated to be £99, £154 and £373 respectively in a community clinic, and £213, £292 and £277 respectively in the home. ', 'The technology': "# Description of the technology\n\nThe Debrisoft range (L&R Medical UK) are sterile and single-use monofilament debridement devices intended for nurses and other healthcare professionals to use on adults and children to remove devitalised tissue, debris, and hyperkeratotic skin around acute or chronic wounds. They are made of monofilament polyester fibres with a reverse side of polyacrylate. The monofilament fibres are cut with angled tips designed to penetrate irregularly shaped areas and remove devitalised skin and wound debris. There are 2\xa0sizes of pad (10\xa0cm\xa0× 10\xa0cm and 13\xa0cm\xa0× 20\xa0cm, both with a hand pocket to facilitate handling) and a version with a handle (Debrisoft Lolly). \n\nThe Debrisoft pad is moistened with tap water, sterile water or saline, folded and then, using the soft fleecy side, wiped across the wound with gentle pressure. Cellular debris, slough tissue, exudate and hyperkeratotic tissues become integrated into the monofilaments and are removed from the wound site. The Debrisoft pad is intended for use without analgesia, and the process takes, on average, 2\xa0to 4\xa0minutes. A new pad is normally needed for each separate wound being treated. For large areas, more than 1\xa0pad may be needed.\n\nThe cost of 1\xa0Debrisoft monofilament debridement pad stated in the sponsor's submission in August 2013 was £6.19 and is currently £6.27 (both excluding VAT).\n\nThe claimed benefits of the Debrisoft pad in the case for adoption presented by the sponsor are:\n\nreduction in pain associated with debridement with no analgesia required in most cases\n\nimproved acceptability to patients with reduced fear and anxiety associated with treatment\n\nfaster treatment and healing with reduced frequency and total episodes of care\n\nreduced risks of trauma to healthy tissue, and of bleeding\n\nreduced time and resources associated with debridement and reduced overall time to healing\n\nuse by nurses and other healthcare professionals in the community leading to lower costs and shorter waiting times for treatment\n\nmore effective debridement facilitating initial assessment with the possibility of reduced referrals, hospital administration and inappropriate treatment through misdiagnosis\n\nimproved patient concordance with reduced costs of analgesia often required with other forms of debridement\n\navoidance of ongoing costs relating to specialist methods of debridement and treatment that require additional consumables.\n\n# Current management\n\nDebridement is the removal of dead, damaged tissue or haematoma from a wound. Several techniques are used for debridement, depending on the nature of the wound. In the community these are likely to include mechanical, autolytic and biosurgical techniques. Debridement can be carried out with or without analgesia depending on the degree of wound pain, the site, size and severity of the wound as well as the patient's preference.\n\nThe NICE guideline on pressure ulcers states that standard practice in the management of chronic wounds includes wound debridement to remove dead tissue, and that clinicians should recognise the potential benefit of debridement in the management of pressure ulcers. NICE includes the technique of debridement in the NICE Pathway on pressure ulcers. \n\nThe NICE guideline on diabetic foot problems recommends that diabetic foot ulcers can be managed using debridement. The guideline states that debridement should be performed only by healthcare professionals from a multidisciplinary foot care team, using the technique that best matches their specialist expertise, clinical experience, patient preference, and the site of the ulcer. \n\nThe clinical pathway for people with burns or with surgical wounds that have ruptured (dehisced) is not well defined and varies by wound type. Treatment for dehisced wounds may include antibiotics, wound packing, and negative pressure wound therapy. Haematomas with overlying necrotic skin can be treated conservatively using autolytic, larvae or honey debridement. If the haematoma is very large, surgical debridement and treatment may be needed dependent on depth, severity, size, position and patient-related factors.", 'Clinical evidence': "# Summary of clinical evidence\n\nFull details of all clinical outcomes considered by the Committee are available in the assessment report overview.\n\nThe key clinical outcomes for the Debrisoft monofilament debridement pad presented in the decision problem were:\n\npain and discomfort for the patient when debriding the wound\n\nwound malodour\n\ntime to complete debridement\n\ntime to healing\n\nwound infection/cellulitis\n\nthe number, frequency and duration of healthcare professional (nurse) visits for each patient\n\nthe number of debridements needed\n\ndevice-related adverse events, including non-selective trauma to healthy surrounding tissue or bleeding.\n\nThe clinical evidence for the Debrisoft pad was based on 15 multiple-patient case-series reports (5\xa0peer-reviewed papers and 10\xa0posters), some of which included retrospective comparators. There were no randomised controlled trials. The External Assessment Centre considered that 7\xa0studies (Bahr et al. 2011; Callaghan and Stephen-Haynes, 2012; Collarte et al. 2011; Johnson et al. 2012a; Mustafi et al. 2011; Pietroletti et al. 2012; Wiser et al. 2012) were directly relevant to the scope because they included appropriate comparators and outcomes. Two of the papers (Bahr et al. 2011; Mustafi et al. 2011) presented results from the same study.\n\n## Multiple patient case-series: peer-reviewed papers\n\nBahr et al. (2011) and Mustafi et al. (2011) compared the overall mean time of each debridement session, using the Debrisoft pad, with hydrogel, gauze and surgical debridement in 60\xa0patients. In minutes, this was 2.51 (SD±0.57) for Debrisoft, 7 (±2.08) for hydrogel, 5 (±1.60) for gauze and 9 (±2.64) for surgical debridement. Complete debridement was achieved in 77% (n=44) of patients using the Debrisoft pad in 12\xa0days compared with an estimate taken from the literature of approximately 20\xa0days for enzymes or hydrogel. Using a 6-point scale (1=excellent to 6=inadequate), Debrisoft users rated its debridement efficacy as 'very good', giving a mean score of 1.98 (±0.68) compared with hydrogel, which scored 2.54 (±0.72). The convenience and ease of use of the Debrisoft pad was rated 'very good' by its users, with a mean score of 2.29 (±0.57) on the 6-point scale. Wet gauze was rated similarly with a mean score of 2.49 (±0.67). When using the Debrisoft pad, there was a significant improvement in wound bed condition after 3\xa0debridement sessions. After 1\xa0session, 60% of wounds (n=34) were categorised as covered in slough with some necrotic tissue, after 3\xa0sessions this was 47% (n=27). After 1\xa0session 28% of wounds (n=16) were categorised as covered in slough with no necrotic tissue, after 3\xa0sessions this was 25% (n=14). After 1\xa0session 12% of wounds (n=7) were clean with less than 20% slough, after 3 sessions this was 7% (n=4). Twenty-one per cent (n=12) of wounds had re-epithelialised. Debridement was effective in 93.4% (142/152) of the sessions. During the debridement procedure 45% (n=26) of patients reported that they experienced no pain, 50.4% (n=29) reported slight discomfort of short duration (mean 2\xa0minutes) and 4.6% (n=2) reported moderate pain of short duration (mean 2.4\xa0minutes). No side effects after the procedure were reported by 56 out of 57\xa0patients. No serious adverse events or adverse events were reported. Clinicians reported that the Debrisoft pad removed debris, slough, dried exudate and crusts efficiently, without damaging the fragile skin surrounding the wound. Photographic analysis confirmed this.\n\nGray et al. (2011) described a case series of 18\xa0patients that evaluated which types of slough and necrotic tissue benefit most from debridement with the Debrisoft pad. One patient was unable to tolerate the use of the pad. Results were reported for 10\xa0patients only. Two patients had hyperkeratotic skin removed on their lower limb in less than 2\xa0minutes. One patient's hyperkeratotic skin was not removed by the Debrisoft pad, but it was thought that this was because an emollient was applied before the treatment. Two patients had their wound beds cleared of any haematoma after it had been debrided for less than 5\xa0minutes. One patient had most (not specified how much) of their haematoma cleared from the wound bed. Two patients with pressure wounds on the heel were reported as having partially successful debridement (not clear how successful). Sloughy leg ulcers in 2\xa0patients were fully debrided. The authors noted that when dry, black necrosis or slough had adhered to the wound bed, the Debrisoft pad did not remove the devitalised tissue.\n\nHammerle et al. (2011) described a case series of 11\xa0patients with chronic wounds from 2\xa0hospitals. The Debrisoft pad was able to remove most of the coatings in exudating, seropurulent wounds with highly viscous yellow slough (indicating local infection) after a single use. Most of the material removed by debridement became attached to the pad. In dry wounds with serocrusts between the new vital granulation and epithelial tissue, the Debrisoft pad was able to remove the crusts without affecting the new healthy tissue. In wounds with necrotic layers, hyperkeratotic debris and crusts of dried exudate, the Debrisoft pad removed the necrotic layers after a single use and revealed the skin of the lower extremity, showing an almost normal epidermis. For both types of wound, the Debrisoft pad was able to debride without affecting the new healthy tissue, which was undisturbed by the debridement process.\n\nJohnson et al. (2012a) described a 2-centre observational study that compared the effectiveness of the Debrisoft pad with other non-specified debridement methods. Ten patients were recruited from each centre. Although it was not stated explicitly, it appears from the results that each wound was treated once using the Debrisoft pad. Patients found the treatment very acceptable with minimal pain reported in 95% of cases. The reported time to debridement was 2–4\xa0minutes for 10\xa0patients, 5–7\xa0minutes for 5\xa0patients and more than 7\xa0minutes for 5\xa0patients. Skin condition after Debrisoft pad use compared with a previous hyperkeratosis method was rated for 8\xa0patients and was 'much better' for 6\xa0patients, 'good' for 1\xa0patient and 'very good' for 1\xa0patient. Debridement performance compared with a previous method was rated for 16\xa0patients by the clinician and was 'much better' for 8\xa0patients, 'good' for 5 and 'very good' for 3.\n\nStephen-Haynes and Callaghan (2012) evaluated the use of the Debrisoft pad by 40\xa0tissue viability nurses, over a 12-week period, on a wound or hyperkeratosis. The Debrisoft pad was used for wound debridement by 25\xa0nurses (62.5%), for hyperkeratosis by 4\xa0nurses (10%), and for both by 11\xa0nurses (27.5%). Thirty-eight of the nurses (95%) said that patients' skin condition improved, whereas 2 (5%) said that it remained the same. Thirty-two of the nurses (80%) reported a positive impact on the wound bed using visual assessment. Thirty-four nurses (85%) reported that after debridement, there was clearer visibility of the wound bed and surrounding skin because of the removal of debris, slough or hyperkeratosis, so they were able to identify clearer wound management objectives. Six out of 40 nurses (15%) said there was no improvement. The time taken to carry out debridement using the Debrisoft pad was 0–2\xa0minutes in 8\xa0patients (20%); 3–5\xa0minutes in 21\xa0patients (52.5%) and 6–10\xa0minutes in 9\xa0patients (22.5%). The overall performance of the Debrisoft pad was rated as 'very good' by 24\xa0nurses (60%), 'good' by 10\xa0nurses (25%), 'fairly good' by 5\xa0nurses (12.5%) and 'poor' by 1\xa0nurse (2.5%).\n\n## Multiple patient case-series: posters\n\nAlbas (2012) evaluated the Debrisoft pad for 10\xa0patients with trauma wounds and bites. Debridement was considered effective in all patients because visible debris and slough were successfully removed. A mean of 2.1\xa0sessions (SD±0.83; range: 1–3) was needed to obtain a clean wound bed. In all sessions, the product remained intact. The mean time for the debridement sessions was 2.57\xa0minutes (SD±0.04; range 2–4). Patients reported slight discomfort for a short duration (2\xa0minutes on average) in 35% of cases and no discomfort in 65% of cases. No secondary infections were reported.\n\nCallaghan and Stephen-Haynes (2012) described a case series of 12\xa0patients with pressure ulcers. The time to achieve debridement was 0–5 minutes in all 12\xa0patients. Four patients had pain during the procedure (visual analogue scale [VAS]: 1, 1, 6, 4) but the first 3 of these patients had pain before treatment started (VAS: 1, 1, 7). No patients reported pain after treatment. There was improved visualisation of the wound bed in 92% (11/12) of the patients. Treatment using the Debrisoft pad reduced wound care visits in 92% (11/12) of the patients. The treatment helped assess the category of pressure ulcer in all 12\xa0patients.\n\nCollarte et al. (2011) evaluated the use of the Debrisoft pad in 10\xa0patients and reported that it was easy to use and removed devitalised tissue and hyperkeratosis more quickly compared with standard treatment. The time to treat was decreased and patients found the treatment to be comfortable. One patient had a venous leg ulcer debrided in 4\xa0minutes using the Debrisoft pad, with no reported pain or discomfort. Previously nurses had attempted to debride the wound with autolytic therapy and larvae, but with limited success.\n\nDam (2012) evaluated the Debrisoft pad in 29\xa0patients with chronic wounds. On average, fibrin was reduced by 30%. It was reported that thin and soft layers of fibrin were easier to remove than thick fibrin and necrotic tissue. The Debrisoft pad was not able to remove fibrin that had firmly adhered to the wound bed. Topical analgesia was used in 11\xa0patients; 8\xa0patients reported no change in pain level and 10\xa0patients reported increased pain during debridement. Keratosis was present in 21\xa0patients and this was removed by the Debrisoft pad in all 21\xa0patients.\n\nJohnson (2012b) described a case series in which the Debrisoft pad facilitated healing in all 10\xa0patients. It was stated that pain scores remained low during debridement, with most patients scoring the same before, during and after the procedure. The average debridement time was 4\xa0minutes (range 2–10). The time to complete healing was recorded as between 2\xa0weeks for 2\xa0patients with venous leg ulcers and 6\xa0weeks for 2\xa0patients with mixed aetiology. The wound of 1 patient treated before a below knee amputation healed with no complications but it was not stated how long this took. The wounds of 2 other patients did not heal before the end of the 12\xa0weeks and 1 patient was lost to follow-up.\n\nPietroletti et al. (2012) assessed the efficacy of the Debrisoft pad in a case series of 27\xa0patients. The data were retrospectively compared with a group of 25\xa0patients who had used an autolytic debridement method of either hydrogel or enzymes. The wound condition in both groups was wound bed coated with fibrin and slough or skin around the wound with keratosis and/or exudate. The maximum area of the wounds was 60\xa0cm2. Results showed that 92% of patients had their wound debrided after 1 application of the Debrisoft pad. This involved 1 visit, whereas 38.4% of patients had debrided wounds after 1 application of the autolytic or enzymatic debridement, which involved 2 visits. The author concluded that based on these results, autolytic debridement would need to be used 8\xa0to 10\xa0times to achieve the same results as the Debrisoft pad.\n\nRieke (2012) reported the results of an observational study of 25\xa0patients in which the Debrisoft pad was used on diabetic foot ulcers. Debridement was effective in all of the sessions and visible debris, slough, hyperkeratosis and scabs were successfully removed. In 8\xa0cases additional surgical debridement was performed to remove the thick callus at the edges. The mean time for each debridement session was 2.59\xa0minutes (±SD 0.06). Eighteen of the 25\xa0ulcers healed within 16\xa0weeks (study end point), 2 needed surgery and 5 did not heal.\n\nSkovgaard-Holm and Simonsens (2012) described a study of 10\xa0patients that was completed by homecare nurses. Debridement using the Debrisoft pad was performed 3\xa0times a week over a 2-week period. The efficacy rate of the Debrisoft pad was found to depend on the thickness and adherence of the slough and the thickness of the hyperkeratotic layer. Debridement reduced the area of thin slough by an average of 24% in 3\xa0patients. In 6\xa0patients, an adherence layer of slough was reduced by an average of 7%. The Debrisoft pad reduced a thick soft layer of slough by 10% in 1\xa0patient. Three patients did not feel increased pain during treatment, but 3\xa0experienced severe pain (VAS scores of 8, 7 and 6). The pain level decreased immediately after treatment to the level at the starting point. The nurses felt that 4\xa0patients would have benefitted from local anaesthesia before treatment.\n\nWiser et al. (2012) retrospectively compared the debridement results using the Debrisoft pad in 15\xa0patients with venous leg ulcers or diabetic foot ulcers with a sloughy wound bed with the results obtained with saline soaks used in a similar patient group. No quantitative results were reported. The Debrisoft pad was shown to deliver effective and fast debridement, but it was reported to be somewhat rigid when used on toes or cavity wounds. Patient-reported pain during the procedure was less than for those treated with saline soaks, especially for the patients with arterial ulcers. The slight discomfort reported with the Debrisoft pad seemed to be better tolerated than debridement using saline soaks. Use of the product did not cause damage to the fragile skin surrounding the wound.\n\n## Adverse events\n\nNo adverse event reports relating to the Debrisoft pad were reported in a search of the US Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. The Medicines and Healthcare products Regulatory Agency (MHRA) has not received any reports of adverse events relating to the Debrisoft pad.\n\n## Committee considerations\n\nThe Committee noted that the clinical evidence base for the Debrisoft pad was limited to 15\xa0studies with 10 of these coming from poster presentations. The Committee agreed with the External Assessment Centre's conclusions that there was a lack of good quality comparative evidence. The Committee recognised that the lack of this type of evidence is common in woundcare management, and it would encourage the collection of better quality comparative evidence to improve decision-making in the debridement of acute or chronic wounds.\n\nThe Committee considered that the studies provided evidence that the Debrisoft pad was safe to use for wound debridement and in some cases had equal or greater efficacy than the comparators. Using expert advice and the available evidence the Committee judged that the Debrisoft pad was likely to completely debride appropriate wounds more quickly than gauze and hydrogel. The Committee accepted that quicker debridement may give earlier visibility of the wound bed and therefore enable better management of the wound. In addition, the Committee considered that the Debrisoft pad was convenient and easy to use, and was well tolerated by patients.\n\nThe Committee considered that there was evidence of efficacy for the use of the Debrisoft pad on sloughy wounds with exudate and hyperkeratotic skin. It noted from the clinical evidence and expert advice that the Debrisoft pad may not be as effective on wounds in which black necrosis or slough had adhered to the wound bed. The Committee considered that little evidence was presented that was specific to use on acute wounds or to the treatment of children. The Committee concluded that appropriate wound selection is important for the use of the Debrisoft pad.\n\nThe Committee noted that NICE clinical guidelines support wound debridement, but that the clinical pathway may vary for different types of wounds. The Committee accepted expert advice that hydrogel and larvae are the most appropriate comparators currently used in the community for the same type of wounds as the Debrisoft pad. The Committee considered that the role of gauze in clinical practice is particularly unclear, but it received expert advice that gauze is unlikely to be used to debride a wound in UK clinical practice, because its use is painful for the patient.\n\nThe Committee received expert clinical advice that the use of larvae is a valid comparator because they are now provided in bags and are regularly used in community wound management.", 'NHS considerations': '# System impact\n\nThe claimed system benefits in the case for adoption presented by the sponsor are that the Debrisoft pad may:\n\nreduce the time and resources associated with debridement, leading to a reduction in the time to healing\n\nachieve more effective debridement facilitating initial assessment, which may result in less frequent and fewer overall care visits\n\nreduce the amount of community care needed, leading to reduced overall costs, shorter waiting times for treatment and reduced referrals to hospital.\n\n## Committee considerations\n\nThe Committee considered that an improvement in clinical outcomes may result from faster treatment and healing of wounds. However, the Committee noted that evidence for the Debrisoft pad was presented as time to complete debridement rather than time to healing.\n\nThe Committee received expert advice that the Debrisoft pad would improve debridement and help further assessment and treatment of the wound. The Committee heard that it is plausible that the Debrisoft pad would debride a wound with 1\xa0application. This may also be the same for larvae. Expert opinion was that it is likely that hydrogel and gauze would each take up to 10\xa0applications to debride a wound. The Committee considered that using the Debrisoft pad instead of the comparators may reduce the number, length and frequency of nurse visits.\n\nThe Committee considered that the Debrisoft pad can be easily included as an option for debridement in wound management in the community. The Debrisoft pads are portable and readily available. No special arrangements are needed for disposal of the used dressings. No evidence was presented by the sponsor to suggest that using the Debrisoft pad would reduce referrals for specialist debridement methods.\n\nThe Committee was advised that nurses and other healthcare professionals should only use the Debrisoft pad after appropriate training in how and when to use it.', 'Cost considerations': "# Cost evidence\n\n## Published evidence\n\nNone of the identified published studies contained cost information relating to the Debrisoft pad. The Soares (2009) study, which reported results from the VenUS II trial, was used to provide clinical effectiveness information for the comparators in the cost analysis.\n\n## Sponsor cost model\n\nThe sponsor submitted a de novo cost analysis that estimated the costs and resource consequences of using the Debrisoft pad in a community setting compared with hydrogel, gauze and larvae. Full details of all cost evidence and modelling considered by the Committee are available in the assessment report overview.\n\nThe sponsor submitted a base-case analysis for 2\xa0community settings: a community-based clinic and home (including a residential or nursing home). The population was adults and children needing debridement of an acute or chronic wound. A single cost analysis was provided in the sponsor's submission to account for all debridement; no distinction was made between adults and children, or between acute or chronic wounds.\n\nClinical effectiveness information for each product was used to inform the 'number of applications to complete debridement' parameter in the cost analysis. Data from the VenUS II trial (Soares et al. 2009) were used to represent the effectiveness of larvae and hydrogel. The effectiveness of gauze was based on clinical opinion obtained by the sponsor. The effectiveness estimate for the Debrisoft pad was obtained from the Bahr et al. (2011) study. The design of this study limited the number of applications of the Debrisoft pad to 3. Results from this study showed that 77% of wounds were completely debrided after 3\xa0applications. In the cost analysis the remaining 23% of patients were assumed to switch to hydrogel after the 3\xa0Debrisoft pad applications.\n\nThe sponsor's base case included several key assumptions:\n\nthe time horizon of the analysis was the time to complete debridement of the wound\n\nall treatments were provided by a district nurse and were based on a wound size of 10\xa0cm\xa0× 10\xa0cm\n\neach nurse visit took 15\xa0minutes\n\nthe number of nurse visits per application depended on the product and its availability\n\nwound was treated per patient.\n\nThe following parameters were based on clinical opinion:\n\nThe Debrisoft pad and hydrogel were pre-ordered for use in a home setting but were available immediately in a clinic setting. Larvae needed pre-ordering in both settings.\n\nFollowing treatment with hydrogel, gauze and larvae, an additional nurse appointment was needed to remove them.\n\nThe External Assessment Centre corrected an error in the implementation of the sponsor's model in which 23% of Debrisoft patients switched to hydrogel (see section 5.4) but the Debrisoft costs for these patients were omitted in the original modelling. Results from the corrected model showed that:\n\nFor the clinic setting, the total cost of complete debridement per patient was £97 for the Debrisoft pad, £165 for hydrogel, £180 for gauze, and £306 for larvae, a cost saving per patient of £68, £83, and £209 respectively.\n\nFor the home setting, the total cost of complete debridement per patient was £189 for Debrisoft, £308 for hydrogel, £330 for gauze and £351 for larvae, a cost saving per patient of £119, £141, and £162 respectively.\n\nThe sponsor explored the uncertainty around the model parameters and the effect this had on the incremental cost of the Debrisoft pad using deterministic sensitivity analysis. The results of the corrected sensitivity analyses showed that the Debrisoft pad remained cost saving for clinic and home visits in all scenarios tested. The key drivers of the cost savings associated with the Debrisoft pad were the fewer nurse visits needed compared with hydrogel and gauze and the cheaper product costs compared with larvae.\n\n## External Assessment Centre cost model\n\nThe External Assessment Centre did not consider that all of the assumptions in the sponsor's cost model were appropriate and presented a revised cost model. Key changes were:\n\nthe use of bagged, rather than loose larvae\n\nchanging the cost of a district nurse to a more accurate hourly rate\n\nincreasing the length of a district nurse visit to 22\xa0minutes in the clinic setting and to 40\xa0minutes in the home setting\n\nthe cost of wound dressings was removed from visits when the debridement products had to be ordered\n\nusing the cheapest option for the cost of hydrogel, gauze and dressings.\n\nResults from the External Assessment Centre's revised analysis showed increased incremental cost savings for the Debrisoft pad compared with the sponsor's model. In a community clinic setting, cost savings per patient for the Debrisoft pad of £99, £152 and £375 compared with hydrogel, gauze and larvae respectively, were obtained. In a home setting, cost savings per patient for the Debrisoft pad of £211, £288 and £280 compared with hydrogel, gauze and larvae respectively, were obtained. The External Assessment Centre re-ran the sponsor's sensitivity analyses using the revised cost model and the Debrisoft pad remained cost saving in almost all scenarios. The External Assessment Centre noted that the increased cost savings were mainly a result of the longer length of nurse visits and the higher cost of bagged larvae.\n\nThe External Assessment Centre also conducted a threshold analysis to identify the number of Debrisoft pad applications needed to make it more expensive than hydrogel in 2\xa0different scenarios:\n\nswitching to hydrogel after a given number of Debrisoft pad applications (applying the stopping rule)\n\napplying the Debrisoft pad until the wound was completely debrided.In the first scenario, the Debrisoft pad was no longer cost saving in both the home and clinic settings if the wound was not completely debrided after 7\xa0applications and the patient had to be switched to hydrogel. In the second scenario, when the Debrisoft pad alone was used, it was no longer cost saving in the clinic setting if more than 9\xa0applications were needed per patient and in the home setting if more than 10\xa0applications were needed per patient.\n\n## Additional External Assessment Centre analysis\n\nAn additional base-case analysis was calculated by the External Assessment Centre based on assumptions that more closely reflect current practice in NHS community settings according to expert advice to the Committee:\n\nFor every larvae application, 5 additional nurse visits were included to allow daily visits to assess and redress the wound.\n\nFor home visits, the Debrisoft pad and hydrogel would be carried by the nurse and so would be available at the first visit if needed.\n\nResults from the additional cost modelling indicated that the costs of complete debridement using the Debrisoft pad were estimated to be even more cost saving per patient compared with the use of hydrogel, gauze and bagged larvae in both community clinic and home settings. When used by a nurse in a community clinic, there were cost savings per patient of £99 for the Debrisoft pad compared with hydrogel, £152 compared with gauze and £484 compared with bagged larvae. When used by a nurse in the home, there were cost savings per patient of £222 for the Debrisoft pad compared with hydrogel, £347 compared with gauze and £469 compared with bagged larvae.\n\n## Committee considerations\n\nThe Committee identified uncertainties in a number of the parameters in the cost analyses presented by the sponsor. The clinical effectiveness data for the products were obtained from 2 clinical trials with different methodologies and in particular the data available for the Debrisoft pad were limited. Many of the key parameters in the model were based on clinical opinion and the Committee was aware of the large variation in practice in wound care. The Committee recognised that the sponsor had tried to address the uncertainties by conducting deterministic sensitivity analyses to explore the robustness of the cost saving.\n\nThe Committee considered the additional analyses carried out by the External Assessment Centre. The Committee heard advice from clinical experts about the scenarios most likely to reflect routine clinical practice in woundcare management in the community. It agreed that the additional cost analysis (see section 5.12) was the most plausible. This model demonstrated cost savings per patient, when complete debridement was achieved, ranging from £99 to £484, depending on the comparator, in a community clinic and from £222 to £469, in the home setting. The Committee noted that although this indicates considerable cost saving for the use of the Debrisoft pad, there are also considerable uncertainties in the model because of the limited data available and the variation in clinical practice. Results from the sensitivity analyses indicated that the cost savings were robust when key parameters were varied. The Committee was also informed by the External Assessment Centre that it had re-run the cost analyses at the increased cost for the Debrisoft pad and that the results did not change substantially.\n\nThe Committee discussed the 'stopping rule' used in the model, which assumes the Debrisoft pad is used for a maximum of 3\xa0applications and then patients are switched to hydrogel. The Committee understood this assumption was based on the limited data available from Bahr et al. (2011) and does not reflect routine clinical practice. It noted that no other switching sequences were considered in the model. Expert advice to the Committee was that for most appropriate wounds the Debrisoft pad would complete debridement in 1 or 2\xa0applications. The Committee noted the results of the threshold analysis conducted by the External Assessment Centre which showed that the Debrisoft pad was no longer cost saving if a wound needed more than 9\xa0applications in the clinic setting or more than 10\xa0applications in a home setting. Based on the clinical evidence and on expert advice, it considered these scenarios to be very unlikely.\n\nThe Committee considered that it was important to note that the cost savings demonstrated in the model do not take into account the type of treated wound. The Committee understood that there is a large variation in wound types, some of which are more suited to different debridement techniques. Expert advice to the Committee was that the Debrisoft pad was not suitable for wounds with black necrotic tissue or hard eschar. The Committee agreed that selection of an appropriate wound was important if the cost savings demonstrated in the model were to be realised.\n\nThe Committee would like to have seen a cost analysis based on time to wound healing, which could have analysed situations that routinely occur in practice when chronic wounds recur and need debriding again. However, it recognised that data were not available to inform such an analysis.\n\n## Revisions to cost model for 2019 guidance review\n\nFor the guidance review, the External Assessment Centre revised the cost model parameters to reflect 2018 values (original guidance values given in brackets). Nurse costs were inflated using the 2015/16 pay and price series. The main parameter changes were the unit costs of Debrisoft at £6.55 (£6.19, 10\xa0cm\xa0× 10\xa0cm), Hydrogel at £1.41 (£1.02), gauze at £0.42 (£0.39) and bagged larvae at £319 (£295). In addition, analysis was done with the larger Debrisoft pad at £16.38 (13\xa0cm\xa0× 20\xa0cm) and Debrisoft Lolly at £5.88. Use of the Debrisoft pad remains cost saving compared with saline and gauze (£292), hydrogel (£213) and larvae (£277) for a 10\xa0cm\xa0×\xa010\xa0cm wound area in the home setting. Larger Debrisoft pads (13\xa0cm\xa0× 20\xa0cm) and the Debrisoft Lolly are also cost saving in the home setting compared with saline and gauze, hydrogel and larvae. In the clinic setting, use of Debrisoft is cost saving for all 3 Debrisoft pads when compared with saline and gauze (£154 for 10\xa0cm\xa0× 10\xa0cm), hydrogel (£99 for 10\xa0cm\xa0× 10\xa0cm) and larvae (£373 for 10\xa0cm\xa0× 10\xa0cm). Full details are in the External Assessment Centre\xa0cost model update report. ", 'Conclusions': 'The Committee concluded that there is sufficient evidence to support the use of the Debrisoft pad in the debridement of wounds in a community setting. The Committee noted that the available evidence is mainly in adults with chronic wounds and accepted that there is little evidence specific to children or the debridement of acute wounds. The Committee also noted, from the limited available evidence, that the Debrisoft pad is particularly suited to the debridement of sloughy wounds with exudate and hyperkeratotic skin. There was some evidence that suggested that the Debrisoft pad is less successful in debriding wounds with black necrotic tissue and hard eschar. It concluded that the use of the Debrisoft pad in community clinic or home settings could lead to quicker debridement, fewer nurse visits and possibly less discomfort for the patient compared with other debridement methods.\n\nThe Committee considered that, although there is uncertainty in the cost model, the use of the Debrisoft pad could generate cost savings compared with hydrogel, gauze and larvae when used for debridement of appropriate wounds in both community clinic and home settings. The Committee concluded that overall, the case for adoption of the Debrisoft pad in the debridement of appropriate acute or chronic wounds in adults and children in a community setting was found to be supported by the evidence.Peter GrovesVice Chair, Medical Technologies Advisory CommitteeMarch 2014'}
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https://www.nice.org.uk/guidance/mtg17
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Evidence-based recommendations on the Debrisoft monofilament debridement pad for use in acute or chronic wounds.
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53b3ddef037c2a94169096ab00e9528dd05bb01d
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nice
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Pertuzumab for adjuvant treatment of HER2-positive early stage breast cancer
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Pertuzumab for adjuvant treatment of HER2-positive early stage breast cancer
Evidence-based recommendations on pertuzumab (Perjeta) for adjuvant treatment of HER2‑positive early stage breast cancer in adults.
# Recommendations
Pertuzumab, with intravenous trastuzumab and chemotherapy, is recommended for the adjuvant treatment of human epidermal growth factor receptor 2 (HER2)-positive early stage breast cancer in adults, only if:
they have lymph node-positive disease
the company provides it according to the commercial arrangement.
This guidance is not intended to affect adjuvant treatment with pertuzumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
There is uncertainty about the size of the clinical benefit for pertuzumab in the adjuvant treatment of HER2‑positive early stage breast cancer at high risk of recurrence. Clinical trial evidence measuring invasive disease-free survival suggests that 1.7% fewer people with this type of cancer have invasive disease at 4 years with adjuvant pertuzumab. Evidence from people with lymph node-positive disease (that is, disease that has spread to lymph nodes in the armpit) suggests more benefit in this population, with 3.2% fewer people having invasive disease at 4 years. However, it is not known whether this means that adjuvant pertuzumab increases the overall length of time people live.
Because of the uncertainty in the clinical-effectiveness evidence, the cost-effectiveness estimates are very uncertain. Given this uncertainty, an estimate above £20,000 per quality-adjusted life year (QALY) gained is not considered a cost-effective use of NHS resources. The company's final model includes only people with lymph node-positive disease, and incorporates the committee's preferred conservative estimates of how long treatment benefit with pertuzumab lasts after treatment is stopped. If the commercial discount to the price of pertuzumab, together with a weighted discount for biosimilar intravenous trastuzumab are taken into consideration, the cost-effectiveness estimate is comfortably below £20,000 per QALY gained. Therefore, adjuvant pertuzumab is recommended for HER2-positive early stage breast cancer in people with lymph node-positive disease.# Information about pertuzumab
Marketing authorisation
Pertuzumab (Perjeta, Roche) is indicated as 'adjuvant treatment of adult patients with human epidermal growth factor receptor 2 (HER2)-positive early stage breast cancer at high risk of recurrence'.
Dosage in the marketing authorisation
Intravenous 840 mg loading dose, then 420 mg every 3 weeks. Pertuzumab should be given with trastuzumab and chemotherapy for 1 year (maximum 18 cycles) for patients with high-risk disease, regardless of the timing of surgery.
Price
Pertuzumab costs £2,395 per 420‑mg vial; trastuzumab costs £407.40 per 150‑mg vial (excluding VAT; British national formulary online, accessed May 2018).
The company has a commercial arrangement. This makes pertuzumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## Patients and their families would welcome new effective treatments that reduce the risk of recurrence
The patient experts explained that human epidermal growth factor receptor 2 (HER2)-positive early stage breast cancer has a considerable effect on patients and their families. Diagnosis can be distressing and treatment is associated with negative side effects. The patient experts emphasised that living with HER2-positive early stage breast cancer affects daily living (including restricting employment and social activities) and puts a strain on relationships. They identified disease recurrence as a common cause of stress and anxiety, both in terms of the possibility of progression to non-curable metastatic disease, and because of the need to have further treatment. The patient experts also noted that all treatments have side effects but targeted therapies, such as pertuzumab, tend to be well tolerated by patients. The patient experts recognised that a potential disadvantage of pertuzumab is that it is administered intravenously, whereas the standard of care (trastuzumab) is now mostly delivered subcutaneously. This means that most people having pertuzumab would need to spend more time in hospital than they do currently. It would also mean that trastuzumab would need to be administered intravenously, in line with the clinical trial protocol. The patient experts noted that not all people would consider the additional treatment benefit of pertuzumab (at the level seen in the APHINITY trial, see section 3.3) to be worthwhile. However, they noted that most patients would consider a reduced risk of recurrence worth the potential inconvenience of spending longer in hospital. The committee concluded that although the absolute benefit of pertuzumab over trastuzumab and chemotherapy in the APHINITY trial is low, patients and their families would welcome any new treatment options that could reduce the risk of recurrence.
# Clinical management
## Pertuzumab is already used as neoadjuvant therapy
A clinical expert explained that, since the publication of NICE technology appraisal guidance on pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer, many patients with HER2-positive early stage breast cancer who are at high risk of recurrence have 4 to 6 cycles of neoadjuvant pertuzumab with trastuzumab and chemotherapy, followed by surgery and adjuvant trastuzumab (and endocrine and radiotherapy if appropriate). The company noted that the marketing authorisation for pertuzumab specifies that it should be given with trastuzumab for 1 year (maximum 18 cycles) for patients with disease at high risk of recurrence, regardless of the timing of surgery. Opinions expressed by clinical experts varied in terms of how the use of adjuvant pertuzumab might affect current practice. The committee heard that patients in APHINITY (the main trial in the adjuvant setting) had not had neoadjuvant therapy. However, it also heard that, if pertuzumab were to be recommended in the adjuvant setting, many patients would continue to have 4 to 6 cycles before surgery and then the balance of up to the maximum licensed dose (that is, 18 cycles) after surgery. However, it is also possible that, if pertuzumab were to be available in the adjuvant setting for patients with nodal disease, clinicians might decide to start treatment after surgery. The committee accepted that the treatment benefit of adjuvant pertuzumab may well be similar whether or not the 18 cycles of treatment are started in the neoadjuvant setting. It therefore concluded that people having neoadjuvant pertuzumab should be considered as part of this appraisal (even though they were excluded from the pivotal clinical trial) because this is consistent with how pertuzumab is used in clinical practice.
# APHINITY trial
## The primary outcome of APHINITY is acceptable but there is an absence of mature overall survival data
The evidence for pertuzumab came from APHINITY, an ongoing randomised controlled trial comparing pertuzumab plus trastuzumab and chemotherapy with placebo plus trastuzumab and chemotherapy in 4,805 patients with HER2-positive early stage breast cancer who had had surgery. The initial APHINITY study protocol (protocol A) included patients with either lymph node-positive or negative disease. Patients with lymph node-negative disease were included only if the tumour was bigger than 1 cm in diameter, or between 0.5 cm and 1 cm in diameter with at least 1 additional high-risk feature (high-grade histology, oestrogen and progesterone receptor-negative, or patient age of under 35 years). However, after 3,655 patients had been randomised, the protocol was amended (protocol B) to stop recruiting patients with lymph node-negative disease and to allow for an additional 1,000 patients with lymph node-positive disease to be recruited. Patients entering the trial were stratified at randomisation according to nodal status, type of adjuvant chemotherapy regimen (anthracycline-based compared with non-anthracycline-based), hormone receptor status and geographical region. The overall survival data are immature and, at the time of the primary analysis, there was no apparent difference in overall survival between the treatment groups. The primary outcome for the trial was invasive disease-free survival excluding second primary non-breast cancer events. The committee noted that this is not the standard definition for invasive disease-free survival, which usually includes second primary non-breast cancer events. A clinical expert noted that although disease-free survival is a widely accepted surrogate for overall survival, recent studies have used invasive disease-free survival as a compound surrogate outcome for overall survival. This incorporates both distant and loco-regional recurrence, which are both relevant to overall survival and important to patients. This outcome definition had been identified as meeting US Food and Drug Administration criteria and the European Medicines Agency requirements for a relevant surrogate end point. The clinical expert commented that there is about a 10% difference between disease-free survival and invasive disease-free survival events, the latter excluding events such as new local cancers that are of little or no prognostic significance. The committee acknowledged the difficulty of obtaining mature overall survival data for adjuvant treatments. It concluded that, in the absence of mature overall survival data, invasive disease-free survival is the only available data for decision making. However, it recognised that the extent to which invasive disease-free survival translates into long-term overall survival benefit is not known.
# Clinical evidence
## Trial results suggest that pertuzumab offers only a small incremental treatment benefit compared with placebo in the whole trial population
In the intention-to-treat population, the absolute difference in invasive disease-free survival event rates between the 2 treatment arms was very small. When pertuzumab was added to trastuzumab and chemotherapy, 1.7% fewer people had invasive disease at 4 years. From this, the committee concluded that the incremental treatment benefit of pertuzumab for the whole population is likely to be small.
## Whether pertuzumab's relative treatment effect is greater for lymph node-positive than lymph node-negative disease is unclear but absolute benefit seems to be greater
The company's initial submission focused on patients with either lymph node-positive disease or hormone receptor-negative disease because these 2 subgroups are considered to be at higher risk of disease recurrence and are covered by the marketing authorisation. The clinical experts stated that pertuzumab is likely to be most beneficial in people with lymph node-positive disease. The committee agreed that it is biologically plausible that patients would be at higher risk of recurrence if there were lymph node involvement (which is an indicator of disease spread and metastatic potential) or if the tumour were hormone receptor-negative (because these patients cannot have endocrine treatment). The committee was concerned that APHINITY was not powered to determine treatment effects within the subgroups of interest. It recognised that the separation of the curves for each treatment arm shown in the Kaplan–Meier plots appeared greater in these subgroups compared with the intention-to-treat population, and this was reflected in the numerically lower hazard ratios for these populations (lymph node positive: hazard ratio 0.77, 95% confidence interval 0.62 to 0.96; hormone receptor negative: HR 0.76, 95% CI 0.56 to 1.04) compared with the intention-to-treat population (HR 0.81, 95% CI 0.66 to 1.00). However, the absolute difference in event rates across the treatment arms of all hormone receptor and lymph node-status subgroups was small (range 0.5% to 3.2%). The committee also noted that statistical tests for interaction did not indicate evidence of heterogeneity in the magnitude of treatment effect defined by lymph node status (p=0.17) or hormone receptor status (p=0.54). However, it also noted that a very small overall number of events occurred in the lymph node-negative subgroup (n=32 in the pertuzumab arm and n=29 in the placebo arm, compared with n=139 and n=181 events in the equivalent arms of the lymph node-positive subgroup). The committee heard from the clinical experts, and accepted the biological plausibility, that people with lymph node-positive disease would have more recurrences, so that even with the same relative effectiveness the numerical reduction in recurrences and absolute benefit would therefore be greater. It also noted that the hazard ratio for this subgroup in the trial reached statistical significance (HR 0.77, 95% CI 0.62 to 0.96). The committee accepted that the subgroup with lymph node-positive disease represents a population at increased risk of recurrence, and that the company's decision to focus on people with lymph node-positive disease is reasonable.
# Adverse events
## Pertuzumab is generally well tolerated
The committee heard that grade 3 or higher adverse events were statistically significantly more common with pertuzumab than with placebo in APHINITY (risk ratio 1.12, 95% CI 1.07 to 1.17; p<0.0001). Rates of diarrhoea, anaemia and 1 of the serious cardiac events measured in the trial (New York Heart Association class III or IV heart failure and substantial decrease in left ventricular ejection fraction) were also statistically significantly more common in the pertuzumab arm. The committee noted that although a very low proportion of patients had a primary cardiac event (0.7% with pertuzumab and 0.3% with placebo), there were 17 in the pertuzumab arm compared with 8 in the placebo arm. Health-related quality of life was measured using a number of validated outcome measures (the EuroQol 5‑Dimension, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and the EORTC QLQ‑BR23). However, the ERG noted that the company's submission stated that the assessment schedule was not designed to detect quality-of-life differences between the treatment arms. The ERG considered that it was also unlikely to have captured the true effect of adverse events because of infrequent data collection. The committee acknowledged this but heard from the clinical and patient experts that pertuzumab is generally well tolerated. The committee also acknowledged that some of the adverse events experienced by patients in APHINITY occurred when they were also having chemotherapy treatment, which may have contributed to some of the adverse events. The committee concluded on the basis of the patient and clinical expert testimony that pertuzumab is acceptable to patients.
# Cost-effectiveness model
## The model structure is appropriate but results in an unusual treatment-effect profile
The company's updated cost-effectiveness model focused on the lymph node-positive population. Inputs were based on data for the relevant subgroups from APHINITY, as well as on information from other relevant sources. Rates of invasive disease-free survival were projected over the lifetime time horizon (52 years) by fitting parametric curves to the data observed in APHINITY. The choice of curve was based on statistical measures of goodness-of-fit with a log-logistic curve used for the lymph node-positive population. To account for non-proportional hazards, the curves were fitted independently to each treatment arm. The time period was split into 3 phases to reflect the anticipated periods of time during which the treatments (intervention or comparator) were expected to be fully effective (phase 1), waning (phase 2) and background mortality rates after treatment effect had ceased (phase 3). The committee noted that this resulted in an unusual treatment-effect profile with increasing benefit of treatment with time over 1 period (during which the curves separated) and then, at a specific time point, a sudden sharp decline and convergence of the curves. The committee found this difficult to explain, noting that it is impossible to predict the treatment-effect duration, or its decline, in the absence of more mature data. It accepted the ERG's conclusion that the choice of parametric curves and the rationale for the adjustments seems reasonable. The committee concluded that although the overall design and structure of the model appears acceptable, there is inherent uncertainty in the extrapolation of treatment benefit.
# Cost-effectiveness estimates
## There is substantial uncertainty in the predicted benefit of adjuvant pertuzumab over a long time horizon
The company revised their cost-effectiveness analysis during the consultation on the appraisal consultation document. This was to make it better aligned to the ERG's preferred assumptions (cure adjustment introduced at year 3, and a maximum cure proportion of 95% at 10 years), and the duration of treatment benefit (waning of treatment effect beginning at year 4 and ending at year 7). It also included an updated commercial access agreement, and updated the proportion of metastatic and non-metastatic recurrence before and after 18 months. The ERG agreed with the revised proportions of metastatic and non-metastatic recurrence because the updated values were based on more recent trial data. The committee accepted that although both the company's and the ERG's revised base-case analyses were informed by data from relevant sources, many assumptions had to be made because of the immaturity of the available trial data. The committee considered the estimate of overall survival, which was not modelled parametrically from the observed data but assessed indirectly based on patient progression through the health states. It noted that many of the ERG's preferred assumptions were used in the company's revised model. However, despite this, there was still uncertainty in projecting a 3% benefit in disease-free survival in the lymph node-positive group to a 0.4 quality-adjusted life year (QALY) gain. It also noted that any assessment of the acceptability of the estimated incremental cost-effectiveness ratio (ICER) should take this uncertain long-term benefit into account. The committee concluded that the long-term QALY gain is highly uncertain.
## Pertuzumab can be recommended for adjuvant treatment of HER2-positive early stage breast cancer in people with lymph node-positive disease
The updated model included assumptions preferred by the committee for the duration of treatment benefit, which had a large impact on the ICER, and a new commercial discount to the price of pertuzumab. The committee noted that biosimilars for intravenous trastuzumab are now available in England, which will reduce the overall cost of pertuzumab combination therapy. It heard from the Cancer Drugs Fund clinical lead that the initial tendering process for biosimilar trastuzumab has only recently been completed, and that prices and market share are likely to change over time. The committee considered the current commercial-in-confidence price and biosimilar trastuzumab market share to be most appropriate for decision making because this is in line with what has been considered in other NICE appraisals. It considered that a weighted-average biosimilar trastuzumab discount gave the best estimate of current price for the purposes of estimating the ICER. The Cancer Drugs Fund clinical lead also confirmed that the effect of introducing biosimilar intravenous trastuzumab only needed to be considered in the intervention arm of the model because, if trastuzumab is delivered without pertuzumab, the current practice of providing adjuvant subcutaneous trastuzumab is unlikely to change. When the weighted-average biosimilar discount and market share estimates were taken into account in the updated model the company's base-case ICER was comfortably lower than £20,000 per QALY gained. The committee was aware that this ICER incorporated considerable uncertainty in: the size of the effect of pertuzumab on overall survival based on the APHINITY trial (see section 3.4), the specific benefit of pertuzumab in the lymph node-positive group (see section 3.5), a modelled QALY gain of 0.4 (see section 3.8), and the estimate weighted-average discount applicable to biosimilar intravenous trastuzumab. Although the committee still had concerns that the 0.4 QALY gain could be an overestimate, it acknowledged that pertuzumab had been shown to be an effective treatment in both the neoadjuvant and metastatic setting. It considered that, because the updated ICER is comfortably below £20,000 per QALY gained using the committee's preferred assumptions, the new commercial offer is sufficient to offset the uncertainty about the estimated QALY gain. The committee therefore concluded that pertuzumab can be recommended in the NHS as a cost-effective treatment option for the adjuvant treatment HER-2 positive early stage breast cancer in people with lymph node-positive disease.
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{'Recommendations': "Pertuzumab, with intravenous trastuzumab and chemotherapy, is recommended for the adjuvant treatment of human epidermal growth factor receptor\xa02 (HER2)-positive early stage breast cancer in adults, only if:\n\nthey have lymph node-positive disease\n\nthe company provides it according to the commercial arrangement.\n\nThis guidance is not intended to affect adjuvant treatment with pertuzumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere is uncertainty about the size of the clinical benefit for pertuzumab in the adjuvant treatment of HER2‑positive early stage breast cancer at high risk of recurrence. Clinical trial evidence measuring invasive disease-free survival suggests that 1.7%\xa0fewer people with this type of cancer have invasive disease at 4\xa0years with adjuvant pertuzumab. Evidence from people with lymph node-positive disease (that is, disease that has spread to lymph nodes in the armpit) suggests more benefit in this population, with 3.2%\xa0fewer people having invasive disease at 4\xa0years. However, it is not known whether this means that adjuvant pertuzumab increases the overall length of time people live.\n\nBecause of the uncertainty in the clinical-effectiveness evidence, the cost-effectiveness estimates are very uncertain. Given this uncertainty, an estimate above £20,000 per quality-adjusted life year (QALY) gained is not considered a cost-effective use of NHS resources. The company's final model includes only people with lymph node-positive disease, and incorporates the committee's preferred conservative estimates of how long treatment benefit with pertuzumab lasts after treatment is stopped. If the commercial discount to the price of pertuzumab, together with a weighted discount for biosimilar intravenous trastuzumab are taken into consideration, the cost-effectiveness estimate is comfortably below £20,000 per QALY gained. Therefore, adjuvant pertuzumab is recommended for HER2-positive early stage breast cancer in people with lymph node-positive disease.", 'Information about pertuzumab': "Marketing authorisation\n\nPertuzumab (Perjeta, Roche) is indicated as 'adjuvant treatment of adult patients with human epidermal growth factor receptor\xa02 (HER2)-positive early stage breast cancer at high risk of recurrence'.\n\nDosage in the marketing authorisation\n\nIntravenous 840\xa0mg loading dose, then 420\xa0mg every 3\xa0weeks. Pertuzumab should be given with trastuzumab and chemotherapy for 1\xa0year (maximum 18\xa0cycles) for patients with high-risk disease, regardless of the timing of surgery.\n\nPrice\n\nPertuzumab costs £2,395 per 420‑mg vial; trastuzumab costs £407.40 per 150‑mg vial (excluding VAT; British national formulary online, accessed May 2018).\n\nThe company has a commercial arrangement. This makes pertuzumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## Patients and their families would welcome new effective treatments that reduce the risk of recurrence\n\nThe patient experts explained that human epidermal growth factor receptor\xa02 (HER2)-positive early stage breast cancer has a considerable effect on patients and their families. Diagnosis can be distressing and treatment is associated with negative side effects. The patient experts emphasised that living with HER2-positive early stage breast cancer affects daily living (including restricting employment and social activities) and puts a strain on relationships. They identified disease recurrence as a common cause of stress and anxiety, both in terms of the possibility of progression to non-curable metastatic disease, and because of the need to have further treatment. The patient experts also noted that all treatments have side effects but targeted therapies, such as pertuzumab, tend to be well tolerated by patients. The patient experts recognised that a potential disadvantage of pertuzumab is that it is administered intravenously, whereas the standard of care (trastuzumab) is now mostly delivered subcutaneously. This means that most people having pertuzumab would need to spend more time in hospital than they do currently. It would also mean that trastuzumab would need to be administered intravenously, in line with the clinical trial protocol. The patient experts noted that not all people would consider the additional treatment benefit of pertuzumab (at the level seen in the APHINITY trial, see section\xa03.3) to be worthwhile. However, they noted that most patients would consider a reduced risk of recurrence worth the potential inconvenience of spending longer in hospital. The committee concluded that although the absolute benefit of pertuzumab over trastuzumab and chemotherapy in the APHINITY trial is low, patients and their families would welcome any new treatment options that could reduce the risk of recurrence.\n\n# Clinical management\n\n## Pertuzumab is already used as neoadjuvant therapy\n\nA clinical expert explained that, since the publication of NICE technology appraisal guidance on pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer, many patients with HER2-positive early stage breast cancer who are at high risk of recurrence have 4\xa0to\xa06\xa0cycles of neoadjuvant pertuzumab with trastuzumab and chemotherapy, followed by surgery and adjuvant trastuzumab (and endocrine and radiotherapy if appropriate). The company noted that the marketing authorisation for pertuzumab specifies that it should be given with trastuzumab for 1\xa0year (maximum 18\xa0cycles) for patients with disease at high risk of recurrence, regardless of the timing of surgery. Opinions expressed by clinical experts varied in terms of how the use of adjuvant pertuzumab might affect current practice. The committee heard that patients in APHINITY (the main trial in the adjuvant setting) had not had neoadjuvant therapy. However, it also heard that, if pertuzumab were to be recommended in the adjuvant setting, many patients would continue to have 4\xa0to\xa06\xa0cycles before surgery and then the balance of up to the maximum licensed dose (that is, 18\xa0cycles) after surgery. However, it is also possible that, if pertuzumab were to be available in the adjuvant setting for patients with nodal disease, clinicians might decide to start treatment after surgery. The committee accepted that the treatment benefit of adjuvant pertuzumab may well be similar whether or not the 18\xa0cycles of treatment are started in the neoadjuvant setting. It therefore concluded that people having neoadjuvant pertuzumab should be considered as part of this appraisal (even though they were excluded from the pivotal clinical trial) because this is consistent with how pertuzumab is used in clinical practice.\n\n# APHINITY trial\n\n## The primary outcome of APHINITY is acceptable but there is an absence of mature overall survival data\n\nThe evidence for pertuzumab came from APHINITY, an ongoing randomised controlled trial comparing pertuzumab plus trastuzumab and chemotherapy with placebo plus trastuzumab and chemotherapy in 4,805\xa0patients with HER2-positive early stage breast cancer who had had surgery. The initial APHINITY study protocol (protocol\xa0A) included patients with either lymph node-positive or negative disease. Patients with lymph node-negative disease were included only if the tumour was bigger than 1\xa0cm in diameter, or between 0.5\xa0cm and 1\xa0cm in diameter with at least 1\xa0additional high-risk feature (high-grade histology, oestrogen and progesterone receptor-negative, or patient age of under 35\xa0years). However, after 3,655\xa0patients had been randomised, the protocol was amended (protocol\xa0B) to stop recruiting patients with lymph node-negative disease and to allow for an additional 1,000\xa0patients with lymph node-positive disease to be recruited. Patients entering the trial were stratified at randomisation according to nodal status, type of adjuvant chemotherapy regimen (anthracycline-based compared with non-anthracycline-based), hormone receptor status and geographical region. The overall survival data are immature and, at the time of the primary analysis, there was no apparent difference in overall survival between the treatment groups. The primary outcome for the trial was invasive disease-free survival excluding second primary non-breast cancer events. The committee noted that this is not the standard definition for invasive disease-free survival, which usually includes second primary non-breast cancer events. A clinical expert noted that although disease-free survival is a widely accepted surrogate for overall survival, recent studies have used invasive disease-free survival as a compound surrogate outcome for overall survival. This incorporates both distant and loco-regional recurrence, which are both relevant to overall survival and important to patients. This outcome definition had been identified as meeting US Food and Drug Administration criteria and the European Medicines Agency requirements for a relevant surrogate end point. The clinical expert commented that there is about a 10%\xa0difference between disease-free survival and invasive disease-free survival events, the latter excluding events such as new local cancers that are of little or no prognostic significance. The committee acknowledged the difficulty of obtaining mature overall survival data for adjuvant treatments. It concluded that, in the absence of mature overall survival data, invasive disease-free survival is the only available data for decision making. However, it recognised that the extent to which invasive disease-free survival translates into long-term overall survival benefit is not known.\n\n# Clinical evidence\n\n## Trial results suggest that pertuzumab offers only a small incremental treatment benefit compared with placebo in the whole trial population\n\nIn the intention-to-treat population, the absolute difference in invasive disease-free survival event rates between the 2\xa0treatment arms was very small. When pertuzumab was added to trastuzumab and chemotherapy, 1.7%\xa0fewer people had invasive disease at 4\xa0years. From this, the committee concluded that the incremental treatment benefit of pertuzumab for the whole population is likely to be small.\n\n## Whether pertuzumab's relative treatment effect is greater for lymph node-positive than lymph node-negative disease is unclear but absolute benefit seems to be greater\n\nThe company's initial submission focused on patients with either lymph node-positive disease or hormone receptor-negative disease because these 2\xa0subgroups are considered to be at higher risk of disease recurrence and are covered by the marketing authorisation. The clinical experts stated that pertuzumab is likely to be most beneficial in people with lymph node-positive disease. The committee agreed that it is biologically plausible that patients would be at higher risk of recurrence if there were lymph node involvement (which is an indicator of disease spread and metastatic potential) or if the tumour were hormone receptor-negative (because these patients cannot have endocrine treatment). The committee was concerned that APHINITY was not powered to determine treatment effects within the subgroups of interest. It recognised that the separation of the curves for each treatment arm shown in the Kaplan–Meier plots appeared greater in these subgroups compared with the intention-to-treat population, and this was reflected in the numerically lower hazard ratios for these populations (lymph node positive: hazard ratio [HR]\xa00.77, 95% confidence interval [CI] 0.62\xa0to\xa00.96; hormone receptor negative: HR\xa00.76, 95%\xa0CI 0.56\xa0to\xa01.04) compared with the intention-to-treat population (HR\xa00.81, 95%\xa0CI 0.66\xa0to\xa01.00). However, the absolute difference in event rates across the treatment arms of all hormone receptor and lymph node-status subgroups was small (range 0.5%\xa0to\xa03.2%). The committee also noted that statistical tests for interaction did not indicate evidence of heterogeneity in the magnitude of treatment effect defined by lymph node status (p=0.17) or hormone receptor status (p=0.54). However, it also noted that a very small overall number of events occurred in the lymph node-negative subgroup (n=32 in the pertuzumab arm and n=29 in the placebo arm, compared with n=139 and n=181 events in the equivalent arms of the lymph node-positive subgroup). The committee heard from the clinical experts, and accepted the biological plausibility, that people with lymph node-positive disease would have more recurrences, so that even with the same relative effectiveness the numerical reduction in recurrences and absolute benefit would therefore be greater. It also noted that the hazard ratio for this subgroup in the trial reached statistical significance (HR\xa00.77, 95%\xa0CI 0.62\xa0to\xa00.96). The committee accepted that the subgroup with lymph node-positive disease represents a population at increased risk of recurrence, and that the company's decision to focus on people with lymph node-positive disease is reasonable.\n\n# Adverse events\n\n## Pertuzumab is generally well tolerated\n\nThe committee heard that grade\xa03 or higher adverse events were statistically significantly more common with pertuzumab than with placebo in APHINITY (risk ratio\xa01.12, 95%\xa0CI 1.07\xa0to\xa01.17; p<0.0001). Rates of diarrhoea, anaemia and 1\xa0of the serious cardiac events measured in the trial (New York Heart Association class\xa0III or\xa0IV heart failure and substantial decrease in left ventricular ejection fraction) were also statistically significantly more common in the pertuzumab arm. The committee noted that although a very low proportion of patients had a primary cardiac event (0.7% with pertuzumab and 0.3% with placebo), there were 17\xa0in the pertuzumab arm compared with 8\xa0in the placebo arm. Health-related quality of life was measured using a number of validated outcome measures (the EuroQol 5‑Dimension, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core\xa030, and the EORTC\xa0QLQ‑BR23). However, the ERG noted that the company's submission stated that the assessment schedule was not designed to detect quality-of-life differences between the treatment arms. The ERG considered that it was also unlikely to have captured the true effect of adverse events because of infrequent data collection. The committee acknowledged this but heard from the clinical and patient experts that pertuzumab is generally well tolerated. The committee also acknowledged that some of the adverse events experienced by patients in APHINITY occurred when they were also having chemotherapy treatment, which may have contributed to some of the adverse events. The committee concluded on the basis of the patient and clinical expert testimony that pertuzumab is acceptable to patients.\n\n# Cost-effectiveness model\n\n## The model structure is appropriate but results in an unusual treatment-effect profile\n\nThe company's updated cost-effectiveness model focused on the lymph node-positive population. Inputs were based on data for the relevant subgroups from APHINITY, as well as on information from other relevant sources. Rates of invasive disease-free survival were projected over the lifetime time horizon (52\xa0years) by fitting parametric curves to the data observed in APHINITY. The choice of curve was based on statistical measures of goodness-of-fit with a log-logistic curve used for the lymph node-positive population. To account for non-proportional hazards, the curves were fitted independently to each treatment arm. The time period was split into 3\xa0phases to reflect the anticipated periods of time during which the treatments (intervention or comparator) were expected to be fully effective (phase\xa01), waning (phase\xa02) and background mortality rates after treatment effect had ceased (phase\xa03). The committee noted that this resulted in an unusual treatment-effect profile with increasing benefit of treatment with time over 1\xa0period (during which the curves separated) and then, at a specific time point, a sudden sharp decline and convergence of the curves. The committee found this difficult to explain, noting that it is impossible to predict the treatment-effect duration, or its decline, in the absence of more mature data. It accepted the ERG's conclusion that the choice of parametric curves and the rationale for the adjustments seems reasonable. The committee concluded that although the overall design and structure of the model appears acceptable, there is inherent uncertainty in the extrapolation of treatment benefit.\n\n# Cost-effectiveness estimates\n\n## There is substantial uncertainty in the predicted benefit of adjuvant pertuzumab over a long time horizon\n\nThe company revised their cost-effectiveness analysis during the consultation on the appraisal consultation document. This was to make it better aligned to the ERG's preferred assumptions (cure adjustment introduced at year\xa03, and a maximum cure proportion of 95% at 10\xa0years), and the duration of treatment benefit (waning of treatment effect beginning at year\xa04 and ending at year\xa07). It also included an updated commercial access agreement, and updated the proportion of metastatic and non-metastatic recurrence before and after 18\xa0months. The ERG agreed with the revised proportions of metastatic and non-metastatic recurrence because the updated values were based on more recent trial data. The committee accepted that although both the company's and the ERG's revised base-case analyses were informed by data from relevant sources, many assumptions had to be made because of the immaturity of the available trial data. The committee considered the estimate of overall survival, which was not modelled parametrically from the observed data but assessed indirectly based on patient progression through the health states. It noted that many of the ERG's preferred assumptions were used in the company's revised model. However, despite this, there was still uncertainty in projecting a 3%\xa0benefit in disease-free survival in the lymph node-positive group to a 0.4\xa0quality-adjusted life year (QALY) gain. It also noted that any assessment of the acceptability of the estimated incremental cost-effectiveness ratio (ICER) should take this uncertain long-term benefit into account. The committee concluded that the long-term QALY gain is highly uncertain.\n\n## Pertuzumab can be recommended for adjuvant treatment of HER2-positive early stage breast cancer in people with lymph node-positive disease\n\nThe updated model included assumptions preferred by the committee for the duration of treatment benefit, which had a large impact on the ICER, and a new commercial discount to the price of pertuzumab. The committee noted that biosimilars for intravenous trastuzumab are now available in England, which will reduce the overall cost of pertuzumab combination therapy. It heard from the Cancer Drugs Fund clinical lead that the initial tendering process for biosimilar trastuzumab has only recently been completed, and that prices and market share are likely to change over time. The committee considered the current commercial-in-confidence price and biosimilar trastuzumab market share to be most appropriate for decision making because this is in line with what has been considered in other NICE appraisals. It considered that a weighted-average biosimilar trastuzumab discount gave the best estimate of current price for the purposes of estimating the ICER. The Cancer Drugs Fund clinical lead also confirmed that the effect of introducing biosimilar intravenous trastuzumab only needed to be considered in the intervention arm of the model because, if trastuzumab is delivered without pertuzumab, the current practice of providing adjuvant subcutaneous trastuzumab is unlikely to change. When the weighted-average biosimilar discount and market share estimates were taken into account in the updated model the company's base-case ICER was comfortably lower than £20,000 per QALY gained. The committee was aware that this ICER incorporated considerable uncertainty in: the size of the effect of pertuzumab on overall survival based on the APHINITY trial (see section\xa03.4), the specific benefit of pertuzumab in the lymph node-positive group (see section\xa03.5), a modelled QALY gain of\xa00.4 (see section\xa03.8), and the estimate weighted-average discount applicable to biosimilar intravenous trastuzumab. Although the committee still had concerns that the 0.4\xa0QALY gain could be an overestimate, it acknowledged that pertuzumab had been shown to be an effective treatment in both the neoadjuvant and metastatic setting. It considered that, because the updated ICER is comfortably below £20,000 per QALY gained using the committee's preferred assumptions, the new commercial offer is sufficient to offset the uncertainty about the estimated QALY gain. The committee therefore concluded that pertuzumab can be recommended in the NHS as a cost-effective treatment option for the adjuvant treatment HER-2 positive early stage breast cancer in people with lymph node-positive disease."}
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https://www.nice.org.uk/guidance/ta569
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Evidence-based recommendations on pertuzumab (Perjeta) for adjuvant treatment of HER2‑positive early stage breast cancer in adults.
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2e6a15618c237a6da24e0b18e7b7d3093da484bd
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nice
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Brigatinib for treating ALK-positive advanced non-small-cell lung cancer after crizotinib
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Brigatinib for treating ALK-positive advanced non-small-cell lung cancer after crizotinib
Evidence-based recommendations on brigatinib (Alunbrig) for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer in adults who have already had crizotinib.
# Recommendations
Brigatinib is recommended, within its marketing authorisation, for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) in adults who have already had crizotinib. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
People with ALK-positive advanced NSCLC that has been treated with crizotinib are currently offered ceritinib as their next treatment.
Clinical evidence based on indirect comparisons of trials suggests that people having brigatinib live longer than those having ceritinib, and that they live longer before their condition worsens. Brigatinib may be more effective for brain metastases and better tolerated than existing treatments.
The cost-effectiveness estimates are uncertain, particularly because of whether brigatinib's treatment benefit continues after stopping treatment. The most plausible estimates for brigatinib compared with ceritinib are around the higher end of what NICE normally considers acceptable for an end-of-life treatment. But the population eligible for brigatinib is small and will decrease because crizotinib is no longer considered first-line treatment for ALK-positive NSCLC. Future treatments will be limited for those who have crizotinib. Taking these exceptional circumstances into account, brigatinib is recommended for ALK-positive advanced NSCLC in adults who have had crizotinib.# Information about brigatinib
Marketing authorisation indication
Brigatinib (Alunbrig, Takeda) has a marketing authorisation for 'the treatment of adult patients with anaplastic lymphoma kinase (ALK)‑positive advanced non-small-cell lung cancer previously treated with crizotinib'.
Dosage in the marketing authorisation
The recommended starting dosage of brigatinib is 90 mg once daily for the first 7 days, then 180 mg once daily. Treatment should continue as long as there is clinical benefit.
If brigatinib treatment is interrupted for 14 days or longer for reasons other than adverse reactions, treatment should be resumed at 90 mg once daily for 7 days before increasing to the previously tolerated dose.
If a dose is missed or vomiting occurs after taking a dose, an additional dose should not be administered, and the next dose should be taken at the scheduled time.
Price
The proposed list price for brigatinib is:
£4,900 for 28×180 mg tablets (the recommended dose), £4,900 for a starter pack (7×90 mg plus 21×180 mg tablets), £3,675 for 28×90 mg tablets, £1,225 for 28×30 mg tablets (company submission).
The company has a commercial arrangement. This makes brigatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Takeda and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need
## A new treatment option would benefit people with ALK-positive advanced NSCLC
People with anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) tend to be younger and are less likely to have a history of smoking than the wider NSCLC population. The patient experts explained that ALK-positive advanced NSCLC is debilitating, and that people with the condition worry about poor outcomes. They also highlighted that an improved quality of life, better management of symptoms and an increase in how long they live is very important to people with the condition and their families. The clinical experts acknowledged that an additional treatment option would be beneficial if it offered better tolerability than existing treatments. The committee understood that additional options are beneficial for ALK-positive advanced NSCLC, and concluded that brigatinib would be a useful option if it is better tolerated than existing treatments.
# Treatment pathway and relevant comparators
## Ceritinib is the relevant comparator for this appraisal
NHS England explained that ALK-status testing is now routine clinical practice, so ALK status is known before starting treatment. Therefore, the committee agreed to focus its discussion on people whose ALK status is known before starting treatment. The committee understood that crizotinib, ceritinib and alectinib are options for people with untreated ALK-positive advanced NSCLC. The clinical experts explained that fewer people are starting treatment on crizotinib because of the availability of ceritinib and alectinib. Therefore, the population eligible for brigatinib after crizotinib is small and will decrease as fewer people start treatment with crizotinib. The committee was aware that NICE has recommended ceritinib as a subsequent treatment option when NSCLC progresses with crizotinib. It therefore concluded that ceritinib was the only relevant comparator for brigatinib in people with ALK-positive advanced NSCLC who have had treatment with crizotinib.
# Clinical evidence
## The main evidence for brigatinib is from 2 single-arm studies and is broadly generalisable to UK clinical practice
There were no studies or clinical trials directly comparing brigatinib with ceritinib. The main clinical evidence for brigatinib came from 2 single-arm studies:
ALTA, a phase II study including 110 people in the study arm and using the dosage in brigatinib's marketing authorisation.
Study‑101, a phase I and II study including 25 people in the relevant subgroup.The primary outcome in both studies was investigator-assessed overall response rate, using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Secondary outcomes in the studies included progression-free and overall survival, safety and tolerability and duration of response. The median follow-up in ALTA was 24.3 months and median overall survival was 34.1 months. Objective response rate was 56% in ALTA and 76% in study‑101 (investigator-assessed). Median progression-free survival was 16 months in ALTA and study‑101 (investigator-assessed). Median duration of response was 14 months (investigator-assessed) and 16 months (independent review committee-assessed) in ALTA and 26 months in study‑101 (investigator-assessed). The committee heard that 74% of people in ALTA had previously had chemotherapy and 67% had brain metastases before starting the study. There were no data available on sites of progression for those who progressed during the study. The clinical experts confirmed that the ALTA population broadly reflected people with ALK-positive advanced NSCLC in England. The committee acknowledged that, because there was no head-to-head evidence with the relevant comparator ceritinib, an indirect treatment comparison would be the only way to judge the relative effectiveness of brigatinib compared with ceritinib (see section 3.6). The committee concluded that, although most people in the studies had had previous chemotherapy, ALTA and study‑101 provided evidence that was generalisable enough to clinical practice for decision making.
## The main evidence for the comparator, ceritinib, comes from ASCEND‑2 and ASCEND‑5
The main clinical evidence for ceritinib came from 2 studies:
ASCEND‑2, a single-arm phase II study including 140 people.
ASCEND‑5, a randomised controlled phase III trial including 231 people in the ceritinib arm.Only 1 arm of the ASCEND-5 study was used in the analysis. This was because its comparator (chemotherapy) was not in the appraisal scope because ALK-status testing is now routine practice in England. The primary outcome in ASCEND‑5 was independent review committee-assessed progression-free survival, using RECIST v1.1, and overall survival was included as a secondary outcome. The primary outcome in ASCEND‑2 was investigator-assessed objective response rate, using RECIST v1.1. Secondary outcomes in ASCEND-2 included overall and progression-free survival. The committee accepted that ASCEND‑2 and ASCEND‑5 were appropriate studies to be considered for the comparator in this appraisal.
## Treatment with an ALK inhibitor may continue after disease progression
In ALTA, treatment could continue after disease progression if there was clinical benefit, as determined by the trial investigator. The clinical experts said that this reflects clinical practice in England for both brigatinib and ceritinib. They explained that treatment is continued after disease progression because it might control cancer at sites other than the lungs. The ALTA time on treatment and progression-free survival curves did not support that all people would remain on treatment after progressing. But the committee accepted that it was usual practice in the UK to continue treatment after radiological disease progression in some circumstances.
# Indirect comparison of brigatinib and ceritinib
## An indirect comparison is appropriate because there are no head-to-head trials comparing brigatinib with ceritinib
Because there were no head-to-head trials comparing brigatinib with ceritinib, the company did an unanchored indirect treatment comparison (ITC). Results from 4 studies (see section 3.3 and section 3.4) were used and the relevant arms treated as though they were single-arm studies. There were 2 approaches taken: a naive ITC and a matching-adjusted indirect comparison (MAIC). The MAIC adjusts for differences in baseline characteristics between study populations whereas naive ITC analyses do not. The company presented several analyses using both approaches. For overall survival these were:
Using combined data for brigatinib (including ALTA and study‑101) and using separate data for ceritinib (that is, analyses using either ASCEND‑2 or ASCEND‑5).
Using only ALTA data for brigatinib, and using separate data for ceritinib (that is, analyses using either ASCEND‑2 or ASCEND‑5).Progression-free survival was not reported as an investigator-assessed outcome in ASCEND-5 or as an independent review committee-assessed outcome in study-101. Therefore, the company presented the results using:
Combined data for brigatinib (including ALTA and study-101) and using ASCEND-2 data for ceritinib (investigator-assessed progression-free survival).
Only ALTA data for brigatinib and using separate data for ceritinib (that is, analyses using either ASCEND-2 or ASCEND-5; independent review committee-assessed progression-free survival).The ERG found the ITC analyses to be broadly appropriate given the available trial data. The ERG agreed with the company that there was broad consistency of the results between the MAIC and naive ITC approaches. The committee concluded that, given the available trial data, the company's approach was appropriate.
# Meta-analysis of the indirect treatment comparison results
## The meta-analyses gave consistent results that are acceptable for decision making
For overall survival, the company did 2 meta-analyses to provide estimates of clinical effectiveness:
It compared pooled brigatinib data (from ALTA and study‑101) with ASCEND-2 and ASCEND-5 data (on ceritinib) separately.
It compared brigatinib data from ALTA only with ASCEND-2 and ASCEND-5 separately.The company's preferred approach was to compare pooled ALTA and study-101 data with ASCEND-2 and ASCEND-5 data separately. For progression-free survival, the analysis only included data from ALTA and meta-analysed the results of the ITC against the data from ASCEND‑2 with ASCEND‑5 separately. This was because data for independent review committee-assessed progression-free survival were not available for study‑101, and data for investigator-assessed progression-free survival were not available from ASCEND‑5. The ERG was concerned that no adjustment was made to account for the brigatinib data being included twice in the meta-analysis. But overall, it was satisfied that consistent results were produced using each analytical strategy to meta-analyse the ITC results. All approaches taken for the meta-analysis showed that brigatinib extended overall and progression-free survival compared with ceritinib, and that the difference between treatments was statistically significant. The committee noted that the results suggested brigatinib improved overall survival by 16 to 19 months and progression-free survival by 9 to 10 months compared with ceritinib. The committee acknowledged that there was uncertainty with single-arm studies and the results should be interpreted with caution. It concluded that the meta-analyses gave consistent results and were acceptable for decision making.
# Clinical evidence in the economic model
## The results from the meta-analysis are broadly appropriate to include in the model
The company's original submission used the results of the MAIC ITC that included ALTA and study‑101 data for brigatinib and ASCEND‑2 data for ceritinib to estimate the progression-free survival hazard ratio between brigatinib and ceritinib (see section 3.6). The hazard ratio was then applied to the brigatinib data to estimate progression-free survival for ceritinib. The committee noted that ASCEND‑5 was a larger trial than study‑101 (110 people compared with 25 in study‑101) and had reported independent review committee-assessed progression-free survival (see section 3.4). The ERG highlighted that ASCEND‑5 was a higher quality trial and a more robust data source. At consultation, the company agreed to use the results of the MAIC that excluded study‑101, but for consistency also excluded study-101 for estimating overall survival. The committee agreed that the approach to remove study‑101 from both progression-free and overall survival estimates was appropriate.
# Extrapolating clinical trial data in the economic model
## The company's extrapolation of brigatinib overall survival is appropriate
At consultation, the company provided an updated model that extrapolated overall survival of brigatinib using the exponential function. This estimated that 29% of people with ALK-positive advanced NSCLC would be alive at 5 years and 2.3% at 10 years. The company explained that this broadly reflected estimates from its clinical advisers. The committee noted the wide range of estimates from the company's advisers. At the appraisal committee meeting, the clinical experts said that it was not possible to accurately estimate the proportion of people with ALK-positive advanced NSCLC who would be alive at specific time points in the future. They explained that overall survival has improved over recent years because of the use of ALK-targeted therapies. The ERG noted that the extrapolation of overall survival was very uncertain because the studies had short follow-ups, making the extrapolation periods relatively long. It highlighted that the conclusions should be treated with caution. The committee noted that the ERG preferred to use the log-logistic distribution to estimate overall survival because it provided a good fit and gave a 10-year survival estimate (4.4% at 10 years) closer to the clinical experts' expectations. The committee concluded that, although there was some uncertainty about the long-term prognosis for this population, both the company's and the ERG's choices of distribution were plausible for modelling overall survival.
## The exponential function is more appropriate for extrapolating progression-free survival
The company extrapolated progression-free survival in its model using the Gompertz function because it provided a reasonable fit to the data and also had both internal and external validity. The committee noted that the ERG's preference for using the exponential function provided a closer fit to both the brigatinib and ceritinib observed data. The committee agreed that both the Gompertz and the exponential functions gave plausible estimates for progression-free survival but considered that the ERG's approach provided a better fit to the available data.
# Time on treatment data
## Using time on treatment data from the trial is preferred
The company used progression-free survival plus 1.53 months to estimate time on treatment for both brigatinib and ceritinib. The 1.53 months is the difference between median time on treatment (17.15 months) and median progression-free survival (15.62 months) from ALTA. The ERG was aware that the time on treatment after progression was 3.10 months in ASCEND-2. The clinical experts highlighted that time on treatment after progression could be similar for both brigatinib and ceritinib. They estimated that, in clinical practice, progressed disease could be treated for a further 2 to 3 months (see section 3.5). However, the committee was aware that time on treatment data were available from ALTA and concluded that data from the available evidence were preferred.
# Benefit after stopping treatment
## The size and duration of any treatment benefit after treatment is stopped is uncertain in the absence of longer-term data
In its original submission, the company assumed a continued treatment benefit associated with overall and progression-free survival for brigatinib and ceritinib over the full time horizon of the model. Clinical experts explained that it was reasonable to assume that treatment benefit of brigatinib over ceritinib would continue for a few months after stopping treatment, because brigatinib appears to have a deeper response on brain metastases than ceritinib. However, they noted that there is no trial evidence to support a continued survival benefit after treatment stops in people with radiological progression. This benefit of brigatinib over ceritinib may have been captured already in the progression-free survival estimate. The committee was aware of NICE's technology appraisal guidance on ceritinib after crizotinib in which the clinical experts had noted that treatment benefit was unlikely to persist beyond treatment. The committee agreed that the size and duration of any treatment benefit after stopping treatment in people with symptomatic progression was uncertain in the absence of longer-term data.
## The ERG's approach of directly linking mortality with time on treatment is preferred
In response to the committee's concerns that lifetime treatment benefit was not clinically plausible, the company updated its economic model. The updated model assumed a full treatment benefit for 161 weeks (3.09 years). This included 148 weeks (based on the maximum follow-up in ALTA) plus 13 weeks of continued treatment benefit (based on clinical inputs estimating this to be 2 to 3 months; see section 3.11). After 161 weeks, the brigatinib mortality rate was tapered until week 377 (7.23 years) when only 1% of people remained on treatment. At this point mortality rates for brigatinib and ceritinib were assumed to be the same (hazard ratio of 1). The ERG considered that the company's approach to modelling a loss of treatment effect did not directly link to the length of time on treatment. The ERG also considered that the mortality rate applied for those who were no longer on treatment should be relative to best supportive care rather than to ceritinib. The ERG's updated model adjusted the mortality rates for both brigatinib and ceritinib during the extrapolated period (after week 161) from ALTA, which therefore kept a direct link between the time on treatment and the time at which loss of effect begins. After this period the ERG applied an estimated mortality rate for best supportive care for those who stop treatment with either brigatinib or ceritinib. Although the committee acknowledged that there was uncertainty with both the company's and the ERG's approaches to modelling treatment benefit after stopping treatment because of a lack of longer-term data, the committee preferred to retain a link between time on treatment and the time at which loss of effect begins.
# Health-related quality of life
## The utility value for pre-progressed disease is acceptable
The company derived the utility value of 0.793 for pre-progressed disease from ALTA. The clinical experts confirmed that this utility value was reasonable. They explained that people with ALK-positive advanced NSCLC are well, even at the end of treatment. The committee concluded that the utility value of 0.793 for pre-progressed disease was appropriate.
## The utility values for people with progressed disease on or off treatment are acceptable
The company estimated the quality of life associated with progressed disease using published utility values. In the original submission, the company used a utility decrement of 0.15 from Chouaid et al. (2013), giving a utility estimate of 0.643 for progressed disease. The committee accepted the 0.15 utility decrement and the 0.643 utility value for those who have progressed on treatment, but did not consider 0.643 appropriate for progressed disease once patients are no longer taking treatment. This was in line with the clinical experts, who felt that it was unlikely that this value would remain constant throughout progression. The company revised the utility values, creating a separate value for progression on and off treatment. The progressed on-treatment value (0.732) was derived from ALTA, and was for patients who had just progressed (both on and off treatment). The company then applied the utility decrement of 0.15 from Chouaid et al. to the progressed on-treatment value, giving a utility estimate of 0.582 for progressed disease off treatment. The committee concluded that the company's updated utility values were reasonable.
# Resource use and costs
## Drug wastage for brigatinib and ceritinib is adequately captured
The company's original submission assumed that there was no drug wastage (that is, the NHS would save all costs associated with the reduced dose intensity seen in the studies). A written statement from NHS England confirmed that there was likely to be more drug wastage with ceritinib than brigatinib. The clinical experts explained that dose reduction is common with ceritinib because of toxicity but dose reduction with brigatinib is uncommon. The company revised its submission in response to consultation, to reflect the committee's preference for the ERG's model assumption to use half the difference between the observed and expected dose for each treatment. The committee accepted the company's amendments to the model.
## It is reasonable to include drug administration and delivery costs
The company included administration costs for both brigatinib and ceritinib in its model (£526 for the first cycle and £217 for subsequent cycles). At the first committee meeting, the Cancer Drugs Fund clinical lead explained that most trusts use a third-party dispenser for oral chemotherapy, which incurs a cost for home delivery. He also suggested that a delivery cost would be applied about 70% of the time. The Cancer Drugs Fund clinical lead also explained that, because brigatinib is a high-cost chemotherapy, the oral chemotherapy administration tariff (£120) should have been used in the company's model and included as a cost per item per cycle. In response to the comments, the company noted that the resource use inputs for dispensing, administration, dose changes and monitoring, as well as administration and dispensing costs for each cycle, were already included in the administration costs used in the model. NHS England confirmed that £217 was more than the current oral administration tariff and it was content that the appropriate costs were contained within the model, as long as they were applied to both treatments. The committee concluded that the administration costs were suitably captured within the model.
# Cost-effectiveness results
## The company's probabilistic base-case ICER comparing brigatinib with ceritinib is above £50,000 per QALY gained
The committee considered the incremental cost-effectiveness ratios (ICERs) from the company's base case, recalculated by the ERG to include the approved patient access scheme discounts for brigatinib and ceritinib (which are confidential so the ICERs cannot be reported here). The company's base-case probabilistic ICER for brigatinib compared with ceritinib was above £50,000 per quality-adjusted life year (QALY) gained. The committee considered that the company's base case was not appropriate for decision making because of concerns about the uncertainty about continued treatment benefit beyond 3 months used in the model (see section 3.12).
## The ERG's preferred assumptions increase the ICER
The ERG's preferred assumptions about clinical benefit after treatment stopped included:
Starting mortality rate decline from week 161 (similar to the company's approach).
Using data from the ALTA Kaplan–Meier plot to estimate time on treatment instead of using progression-free survival plus 1.53 months, thereby maintaining a direct link between time on treatment and progression-free survival.
Using mortality rates for those no longer on treatment with either brigatinib or ceritinib based on best supportive care (applying a hazard ratio of 0.75 between best supportive care and ceritinib).
Using an exponential distribution for progression-free survival and a log-logistic distribution for overall survival.The committee noted that combining the ERG's preferred assumptions increased the ICERs compared with the company's base case. The ERG's base case with its preferred assumptions gave an ICER for brigatinib compared with ceritinib that was more than £50,000 per QALY gained. The committee noted that the ERG's base case may have underestimated the time on treatment for ceritinib (around 3.7 months compared with a median of 5.5 months in the company model). The ERG explored scenarios that adjusted the hazard ratio for time on treatment for brigatinib compared with ceritinib, some of which gave time on treatment estimates that were more consistent with ASCEND-5. Some of these scenarios decreased the ICER to below £50,000 per QALY gained. The committee agreed with the ERG's general approach and preferred the hazard ratios that gave a median time on treatment for ceritinib of between 6.4 and 7.4 months, which was consistent with ASCEND-5 (which had a median time on treatment of about 7 months in the published results).
## Changes to clinical practice mean that the population eligible for brigatinib after crizotinib is decreasing, with limited future treatment options
The committee was aware that crizotinib was no longer standard care for ALK-positive NSCLC because most people now start treatment with alectinib. The committee considered that future treatment options for people who start treatment with crizotinib will probably be limited. Also, the committee was aware that the population eligible for brigatinib after crizotinib is small (less than 50 people) and will decrease as fewer people start treatment with crizotinib (see section 3.2). Therefore, the committee recognised that there was a need for effective and well tolerated treatments for this small and diminishing group of people who started treatment with crizotinib and who are affected by this change in treatment pathway. The committee concluded that these were exceptional circumstances, which should be taken into consideration in its decision making.
# End of life
## Life expectancy for people with ALK-positive advanced NSCLC is considered to be less than 24 months
The committee considered advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company considered that the life expectancy of people with ALK-positive advanced NSCLC would be less than 24 months, which meets the first criterion for an end-of-life treatment. Median life expectancy reported in ASCEND-2 was 14.9 months and in ASCEND-5 it was 18.1 months. Mean overall survival was not reported in ASCEND-2 and ASCEND-5. The company's model predicted a mean overall survival of 22 months for people with ALK-positive advanced NSCLC. The committee concluded that the life expectancy of people with ALK-positive advanced NSCLC having ceritinib is less than 24 months.
## Brigatinib extends life by at least 3 months
The company estimated a mean life extension of 21 months with brigatinib compared with ceritinib, which meets the second criterion for an end-of-life treatment. The committee understood that estimating overall survival for this population was very uncertain (see section 3.9). The ERG highlighted that the data used to estimate the extension to life were not robust but extension to life was likely to be at least 3 months. The committee concluded that brigatinib for ALK-positive advanced NSCLC would likely extend life by at least 3 months.
## Brigatinib meets the criteria for end-of-life treatments
The committee concluded that, although the most plausible estimate of life expectancy for people with previously treated ALK-positive advanced NSCLC was less than 24 months, the potential life extension benefit of brigatinib was proportionally substantial. It was therefore satisfied that brigatinib met the criteria for end-of-life treatments.
# Innovation
## The benefits of brigatinib are adequately captured in the model
The company considered brigatinib to be innovative because it offers meaningful extension to life and longer progression-free life. The clinical experts explained that brigatinib has a lower toxicity than ceritinib and so is better tolerated. They said that brigatinib treatment is not a step change but is innovative because it is well tolerated. The committee agreed that the benefits of brigatinib over ceritinib in the central nervous system were adequately captured in the analysis through health-related quality of life. It concluded that although brigatinib may be innovative, it had not been presented with any additional evidence of benefits that were not captured in the economic model and resulting cost-effectiveness estimates.
# Conclusion
## Brigatinib after crizotinib is recommended for people with ALK-positive advanced NSCLC
The committee considered the strengths and weaknesses of the company's and the ERG's base cases, noting the overall uncertainty in the results from both approaches. Having considered the ICERs from both approaches, the committee agreed that the most plausible ICER for brigatinib compared with ceritinib in people with ALK-positive advanced NSCLC was around the higher end of what would normally be considered cost effective for an end-of-life treatment. The committee also considered that the population was small and decreasing over time, with limited future treatment options for people who started treatment with crizotinib. It also considered that brigatinib is a treatment option that could offer benefits in terms of progression-free and overall survival as well as better tolerability than ceritinib. Although the most plausible ICER was around the higher end of what NICE normally considers cost effective for an end-of-life treatment, the committee agreed that there were exceptional circumstances for this population that should be taken into account (see section 3.5 and section 3.20). Therefore, the committee concluded that brigatinib was recommended for routine use in the NHS for ALK-positive advanced NSCLC after crizotinib.
|
{'Recommendations': "Brigatinib is recommended, within its marketing authorisation, for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) in adults who have already had crizotinib. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nPeople with ALK-positive advanced NSCLC that has been treated with crizotinib are currently offered ceritinib as their next treatment.\n\nClinical evidence based on indirect comparisons of trials suggests that people having brigatinib live longer than those having ceritinib, and that they live longer before their condition worsens. Brigatinib may be more effective for brain metastases and better tolerated than existing treatments.\n\nThe cost-effectiveness estimates are uncertain, particularly because of whether brigatinib's treatment benefit continues after stopping treatment. The most plausible estimates for brigatinib compared with ceritinib are around the higher end of what NICE normally considers acceptable for an end-of-life treatment. But the population eligible for brigatinib is small and will decrease because crizotinib is no longer considered first-line treatment for ALK-positive NSCLC. Future treatments will be limited for those who have crizotinib. Taking these exceptional circumstances into account, brigatinib is recommended for ALK-positive advanced NSCLC in adults who have had crizotinib.", 'Information about brigatinib': "Marketing authorisation indication\n\nBrigatinib (Alunbrig, Takeda) has a marketing authorisation for 'the treatment of adult patients with anaplastic lymphoma kinase (ALK)‑positive advanced non-small-cell lung cancer previously treated with crizotinib'.\n\nDosage in the marketing authorisation\n\nThe recommended starting dosage of brigatinib is 90\xa0mg once daily for the first 7\xa0days, then 180\xa0mg once daily. Treatment should continue as long as there is clinical benefit.\n\nIf brigatinib treatment is interrupted for 14\xa0days or longer for reasons other than adverse reactions, treatment should be resumed at 90\xa0mg once daily for 7\xa0days before increasing to the previously tolerated dose.\n\nIf a dose is missed or vomiting occurs after taking a dose, an additional dose should not be administered, and the next dose should be taken at the scheduled time.\n\nPrice\n\nThe proposed list price for brigatinib is:\n\n£4,900 for 28×180\xa0mg tablets (the recommended dose), £4,900 for a starter pack (7×90\xa0mg plus 21×180\xa0mg tablets), £3,675 for 28×90\xa0mg tablets, £1,225 for 28×30\xa0mg tablets (company submission).\n\nThe company has a commercial arrangement. This makes brigatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Takeda and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## A new treatment option would benefit people with ALK-positive advanced NSCLC\n\nPeople with anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) tend to be younger and are less likely to have a history of smoking than the wider NSCLC population. The patient experts explained that ALK-positive advanced NSCLC is debilitating, and that people with the condition worry about poor outcomes. They also highlighted that an improved quality of life, better management of symptoms and an increase in how long they live is very important to people with the condition and their families. The clinical experts acknowledged that an additional treatment option would be beneficial if it offered better tolerability than existing treatments. The committee understood that additional options are beneficial for ALK-positive advanced NSCLC, and concluded that brigatinib would be a useful option if it is better tolerated than existing treatments.\n\n# Treatment pathway and relevant comparators\n\n## Ceritinib is the relevant comparator for this appraisal\n\nNHS England explained that ALK-status testing is now routine clinical practice, so ALK status is known before starting treatment. Therefore, the committee agreed to focus its discussion on people whose ALK status is known before starting treatment. The committee understood that crizotinib, ceritinib and alectinib are options for people with untreated ALK-positive advanced NSCLC. The clinical experts explained that fewer people are starting treatment on crizotinib because of the availability of ceritinib and alectinib. Therefore, the population eligible for brigatinib after crizotinib is small and will decrease as fewer people start treatment with crizotinib. The committee was aware that NICE has recommended ceritinib as a subsequent treatment option when NSCLC progresses with crizotinib. It therefore concluded that ceritinib was the only relevant comparator for brigatinib in people with ALK-positive advanced NSCLC who have had treatment with crizotinib.\n\n# Clinical evidence\n\n## The main evidence for brigatinib is from 2\xa0single-arm studies and is broadly generalisable to UK clinical practice\n\nThere were no studies or clinical trials directly comparing brigatinib with ceritinib. The main clinical evidence for brigatinib came from 2\xa0single-arm studies:\n\nALTA, a phase\xa0II study including 110\xa0people in the study arm and using the dosage in brigatinib's marketing authorisation.\n\nStudy‑101, a phase\xa0I and II study including 25\xa0people in the relevant subgroup.The primary outcome in both studies was investigator-assessed overall response rate, using Response Evaluation Criteria in Solid Tumors (RECIST\xa0v1.1). Secondary outcomes in the studies included progression-free and overall survival, safety and tolerability and duration of response. The median follow-up in ALTA was 24.3\xa0months and median overall survival was 34.1\xa0months. Objective response rate was 56% in ALTA and 76% in study‑101 (investigator-assessed). Median progression-free survival was 16\xa0months in ALTA and study‑101 (investigator-assessed). Median duration of response was 14\xa0months (investigator-assessed) and 16\xa0months (independent review committee-assessed) in ALTA and 26\xa0months in study‑101 (investigator-assessed). The committee heard that 74% of people in ALTA had previously had chemotherapy and 67% had brain metastases before starting the study. There were no data available on sites of progression for those who progressed during the study. The clinical experts confirmed that the ALTA population broadly reflected people with ALK-positive advanced NSCLC in England. The committee acknowledged that, because there was no head-to-head evidence with the relevant comparator ceritinib, an indirect treatment comparison would be the only way to judge the relative effectiveness of brigatinib compared with ceritinib (see section\xa03.6). The committee concluded that, although most people in the studies had had previous chemotherapy, ALTA and study‑101 provided evidence that was generalisable enough to clinical practice for decision making.\n\n## The main evidence for the comparator, ceritinib, comes from ASCEND‑2 and ASCEND‑5\n\nThe main clinical evidence for ceritinib came from 2\xa0studies:\n\nASCEND‑2, a single-arm phase\xa0II study including 140\xa0people.\n\nASCEND‑5, a randomised controlled phase\xa0III trial including 231\xa0people in the ceritinib arm.Only 1\xa0arm of the ASCEND-5 study was used in the analysis. This was because its comparator (chemotherapy) was not in the appraisal scope because ALK-status testing is now routine practice in England. The primary outcome in ASCEND‑5 was independent review committee-assessed progression-free survival, using RECIST\xa0v1.1, and overall survival was included as a secondary outcome. The primary outcome in ASCEND‑2 was investigator-assessed objective response rate, using RECIST\xa0v1.1. Secondary outcomes in ASCEND-2 included overall and progression-free survival. The committee accepted that ASCEND‑2 and ASCEND‑5 were appropriate studies to be considered for the comparator in this appraisal.\n\n## Treatment with an ALK inhibitor may continue after disease progression\n\nIn ALTA, treatment could continue after disease progression if there was clinical benefit, as determined by the trial investigator. The clinical experts said that this reflects clinical practice in England for both brigatinib and ceritinib. They explained that treatment is continued after disease progression because it might control cancer at sites other than the lungs. The ALTA time on treatment and progression-free survival curves did not support that all people would remain on treatment after progressing. But the committee accepted that it was usual practice in the UK to continue treatment after radiological disease progression in some circumstances.\n\n# Indirect comparison of brigatinib and ceritinib\n\n## An indirect comparison is appropriate because there are no head-to-head trials comparing brigatinib with ceritinib\n\nBecause there were no head-to-head trials comparing brigatinib with ceritinib, the company did an unanchored indirect treatment comparison (ITC). Results from 4\xa0studies (see section\xa03.3 and section\xa03.4) were used and the relevant arms treated as though they were single-arm studies. There were 2\xa0approaches taken: a naive ITC and a matching-adjusted indirect comparison (MAIC). The MAIC adjusts for differences in baseline characteristics between study populations whereas naive ITC analyses do not. The company presented several analyses using both approaches. For overall survival these were:\n\nUsing combined data for brigatinib (including ALTA and study‑101) and using separate data for ceritinib (that is, analyses using either ASCEND‑2 or ASCEND‑5).\n\nUsing only ALTA data for brigatinib, and using separate data for ceritinib (that is, analyses using either ASCEND‑2 or ASCEND‑5).Progression-free survival was not reported as an investigator-assessed outcome in ASCEND-5 or as an independent review committee-assessed outcome in study-101. Therefore, the company presented the results using:\n\nCombined data for brigatinib (including ALTA and study-101) and using ASCEND-2 data for ceritinib (investigator-assessed progression-free survival).\n\nOnly ALTA data for brigatinib and using separate data for ceritinib (that is, analyses using either ASCEND-2 or ASCEND-5; independent review committee-assessed progression-free survival).The ERG found the ITC analyses to be broadly appropriate given the available trial data. The ERG agreed with the company that there was broad consistency of the results between the MAIC and naive ITC approaches. The committee concluded that, given the available trial data, the company's approach was appropriate.\n\n# Meta-analysis of the indirect treatment comparison results\n\n## The meta-analyses gave consistent results that are acceptable for decision making\n\nFor overall survival, the company did 2\xa0meta-analyses to provide estimates of clinical effectiveness:\n\nIt compared pooled brigatinib data (from ALTA and study‑101) with ASCEND-2 and ASCEND-5 data (on ceritinib) separately.\n\nIt compared brigatinib data from ALTA only with ASCEND-2 and ASCEND-5 separately.The company's preferred approach was to compare pooled ALTA and study-101 data with ASCEND-2 and ASCEND-5 data separately. For progression-free survival, the analysis only included data from ALTA and meta-analysed the results of the ITC against the data from ASCEND‑2 with ASCEND‑5 separately. This was because data for independent review committee-assessed progression-free survival were not available for study‑101, and data for investigator-assessed progression-free survival were not available from ASCEND‑5. The ERG was concerned that no adjustment was made to account for the brigatinib data being included twice in the meta-analysis. But overall, it was satisfied that consistent results were produced using each analytical strategy to meta-analyse the ITC results. All approaches taken for the meta-analysis showed that brigatinib extended overall and progression-free survival compared with ceritinib, and that the difference between treatments was statistically significant. The committee noted that the results suggested brigatinib improved overall survival by 16\xa0to 19\xa0months and progression-free survival by 9\xa0to 10\xa0months compared with ceritinib. The committee acknowledged that there was uncertainty with single-arm studies and the results should be interpreted with caution. It concluded that the meta-analyses gave consistent results and were acceptable for decision making.\n\n# Clinical evidence in the economic model\n\n## The results from the meta-analysis are broadly appropriate to include in the model\n\nThe company's original submission used the results of the MAIC ITC that included ALTA and study‑101 data for brigatinib and ASCEND‑2 data for ceritinib to estimate the progression-free survival hazard ratio between brigatinib and ceritinib (see section\xa03.6). The hazard ratio was then applied to the brigatinib data to estimate progression-free survival for ceritinib. The committee noted that ASCEND‑5 was a larger trial than study‑101 (110\xa0people compared with 25\xa0in study‑101) and had reported independent review committee-assessed progression-free survival (see section\xa03.4). The ERG highlighted that ASCEND‑5 was a higher quality trial and a more robust data source. At consultation, the company agreed to use the results of the MAIC that excluded study‑101, but for consistency also excluded study-101 for estimating overall survival. The committee agreed that the approach to remove study‑101 from both progression-free and overall survival estimates was appropriate.\n\n# Extrapolating clinical trial data in the economic model\n\n## The company's extrapolation of brigatinib overall survival is appropriate\n\nAt consultation, the company provided an updated model that extrapolated overall survival of brigatinib using the exponential function. This estimated that 29% of people with ALK-positive advanced NSCLC would be alive at 5\xa0years and 2.3% at 10\xa0years. The company explained that this broadly reflected estimates from its clinical advisers. The committee noted the wide range of estimates from the company's advisers. At the appraisal committee meeting, the clinical experts said that it was not possible to accurately estimate the proportion of people with ALK-positive advanced NSCLC who would be alive at specific time points in the future. They explained that overall survival has improved over recent years because of the use of ALK-targeted therapies. The ERG noted that the extrapolation of overall survival was very uncertain because the studies had short follow-ups, making the extrapolation periods relatively long. It highlighted that the conclusions should be treated with caution. The committee noted that the ERG preferred to use the log-logistic distribution to estimate overall survival because it provided a good fit and gave a 10-year survival estimate (4.4% at 10\xa0years) closer to the clinical experts' expectations. The committee concluded that, although there was some uncertainty about the long-term prognosis for this population, both the company's and the ERG's choices of distribution were plausible for modelling overall survival.\n\n## The exponential function is more appropriate for extrapolating progression-free survival\n\nThe company extrapolated progression-free survival in its model using the Gompertz function because it provided a reasonable fit to the data and also had both internal and external validity. The committee noted that the ERG's preference for using the exponential function provided a closer fit to both the brigatinib and ceritinib observed data. The committee agreed that both the Gompertz and the exponential functions gave plausible estimates for progression-free survival but considered that the ERG's approach provided a better fit to the available data.\n\n# Time on treatment data\n\n## Using time on treatment data from the trial is preferred\n\nThe company used progression-free survival plus 1.53\xa0months to estimate time on treatment for both brigatinib and ceritinib. The 1.53\xa0months is the difference between median time on treatment (17.15\xa0months) and median progression-free survival (15.62\xa0months) from ALTA. The ERG was aware that the time on treatment after progression was 3.10\xa0months in ASCEND-2. The clinical experts highlighted that time on treatment after progression could be similar for both brigatinib and ceritinib. They estimated that, in clinical practice, progressed disease could be treated for a further 2\xa0to 3\xa0months (see section\xa03.5). However, the committee was aware that time on treatment data were available from ALTA and concluded that data from the available evidence were preferred.\n\n# Benefit after stopping treatment\n\n## The size and duration of any treatment benefit after treatment is stopped is uncertain in the absence of longer-term data\n\nIn its original submission, the company assumed a continued treatment benefit associated with overall and progression-free survival for brigatinib and ceritinib over the full time horizon of the model. Clinical experts explained that it was reasonable to assume that treatment benefit of brigatinib over ceritinib would continue for a few months after stopping treatment, because brigatinib appears to have a deeper response on brain metastases than ceritinib. However, they noted that there is no trial evidence to support a continued survival benefit after treatment stops in people with radiological progression. This benefit of brigatinib over ceritinib may have been captured already in the progression-free survival estimate. The committee was aware of NICE's technology appraisal guidance on ceritinib after crizotinib in which the clinical experts had noted that treatment benefit was unlikely to persist beyond treatment. The committee agreed that the size and duration of any treatment benefit after stopping treatment in people with symptomatic progression was uncertain in the absence of longer-term data.\n\n## The ERG's approach of directly linking mortality with time on treatment is preferred\n\nIn response to the committee's concerns that lifetime treatment benefit was not clinically plausible, the company updated its economic model. The updated model assumed a full treatment benefit for 161\xa0weeks (3.09\xa0years). This included 148\xa0weeks (based on the maximum follow-up in ALTA) plus 13\xa0weeks of continued treatment benefit (based on clinical inputs estimating this to be 2\xa0to 3\xa0months; see section\xa03.11). After 161\xa0weeks, the brigatinib mortality rate was tapered until week\xa0377 (7.23\xa0years) when only 1% of people remained on treatment. At this point mortality rates for brigatinib and ceritinib were assumed to be the same (hazard ratio of 1). The ERG considered that the company's approach to modelling a loss of treatment effect did not directly link to the length of time on treatment. The ERG also considered that the mortality rate applied for those who were no longer on treatment should be relative to best supportive care rather than to ceritinib. The ERG's updated model adjusted the mortality rates for both brigatinib and ceritinib during the extrapolated period (after week\xa0161) from ALTA, which therefore kept a direct link between the time on treatment and the time at which loss of effect begins. After this period the ERG applied an estimated mortality rate for best supportive care for those who stop treatment with either brigatinib or ceritinib. Although the committee acknowledged that there was uncertainty with both the company's and the ERG's approaches to modelling treatment benefit after stopping treatment because of a lack of longer-term data, the committee preferred to retain a link between time on treatment and the time at which loss of effect begins.\n\n# Health-related quality of life\n\n## The utility value for pre-progressed disease is acceptable\n\nThe company derived the utility value of 0.793 for pre-progressed disease from ALTA. The clinical experts confirmed that this utility value was reasonable. They explained that people with ALK-positive advanced NSCLC are well, even at the end of treatment. The committee concluded that the utility value of 0.793 for pre-progressed disease was appropriate.\n\n## The utility values for people with progressed disease on or off treatment are acceptable\n\nThe company estimated the quality of life associated with progressed disease using published utility values. In the original submission, the company used a utility decrement of 0.15 from Chouaid et al. (2013), giving a utility estimate of 0.643 for progressed disease. The committee accepted the 0.15 utility decrement and the 0.643 utility value for those who have progressed on treatment, but did not consider 0.643 appropriate for progressed disease once patients are no longer taking treatment. This was in line with the clinical experts, who felt that it was unlikely that this value would remain constant throughout progression. The company revised the utility values, creating a separate value for progression on and off treatment. The progressed on-treatment value (0.732) was derived from ALTA, and was for patients who had just progressed (both on and off treatment). The company then applied the utility decrement of 0.15 from Chouaid et al. to the progressed on-treatment value, giving a utility estimate of 0.582 for progressed disease off treatment. The committee concluded that the company's updated utility values were reasonable.\n\n# Resource use and costs\n\n## Drug wastage for brigatinib and ceritinib is adequately captured\n\nThe company's original submission assumed that there was no drug wastage (that is, the NHS would save all costs associated with the reduced dose intensity seen in the studies). A written statement from NHS England confirmed that there was likely to be more drug wastage with ceritinib than brigatinib. The clinical experts explained that dose reduction is common with ceritinib because of toxicity but dose reduction with brigatinib is uncommon. The company revised its submission in response to consultation, to reflect the committee's preference for the ERG's model assumption to use half the difference between the observed and expected dose for each treatment. The committee accepted the company's amendments to the model.\n\n## It is reasonable to include drug administration and delivery costs\n\nThe company included administration costs for both brigatinib and ceritinib in its model (£526 for the first cycle and £217 for subsequent cycles). At the first committee meeting, the Cancer Drugs Fund clinical lead explained that most trusts use a third-party dispenser for oral chemotherapy, which incurs a cost for home delivery. He also suggested that a delivery cost would be applied about 70% of the time. The Cancer Drugs Fund clinical lead also explained that, because brigatinib is a high-cost chemotherapy, the oral chemotherapy administration tariff (£120) should have been used in the company's model and included as a cost per item per cycle. In response to the comments, the company noted that the resource use inputs for dispensing, administration, dose changes and monitoring, as well as administration and dispensing costs for each cycle, were already included in the administration costs used in the model. NHS England confirmed that £217 was more than the current oral administration tariff and it was content that the appropriate costs were contained within the model, as long as they were applied to both treatments. The committee concluded that the administration costs were suitably captured within the model.\n\n# Cost-effectiveness results\n\n## The company's probabilistic base-case ICER comparing brigatinib with ceritinib is above £50,000 per QALY gained\n\nThe committee considered the incremental cost-effectiveness ratios (ICERs) from the company's base case, recalculated by the ERG to include the approved patient access scheme discounts for brigatinib and ceritinib (which are confidential so the ICERs cannot be reported here). The company's base-case probabilistic ICER for brigatinib compared with ceritinib was above £50,000 per quality-adjusted life year (QALY) gained. The committee considered that the company's base case was not appropriate for decision making because of concerns about the uncertainty about continued treatment benefit beyond 3\xa0months used in the model (see section\xa03.12).\n\n## The ERG's preferred assumptions increase the ICER\n\nThe ERG's preferred assumptions about clinical benefit after treatment stopped included:\n\nStarting mortality rate decline from week\xa0161 (similar to the company's approach).\n\nUsing data from the ALTA Kaplan–Meier plot to estimate time on treatment instead of using progression-free survival plus 1.53\xa0months, thereby maintaining a direct link between time on treatment and progression-free survival.\n\nUsing mortality rates for those no longer on treatment with either brigatinib or ceritinib based on best supportive care (applying a hazard ratio of 0.75 between best supportive care and ceritinib).\n\nUsing an exponential distribution for progression-free survival and a log-logistic distribution for overall survival.The committee noted that combining the ERG's preferred assumptions increased the ICERs compared with the company's base case. The ERG's base case with its preferred assumptions gave an ICER for brigatinib compared with ceritinib that was more than £50,000 per QALY gained. The committee noted that the ERG's base case may have underestimated the time on treatment for ceritinib (around 3.7\xa0months compared with a median of 5.5\xa0months in the company model). The ERG explored scenarios that adjusted the hazard ratio for time on treatment for brigatinib compared with ceritinib, some of which gave time on treatment estimates that were more consistent with ASCEND-5. Some of these scenarios decreased the ICER to below £50,000 per QALY gained. The committee agreed with the ERG's general approach and preferred the hazard ratios that gave a median time on treatment for ceritinib of between 6.4\xa0and 7.4\xa0months, which was consistent with ASCEND-5 (which had a median time on treatment of about 7\xa0months in the published results).\n\n## Changes to clinical practice mean that the population eligible for brigatinib after crizotinib is decreasing, with limited future treatment options\n\nThe committee was aware that crizotinib was no longer standard care for ALK-positive NSCLC because most people now start treatment with alectinib. The committee considered that future treatment options for people who start treatment with crizotinib will probably be limited. Also, the committee was aware that the population eligible for brigatinib after crizotinib is small (less than 50\xa0people) and will decrease as fewer people start treatment with crizotinib (see section\xa03.2). Therefore, the committee recognised that there was a need for effective and well tolerated treatments for this small and diminishing group of people who started treatment with crizotinib and who are affected by this change in treatment pathway. The committee concluded that these were exceptional circumstances, which should be taken into consideration in its decision making.\n\n# End of life\n\n## Life expectancy for people with ALK-positive advanced NSCLC is considered to be less than 24\xa0months\n\nThe committee considered advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company considered that the life expectancy of people with ALK-positive advanced NSCLC would be less than 24\xa0months, which meets the first criterion for an end-of-life treatment. Median life expectancy reported in ASCEND-2 was 14.9\xa0months and in ASCEND-5 it was 18.1\xa0months. Mean overall survival was not reported in ASCEND-2 and ASCEND-5. The company's model predicted a mean overall survival of 22\xa0months for people with ALK-positive advanced NSCLC. The committee concluded that the life expectancy of people with ALK-positive advanced NSCLC having ceritinib is less than 24\xa0months.\n\n## Brigatinib extends life by at least 3\xa0months\n\nThe company estimated a mean life extension of 21\xa0months with brigatinib compared with ceritinib, which meets the second criterion for an end-of-life treatment. The committee understood that estimating overall survival for this population was very uncertain (see section\xa03.9). The ERG highlighted that the data used to estimate the extension to life were not robust but extension to life was likely to be at least 3\xa0months. The committee concluded that brigatinib for ALK-positive advanced NSCLC would likely extend life by at least 3\xa0months.\n\n## Brigatinib meets the criteria for end-of-life treatments\n\nThe committee concluded that, although the most plausible estimate of life expectancy for people with previously treated ALK-positive advanced NSCLC was less than 24\xa0months, the potential life extension benefit of brigatinib was proportionally substantial. It was therefore satisfied that brigatinib met the criteria for end-of-life treatments.\n\n# Innovation\n\n## The benefits of brigatinib are adequately captured in the model\n\nThe company considered brigatinib to be innovative because it offers meaningful extension to life and longer progression-free life. The clinical experts explained that brigatinib has a lower toxicity than ceritinib and so is better tolerated. They said that brigatinib treatment is not a step change but is innovative because it is well tolerated. The committee agreed that the benefits of brigatinib over ceritinib in the central nervous system were adequately captured in the analysis through health-related quality of life. It concluded that although brigatinib may be innovative, it had not been presented with any additional evidence of benefits that were not captured in the economic model and resulting cost-effectiveness estimates.\n\n# Conclusion\n\n## Brigatinib after crizotinib is recommended for people with ALK-positive advanced NSCLC\n\nThe committee considered the strengths and weaknesses of the company's and the ERG's base cases, noting the overall uncertainty in the results from both approaches. Having considered the ICERs from both approaches, the committee agreed that the most plausible ICER for brigatinib compared with ceritinib in people with ALK-positive advanced NSCLC was around the higher end of what would normally be considered cost effective for an end-of-life treatment. The committee also considered that the population was small and decreasing over time, with limited future treatment options for people who started treatment with crizotinib. It also considered that brigatinib is a treatment option that could offer benefits in terms of progression-free and overall survival as well as better tolerability than ceritinib. Although the most plausible ICER was around the higher end of what NICE normally considers cost effective for an end-of-life treatment, the committee agreed that there were exceptional circumstances for this population that should be taken into account (see section\xa03.5 and section\xa03.20). Therefore, the committee concluded that brigatinib was recommended for routine use in the NHS for ALK-positive advanced NSCLC after crizotinib."}
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https://www.nice.org.uk/guidance/ta571
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Evidence-based recommendations on brigatinib (Alunbrig) for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer in adults who have already had crizotinib.
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1dc67091b26d1e4cd117ab3027723c5fcf0bff70
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nice
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Radially emitting laser fibre treatment of an anal fistula
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Radially emitting laser fibre treatment of an anal fistula
Evidence-based recommendations on radially emitting laser fibre treatment of an anal fistula in adults. This involves applying laser energy to the fistula.
# Recommendations
Current evidence on the safety and efficacy of radially emitting laser fibre treatment of an anal fistula is limited in quantity and quality. Therefore, although there are no major safety concerns, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do radially emitting laser fibre treatment of an anal fistula should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public on radially emitting laser fibre treatment of an anal fistula is recommended.
Audit and review clinical outcomes of all patients having radially emitting laser fibre treatment of an anal fistula. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
The procedure should only be done by clinicians experienced in cannulating fistulas, and who are trained in the use of lasers.
Further research should report details of patient selection, including fistula size, recurrence rates in the medium and long term, and quality-of-life outcomes.# The condition, current treatments and procedure
# The condition
An anal fistula is an abnormal tract between the anal canal and the skin around the anus. It may cause symptoms such as pain or discomfort in the anal area, and leakage of blood or pus. It usually results from previous anal abscesses (cryptoglandular), and can be associated with other conditions such as inflammatory bowel disease and cancer.
Anal fistulas can be classified according to their relationship with the external sphincter. Intersphincteric fistulas are the most common type and cross only the internal sphincter. Trans-sphincteric fistulas pass through the internal and external sphincter.
# Current treatments
Treatment of anal fistulas commonly involves surgery. The type of surgery depends on the location and complexity of the fistula. For intersphincteric and low trans-sphincteric anal fistulas, the most common treatment is a fistulotomy or laying open of the fistula track. For deeper fistulas that involve more muscle, and for recurrent fistulas, a seton (a piece of suture material or rubber sling) may be used, either alone or with fistulotomy. Setons can be loose (designed to drain the sepsis but not for cure), or snug or tight (designed to cut through the muscles in a slow controlled fashion). Fistulas that cross the external sphincter at a high level are sometimes treated with a mucosal advancement flap or other procedures to close the internal opening. Another less commonly used option for treating anal fistulas is to fill the track with either a plug or paste; for example, 1 type of filler is fibrin glue (a solution of fibrinogen and thrombin).
# The procedure
Radially emitting laser fibre treatment of an anal fistula can be done with the patient under regional or general anaesthesia. With the patient in lithotomy position, the external and internal openings of the fistula tract are identified. The fistula is then catheterised using a probe and cleaned by irrigation. Under ultrasound guidance, a radially emitting laser fibre is advanced from the external to internal orifice, activated and gradually withdrawn at about 1 mm/second. The aim is to cause destruction and sealing of the fistula tract, allowing primary closure. The procedure may be used with techniques that close the internal orifice of the tract such as an advancement flap.
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{'Recommendations': "Current evidence on the safety and efficacy of radially emitting laser fibre treatment of an anal fistula is limited in quantity and quality. Therefore, although there are no major safety concerns, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do radially emitting laser fibre treatment of an anal fistula should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. Provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public on radially emitting laser fibre treatment of an anal fistula is recommended.\n\nAudit and review clinical outcomes of all patients having radially emitting laser fibre treatment of an anal fistula. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nThe procedure should only be done by clinicians experienced in cannulating fistulas, and who are trained in the use of lasers.\n\nFurther research should report details of patient selection, including fistula size, recurrence rates in the medium and long term, and quality-of-life outcomes.", 'The condition, current treatments and procedure': '# The condition\n\nAn anal fistula is an abnormal tract between the anal canal and the skin around the anus. It may cause symptoms such as pain or discomfort in the anal area, and leakage of blood or pus. It usually results from previous anal abscesses (cryptoglandular), and can be associated with other conditions such as inflammatory bowel disease and cancer.\n\nAnal fistulas can be classified according to their relationship with the external sphincter. Intersphincteric fistulas are the most common type and cross only the internal sphincter. Trans-sphincteric fistulas pass through the internal and external sphincter.\n\n# Current treatments\n\nTreatment of anal fistulas commonly involves surgery. The type of surgery depends on the location and complexity of the fistula. For intersphincteric and low trans-sphincteric anal fistulas, the most common treatment is a fistulotomy or laying open of the fistula track. For deeper fistulas that involve more muscle, and for recurrent fistulas, a seton (a piece of suture material or rubber sling) may be used, either alone or with fistulotomy. Setons can be loose (designed to drain the sepsis but not for cure), or snug or tight (designed to cut through the muscles in a slow controlled fashion). Fistulas that cross the external sphincter at a high level are sometimes treated with a mucosal advancement flap or other procedures to close the internal opening. Another less commonly used option for treating anal fistulas is to fill the track with either a plug or paste; for example, 1\xa0type of filler is fibrin glue (a solution of fibrinogen and thrombin).\n\n# The procedure\n\nRadially emitting laser fibre treatment of an anal fistula can be done with the patient under regional or general anaesthesia. With the patient in lithotomy position, the external and internal openings of the fistula tract are identified. The fistula is then catheterised using a probe and cleaned by irrigation. Under ultrasound guidance, a radially emitting laser fibre is advanced from the external to internal orifice, activated and gradually withdrawn at about 1\xa0mm/second. The aim is to cause destruction and sealing of the fistula tract, allowing primary closure. The procedure may be used with techniques that close the internal orifice of the tract such as an advancement flap.'}
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https://www.nice.org.uk/guidance/ipg644
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Evidence-based recommendations on radially emitting laser fibre treatment of an anal fistula in adults. This involves applying laser energy to the fistula.
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6b89a10193c4eac3251fe85ce85e4c734bca6da0
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nice
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Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies
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Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies
Evidence-based recommendations on tisagenlecleucel therapy (Kymriah) for treating relapsed or refractory diffuse large B-cell lymphoma in adults after 2 or more systemic therapies.
# Recommendations
Tisagenlecleucel therapy is recommended for use within the Cancer Drugs Fund as an option for treating relapsed or refractory diffuse large B-cell lymphoma in adults after 2 or more systemic therapies, only if the conditions in the managed access agreement are followed.
This recommendation is not intended to affect both treatment in preparation for and treatment with tisagenlecleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
There is no standard treatment for relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies. Salvage chemotherapy (that is, chemotherapy to control the disease) is the most common treatment option. Tisagenlecleucel is a chimeric antigen receptor (CAR) T‑cell therapy. It contains the patient's own T cells that have been modified to attach to and kill cancer cells.
Evidence from a single-arm study with short follow-up and a small observational study suggests that people having tisagenlecleucel may live for longer, or have more time before their disease relapses. But longer follow-up from the study is needed and there are no data directly comparing tisagenlecleucel with salvage chemotherapy. To assess the comparative effectiveness of tisagenlecleucel and salvage chemotherapy, data from the first CORAL extension study are used. Limitations in the available data mean that the exact size of the benefit of tisagenlecleucel compared with salvage chemotherapy is difficult to establish.
Tisagenlecleucel meets NICE's criteria to be considered a life-extending treatment at the end of life. All the cost-effectiveness estimates for tisagenlecleucel compared with salvage chemotherapy are uncertain because of limitations in the data. Because some of these estimates are higher than what NICE normally considers an acceptable use of NHS resources and are associated with a high degree of uncertainty, tisagenlecleucel cannot be recommended for routine use in the NHS.
Collecting more data on progression-free survival, overall survival and immunoglobulin usage will reduce the uncertainty in the evidence. Therefore, tisagenlecleucel is recommended for use in the Cancer Drugs Fund.# Information about tisagenlecleucel
# Marketing authorisation
Tisagenlecleucel (Kymriah, Novartis) is indicated for the 'treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma after 2 or more lines of systemic therapy'. Tisagenlecleucel is an immunocellular CAR T cell therapy. It contains the patient's own T cells (a type of white blood cell) that have been modified genetically in the laboratory so that they make a protein called chimeric antigen receptor (CAR). CAR can attach to another protein on the surface of cancer cells called CD-19. When tisagenlecleucel is given to the patient, the modified T cells attach to and kill cancer cells, thereby helping to clear the cancer from the body.
# Dosage in the marketing authorisation
Treatment with tisagenlecleucel comprises a single dose intravenous infusion of tisagenlecleucel. It is intended for autologous use only and the dosage for adults with diffuse large B-cell lymphoma is 0.6 to 6.0x108 CAR-positive viable T cells.
# Price
The list price for tisagenlecleucel is £282,000 per infusion (company submission). The company has a commercial arrangement. This makes tisagenlecleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## There is an unmet need for more effective treatment options
Diffuse large B-cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma. Outcomes for people with refractory or relapsed disease are poor. The disease has low levels of response to treatment, and is associated with limited survival. A patient expert explained that in a survey of over 100 people with the disease, the most commonly reported side effects of treatment included fatigue, hair loss, memory loss and joint pain. The clinical experts explained that there is no standard treatment for people with relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies and there are limited curative options. The clinical experts explained that treatment after 2 or more systemic therapies may be offered with palliative intent, but chimeric antigen receptor (CAR) T‑cell therapy offers a potential cure. The committee understood that CAR T‑cell therapies (such as tisagenlecleucel) are advanced therapies for cancers and belong to a new generation of personalised cancer immunotherapies that are based on collecting and modifying patients' own immune cells to treat their cancer. The committee concluded that there is an unmet need in this population and that as a CAR T‑cell therapy, tisagenlecleucel offers a potential new treatment option that may improve the chance of survival.
# Treatment pathway and comparators
## The population in the full marketing authorisation for tisagenlecleucel is appropriate
People with relapsed or refractory disease usually have salvage chemotherapy with or without autologous stem cell transplant as a second treatment. The committee heard that current treatment options after 2 or more systemic therapies include further salvage chemotherapy that may be palliative. The company originally positioned tisagenlecleucel as a potential treatment for diffuse large B-cell lymphoma only in people who cannot have autologous stem cell transplant. The committee understood that this was narrower than the marketing authorisation, which does not specify treatment based on eligibility for autologous stem cell transplant. However, it was aware that the clinical evidence for tisagenlecleucel was limited to patients who could not have autologous stem cell transplant or whose disease had not responded to it (see section 3.4). The clinical experts explained that defining the population who cannot have autologous stem cell transplant using objective clinical criteria is difficult. Moreover, there is a subgroup of older patients who potentially cannot have stem cell transplant but for whom CAR T‑cell therapy may be suitable. The experts also advised that eligibility for stem cell transplant may change over time as response to chemotherapy and fitness to tolerate treatment changes. The committee noted that in its response to consultation, the company included the whole population in the marketing authorisation. The committee concluded that people who cannot have stem cell transplant cannot be easily defined, so its recommendations should cover the full marketing authorisation.
## Salvage chemotherapy excluding pixantrone is the appropriate comparator
The committee was aware that although there is no standard salvage chemotherapy regimen for relapsed or refractory diffuse large B-cell lymphoma, there are a number of salvage chemotherapy regimens that clinicians consider to be equally effective (including gemcitabine with oxaliplatin and gemcitabine, cisplatin and dexamethasone with or without rituximab). The clinical experts also advised that Gem-Ox with or without rituximab is more likely to be used with palliative intent. The committee noted that the company had included pixantrone monotherapy as a comparator for some people in line with NICE's technology appraisal guidance on pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. The clinical experts explained that pixantrone is rarely used in clinical practice, has poor efficacy and should not be considered a comparator for most people in this appraisal population. The committee agreed that tisagenlecleucel would be used as an alternative to salvage chemotherapy (excluding pixantrone), and concluded that salvage chemotherapy was the most appropriate comparator.
# Clinical evidence
## Tisagenlecleucel is clinically effective but immature data and the lack of direct comparative trial data means the size of this benefit is difficult to establish
The clinical evidence for tisagenlecleucel came from a phase II, open-label single-arm study (JULIET) and a small observational study (Schuster 2017). The committee understood that both studies included patients who could not have autologous stem cell transplant or whose disease had not responded to it. The company presented results from 111 patients from JULIET and 14 patients from Schuster (see table 1, below). All patients had a tisagenlecleucel infusion. At the December 2017 data-cut, the median follow-up in JULIET was short and the survival data were immature so there was uncertainty in the robustness of all survival data. The committee noted the plateau in the Kaplan–Meier curves for overall and progression-free survival, but was aware that from month 20 onwards there were very few patients remaining at risk so the tails of the survival curves were highly uncertain. The clinical experts stated that the results were clinically very promising: with current treatments, if relapse occurs, it usually does so in 6 months to 12 months. The committee was aware that Schuster had a longer median follow-up of 28.6 months and provided longer-term data, but only included 14 patients. The committee noted that there was no evidence on the effectiveness of tisagenlecleucel directly compared with that of salvage chemotherapy. At the technical engagement stage and after consultation, the company presented data from JULIET using a more recent data-cut (May 2018); results were similar to the previous data-cut (exact results are confidential and cannot be reported here). The committee concluded that tisagenlecleucel is clinically effective, but immature survival data and the lack of trial data directly comparing tisagenlecleucel with salvage chemotherapy means the size of this benefit is difficult to establish.
Outcome
JULIET (December 2017 data-cut)
Schuster (2017)
Overall response rate
% (41% to 62%)
% (23% to 77%)
Complete response
% (not reported)
% (18% to 71%)
Median overall survival
months (6.6 months to not reached)
months (not reached)
Median progression-free survival
Results are confidential and cannot be reported here
months (0.9 months to not estimable)
## Both tisagenlecleucel studies are generalisable to the population in England
The committee considered whether the tisagenlecleucel studies were relevant to clinical practice in the NHS because they were not done in the UK. It understood that JULIET recruited people with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, which means that their activities are relatively unrestricted by their disease. Also, all patients in JULIET had previously had rituximab. The clinical experts stated that people with relapsed or refractory disease having tisagenlecleucel would need to have good performance status to tolerate the toxicity of the treatment. Both the clinical experts and NHS England's clinical lead for the Cancer Drugs Fund noted that patients in JULIET and Schuster were representative of the patients who would be eligible for tisagenlecleucel in England in the marketing authorisation. The committee concluded that the results from JULIET and Schuster were generalisable to patients in England.
## It is reasonable to use unadjusted pooled survival data from both studies
The company reported unadjusted pooled data from JULIET and Schuster for overall and progression-free survival. The committee understood that median follow-up for overall survival was much longer in Schuster than in JULIET (see section 3.4). It noted that there were some differences between the JULIET and Schuster studies, for example in the regimens used to deplete lymphocytes and the proportion of patients having bridging chemotherapy. It agreed that it was reasonable to pool the survival results given that the baseline data were similar across the 2 studies. The unadjusted pooled results for overall and progression-free survival were similar to those reported in JULIET (exact results are confidential and cannot be reported here). The committee concluded that it was reasonable to use unadjusted pooled survival data from JULIET and Schuster in its decision making.
## Using comparator data from PIX301 or Eyre has serious limitations
The company's preferred comparator data for both pixantrone monotherapy and salvage chemotherapy came from a retrospective observational study of 90 people with relapsed or refractory diffuse large B-cell lymphoma who had pixantrone monotherapy (Eyre 2016). The committee understood that in both JULIET (tisagenlecleucel) and Eyre (pixantrone monotherapy), most people had previous rituximab. However, it noted that pixantrone is rarely used in clinical practice (see section 3.3) and that there were several imbalances in important prognostic factors at baseline in Eyre compared with JULIET. In particular, 54% of patients in Eyre had an ECOG performance status of 2 to 4 whereas JULIET only included patients with ECOG status of 0 or 1. Also, in Eyre a higher proportion of patients had over 2 risk factors from the International Prognostic Index, so patients may not have been well enough for CAR T‑cell therapy. The committee was aware that the ERG used comparator data from a subgroup of PIX301, a randomised, controlled, open-label phase III trial that compared pixantrone monotherapy with the physician's choice of single-agent chemotherapy. It also noted that the comparator arm in PIX301 was limited to single-agent chemotherapy and that the clinical experts said that some patients in the trial would not have been well enough to have CAR T‑cell therapy. The committee concluded that there were serious limitations using either PIX301 or Eyre as a source of comparator data.
## All potential sources of comparator data have limitations but the CORAL extension study is acceptable for decision making
The CORAL trial compared 2 salvage chemotherapy regimens with or without rituximab (ifosfamide, cisplatin/carboplatin and etoposide or cisplatin, cytarabine and dexamethasone ) followed by autologous stem cell transplant in patients aged 18 years to 65 years. The first CORAL extension study comprised 203 patients who did not have stem cell transplant because of treatment failure and the second extension study comprised 75 patients whose disease had relapsed after having stem cell transplant in CORAL. The ERG considered that although there were limited baseline data for the subgroup after 2 systemic treatments (International Prognostic Index 0 or 1, median age 55 years and prior rituximab), these were similar to JULIET and were in line with the full marketing authorisation. The committee noted that the first extension study provided separate survival data for patients having subsequent stem cell transplant and for those who did not have stem cell transplant. The committee also considered SCHOLAR-1, a retrospective study with pooled data from 4 datasets, and understood that it included patients with primary refractory disease and patients with ECOG status of 0 to 4. The committee agreed that the population in SCHOLAR-1 was not representative of the population covered by the marketing authorisation in clinical practice in England. The committee was aware of 2 other possible comparator data sources: a subpopulation of ORCHARRD and the Haematological Malignancy Research Network (HMRN), which were not included in the original analyses from the company or ERG. In response to consultation, the company submitted additional real-world data from patients in the HMRN having fourth- or fifth-line treatment. However, the ERG explained that it is unclear whether the HMRN population would be eligible for tisagenlecleucel because it included people with ECOG performance status 2 to 4 and the baseline characteristics were not available by line of therapy. The committee discussed the HMRN data but considered that tisagenlecleucel was most likely to be used as a third-line treatment if it were available in clinical practice. It recognised that patients having third-line treatment were not included in the company's analyses of the HMRN data, so it did not consider them in its decision making. The committee recognised the limitations of all the potential data sources for the comparator arm (see section 3.7), including the lack of robust long-term data, but agreed that no alternative data were available. It concluded that the first CORAL extension study was acceptable for decision making.
## An unadjusted naive indirect comparison is acceptable but increases uncertainty about how much benefit there is with tisagenlecleucel
At the clarification stage, the company submitted a matched adjusted indirect comparison between JULIET and Eyre that aimed to control for baseline imbalances in important prognostic variables. The company reported a small improvement in overall survival with tisagenlecleucel after adjustment. However, the ERG was concerned that insufficient information had been reported about the matching analysis and the sample size used from JULIET. The committee noted that the results seemed implausible because there was improved survival in a population with worse prognostic factors. It concluded that considering the lack of available data in this disease area, an unadjusted naive indirect comparison of tisagenlecleucel (using data from JULIET and Schuster) compared with salvage chemotherapy (using data from the first CORAL extension study) was most appropriate but increased uncertainty about the size of the benefit with tisagenlecleucel.
## Tisagenlecleucel is associated with frequent adverse events
Results from JULIET showed that all patients having tisagenlecleucel as a CAR T‑cell therapy had an adverse event after treatment. Most patients had severe adverse events (over grade 3). Cytokine release syndrome is a common toxicity of cellular immunotherapy and it affected similar proportions of patients in both Schuster and JULIET. The clinical experts explained that cytokine release syndrome is often mild and can be managed by tocilizumab treatment, close observation and supportive care. The committee was aware that tocilizumab recently received a marketing authorisation for treating cytokine release syndrome. However, severely affected patients need time in intensive care and may have unstable blood pressure and circulation and other organ toxicity. The committee also noted that more patients in Schuster had neurotoxicity than in JULIET. Neurotoxicity may also need intensive care treatment and monitoring. A patient expert explained that although patients may find the potential side effects worrying, they would feel prepared to deal with them. The patient experts also commented that the inconvenience of needing to stay close to hospital for adverse event monitoring was insignificant compared with the possibility of a positive treatment outcome. The commissioning expert from NHS England explained that healthcare professionals would need extensive training in managing and supporting patients who have CAR T‑cell therapies and that NHS England has developed a new service to implement this. The committee concluded that tisagenlecleucel is associated with frequent adverse events and the costs associated with managing and treating those events should be reflected in the cost-effectiveness modelling (see section 3.16).
# Cost effectiveness
## The company's model is acceptable for decision making
The company submitted a partitioned survival model with 3 health states (progression-free, progressed disease and death) that also included a decision tree element for the tisagenlecleucel arm. Progression-free and overall survival estimates were modelled independently, with the proportion of progressed patients at each cycle calculated as the difference between the values for the overall survival and progression-free survival curves. In its revised base case after consultation, the company modelled tisagenlecleucel using data from JULIET and Schuster, and salvage chemotherapy using data from HMRN and the first CORAL extension study. It also included scenarios using CORAL data alone. The committee noted this covered the whole population in the marketing authorisation (see section 3.2). The committee was aware that the ERG reported cost-effectiveness analyses comparing tisagenlecleucel with GDP only because it better reflected treatment after 2 or more systemic therapies in clinical practice. After consultation, the company provided new evidence which compared tisagenlecleucel with GDP only. The committee concluded that the model structure was acceptable for decision making.
# Survival extrapolations
## The company's hybrid survival model with a 1-knot spline extrapolation is appropriate to model overall survival for tisagenlecleucel
In its revised base case after consultation, the company modelled overall survival in the tisagenlecleucel arm using a hybrid model with a 1-knot spline extrapolation and a 3-knot spline extrapolation for progression-free survival. The committee understood that the company's scenario analysis using an alternative Gompertz curve had overestimated survival, and this had a larger effect with cure points after 2 years. It noted the more favourable cost-effectiveness estimates for tisagenlecleucel using the alternative Gompertz extrapolation. The committee accepted the hybrid model with a 1-knot spline, noting that it was easier to validate clinically and allowed clinical experts to specify a time point at which patients were assumed to be cured. The committee concluded that the company's hybrid model with a 1-knot spline extrapolation was appropriate to model overall survival for tisagenlecleucel.
## A cure point between 2 years and 5 years with excess mortality after a cure is plausible but further long-term data are needed
The company's revised base case after consultation assumed that patients alive after 2 years were functionally cured and had mortality rates similar to those of the general population without any excess mortality risk after a cure (that is, general population mortality using a standardised mortality ratio of 1.00 was applied after 2 years). The company also reported scenario analyses with a 3-year cure point. The company chose these cure points based on clinical feedback, evidence from Maurer et al. (2014) and clinical guidelines suggesting that regular monitoring for relapse is stopped after 3 years of remission. The committee agreed that the company's revised base case after consultation was clinically plausible but, in the absence of longer-term data, had concerns that the disease may still relapse after 2 years. It considered 2 years too short to switch to general population mortality: there were limited follow-up data and some studies showed excess mortality that persisted for up to 5 years (Howlader et al. 2017). The committee understood that both Maurer et al. and Howlader et al. reported data based on time since diagnosis and did not specifically include patients having treatment after 2 or more systemic therapies (the relevant population in this appraisal). The clinical experts explained that patients whose disease had not relapsed after 2 years were often considered to be cured and did not usually need further clinical follow-up. Having recalled the uncertainty in the long-term survival data for tisagenlecleucel, the committee considered the ERG's analyses using alternative cure points of 4 years and 5 years and some excess mortality after a cure (that is, a standardised mortality ratio of 1.09 was applied after a cure). It understood that survival outcomes in the ERG's exploratory and preferred analyses were less favourable than those in the company's revised base case. The committee concluded that a cure point between 2 years and 5 years was plausible but the former was optimistic while the latter was pessimistic especially when including excess mortality after 5 years. The committee agreed that collecting further long-term data for tisagenlecleucel was essential to address this uncertainty.
## It is appropriate to model the comparator arm using the first CORAL extension study and assume that 12.5% of people have subsequent stem cell transplant
The committee recalled that the first CORAL extension study was an appropriate data source for the comparator arm (see section 3.8) but understood that the subsequent stem cell transplant rate in the CORAL trial was over 30%. NHS England's clinical lead for the Cancer Drugs Fund explained that in England, rates of subsequent stem cell transplant are around 10% to 15%. The committee noted that the ERG's preferred analyses assumed that 12.5% of patients in the CORAL extension studies had subsequent stem cell transplant after salvage chemotherapy, because this was the mid-point between the ERG's and company's predicted rates. The ERG clarified that the cost-effectiveness modelling only included data from the first CORAL extension study and excluded data from the second extension study of 75 patients with relapse after stem cell transplant. The committee noted it had not seen any analyses that included this potentially relevant data. It concluded that there was uncertainty around the use of stem cell transplant in clinical practice but using data from the first CORAL extension study and assuming that 12.5% of patients have subsequent stem cell transplant was appropriate to model the salvage chemotherapy comparator arm.
## Gompertz distribution is appropriate to model the survival benefit for salvage chemotherapy but other extrapolations are plausible
Both the ERG and company modelled overall and progression-free survival for salvage chemotherapy using a single parametric curve. In its revised base case after consultation, the company used data from CORAL to model overall survival in patients having third-line salvage chemotherapy and data from HMRN to model overall survival in patients having fourth- or fifth-line treatment. However, the committee recalled that the HMRN data used in the company's revised modelling was not relevant (see section 3.8). Using these data substantially lowered the cost-effectiveness estimate for tisagenlecleucel, such that the committee preferred to use comparator data from the first CORAL extension study alone. The ERG used a Gompertz curve to model overall survival in the 2 groups of patients who did or did not have a subsequent stem cell transplant. The ERG then weighted these parametric curves to combine data from all patients in the first CORAL extension study and assumed that 12.5% of patients had a subsequent stem cell transplant. The committee understood that because progression-free survival was not reported in the CORAL extension study, the ERG assumed a proportional relationship between overall and progression-free survival. In its revised base case after consultation, the company used a 2-knot spline model to extrapolate survival in patients who did not have a subsequent stem cell transplant. The company explained this was because the Gompertz curve overestimated survival and produced a survival plateau that would not be expected in patients having treatment with palliative intent only. The committee considered the clinical plausibility of the extrapolated curve and the survival plateau for patients who had not had subsequent stem cell transplants. It noted that when developing NICE's technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma after 2 or more systemic therapies, the committee had accepted an alternative generalised gamma extrapolation after considering external and internal validity. The committee acknowledged that there was a high degree of uncertainty surrounding the overall survival extrapolations for salvage chemotherapy and that the choice of function had important implications for end-of-life considerations (see section 3.18). The committee understood that the company's alternative 2-knot spline extrapolation provided more favourable cost-effectiveness results for tisagenlecleucel but that it was not robustly supported by the goodness-of-fit data. The committee concluded that a single parametric survival model applying a Gompertz curve to overall survival data for patients who did or did not have subsequent stem cell transplant was appropriate to model survival benefit for salvage chemotherapy, but that other extrapolations may also be plausible.
# Resource use and costs
## The ERG's changes to resource use and costs are appropriate
In its base case, the company included resource use and costs based on JULIET. However, the committee noted that in the company's model, only patients with grade 3 or 4 cytokine release syndrome were assumed to be admitted to intensive care. There was also uncertainty around the frequency and duration of B-cell aplasia and how much replacement intravenous immunoglobulin (IVIG) would be used in routine NHS practice. Not all patients in the full analysis set of JULIET would have had a response assessment after subsequent stem cell transplant. Also, the costs of a subsequent stem cell transplant were not discounted in the second year. The committee understood that the ERG's preferred analyses addressed these concerns by including:
a higher rate of admission to intensive care to treat cytokine release syndrome
B-cell aplasia that persists for 3 years
administration of tisagenlecleucel in an inpatient setting only
rates of subsequent stem cell transplant from the efficacy analysis set in JULIET and discounted long-term follow-up costs.The committee understood that the ERG's changes did not have a large effect on the cost-effectiveness results. Nevertheless, the committee concluded that it was appropriate to include these changes in the modelling.
# Health-related quality of life
## The use of progression-free utility values and costs should be consistent with the assumed cure point
The company's model assumed that patients who were still alive after 2 years in either treatment group would have the same health-related quality of life as those in the progression-free health state. The committee recalled that the clinical experts considered patients having current treatment who had not relapsed after 2 years to be cured (see section 3.12). The committee agreed that in the hybrid survival model, the time at which utility values and costs revert to the progression-free health state should be the same as the time at which patients are assumed to be functionally cured to produce clinically plausible results. It also agreed with the ERG's preferred analyses including an age-adjusted utility decrement for patients in the progression-free and progressed health states, but understood that this did not have a large effect on the cost-effectiveness results. The committee concluded that the use of progression-free utility values and costs should be consistent with the assumed cure point.
# End of life
## Tisagenlecleucel meets both criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that tisagenlecleucel met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24 months). The committee noted that the company's revised base case after consultation (including the HMRN data) predicted a mean overall survival for salvage chemotherapy of 20.4 months and a median of 5.0 months. However, it recalled that the fourth- and fifth-line HMRN data were not directly relevant (see section 3.8). The model using the committee's preferred comparator data (from CORAL alone) predicted a mean overall survival for salvage chemotherapy of 43.0 months and a median of around 4.0 months. The committee understood that this included optimistic survival predictions using the Gompertz extrapolation; mean overall survival was less than 24 months using other distributions which may also be plausible. It noted the large difference in the median and mean values and understood that the mean overall survival predicted by the model was driven by the assumption that a small proportion of people having salvage chemotherapy would survive for a long time. The committee considered the proportion of people alive at 2 years using its preferred comparator data and noted this was small (14%). Having considered the median and mean survival data from CORAL, the uncertainty in long-term outcomes and the end-of-life decision in a related appraisal (see NICE's technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma), the committee concluded that tisagenlecleucel met the end-of-life criterion for short life expectancy. The committee noted the short median overall survival follow-up for tisagenlecleucel in JULIET, but understood that both the company's and ERG's modelling suggested that tisagenlecleucel was associated with a gain in overall survival of over 3 months irrespective of the choice of survival modelling and data source for the comparator (exact data are confidential and cannot be reported here). The committee concluded that tisagenlecleucel met both of NICE's criteria to be considered a life-extending treatment at the end of life.
# Cost-effectiveness results
## The ICERs are associated with uncertainty and some are higher than what NICE normally considers an acceptable use of NHS resources
The company's revised base case after consultation showed that the deterministic incremental cost-effectiveness ratio (ICER) was £46,325 per quality-adjusted life year (QALY) gained for tisagenlecleucel compared with GDP (with or without rituximab). All analyses included the patient access scheme for tisagenlecleucel but probabilistic ICERs were not reported. The company's revised base case included most of the committee's preferred assumptions, specifically:
updated survival data from JULIET (see section 3.4)
alternative costs and utility values (see section 3.16)
an age-adjusted utility decrement (see section 3.17)
a 12.5% subsequent stem cell transplant rate in the comparator arm (see section 3.14)
a hybrid survival model using a 1-knot spline to extrapolate overall survival for tisagenlecleucel (see section 3.12)
a 3-knot spline model to extrapolate progression-free survival for tisagenlecleucel (see section 3.12).However, the revised base case did not include the committee's preferred assumptions of a cure point between 2 years and 5 years for tisagenlecleucel with some excess mortality (see section 3.13) and using CORAL data alone to model the comparator arm using the Gompertz curve for patients who did and did not have subsequent stem cell transplant (see section 3.8 and section 3.15). The committee therefore agreed to use the ERG's analyses that included its preferred assumptions; these analyses produced ICERs of £42,991 per QALY gained with a 2-year cure point, £49,963 per QALY gained with a 3-year cure point and £55,403 per QALY gained with a 4-year cure point. The committee was aware that these were based on Gompertz extrapolations, but it recalled that other distributions may also be plausible (see section 3.15). Based on the available evidence, the committee concluded that the ICER (with the discount agreed in the commercial arrangement) ranged between £42,991 and £55,403 per QALY gained. The committee concluded that the ICER range on which it was basing its decision was associated with uncertainty which needed to be accounted for when making its judgement about the acceptability of tisagenlecleucel as an effective use of NHS resources. Considering the risk to the NHS of paying for a treatment that was not cost effective, the committee concluded tisagenlecleucel could not be recommended for routine use in the NHS.
# Innovation
## Tisagenlecleucel is innovative but there are no benefits not captured in the analysis
The committee considered tisagenlecleucel to be innovative because it represents a step change in the treatment of relapsed or refractory diffuse large B-cell lymphoma. It noted that tisagenlecleucel had been designated as a priority medicine (PRIME) by the European Medicines Agency. The company did not present any evidence to suggest that there were additional benefits that were not captured in the QALY calculations. The committee concluded that there were no benefits not captured in the analysis.
# Cancer Drugs Fund
## Further data collection could address uncertainties in the clinical- and cost-effectiveness evidence
Having concluded that tisagenlecleucel was not recommended for routine use, the committee then considered if it could be recommended for use within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE technology appraisal methods guide. The committee recognised that tisagenlecleucel is innovative and therefore considered whether the clinical uncertainty associated with its use could be addressed through collecting more data. The committee was aware that more data from JULIET are expected and agreed that:
Further data from the JULIET trial on progression-free, post-progression and overall survival up to 5 years would be a valuable addition to the clinical evidence base and would likely resolve uncertainties around longer-term relapse rates and survival.
With further evidence, it may be possible to gain a more complete understanding of the costs of IVIG treatment for B-cell aplasia.
Using tisagenlecleucel in the NHS would allow data to be collected using the Systemic Anti-Cancer Therapy (SACT) dataset which would more accurately reflect the costs and benefits of its use in clinical practice. Specifically it may be possible to gain a more complete understanding of the costs of IVIG treatment for B-cell aplasia.
## Tisagenlecleucel meets the criteria to be included in the Cancer Drugs Fund
Data from JULIET showed that people having tisagenlecleucel may have good response rates, overall survival and progression-free survival (see table 1). The committee acknowledged that the published evidence for comparator treatments was limited but that the first extension study from CORAL was suitable for decision making (see section 3.8). It noted that the company's revised base-case ICER for tisagenlecleucel compared with salvage chemotherapy was below £50,000 per QALY gained, but recognised that using its preferred assumptions the most plausible ICER ranged between £42,991 and £55,403 per QALY gained. The committee acknowledged that all the ICERs for tisagenlecleucel compared with salvage chemotherapy were uncertain, but concluded that tisagenlecleucel had the plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced. The committee recognised that more long-term survival data for tisagenlecleucel and further data on post-progression survival would allow for a more robust cost-effectiveness estimate and could address some of the uncertainty around the most plausible cure point. Data on the use of IVIG in NHS practice should also be collected. The committee agreed that tisagenlecleucel met the criteria to be included in the Cancer Drugs Fund for treating relapsed or refractory diffuse large B-cell lymphoma in adults after 2 or more systemic therapies.
# Equality considerations
## There are no equality issues relevant to the recommendations
The company highlighted that diffuse large B-cell lymphoma is more common in men and older people because of the epidemiology of the disease. The committee noted that the first CORAL extension study excluded patients aged over 65 years and agreed there was a lack of data for this age group. The clinical experts also noted that there may be issues related to accessing tisagenlecleucel, because it is only available at specialist centres. However, because the recommendations for tisagenlecleucel apply to the whole population in the marketing authorisation, the committee agreed that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. The commissioning expert from NHS England confirmed that national multidisciplinary teams would be established to ensure equality of referral and treatment access. The committee concluded that there were no relevant equality issues.
|
{'Recommendations': "Tisagenlecleucel therapy is recommended for use within the Cancer Drugs Fund as an option for treating relapsed or refractory diffuse large B-cell lymphoma in adults after 2 or more systemic therapies, only if the conditions in the managed access agreement are followed.\n\nThis recommendation is not intended to affect both treatment in preparation for and treatment with tisagenlecleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere is no standard treatment for relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies. Salvage chemotherapy (that is, chemotherapy to control the disease) is the most common treatment option. Tisagenlecleucel is a chimeric antigen receptor (CAR)\xa0T‑cell therapy. It contains the patient's own T cells that have been modified to attach to and kill cancer cells.\n\nEvidence from a single-arm study with short follow-up and a small observational study suggests that people having tisagenlecleucel may live for longer, or have more time before their disease relapses. But longer follow-up from the study is needed and there are no data directly comparing tisagenlecleucel with salvage chemotherapy. To assess the comparative effectiveness of tisagenlecleucel and salvage chemotherapy, data from the first CORAL extension study are used. Limitations in the available data mean that the exact size of the benefit of tisagenlecleucel compared with salvage chemotherapy is difficult to establish.\n\nTisagenlecleucel meets NICE's criteria to be considered a life-extending treatment at the end of life. All the cost-effectiveness estimates for tisagenlecleucel compared with salvage chemotherapy are uncertain because of limitations in the data. Because some of these estimates are higher than what NICE normally considers an acceptable use of NHS resources and are associated with a high degree of uncertainty, tisagenlecleucel cannot be recommended for routine use in the NHS.\n\nCollecting more data on progression-free survival, overall survival and immunoglobulin usage will reduce the uncertainty in the evidence. Therefore, tisagenlecleucel is recommended for use in the Cancer Drugs Fund.", 'Information about tisagenlecleucel': "# Marketing authorisation\n\nTisagenlecleucel (Kymriah, Novartis) is indicated for the 'treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma after 2 or more lines of systemic therapy'. Tisagenlecleucel is an immunocellular CAR T cell therapy. It contains the patient's own T cells (a type of white blood cell) that have been modified genetically in the laboratory so that they make a protein called chimeric antigen receptor (CAR). CAR can attach to another protein on the surface of cancer cells called CD-19. When tisagenlecleucel is given to the patient, the modified T cells attach to and kill cancer cells, thereby helping to clear the cancer from the body.\n\n# Dosage in the marketing authorisation\n\nTreatment with tisagenlecleucel comprises a single dose intravenous infusion of tisagenlecleucel. It is intended for autologous use only and the dosage for adults with diffuse large B-cell lymphoma is 0.6 to 6.0x108 CAR-positive viable T cells.\n\n# Price\n\nThe list price for tisagenlecleucel is £282,000 per infusion (company submission). The company has a commercial arrangement. This makes tisagenlecleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## There is an unmet need for more effective treatment options\n\nDiffuse large B-cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma. Outcomes for people with refractory or relapsed disease are poor. The disease has low levels of response to treatment, and is associated with limited survival. A patient expert explained that in a survey of over 100 people with the disease, the most commonly reported side effects of treatment included fatigue, hair loss, memory loss and joint pain. The clinical experts explained that there is no standard treatment for people with relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies and there are limited curative options. The clinical experts explained that treatment after 2 or more systemic therapies may be offered with palliative intent, but chimeric antigen receptor (CAR)\xa0T‑cell therapy offers a potential cure. The committee understood that CAR\xa0T‑cell therapies (such as tisagenlecleucel) are advanced therapies for cancers and belong to a new generation of personalised cancer immunotherapies that are based on collecting and modifying patients' own immune cells to treat their cancer. The committee concluded that there is an unmet need in this population and that as a CAR\xa0T‑cell therapy, tisagenlecleucel offers a potential new treatment option that may improve the chance of survival.\n\n# Treatment pathway and comparators\n\n## The population in the full marketing authorisation for tisagenlecleucel is appropriate\n\nPeople with relapsed or refractory disease usually have salvage chemotherapy with or without autologous stem cell transplant as a second treatment. The committee heard that current treatment options after 2 or more systemic therapies include further salvage chemotherapy that may be palliative. The company originally positioned tisagenlecleucel as a potential treatment for diffuse large B-cell lymphoma only in people who cannot have autologous stem cell transplant. The committee understood that this was narrower than the marketing authorisation, which does not specify treatment based on eligibility for autologous stem cell transplant. However, it was aware that the clinical evidence for tisagenlecleucel was limited to patients who could not have autologous stem cell transplant or whose disease had not responded to it (see section\xa03.4). The clinical experts explained that defining the population who cannot have autologous stem cell transplant using objective clinical criteria is difficult. Moreover, there is a subgroup of older patients who potentially cannot have stem cell transplant but for whom CAR\xa0T‑cell therapy may be suitable. The experts also advised that eligibility for stem cell transplant may change over time as response to chemotherapy and fitness to tolerate treatment changes. The committee noted that in its response to consultation, the company included the whole population in the marketing authorisation. The committee concluded that people who cannot have stem cell transplant cannot be easily defined, so its recommendations should cover the full marketing authorisation.\n\n## Salvage chemotherapy excluding pixantrone is the appropriate comparator\n\nThe committee was aware that although there is no standard salvage chemotherapy regimen for relapsed or refractory diffuse large B-cell lymphoma, there are a number of salvage chemotherapy regimens that clinicians consider to be equally effective (including gemcitabine with oxaliplatin [Gem-Ox] and gemcitabine, cisplatin and dexamethasone [GDP] with or without rituximab). The clinical experts also advised that Gem-Ox with or without rituximab is more likely to be used with palliative intent. The committee noted that the company had included pixantrone monotherapy as a comparator for some people in line with NICE's technology appraisal guidance on pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. The clinical experts explained that pixantrone is rarely used in clinical practice, has poor efficacy and should not be considered a comparator for most people in this appraisal population. The committee agreed that tisagenlecleucel would be used as an alternative to salvage chemotherapy (excluding pixantrone), and concluded that salvage chemotherapy was the most appropriate comparator.\n\n# Clinical evidence\n\n## Tisagenlecleucel is clinically effective but immature data and the lack of direct comparative trial data means the size of this benefit is difficult to establish\n\nThe clinical evidence for tisagenlecleucel came from a phase II, open-label single-arm study (JULIET) and a small observational study (Schuster 2017). The committee understood that both studies included patients who could not have autologous stem cell transplant or whose disease had not responded to it. The company presented results from 111 patients from JULIET and 14 patients from Schuster (see table\xa01, below). All patients had a tisagenlecleucel infusion. At the December 2017 data-cut, the median follow-up in JULIET was short and the survival data were immature so there was uncertainty in the robustness of all survival data. The committee noted the plateau in the Kaplan–Meier curves for overall and progression-free survival, but was aware that from month 20 onwards there were very few patients remaining at risk so the tails of the survival curves were highly uncertain. The clinical experts stated that the results were clinically very promising: with current treatments, if relapse occurs, it usually does so in 6\xa0months to 12\xa0months. The committee was aware that Schuster had a longer median follow-up of 28.6\xa0months and provided longer-term data, but only included 14 patients. The committee noted that there was no evidence on the effectiveness of tisagenlecleucel directly compared with that of salvage chemotherapy. At the technical engagement stage and after consultation, the company presented data from JULIET using a more recent data-cut (May 2018); results were similar to the previous data-cut (exact results are confidential and cannot be reported here). The committee concluded that tisagenlecleucel is clinically effective, but immature survival data and the lack of trial data directly comparing tisagenlecleucel with salvage chemotherapy means the size of this benefit is difficult to establish.\n\nOutcome\n\nJULIET (December 2017 data-cut)\n\nSchuster (2017)\n\nOverall response rate\n\n% (41% to 62%)\n\n% (23% to 77%)\n\nComplete response\n\n% (not reported)\n\n% (18% to 71%)\n\nMedian overall survival\n\nmonths (6.6 months to not reached)\n\nmonths (not reached)\n\nMedian progression-free survival\n\nResults are confidential and cannot be reported here\n\nmonths (0.9 months to not estimable)\n\n## Both tisagenlecleucel studies are generalisable to the population in England\n\nThe committee considered whether the tisagenlecleucel studies were relevant to clinical practice in the NHS because they were not done in the UK. It understood that JULIET recruited people with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, which means that their activities are relatively unrestricted by their disease. Also, all patients in JULIET had previously had rituximab. The clinical experts stated that people with relapsed or refractory disease having tisagenlecleucel would need to have good performance status to tolerate the toxicity of the treatment. Both the clinical experts and NHS England's clinical lead for the Cancer Drugs Fund noted that patients in JULIET and Schuster were representative of the patients who would be eligible for tisagenlecleucel in England in the marketing authorisation. The committee concluded that the results from JULIET and Schuster were generalisable to patients in England.\n\n## It is reasonable to use unadjusted pooled survival data from both studies\n\nThe company reported unadjusted pooled data from JULIET and Schuster for overall and progression-free survival. The committee understood that median follow-up for overall survival was much longer in Schuster than in JULIET (see section 3.4). It noted that there were some differences between the JULIET and Schuster studies, for example in the regimens used to deplete lymphocytes and the proportion of patients having bridging chemotherapy. It agreed that it was reasonable to pool the survival results given that the baseline data were similar across the 2\xa0studies. The unadjusted pooled results for overall and progression-free survival were similar to those reported in JULIET (exact results are confidential and cannot be reported here). The committee concluded that it was reasonable to use unadjusted pooled survival data from JULIET and Schuster in its decision making.\n\n## Using comparator data from PIX301 or Eyre has serious limitations\n\nThe company's preferred comparator data for both pixantrone monotherapy and salvage chemotherapy came from a retrospective observational study of 90 people with relapsed or refractory diffuse large B-cell lymphoma who had pixantrone monotherapy (Eyre 2016). The committee understood that in both JULIET (tisagenlecleucel) and Eyre (pixantrone monotherapy), most people had previous rituximab. However, it noted that pixantrone is rarely used in clinical practice (see section 3.3) and that there were several imbalances in important prognostic factors at baseline in Eyre compared with JULIET. In particular, 54% of patients in Eyre had an ECOG performance status of 2 to 4 whereas JULIET only included patients with ECOG status of 0 or 1. Also, in Eyre a higher proportion of patients had over 2 risk factors from the International Prognostic Index, so patients may not have been well enough for CAR\xa0T‑cell therapy. The committee was aware that the ERG used comparator data from a subgroup of PIX301, a randomised, controlled, open-label phase III trial that compared pixantrone monotherapy with the physician's choice of single-agent chemotherapy. It also noted that the comparator arm in PIX301 was limited to single-agent chemotherapy and that the clinical experts said that some patients in the trial would not have been well enough to have CAR\xa0T‑cell therapy. The committee concluded that there were serious limitations using either PIX301 or Eyre as a source of comparator data.\n\n## All potential sources of comparator data have limitations but the CORAL extension study is acceptable for decision making\n\nThe CORAL trial compared 2 salvage chemotherapy regimens with or without rituximab (ifosfamide, cisplatin/carboplatin and etoposide [ICE] or cisplatin, cytarabine and dexamethasone [DHAP]) followed by autologous stem cell transplant in patients aged 18\xa0years to 65\xa0years. The first CORAL extension study comprised 203 patients who did not have stem cell transplant because of treatment failure and the second extension study comprised 75 patients whose disease had relapsed after having stem cell transplant in CORAL. The ERG considered that although there were limited baseline data for the subgroup after 2 systemic treatments (International Prognostic Index 0\xa0or\xa01, median age 55\xa0years and prior rituximab), these were similar to JULIET and were in line with the full marketing authorisation. The committee noted that the first extension study provided separate survival data for patients having subsequent stem cell transplant and for those who did not have stem cell transplant. The committee also considered SCHOLAR-1, a retrospective study with pooled data from 4 datasets, and understood that it included patients with primary refractory disease and patients with ECOG status of 0 to 4. The committee agreed that the population in SCHOLAR-1 was not representative of the population covered by the marketing authorisation in clinical practice in England. The committee was aware of 2 other possible comparator data sources: a subpopulation of ORCHARRD and the Haematological Malignancy Research Network (HMRN), which were not included in the original analyses from the company or ERG. In response to consultation, the company submitted additional real-world data from patients in the HMRN having fourth- or fifth-line treatment. However, the ERG explained that it is unclear whether the HMRN population would be eligible for tisagenlecleucel because it included people with ECOG performance status 2 to 4 and the baseline characteristics were not available by line of therapy. The committee discussed the HMRN data but considered that tisagenlecleucel was most likely to be used as a third-line treatment if it were available in clinical practice. It recognised that patients having third-line treatment were not included in the company's analyses of the HMRN data, so it did not consider them in its decision making. The committee recognised the limitations of all the potential data sources for the comparator arm (see section 3.7), including the lack of robust long-term data, but agreed that no alternative data were available. It concluded that the first CORAL extension study was acceptable for decision making.\n\n## An unadjusted naive indirect comparison is acceptable but increases uncertainty about how much benefit there is with tisagenlecleucel\n\nAt the clarification stage, the company submitted a matched adjusted indirect comparison between JULIET and Eyre that aimed to control for baseline imbalances in important prognostic variables. The company reported a small improvement in overall survival with tisagenlecleucel after adjustment. However, the ERG was concerned that insufficient information had been reported about the matching analysis and the sample size used from JULIET. The committee noted that the results seemed implausible because there was improved survival in a population with worse prognostic factors. It concluded that considering the lack of available data in this disease area, an unadjusted naive indirect comparison of tisagenlecleucel (using data from JULIET and Schuster) compared with salvage chemotherapy (using data from the first CORAL extension study) was most appropriate but increased uncertainty about the size of the benefit with tisagenlecleucel.\n\n## Tisagenlecleucel is associated with frequent adverse events\n\nResults from JULIET showed that all patients having tisagenlecleucel as a CAR\xa0T‑cell therapy had an adverse event after treatment. Most patients had severe adverse events (over grade 3). Cytokine release syndrome is a common toxicity of cellular immunotherapy and it affected similar proportions of patients in both Schuster and JULIET. The clinical experts explained that cytokine release syndrome is often mild and can be managed by tocilizumab treatment, close observation and supportive care. The committee was aware that tocilizumab recently received a marketing authorisation for treating cytokine release syndrome. However, severely affected patients need time in intensive care and may have unstable blood pressure and circulation and other organ toxicity. The committee also noted that more patients in Schuster had neurotoxicity than in JULIET. Neurotoxicity may also need intensive care treatment and monitoring. A patient expert explained that although patients may find the potential side effects worrying, they would feel prepared to deal with them. The patient experts also commented that the inconvenience of needing to stay close to hospital for adverse event monitoring was insignificant compared with the possibility of a positive treatment outcome. The commissioning expert from NHS England explained that healthcare professionals would need extensive training in managing and supporting patients who have CAR\xa0T‑cell therapies and that NHS England has developed a new service to implement this. The committee concluded that tisagenlecleucel is associated with frequent adverse events and the costs associated with managing and treating those events should be reflected in the cost-effectiveness modelling (see section 3.16).\n\n# Cost effectiveness\n\n## The company's model is acceptable for decision making\n\nThe company submitted a partitioned survival model with 3 health states (progression-free, progressed disease and death) that also included a decision tree element for the tisagenlecleucel arm. Progression-free and overall survival estimates were modelled independently, with the proportion of progressed patients at each cycle calculated as the difference between the values for the overall survival and progression-free survival curves. In its revised base case after consultation, the company modelled tisagenlecleucel using data from JULIET and Schuster, and salvage chemotherapy using data from HMRN and the first CORAL extension study. It also included scenarios using CORAL data alone. The committee noted this covered the whole population in the marketing authorisation (see section 3.2). The committee was aware that the ERG reported cost-effectiveness analyses comparing tisagenlecleucel with GDP only because it better reflected treatment after 2 or more systemic therapies in clinical practice. After consultation, the company provided new evidence which compared tisagenlecleucel with GDP only. The committee concluded that the model structure was acceptable for decision making.\n\n# Survival extrapolations\n\n## The company's hybrid survival model with a 1-knot spline extrapolation is appropriate to model overall survival for tisagenlecleucel\n\nIn its revised base case after consultation, the company modelled overall survival in the tisagenlecleucel arm using a hybrid model with a 1-knot spline extrapolation and a 3-knot spline extrapolation for progression-free survival. The committee understood that the company's scenario analysis using an alternative Gompertz curve had overestimated survival, and this had a larger effect with cure points after 2\xa0years. It noted the more favourable cost-effectiveness estimates for tisagenlecleucel using the alternative Gompertz extrapolation. The committee accepted the hybrid model with a 1-knot spline, noting that it was easier to validate clinically and allowed clinical experts to specify a time point at which patients were assumed to be cured. The committee concluded that the company's hybrid model with a 1-knot spline extrapolation was appropriate to model overall survival for tisagenlecleucel.\n\n## A cure point between 2\xa0years and 5\xa0years with excess mortality after a cure is plausible but further long-term data are needed\n\nThe company's revised base case after consultation assumed that patients alive after 2\xa0years were functionally cured and had mortality rates similar to those of the general population without any excess mortality risk after a cure (that is, general population mortality using a standardised mortality ratio of 1.00 was applied after 2\xa0years). The company also reported scenario analyses with a 3-year cure point. The company chose these cure points based on clinical feedback, evidence from Maurer\xa0et\xa0al. (2014) and clinical guidelines suggesting that regular monitoring for relapse is stopped after 3\xa0years of remission. The committee agreed that the company's revised base case after consultation was clinically plausible but, in the absence of longer-term data, had concerns that the disease may still relapse after 2\xa0years. It considered 2\xa0years too short to switch to general population mortality: there were limited follow-up data and some studies showed excess mortality that persisted for up to 5\xa0years (Howlader\xa0et\xa0al. 2017). The committee understood that both Maurer\xa0et\xa0al. and Howlader\xa0et\xa0al. reported data based on time since diagnosis and did not specifically include patients having treatment after 2\xa0or more systemic therapies (the relevant population in this appraisal). The clinical experts explained that patients whose disease had not relapsed after 2\xa0years were often considered to be cured and did not usually need further clinical follow-up. Having recalled the uncertainty in the long-term survival data for tisagenlecleucel, the committee considered the ERG's analyses using alternative cure points of 4\xa0years and 5\xa0years and some excess mortality after a cure (that is, a standardised mortality ratio of 1.09 was applied after a cure). It understood that survival outcomes in the ERG's exploratory and preferred analyses were less favourable than those in the company's revised base case. The committee concluded that a cure point between 2\xa0years and 5\xa0years was plausible but the former was optimistic while the latter was pessimistic especially when including excess mortality after 5\xa0years. The committee agreed that collecting further long-term data for tisagenlecleucel was essential to address this uncertainty.\n\n## It is appropriate to model the comparator arm using the first CORAL extension study and assume that 12.5% of people have subsequent stem cell transplant\n\nThe committee recalled that the first CORAL extension study was an appropriate data source for the comparator arm (see section 3.8) but understood that the subsequent stem cell transplant rate in the CORAL trial was over 30%. NHS England's clinical lead for the Cancer Drugs Fund explained that in England, rates of subsequent stem cell transplant are around 10% to 15%. The committee noted that the ERG's preferred analyses assumed that 12.5% of patients in the CORAL extension studies had subsequent stem cell transplant after salvage chemotherapy, because this was the mid-point between the ERG's and company's predicted rates. The ERG clarified that the cost-effectiveness modelling only included data from the first CORAL extension study and excluded data from the second extension study of 75 patients with relapse after stem cell transplant. The committee noted it had not seen any analyses that included this potentially relevant data. It concluded that there was uncertainty around the use of stem cell transplant in clinical practice but using data from the first CORAL extension study and assuming that 12.5% of patients have subsequent stem cell transplant was appropriate to model the salvage chemotherapy comparator arm.\n\n## Gompertz distribution is appropriate to model the survival benefit for salvage chemotherapy but other extrapolations are plausible\n\nBoth the ERG and company modelled overall and progression-free survival for salvage chemotherapy using a single parametric curve. In its revised base case after consultation, the company used data from CORAL to model overall survival in patients having third-line salvage chemotherapy and data from HMRN to model overall survival in patients having fourth- or fifth-line treatment. However, the committee recalled that the HMRN data used in the company's revised modelling was not relevant (see section 3.8). Using these data substantially lowered the cost-effectiveness estimate for tisagenlecleucel, such that the committee preferred to use comparator data from the first CORAL extension study alone. The ERG used a Gompertz curve to model overall survival in the 2 groups of patients who did or did not have a subsequent stem cell transplant. The ERG then weighted these parametric curves to combine data from all patients in the first CORAL extension study and assumed that 12.5% of patients had a subsequent stem cell transplant. The committee understood that because progression-free survival was not reported in the CORAL extension study, the ERG assumed a proportional relationship between overall and progression-free survival. In its revised base case after consultation, the company used a 2-knot spline model to extrapolate survival in patients who did not have a subsequent stem cell transplant. The company explained this was because the Gompertz curve overestimated survival and produced a survival plateau that would not be expected in patients having treatment with palliative intent only. The committee considered the clinical plausibility of the extrapolated curve and the survival plateau for patients who had not had subsequent stem cell transplants. It noted that when developing NICE's technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma after 2 or more systemic therapies, the committee had accepted an alternative generalised gamma extrapolation after considering external and internal validity. The committee acknowledged that there was a high degree of uncertainty surrounding the overall survival extrapolations for salvage chemotherapy and that the choice of function had important implications for end-of-life considerations (see section 3.18). The committee understood that the company's alternative 2-knot spline extrapolation provided more favourable cost-effectiveness results for tisagenlecleucel but that it was not robustly supported by the goodness-of-fit data. The committee concluded that a single parametric survival model applying a Gompertz curve to overall survival data for patients who did or did not have subsequent stem cell transplant was appropriate to model survival benefit for salvage chemotherapy, but that other extrapolations may also be plausible.\n\n# Resource use and costs\n\n## The ERG's changes to resource use and costs are appropriate\n\nIn its base case, the company included resource use and costs based on JULIET. However, the committee noted that in the company's model, only patients with grade 3 or 4 cytokine release syndrome were assumed to be admitted to intensive care. There was also uncertainty around the frequency and duration of B-cell aplasia and how much replacement intravenous immunoglobulin (IVIG) would be used in routine NHS practice. Not all patients in the full analysis set of JULIET would have had a response assessment after subsequent stem cell transplant. Also, the costs of a subsequent stem cell transplant were not discounted in the second year. The committee understood that the ERG's preferred analyses addressed these concerns by including:\n\na higher rate of admission to intensive care to treat cytokine release syndrome\n\nB-cell aplasia that persists for 3\xa0years\n\nadministration of tisagenlecleucel in an inpatient setting only\n\nrates of subsequent stem cell transplant from the efficacy analysis set in JULIET and discounted long-term follow-up costs.The committee understood that the ERG's changes did not have a large effect on the cost-effectiveness results. Nevertheless, the committee concluded that it was appropriate to include these changes in the modelling.\n\n# Health-related quality of life\n\n## The use of progression-free utility values and costs should be consistent with the assumed cure point\n\nThe company's model assumed that patients who were still alive after 2\xa0years in either treatment group would have the same health-related quality of life as those in the progression-free health state. The committee recalled that the clinical experts considered patients having current treatment who had not relapsed after 2\xa0years to be cured (see section\xa03.12). The committee agreed that in the hybrid survival model, the time at which utility values and costs revert to the progression-free health state should be the same as the time at which patients are assumed to be functionally cured to produce clinically plausible results. It also agreed with the ERG's preferred analyses including an age-adjusted utility decrement for patients in the progression-free and progressed health states, but understood that this did not have a large effect on the cost-effectiveness results. The committee concluded that the use of progression-free utility values and costs should be consistent with the assumed cure point.\n\n# End of life\n\n## Tisagenlecleucel meets both criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that tisagenlecleucel met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24\xa0months). The committee noted that the company's revised base case after consultation (including the HMRN data) predicted a mean overall survival for salvage chemotherapy of 20.4\xa0months and a median of 5.0\xa0months. However, it recalled that the fourth- and fifth-line HMRN data were not directly relevant (see section 3.8). The model using the committee's preferred comparator data (from CORAL alone) predicted a mean overall survival for salvage chemotherapy of 43.0\xa0months and a median of around 4.0\xa0months. The committee understood that this included optimistic survival predictions using the Gompertz extrapolation; mean overall survival was less than 24\xa0months using other distributions which may also be plausible. It noted the large difference in the median and mean values and understood that the mean overall survival predicted by the model was driven by the assumption that a small proportion of people having salvage chemotherapy would survive for a long time. The committee considered the proportion of people alive at 2\xa0years using its preferred comparator data and noted this was small (14%). Having considered the median and mean survival data from CORAL, the uncertainty in long-term outcomes and the end-of-life decision in a related appraisal (see NICE's technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma), the committee concluded that tisagenlecleucel met the end-of-life criterion for short life expectancy. The committee noted the short median overall survival follow-up for tisagenlecleucel in JULIET, but understood that both the company's and ERG's modelling suggested that tisagenlecleucel was associated with a gain in overall survival of over 3\xa0months irrespective of the choice of survival modelling and data source for the comparator (exact data are confidential and cannot be reported here). The committee concluded that tisagenlecleucel met both of NICE's criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness results\n\n## The ICERs are associated with uncertainty and some are higher than what NICE normally considers an acceptable use of NHS resources\n\nThe company's revised base case after consultation showed that the deterministic incremental cost-effectiveness ratio (ICER) was £46,325 per quality-adjusted life year (QALY) gained for tisagenlecleucel compared with GDP (with or without rituximab). All analyses included the patient access scheme for tisagenlecleucel but probabilistic ICERs were not reported. The company's revised base case included most of the committee's preferred assumptions, specifically:\n\nupdated survival data from JULIET (see section 3.4)\n\nalternative costs and utility values (see section 3.16)\n\nan age-adjusted utility decrement (see section 3.17)\n\na 12.5% subsequent stem cell transplant rate in the comparator arm (see section 3.14)\n\na hybrid survival model using a 1-knot spline to extrapolate overall survival for tisagenlecleucel (see section 3.12)\n\na 3-knot spline model to extrapolate progression-free survival for tisagenlecleucel (see section 3.12).However, the revised base case did not include the committee's preferred assumptions of a cure point between 2\xa0years and 5\xa0years for tisagenlecleucel with some excess mortality (see section 3.13) and using CORAL data alone to model the comparator arm using the Gompertz curve for patients who did and did not have subsequent stem cell transplant (see section 3.8 and section 3.15). The committee therefore agreed to use the ERG's analyses that included its preferred assumptions; these analyses produced ICERs of £42,991 per QALY gained with a 2-year cure point, £49,963 per QALY gained with a 3-year cure point and £55,403 per QALY gained with a 4-year cure point. The committee was aware that these were based on Gompertz extrapolations, but it recalled that other distributions may also be plausible (see section 3.15). Based on the available evidence, the committee concluded that the ICER (with the discount agreed in the commercial arrangement) ranged between £42,991 and £55,403 per QALY gained. The committee concluded that the ICER range on which it was basing its decision was associated with uncertainty which needed to be accounted for when making its judgement about the acceptability of tisagenlecleucel as an effective use of NHS resources. Considering the risk to the NHS of paying for a treatment that was not cost effective, the committee concluded tisagenlecleucel could not be recommended for routine use in the NHS.\n\n# Innovation\n\n## Tisagenlecleucel is innovative but there are no benefits not captured in the analysis\n\nThe committee considered tisagenlecleucel to be innovative because it represents a step change in the treatment of relapsed or refractory diffuse large B-cell lymphoma. It noted that tisagenlecleucel had been designated as a priority medicine (PRIME) by the European Medicines Agency. The company did not present any evidence to suggest that there were additional benefits that were not captured in the QALY calculations. The committee concluded that there were no benefits not captured in the analysis.\n\n# Cancer Drugs Fund\n\n## Further data collection could address uncertainties in the clinical- and cost-effectiveness evidence\n\nHaving concluded that tisagenlecleucel was not recommended for routine use, the committee then considered if it could be recommended for use within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE technology appraisal methods guide. The committee recognised that tisagenlecleucel is innovative and therefore considered whether the clinical uncertainty associated with its use could be addressed through collecting more data. The committee was aware that more data from JULIET are expected and agreed that:\n\nFurther data from the JULIET trial on progression-free, post-progression and overall survival up to 5\xa0years would be a valuable addition to the clinical evidence base and would likely resolve uncertainties around longer-term relapse rates and survival.\n\nWith further evidence, it may be possible to gain a more complete understanding of the costs of IVIG treatment for B-cell aplasia.\n\nUsing tisagenlecleucel in the NHS would allow data to be collected using the Systemic Anti-Cancer Therapy (SACT) dataset which would more accurately reflect the costs and benefits of its use in clinical practice. Specifically it may be possible to gain a more complete understanding of the costs of IVIG treatment for B-cell aplasia.\n\n## Tisagenlecleucel meets the criteria to be included in the Cancer Drugs Fund\n\nData from JULIET showed that people having tisagenlecleucel may have good response rates, overall survival and progression-free survival (see table 1). The committee acknowledged that the published evidence for comparator treatments was limited but that the first extension study from CORAL was suitable for decision making (see section 3.8). It noted that the company's revised base-case ICER for tisagenlecleucel compared with salvage chemotherapy was below £50,000 per QALY gained, but recognised that using its preferred assumptions the most plausible ICER ranged between £42,991 and £55,403 per QALY gained. The committee acknowledged that all the ICERs for tisagenlecleucel compared with salvage chemotherapy were uncertain, but concluded that tisagenlecleucel had the plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced. The committee recognised that more long-term survival data for tisagenlecleucel and further data on post-progression survival would allow for a more robust cost-effectiveness estimate and could address some of the uncertainty around the most plausible cure point. Data on the use of IVIG in NHS practice should also be collected. The committee agreed that tisagenlecleucel met the criteria to be included in the Cancer Drugs Fund for treating relapsed or refractory diffuse large B-cell lymphoma in adults after 2 or more systemic therapies.\n\n# Equality considerations\n\n## There are no equality issues relevant to the recommendations\n\nThe company highlighted that diffuse large B-cell lymphoma is more common in men and older people because of the epidemiology of the disease. The committee noted that the first CORAL extension study excluded patients aged over 65\xa0years and agreed there was a lack of data for this age group. The clinical experts also noted that there may be issues related to accessing tisagenlecleucel, because it is only available at specialist centres. However, because the recommendations for tisagenlecleucel apply to the whole population in the marketing authorisation, the committee agreed that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. The commissioning expert from NHS England confirmed that national multidisciplinary teams would be established to ensure equality of referral and treatment access. The committee concluded that there were no relevant equality issues."}
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https://www.nice.org.uk/guidance/ta567
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Evidence-based recommendations on tisagenlecleucel therapy (Kymriah) for treating relapsed or refractory diffuse large B-cell lymphoma in adults after 2 or more systemic therapies.
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adbdeda8181075c8a152b5e261c010654ae0dccc
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nice
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Cochlear implants for children and adults with severe to profound deafness
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Cochlear implants for children and adults with severe to profound deafness
Evidence-based recommendations on cochlear implants for children and adults with severe to profound deafness.
# Recommendations
This technology appraisal examined the currently available devices for cochlear implantation. No evidence was available to the committee to allow recommendations to be made for devices manufactured by Neurelec.
Unilateral cochlear implantation is recommended as an option for people with severe to profound deafness who do not receive adequate benefit from acoustic hearing aids, as defined in 1.5.If different cochlear implant systems are considered to be equally appropriate, the least costly should be used. Assessment of cost should take into account acquisition costs, long-term reliability and the support package offered.
Simultaneous bilateral cochlear implantation is recommended as an option for the following groups of people with severe to profound deafness who do not receive adequate benefit from acoustic hearing aids, as defined in 1.5:
children
adults who are blind or who have other disabilities that increase their reliance on auditory stimuli as a primary sensory mechanism for spatial awareness.Acquisition of cochlear implant systems for bilateral implantation should be at the lowest cost and include currently available discounts on list prices equivalent to 40% or more for the second implant.
Sequential bilateral cochlear implantation is not recommended as an option for people with severe to profound deafness.
People who had a unilateral implant before publication of this guidance, and who fall into one of the categories described in 1.2, should have the option of an additional contralateral implant only if this is considered to provide sufficient benefit by the responsible clinician after an informed discussion with the individual person and their carers.
For the purposes of this guidance, severe to profound deafness is defined as hearing only sounds that are louder than 80 dB HL (pure-tone audiometric threshold equal to or greater than 80 dB HL) at 2 or more frequencies (500 Hz, 1,000 Hz, 2,000 Hz, 3,000 Hz and 4,000 Hz) bilaterally without acoustic hearing aids. Adequate benefit from acoustic hearing aids is defined for this guidance as:
for adults, a phoneme score of 50% or greater on the Arthur Boothroyd word test presented at 70 dBA
for children, speech, language and listening skills appropriate to age, developmental stage and cognitive ability.
Cochlear implantation should be considered for children and adults only after an assessment by a multidisciplinary team. As part of the assessment children and adults should also have had a valid trial of an acoustic hearing aid for at least 3 months (unless contraindicated or inappropriate).
When considering the assessment of adequacy of acoustic hearing aids, the multidisciplinary team should be mindful of the need to ensure equality of access. Tests should take into account a person's disabilities (such as physical and cognitive impairments), or linguistic or other communication difficulties, and may need to be adapted. If it is not possible to administer tests in a language in which a person is sufficiently fluent for the tests to be appropriate, other methods of assessment should be considered. # Clinical need and practice
Hearing loss may be caused by interference with the transmission of sound from the outer to the inner ear (conductive hearing loss) or damage within the cochlea, the auditory nerve or auditory centres in the brain (sensorineural hearing loss). In adults the most common cause of sensorineural hearing loss is presbycusis. This is a progressive condition caused by the loss of function of hair cells in the inner ear, leading to deafness. Hearing loss in adults may also be caused by excessive exposure to noise, or by ototoxic drugs, metabolic disorders, infections or genetic factors. Severe to profound hearing loss in children may have a genetic aetiology, or have prenatal, perinatal or postnatal causes. These include conditions such as meningitis and viral infection of the inner ear (for example, rubella or measles), as well as premature birth and congenital infections. Deafness that occurs before the development of language is described as prelingual, whereas deafness that occurs after the development of language is described as postlingual.
Approximately 370 children in England and 20 children in Wales are born with permanent severe to profound deafness each year. Approximately 90% of these children have 2 parents who can hear. About 1 in every 1,000 children is severely or profoundly deaf at 3 years old. This rises to 2 in every 1,000 children aged 9 to 16 years. There are approximately 613,000 people older than 16 years with severe to profound deafness in England and Wales. In the UK around 3% of people older than 50 and 8% of those older than 70 years have severe to profound hearing loss. Approximately 40% of children who are deaf and 45% of people younger than 60 years who are deaf have additional difficulties, such as other physical disabilities.
Deafness is not typically associated with increased mortality, and need not be associated with significant morbidity. Some people who are deaf identify with a cultural model of deafness in which deafness is not considered an impairment. These people, who often use sign language as their preferred language and grow up as members of the Deaf community, may not perceive deafness to have a major impact on their quality of life. However, for a child who is born deaf within a hearing family or for a person who becomes deaf and is used to functioning in a hearing environment, deafness can have a significant impact on their quality of life. For children, deafness may have significant consequences for linguistic, cognitive, emotional, educational and social development. Loss of hearing affects an adult's ability to hear environmental noises and to understand speech; this can affect their ability to take part in their daily activities and be part of their usual social and professional networks, which can lead to isolation and mental health problems.
Services for people who are deaf aim to improve their quality of life by maximising their ability to communicate, using the means most appropriate for the person and their environment, and to enable the person to move safely within their environment. There are approximately 50,000 people in the UK who communicate using British Sign Language. These are generally people who were born deaf or became deaf shortly after birth. Most people who are deaf use oral and aural communication supplemented by lip reading, cued speech (visual cues to clarify the sounds of English), signs (finger spelling or sign-supported English) and the written word. Regardless of the chosen means of communication, people may also use powerful hearing aids to help them identify environmental noises and to hear spoken language. However, for some people there are too few functioning hair cells for hearing aids to be of use.
National frameworks covering audiology include the NHS newborn hearing screening programme and the NHS modernising hearing aid services programme for children and adults. The NHS newborn hearing screening programme screens all newborn babies within 26 days of birth for possible hearing difficulties. Babies who at screening are identified as having possible hearing difficulties are referred to NHS audiology services. Those who are then confirmed deaf should receive a hearing aid within 2 months. This initial diagnosis is followed by ongoing support, which includes regular audiological assessment and consideration of the appropriateness of a cochlear implant (usually within the first year). Hearing services for adults are coordinated by audiology departments and normally include a review every 4 years, although this varies across the UK.
Potential candidates for cochlear implants are referred to one of the cochlear implant centres in England and Wales, where they receive a multidisciplinary assessment to determine whether cochlear implantation is suitable. Both audiological hearing and functional hearing are assessed as part of the multidisciplinary assessment, as well as other factors such as fitness for surgery, structure of the cochlea, the presence of a functioning auditory nerve and the likely ability of the person to derive benefit from the stimuli produced by the cochlear implant system.
Audiological testing identifies the additional intensity that a pure-tone sound must possess to be detected relative to the intensity that can be detected by young adults without hearing impairment. At the time of the original appraisal, guidelines from the British Cochlear Implant Group suggested that people who could not hear sounds quieter than an average of 90 dB HL when tested at frequencies of 2 kHz and 4 kHz without acoustic hearing aids would be considered for cochlear implantation if they did not derive adequate benefit from acoustic hearing aids. But after a review of the guidance in 2018 stakeholders agreed that this was out of date (see section 4.4).
Functional hearing is tested with optimum acoustic hearing aids and focuses on a person's ability to perceive speech. At the time of the original appraisal, for adults, functional hearing was usually assessed using Bamford-Kowal-Bench (BKB) sentences. Guidelines from the British Cochlear Implant Group stated that an adult who identified 50% or more of keywords at a sound intensity of 70 dB SPL in quiet conditions was considered to be deriving an adequate benefit from their hearing aids. But after a review of the guidance in 2018 stakeholders agreed that the test and the guidelines were out of date (see section 4.4). Functional hearing in children is assessed through the development and maintenance of speech, language, communication and listening skills that are appropriate for the age, developmental stage and cognitive ability of the child. For this reason no single test is used.
During the year ending March 2007, 374 adults and 221 children had unilateral cochlear implantations in England and 8 adults and 22 children in Wales. A further 451 adults and 446 children were under assessment. In the UK, in the year ending March 2007, 32 bilateral implantations were performed in children and 11 in adults. A survey of 15 of the 18 cochlear implant centres in England and Wales showed that 704 children and adults had received a unilateral cochlear implant during the financial year ending March 2008. In addition, there were 77 children and adults who had received bilateral cochlear implants. Of these, 39 were simultaneous implants and 38 were sequential implants. # The technology
Cochlear implant systems consist of internal and external components. A microphone and sound processor are worn externally behind the ear. The sound processor is connected to a transmitter coil, which is worn on the side of the head. Data from the transmitter coil are passed to a receiver–stimulator package that is implanted into a surgically fashioned depression in the mastoid bone. The receiver–stimulator translates the data into electrical pulses that are delivered to an array of electrodes. These are placed surgically within the cochlea. The electrodes stimulate spiral ganglion cells that innervate fibres of the auditory nerve. The activation of electrodes provides a sensation of hearing, but does not restore hearing.
The NHS buys cochlear implant systems under a long-term procurement contract between the 4 companies and the NHS supply chain. The procurement contract in use during this appraisal applied until 31 October 2008 and there was an option for an extension of a further 24 months. The costs of the implant systems noted below are based on information from the NHS supply chain on the national procurement contract. In addition to the main procurement contract, companies offer local discounts based on volume of sales; therefore costs may vary in different settings. Except for the discount for the Neurelec system, discounts for second implant systems are not part of the NHS supply chain contract, but are offered nationally by some companies.
The Clarion CII Bionic Ear System and the HiResolution Bionic Ear System (Advanced Bionics UK) are indicated for adults (18 years or older) with postlingual onset of severe to profound, bilateral sensorineural hearing loss (only hearing sounds with an intensity equal to or greater than an average of 70 dB HL) who derive limited benefit from appropriately fitted hearing aids. For children aged 12 months to 17 years the implants are indicated for profound bilateral sensorineural deafness (only hearing sounds with an intensity equal to or greater than an average of 90 dB HL) who derive limited benefit from acoustic hearing aids. The current NHS supply chain list price of the implant system (which includes the implant and processor) is £16,550 and the price paid by the NHS supply chain for the implant system is £14,900. Information supplied by the company indicates that a 40% discount on the list price for a second implant (list price for implant without processor and without discount: £10,500) is only offered when the second implant is used for simultaneous bilateral implantation. A 25% discount on the list price of £10,500 is offered when the second implant is used for sequential bilateral implantation. No discounts are offered for the purchase of a second processor. Costs may vary in different settings because of negotiated procurement discounts.
The Nucleus 24 and Nucleus Freedom cochlear implants (Cochlear Europe) are indicated for adults (18 years or older) who have bilateral postlingual sensorineural hearing loss and who have limited benefit from binaural hearing aids. For children (aged 12 months to 17 years) the implants are indicated for bilateral sensorineural hearing loss if little or no benefit is derived from binaural hearing aids. The implants are also indicated for adults who have prelingual or perilingual profound sensorineural deafness and who obtain no benefit from a hearing aid. However, the package insert notes that these people are likely to have limited benefit from a cochlear implant. The current NHS supply chain list prices of the Nucleus 24 and Nucleus Freedom cochlear implant systems are £14,350 and £15,250 to £15,550 respectively. The price paid by the NHS is based on the volume acquired by each cochlear implant centre and the company offers a 10% discount for every 10 implant systems purchased. Additional information supplied by the company indicates that discounts for a second implant system (implant and processor) for bilateral cochlear implantation are offered on a case-by-case basis. Costs may vary in different settings because of negotiated procurement discounts.
The Pulsar CI-100 (MED-EL) is indicated for people with severe to profound deafness who derive limited benefit from conventional acoustic amplification in the best-aided condition. It is recommended that individuals have a trial of acoustic hearing aids unless this is contraindicated. The current list price of the Pulsar CI-100 cochlear implant system is £17,375 and the price paid by the NHS is £15,600. Discounts are available from the company, but the details of the discounts were provided as commercial in confidence.
The Digisonic SP (Neurelec) is indicated for adults and children with bilateral profound to total sensorineural hearing loss. The price paid by the NHS supply chain for the Digisonic cochlear implant system is £12,250. A 50% discount on the second implant system for bilateral implantation is currently in place with the NHS supply chain (equating to £18,375 for 2 implant systems).
Information on discounts was also obtained from a survey of the 18 cochlear implant centres in England and Wales. Responses were received from 15 centres: 3 paediatric centres, 2 adult centres and 10 with paediatric and adult caseloads. Four of the centres that responded did not carry out any bilateral implants during this period. The results of the survey suggested variation in the discounts received by the implant centres. For sequential bilateral implantation, the discounts ranged from 0% to 40% for the second implant. For simultaneous bilateral implantation the range was 0% to 50% for the second implant. # Evidence and interpretation
The appraisal committee (section 7) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Clinical effectiveness
The assessment group identified studies of cochlear implants that included adults and/or children with severe to profound deafness. The assessment group included only studies of multichannel cochlear implants that used whole-speech processing coding strategies, because these most closely represent the type of device available to the NHS. The assessment group included randomised and non-randomised controlled trials, including studies in which participants acted as their own controls.
The systematic review by the assessment group comprised 33 studies, of which 13 involved adults and 20 involved children. Meta-analysis of the data was not possible because of heterogeneity between the studies. Only 2 implant systems in the NHS contract (both supplied by Cochlear Europe) were represented in studies included in the systematic review. Three companies – Advanced Bionics UK, Cochlear Europe and MED-EL UK – submitted additional studies reporting the clinical effectiveness of their implant systems. Neurelec did not submit evidence of clinical effectiveness to this appraisal.
## Children: unilateral cochlear implantation
Eight studies compared a unilateral cochlear implant with non- technological support (that is, without acoustic hearing aids, but permitting lip reading or sign language), and 6 studies compared unilateral cochlear implants with acoustic hearing aids. In 10 of the studies children acted as their own controls and in 4 of the studies there was a separate non-randomised control group. The studies reported benefits from cochlear implants in auditory, speech perception and speech production outcomes. In the 4 studies that reported statistical significance, the benefits were statistically significant. Two of these studies suggested that children who have devices implanted earlier may have better outcomes.
## Children: bilateral cochlear implantation
Three studies compared bilateral cochlear implants with a unilateral cochlear implant, and 3 studies compared bilateral cochlear implants with a unilateral cochlear implant and a contralateral hearing aid. In 4 studies the children acted as their own controls, whereas the other 2 studies included a non-randomised control group. Benefits were reported for auditory and speech perception outcomes with bilateral cochlear implantation. In the 5 studies that reported levels of statistical significance, 3 reported statistically significant improvements in the ability to identify the direction from which a sound is coming with bilateral cochlear implants. In addition, 2 studies reported statistically significant improvements in speech perception in noisy conditions with bilateral cochlear implants. However, differences for speech perception outcomes in quiet conditions were statistically significant for only 2 out of 7 outcome measures.
## Children: quality of life and education outcomes
None of the studies in the assessment group's systematic review reported either quality of life or educational outcomes. Further searches identified 4 studies that measured quality of life and 7 studies that measured educational outcomes. Studies assessing quality of life suggest that a cochlear implant can improve a child's quality of life and their quality of life as perceived by their parents.
The studies of educational outcomes suggest that children who are profoundly deaf and have a cochlear implant may be more likely to be educated within a mainstream school than children with a similar level of deafness but without a cochlear implant. The studies also suggest that children who are profoundly deaf and have a cochlear implant may have a higher level of academic performance than those who are profoundly deaf but have no cochlear implant.
## Adults: unilateral cochlear implantation
Four studies compared a unilateral cochlear implant with non-technological support (for example, without acoustic hearing aids, but permitting lip reading or sign language), and 4 studies compared a unilateral cochlear implant with an acoustic hearing aid. In 7 studies participants acted as their own controls; the eighth study included a non-randomised control group. The studies measured speech perception outcomes. Four also measured quality of life and 1 measured an auditory outcome. The studies suggested that there were benefits from the use of cochlear implants in all the outcomes measured. When statistical significance levels were reported, these benefits were statistically significant, except for the auditory outcome. One study suggested that the benefits of a unilateral cochlear implant may be greater for younger people and people who have been deaf for a shorter time.
## Adults: bilateral cochlear implantation
Five studies compared unilateral cochlear implants with bilateral cochlear implants. The assessment group did not identify any studies of adults that compared bilateral cochlear implants with a unilateral cochlear implant and a contralateral hearing aid. Two studies were randomised controlled trials and in the other 3, participants acted as their own controls. There was some overlap in the participants included in 3 of the studies. The studies measured auditory, speech perception and quality-of-life outcomes. Auditory outcomes were statistically significantly better for bilateral cochlear implants than for a unilateral implant. However, the results for speech perception and quality of life were more mixed, with some outcomes suggesting a negative impact of bilateral implantation owing to worsening of tinnitus after the second implantation.
## Adults: quality of life
Three studies that measured quality of life were included in the systematic review. However, because of the importance of this outcome, further searches were completed to identify other studies that measured quality of life. Six further studies were identified, all of which reported benefits in quality of life associated with cochlear implants. Four studies reported levels of statistical significance, and 3 of these reported statistically significant benefits for quality of life after cochlear implantation.
# Cost effectiveness
Submissions were received from 3 companies. Two (Cochlear Europe, Advanced Bionics UK) provided de novo economic evaluations. The third (MED-EL UK) provided a narrative summary of existing published economic analyses. The assessment group identified a total of 9 studies that reported cost effectiveness or cost–benefit ratios from the perspective of the NHS. These reported incremental cost-effectiveness ratios (ICERs) for unilateral cochlear implantation ranging from £2,000 to £20,000 per quality-adjusted life year (QALY) gained for children and £11,000 to £18,000 per QALY gained for adults. In addition, the assessment group carried out a de novo economic evaluation.
## The economic submission from Cochlear Europe
The company submitted a Markov model that evaluated the cost effectiveness of unilateral and bilateral cochlear implantation compared with 'standard of care' (in which a proportion of people receive acoustic hearing aids) from an NHS and personal social services (PSS) perspective. The decision problem was assessed in relation to the Nucleus and Nucleus Freedom products using costs and failure rates specific to these systems. Health-related utility data were derived from clinical studies and mapped speech recognition scores onto health utility index 3 (HUI3) utility values. The assessment group expressed concern about the way the mapping was undertaken.
The comparison of unilateral implantation with 'standard of care' gave an ICER of £10,500 per QALY gained for children with severe to profound sensorineural deafness and £7,100 per QALY gained for adults with postlingual severe to profound sensorineural deafness. The comparison of bilateral implantation and unilateral implantation gave an ICER of £39,000 and £32,900 per QALY gained in adults and children, respectively.
## The economic submission from Advanced Bionics UK
The company submitted a Markov model that evaluated the cost effectiveness of unilateral cochlear implantation compared with no cochlear implants from an NHS and PSS perspective. Four specific subgroups were identified: children with prelingual profound deafness; children with postlingual profound deafness; adults with postlingual profound deafness; and adults with postlingual severe deafness. Cost-effectiveness analyses were not presented for bilateral cochlear implantation.
Costs were derived from a published study of cochlear implantation in children, and applied to both children and adults. Health-related utility data were derived from published studies using HUI3. The ICERs associated with unilateral implantation at 3 and 6 years were £13,300 and £17,200 per QALY gained, respectively. The ICERs for unilateral implantation in 50-year-old adults with profound and severe deafness were £20,000 and £37,000 per QALY gained, respectively.
## The economic submission from MED-EL UK
The submission from the company does not include an economic model and primarily summarises some of the existing published economic literature. The submission presents an ICER of approximately £18,000 per QALY gained for unilateral cochlear implantation in children. For adults, estimates of cost effectiveness for unilateral cochlear implantation are presented for the group as a whole and for 2 subgroups: adults with profound deafness who derive no functional benefit from acoustic hearing aids; and adults with profound deafness who derive some functional benefit from hearing aids. The corresponding ICERs were £20,600, £19,200 and £25,400 per QALY gained, respectively.
## The economic model from the assessment group
The assessment group developed a Markov model to consider 2 questions. The first was the cost effectiveness of unilateral cochlear implantation compared with standard treatment (which may or may not include acoustic hearing aids) in children and adults who were profoundly deaf. The second was the cost effectiveness of providing an adult or a child who is profoundly deaf and currently receiving standard treatment (which may or may not include acoustic hearing aids) with a simultaneous or sequential (defined as 3 years between the first and second implant) bilateral cochlear implant compared with a unilateral cochlear implant.
The effectiveness of cochlear implants in the model was based on a separate review of studies that reported health-related utility values for severe or profound deafness for unilateral or bilateral cochlear implantation. The most relevant studies that were identified derived quality-of-life data from the HUI3. For children, changes in quality of life were reported by their parents or their teachers as proxies. In the base-case analyses, utilities were assumed to remain constant over the lifetime of the person.
The health-related utility for a child without a cochlear implant was obtained from all children in the UK with profound deafness and no cochlear implant. The health-related utility value from this population was 0.421. The gains in health-related utility from having a cochlear implant were 0.066, 0.212 and 0.232 in the first 2 years following implantation, 2 to 4 years and 4 years onwards, respectively. The health-related utility data for adults were obtained from a prospective cohort study that measured health-related utility before and after cochlear implantation in a group of adults with postlingual severe to profound deafness. The utility value without a cochlear implant was 0.433. The gain in utility associated with having a unilateral cochlear implant was estimated to be 0.197.
The health-related utility data for bilateral implantation were obtained from data from 24 adults with postlingual deafness who had a unilateral cochlear implant and were then randomised to receive a second contralateral implant immediately or 11 months later. At 9 months follow-up a comparison of those who had bilateral implants with those waiting for their second implant suggested a difference in utility of 0.10. A subsequent analysis of the whole group (before and after implantation) suggested a utility gain of –0.015. Regression analyses of the trial data, controlling for changes in tinnitus after implantation, suggested that the additional utility gain associated with bilateral cochlear implantation was 0.03. The assessment group used the latter value (0.03) in their analyses. In the absence of health-related utility data for bilateral cochlear implantation in children, the data from adults were applied to children.
The assessment group was unable to identify adequate health-related utility data to model the cost effectiveness of implanting a second device in a person with 1 established cochlear implant. The assessment group did not examine the following subgroups in its economic analysis: children and adults with severe deafness; adults with prelingual deafness; children with postlingual deafness; and children and adults who are both deaf and blind or are deaf and have other disabilities. This was because of the lack of health-related utility data to define either the health-related utility without a cochlear implant or the gain in health-related utility following cochlear implantation.
Costs included in the model are taken from 2 large UK costing studies that identified the cochlear implant centre costs associated with cochlear implantation in adults and children. The cost data for adults were taken from the same study from which utility data were taken. The data for children were collected from a survey of UK cochlear implant centres providing cochlear implants for the financial year 1998/99. In the base-case analyses, the cost of the cochlear implant (£14,661) was the mean cost of the 9 devices in the NHS supply chain purchasing contract. For bilateral implantation, the cost of a single device was doubled (£29,222). Discounts on the second implant system were considered in sensitivity analyses.
## Cost effectiveness for children
The ICER for unilateral implantation in children who are prelingually deaf and receive an implant at the age of 1 year was £13,400 per QALY gained. The corresponding ICERs for simultaneous and sequential bilateral implantation compared with unilateral implantation were £40,400 and £54,100 per QALY gained, respectively.
Analyses suggested that the estimates of cost effectiveness were sensitive to the time horizon, maintenance costs and utility. Scenario analyses that included educational costs or a later age at implantation had little impact on the estimates of cost effectiveness. Sensitivity analyses suggested that the estimates of cost effectiveness for simultaneous bilateral implantation were sensitive to changes in device costs and the utility gained. With a cost of £14,661 for a unilateral implant system, reductions of 25% and 50% in the cost of the second implant system reduced the ICER for simultaneous bilateral implantation to £36,139 and £31,900 per QALY gained, respectively. Without a cost discount for the second implant system, an increase of the utility gain from 0.03 to 0.04 reduced the ICER from £40,400 to £31,300 per incremental QALY gained.
The assessment group conducted additional 2-way sensitivity analyses to investigate the impact of combining the discounts reported by the cochlear implant centres (see section 3.7) with alternative assumptions about utility gain associated with bilateral implantation for simultaneous bilateral cochlear implantation in children. In the analyses, the cost of a unilateral implant system was assumed to be £15,534, which was the mean of the published list prices of the devices used in the cochlear implant centres. Assuming a discount of 30% on the second implant system and a utility of 0.03 produced an ICER of £36,040 per QALY gained. When the 30% discount was maintained and a utility of 0.04 instead of 0.03 was assumed, the ICER was reduced to £27,886 per QALY gained. Increasing the utility gain to 0.05 further reduced the ICER to £22,740 per QALY gained.
## Cost effectiveness for adults
The ICER for unilateral implantation in adults who are postlingually deaf was £14,200 per QALY gained. The corresponding ICERs for simultaneous and sequential bilateral implantation compared with unilateral implantation were £49,600 and £60,300 per QALY gained, respectively.
Analyses suggested that the estimates of cost effectiveness were sensitive to the time horizon, age of the cohort, device costs and utility gain. Scenario analysis using an age-dependent utility gain had little impact on the estimate of cost effectiveness. Sensitivity analyses for simultaneous bilateral implantation showed that the estimates were sensitive to changes in device costs and the utility gained. Reductions of 25% and 50% in the cost of the second implant system reduced the estimate of cost effectiveness to £43,028 and £36,497 per QALY gained, respectively. Without a cost discount for the second implant system, but with a utility gain of 0.04 as opposed to 0.03 the estimate of cost effectiveness was reduced from £49,600 to £37,725 per incremental QALY gained.
Following completion of the assessment report, consultees provided new evidence on the additional utility gain associated with bilateral compared with unilateral implantation for children and adults. One estimate came from a cross-sectional study of 15 children with unilateral cochlear implants and 26 children with bilateral cochlear implants. In this study, parents rated their children's health-related quality of life using the HUI3. The utility of children with a unilateral cochlear implant was reported as 0.72, whereas the utility of children with bilateral cochlear implants was reported as 0.73, reflecting a change in utility of 0.01. A second estimate came from a study of 23 people (children and adults) with bilateral cochlear implants. In this study participants were asked to retrospectively rate their health-related quality of life using the HUI3 before and after receiving a unilateral implant (that is, unilateral compared with no implants). Participants were then asked to rate their health-related quality of life using the HUI3 with bilateral implants. This study reported a utility of 0.69 associated with unilateral cochlear implantation compared with 0.81 for bilateral cochlear implantation, which was reported in the paper as a change in utility of 0.11. A further study asked 180 people including parents, clinicians and students to rate the hypothetical health-related quality of life of children described in vignettes. This study reported utility values of 0.77 for a child with a unilateral cochlear implant, 0.82 for a child using a unilateral cochlear implant and a contralateral hearing aid, and 0.88 for a child with bilateral cochlear implants.
# Consideration of the evidence
The appraisal committee reviewed the data available on the clinical and cost effectiveness of cochlear implants for children and adults with severe to profound deafness, having considered evidence on the nature of the condition and the value placed on the benefits of cochlear implants by people who are deaf, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.
The committee considered the distinction between audiological and functional deafness. The committee heard from clinical experts that audiological hearing was not necessarily related to functional hearing. Therefore, in clinical practice a person's hearing is assessed not just by audiological tests, but also by a functional test of hearing, specifically their ability to perceive speech in quiet conditions with acoustic hearing aids. The committee concluded that decisions about the appropriateness of cochlear implants should take into consideration a person's functional hearing and the benefit they gain from acoustic hearing aids.
The committee considered how functional deafness could be defined in clinical practice. At the time of the original appraisal it heard from clinical experts that guidelines for adults from the British Cochlear Implant Group recommend Bamford-Kowal-Bench (BKB) sentence testing. Using this approach, an adequate benefit from hearing aids is defined as a score of 50% or greater at a sound intensity of 70 dB SPL. But after a review of the guidance in 2018 stakeholders agreed that the test and the criteria were out of date and the committee agreed to update recommendation 1.5 (see section 4.4). The committee heard that tests for children should assess whether speech, language and listening skills are appropriate to the age, development stage and cognitive ability of the child. The committee heard that the most appropriate test would differ according to the age and developmental stage of the child. The committee considered that the BKB sentences may not be appropriate for assessing hearing in adults for whom English is a second language, and for adults with other linguistic or cognitive difficulties. The committee considered that those making the hearing assessments should take these factors into account. In these situations, modification of the testing procedure or alternative tests may be required.
The committee recognised that identifying people for whom cochlear implantation was appropriate took account of not only the results of audiological and functional hearing tests but also other factors such as fitness for surgery, structure of the cochlea, the presence of functioning auditory nerves and the likelihood of benefiting from the stimuli produced by the device. The committee heard from clinical experts that these factors were assessed as part of a multidisciplinary assessment, which would also include a trial of acoustic hearing aids that usually lasts for 3 months, if this was not contraindicated or inappropriate. The committee concluded that it was essential to determine the appropriateness of cochlear implantation through a multidisciplinary assessment, with input from a range of professionals involved in the care of children and adults with cochlear implants. This was in addition to audiological and functional hearing tests and a valid trial of acoustic hearing aids that usually lasted 3 months.
The committee considered the perspective of people who may not consider deafness a disability that needs to be treated. The committee heard from clinical experts that most children who are deaf have families who are hearing and who have no access to Deaf culture. In addition, it is unlikely that adults who become deaf will become proficient users of sign language and integrate into the Deaf community. The committee concluded that for many people deafness would have a significant adverse impact on their quality of life, and that it was appropriate to consider cochlear implants as a means of reducing this impact.
The committee noted that the evidence for clinical and cost effectiveness was derived from data based on cochlear implant systems from 3 companies making cochlear implants (Advanced Bionics UK, Cochlear Europe, MED-EL UK), and that no data for clinical effectiveness were identified for cochlear implant systems from the fourth company (Neurelec). The committee was aware that cochlear implant systems from Neurelec are included in the current NHS procurement contract, but heard from clinical experts that Neurelec implants are rarely used in the NHS. The committee concluded that it was only able to issue recommendations about the devices for which there was evidence available.
The committee examined the evidence for the clinical effectiveness of the use of unilateral cochlear implants for adults and children with severe to profound deafness. The committee considered that, despite methodological limitations, the studies showed benefits for providing unilateral cochlear implants compared with hearing aids or non-technological support for people who were appropriately assessed. The committee concluded that unilateral cochlear implants had been shown to be clinically effective.
The committee examined the evidence for the cost effectiveness of unilateral cochlear implantation. The committee noted that both the assessment group and the companies obtained similar estimates of cost effectiveness. The committee considered that the analyses of cost effectiveness for unilateral implantation were a reasonable reflection of the costs and benefits. The committee concluded that unilateral cochlear implantation for adults and children with severe to profound deafness who did not derive adequate benefit from acoustic hearing aids would be a cost-effective use of NHS resources.
The committee considered the evidence for the clinical effectiveness of bilateral cochlear implants. The committee considered that the additional benefits of bilateral cochlear implantation were less certain than the benefits of unilateral cochlear implantation. This was because of the limitations of the evidence base owing to the small number of studies and the small numbers of participants. However, the committee considered that the studies had shown additional benefits to having a second cochlear implant in relation to speech perception in noisy situations and directional perception of sound. The committee heard from patient experts that they considered that there were other benefits from bilateral cochlear implantation. These benefits included easier, less exhausting communication (for example, determining the direction of the sound in group conversations without unnecessary head movement). The committee concluded that there were additional benefits of bilateral cochlear implants that had not been adequately evaluated in the published studies, although these may vary among individuals.
The committee heard from clinical experts that it was important that the auditory nerve was provided with stimulation early in a child's development because it became less sensitive to stimulation as the child became older. Hence, failure to stimulate the auditory nerve early impaired the development of central pathways necessary for the appreciation and understanding of sound. The committee was persuaded on the basis of consultee comments that the potential benefits of bilateral auditory stimulation would apply to both prelingual and postlingual children with severe to profound deafness because neurosensory development continues after the development of language. The committee concluded that making a distinction between children based on the time of language development would not be appropriate.
The committee then considered the cost effectiveness of bilateral cochlear implantation. The committee first examined the cost of cochlear implant systems and in particular the availability of nationally agreed discounts for the second cochlear implant system. The committee noted that the current NHS supply chain contract only included 1 discount on a bilateral system from a single company (Neurelec). The committee then considered the information about discounts provided by the other 3 companies. The committee noted that 2 of the 3 companies reported their discounts as being standardised and nationally available. The committee recognised that these discounts were sometimes given on the implant alone and other times on the whole implant system (that is implant plus processor), and that this would affect the total cost of the system. The committee examined the information on discounts from the survey of cochlear implant centres (described in section 3.7). The committee noted that there was some variation in the size of the discount received by the cochlear implant centres that was not reflected in the information from the companies. The committee noted this did not appear to relate directly to volume of implants purchased. The committee considered that the data showed that discounts of 40% or more on the second implant were being attained by a large proportion of implant centres, and therefore could be considered as being available nationally. Therefore the committee concluded that it was appropriate for this size of discount to be taken into account when considering the estimates of incremental cost effectiveness of bilateral implantation.
The committee then considered the cost effectiveness of bilateral cochlear implantation in adults. The committee noted that the base-case economic analyses provided by the assessment group obtained an ICER for simultaneous bilateral cochlear implantation of approximately £50,000 per QALY gained. The committee noted that the utility data used in this analysis were associated with uncertainty because the data were derived from a small number of adults over a short follow-up period. However, the committee noted that these were the only data available for people who had been studied prospectively before and after they had received a second cochlear implant. Therefore the committee considered that this was the most appropriate source of data for estimating health utility gain following a second implant. The committee noted concerns from consultees about the impact of tinnitus on the utility results from this study. It accepted the analysis of the study data that had controlled for the impact of tinnitus and gave a health utility gain following a second implant of 0.03. Therefore the committee considered that 0.03 was currently the most appropriate estimate of the additional utility gain for a second implant for adults with severe to profound deafness. The committee noted the assessment group's assumption of no discount for the second implant in their base-case analysis. The committee considered the situation of a 25% to 50% discount on the second implant system as discussed in section 4.2.17. Under these circumstances the ICER for bilateral implantation for adults was between £43,000 and £36,500. The committee noted from the assessment group's analysis that with a utility gain of 0.03, discounts on the second implant system had to be greater than 75% for the ICER for bilateral implantation in adults to fall between £20,000 and £30,000 per QALY gained. Therefore the committee concluded that it was not possible to recommend routine bilateral cochlear implantation in adults as a cost-effective use of NHS resources.
The committee next examined the evidence for the cost effectiveness of bilateral cochlear implantation for children with severe to profound deafness. The committee noted that the assessment group had been unable to identify any health-related quality-of-life data for bilateral cochlear implantation in children, and had used the data from adults for children (that is, an additional gain in health-related utility of 0.03 for the second implant). The committee noted comments from consultees that for children with severe to profound deafness, a utility gain of 0.03 could potentially be an underestimate. These comments focused on the view that bilateral cochlear implantation could afford more quality-of-life gains for children than for adults, through improved language learning and spatial awareness, which would increase opportunities for interaction and communication, the ability to participate in play activities, and benefits from education. The committee was persuaded that additional utility gains for children above that for adults were plausible. However, the size of these additional gains was associated with considerable uncertainty, given that there were limited data for children, and for adults the additional gains in health-related quality of life were associated with methodological concerns. The committee recognised that the economic analyses were sensitive to utility gains, and that if the gain in utility for children was assumed to be more than for adults, the ICER for bilateral cochlear implantation would be considerably reduced from the base case.
The committee then considered the impact on the ICERs of combining additional gains in utility for simultaneous bilateral cochlear implantation of children with discounts on the second implant. The committee noted that the 40% discount for the second cochlear implant for simultaneous bilateral implantation, which was being received by many cochlear implant centres, equated to approximately 30% off the cochlear implant system (implant plus processor). The committee noted that with a discount of 30% on the implant system and a utility gain of 0.04, the ICER for children would be £27,900 per QALY gained. If the same discount was applied and the utility gain was assumed to be 0.05, then the ICER for children would be £22,700 per QALY gained. The committee was mindful that the size of the additional utility gain following simultaneous bilateral implantation for children was very uncertain, but was persuaded that with the discounts on second implants currently available, it could accept the uncertainty associated with the gains in utility. Therefore the committee concluded that if cochlear implants for bilateral implantation could be acquired at the lowest price, including a discount equivalent to 40% or more off the current list prices of the second implant, then simultaneous bilateral cochlear implantation for appropriately assessed children with severe to profound deafness could be considered a cost-effective use of NHS resources.
The committee recognised that some people who were deaf could also be at risk of ossification of the cochlea (for example, after meningitis). The committee heard from clinical experts that ossification caused damage to the cochlea, which could make both initial implantation and successful re-implantation in the case of device failure difficult. The committee noted that the incidence of ossification after meningitis is unclear. However, it understood that a minority of people at risk of cochlear ossification went on to have cochlear ossification, and that the extent of the ossification varied. The committee noted the evidence that, in general, device failure rates after successful implantation were low (less than 5% over 15 years), and considered that the probability of cochlear ossification occurring in adults with severe to profound deafness combined with failure of the unilateral implant and an inability to re-implant the first ear was therefore likely to be very small. On balance the committee considered that this very low risk was not in itself a reason to recommend bilateral implantation in this group when for adults overall it had not considered this a cost-effective use of NHS resources.
The committee recognised that there were additional considerations for people who are deaf and also have other disabilities. The committee heard from clinical experts that specifically for people who are both deaf and blind, the gains in quality of life following bilateral implantation are greater than for people who are not blind. This is because people who are deaf and blind rely more on auditory stimuli for spatial awareness. The committee recognised that in addition to people who are deaf and blind, there are people with other co-disabilities who also rely on auditory stimuli as a primary sensory mechanism for spatial awareness. The committee considered that these individuals would be most appropriately identified by healthcare professionals as part of a multidisciplinary assessment. The committee was persuaded by the evidence from clinical experts that bilateral cochlear implantation did produce greater quality-of-life gains for deaf people who are blind or have other co-disabilities that increase reliance on hearing as a primary sensory mechanism for spatial awareness than it did for people who are deaf and who do not have other disabilities of this nature. The committee agreed that the inclusion of discounts equivalent to 40% or more off the list prices of the second implant was appropriate in the cost-effectiveness analyses, as these reflected current nationally available discounts. The committee was mindful of the uncertainty over the magnitude of the additional quality of life gains associated with bilateral cochlear implantation in this group of people, but was persuaded that using the currently available discounts would result in an acceptable cost-effectiveness estimate. Therefore the committee was persuaded that if cochlear implants for bilateral implantation were acquired at the lowest price, including currently available discounts on list prices equivalent to 40% or more off the second implant, then it was appropriate to recommend bilateral cochlear implantation in this group of people as a cost-effective use of NHS resources.
The committee noted that sequential implantation was associated with higher cost-effectiveness estimates than simultaneous bilateral implantation for both children and adults, and therefore concluded that sequential bilateral implantation is not an appropriate use of NHS resources. However, the committee recognised that some children who have previously received unilateral implants may now be considered to have met the criteria in the current guidance for simultaneous bilateral implantation. Similarly, this is the case for adults who are deaf and have other disabilities that increase their reliance on auditory stimuli as a primary sensory mechanism for spatial awareness. The committee considered that it is important to promote equity of treatment between groups of people who are in the same circumstances except that one group had previously had a unilateral cochlear implant and the other becomes eligible now. However, the committee was mindful that the duration of deafness and length of time since unilateral implantation could reduce the benefits of any additional contralateral cochlear implant. The committee was persuaded that in situations where the responsible clinician considers that an additional contralateral cochlear implant would provide sufficient benefit, people in the above 2 groups who have already received a unilateral cochlear implant prior to publication of this guidance should have the option of an additional contralateral implant. However, the committee considered that an additional implant should be offered only after a fully informed discussion between the individual person, their carers and clinicians involved in their care.
The committee noted that in the economic analyses cochlear implants had been modelled as a class. The committee was aware from clinical experts that there may be differences between the devices, in particular the processing strategies used. The committee did not consider that it had been demonstrated that the different cochlear implant systems were associated with different cost-effectiveness profiles. Therefore it was not appropriate to preferentially recommend a specific device. However, the committee did consider that if there was more than one cochlear implant system that was considered clinically appropriate, the least costly implant system, taking into account discounts as available, should be used. The committee recognised that the cost of a system would depend on the support package offered, the long-term reliability of the device and whether it was to be used unilaterally or bilaterally.
# Partial update
In 2018, as part of a review of this guidance, stakeholders highlighted that the eligibility criteria in recommendation 1.5 were out of date and did not reflect clinical practice.
The British Cochlear Implant Group (BCIG) suggested that the definition of severe to profound deafness should be hearing only sounds louder than or equal to 80 db HL without acoustic hearing aids, which was supported by most stakeholders.
Stakeholders also suggested that testing should be at a wider range of frequencies than stated in the original guidance. They noted that important frequencies for speech perception are between 750 Hz and 3000 Hz.
Stakeholders further highlighted that the BKB sentence test was no longer considered appropriate for assessing benefit of acoustic hearing aids. The consensus among the professional and patient organisations was that the Arthur Boothroyd word test is a more appropriate test.
Changing the criteria in section 1.5 of the guidance is not expected to have a substantial impact on the cost effectiveness of cochlear implants. This is because:
The criteria in the original guidance captured the population for whom the BCIG thought cochlear implants were appropriate and necessary. The proposed amendments to the criteria do not broaden the population outside of this group. Rather, new research shows that the group for whom cochlear implants are appropriate and necessary can be better identified through the updated criteria. The population therefore continues to reflect the population considered in the cost-effectiveness modelling.
Since NICE's technology appraisal guidance 166 was published, there has been around a 15% reduction in device costs, which would improve their cost effectiveness.
The committee considered that the wording suggested by stakeholders was appropriate and would not have a substantial impact on the cost effectiveness of cochlear implants. It concluded that the criteria in section 1.5 of the guidance should be updated to:
For the purposes of this guidance, severe to profound deafness is defined as hearing only sounds that are louder than 80 dB HL (pure-tone audiometric threshold equal to or greater than 80 dB HL) at 2 or more frequencies (500 Hz, 1,000 Hz, 2,000 Hz and 4,000 Hz) bilaterally without acoustic hearing aids. Adequate benefit from acoustic hearing aids is defined for this guidance as:
for adults, a phoneme score of 50% or greater on the Arthur Boothroyd word test presented at 70 dBA
for children, speech, language and listening skills appropriate to age, developmental stage and cognitive ability. # Recommendations for further research
The committee recommended that a randomised controlled trial should be carried out to examine the benefit of bilateral cochlear implantation compared with unilateral cochlear implantation in adults with severe to profound deafness.
The committee recommended that data on the health-related quality of life of children with bilateral cochlear implants should be collected and measured in accordance with NICE's guide to the methods of technology appraisal.
|
{'Recommendations': "This technology appraisal examined the currently available devices for cochlear implantation. No evidence was available to the committee to allow recommendations to be made for devices manufactured by Neurelec. \n\nUnilateral cochlear implantation is recommended as an option for people with severe to profound deafness who do not receive adequate benefit from acoustic hearing aids, as defined in\xa01.5.If different cochlear implant systems are considered to be equally appropriate, the least costly should be used. Assessment of cost should take into account acquisition costs, long-term reliability and the support package offered. \n\nSimultaneous bilateral cochlear implantation is recommended as an option for the following groups of people with severe to profound deafness who do not receive adequate benefit from acoustic hearing aids, as defined in\xa01.5:\n\nchildren\n\nadults who are blind or who have other disabilities that increase their reliance on auditory stimuli as a primary sensory mechanism for spatial awareness.Acquisition of cochlear implant systems for bilateral implantation should be at the lowest cost and include currently available discounts on list prices equivalent to 40% or more for the second implant. \n\nSequential bilateral cochlear implantation is not recommended as an option for people with severe to profound deafness. \n\nPeople who had a unilateral implant before publication of this guidance, and who fall into one of the categories described in\xa01.2, should have the option of an additional contralateral implant only if this is considered to provide sufficient benefit by the responsible clinician after an informed discussion with the individual person and their carers. \n\nFor the purposes of this guidance, severe to profound deafness is defined as hearing only sounds that are louder than 80\xa0dB\xa0HL (pure-tone audiometric threshold equal to or greater than 80\xa0dB\xa0HL) at 2 or more frequencies (500\xa0Hz, 1,000\xa0Hz, 2,000\xa0Hz, 3,000\xa0Hz and 4,000\xa0Hz) bilaterally without acoustic hearing aids. Adequate benefit from acoustic hearing aids is defined for this guidance as:\n\nfor adults, a phoneme score of 50% or greater on the Arthur Boothroyd word test presented at 70\xa0dBA\n\nfor children, speech, language and listening skills appropriate to age, developmental stage and cognitive ability. [2009, amended 2018]\n\nCochlear implantation should be considered for children and adults only after an assessment by a multidisciplinary team. As part of the assessment children and adults should also have had a valid trial of an acoustic hearing aid for at least 3\xa0months (unless contraindicated or inappropriate). \n\nWhen considering the assessment of adequacy of acoustic hearing aids, the multidisciplinary team should be mindful of the need to ensure equality of access. Tests should take into account a person's disabilities (such as physical and cognitive impairments), or linguistic or other communication difficulties, and may need to be adapted. If it is not possible to administer tests in a language in which a person is sufficiently fluent for the tests to be appropriate, other methods of assessment should be considered. ", 'Clinical need and practice ': "Hearing loss may be caused by interference with the transmission of sound from the outer to the inner ear (conductive hearing loss) or damage within the cochlea, the auditory nerve or auditory centres in the brain (sensorineural hearing loss). In adults the most common cause of sensorineural hearing loss is presbycusis. This is a progressive condition caused by the loss of function of hair cells in the inner ear, leading to deafness. Hearing loss in adults may also be caused by excessive exposure to noise, or by ototoxic drugs, metabolic disorders, infections or genetic factors. Severe to profound hearing loss in children may have a genetic aetiology, or have prenatal, perinatal or postnatal causes. These include conditions such as meningitis and viral infection of the inner ear (for example, rubella or measles), as well as premature birth and congenital infections. Deafness that occurs before the development of language is described as prelingual, whereas deafness that occurs after the development of language is described as postlingual. \n\nApproximately 370\xa0children in England and 20\xa0children in Wales are born with permanent severe to profound deafness each year. Approximately 90% of these children have 2\xa0parents who can hear. About 1\xa0in every 1,000\xa0children is severely or profoundly deaf at 3\xa0years old. This rises to 2\xa0in every 1,000\xa0children aged 9\xa0to 16\xa0years. There are approximately 613,000\xa0people older than 16\xa0years with severe to profound deafness in England and Wales. In the UK around 3% of people older than\xa050 and 8% of those older than 70\xa0years have severe to profound hearing loss. Approximately 40% of children who are deaf and 45% of people younger than 60\xa0years who are deaf have additional difficulties, such as other physical disabilities. \n\nDeafness is not typically associated with increased mortality, and need not be associated with significant morbidity. Some people who are deaf identify with a cultural model of deafness in which deafness is not considered an impairment. These people, who often use sign language as their preferred language and grow up as members of the Deaf community, may not perceive deafness to have a major impact on their quality of life. However, for a child who is born deaf within a hearing family or for a person who becomes deaf and is used to functioning in a hearing environment, deafness can have a significant impact on their quality of life. For children, deafness may have significant consequences for linguistic, cognitive, emotional, educational and social development. Loss of hearing affects an adult's ability to hear environmental noises and to understand speech; this can affect their ability to take part in their daily activities and be part of their usual social and professional networks, which can lead to isolation and mental health problems. \n\nServices for people who are deaf aim to improve their quality of life by maximising their ability to communicate, using the means most appropriate for the person and their environment, and to enable the person to move safely within their environment. There are approximately 50,000\xa0people in the UK who communicate using British Sign Language. These are generally people who were born deaf or became deaf shortly after birth. Most people who are deaf use oral and aural communication supplemented by lip reading, cued speech (visual cues to clarify the sounds of English), signs (finger spelling or sign-supported English) and the written word. Regardless of the chosen means of communication, people may also use powerful hearing aids to help them identify environmental noises and to hear spoken language. However, for some people there are too few functioning hair cells for hearing aids to be of use. \n\nNational frameworks covering audiology include the NHS newborn hearing screening programme and the NHS modernising hearing aid services programme for children and adults. The NHS newborn hearing screening programme screens all newborn babies within 26\xa0days of birth for possible hearing difficulties. Babies who at screening are identified as having possible hearing difficulties are referred to NHS audiology services. Those who are then confirmed deaf should receive a hearing aid within 2\xa0months. This initial diagnosis is followed by ongoing support, which includes regular audiological assessment and consideration of the appropriateness of a cochlear implant (usually within the first year). Hearing services for adults are coordinated by audiology departments and normally include a review every 4\xa0years, although this varies across the UK. \n\nPotential candidates for cochlear implants are referred to one of the cochlear implant centres in England and Wales, where they receive a multidisciplinary assessment to determine whether cochlear implantation is suitable. Both audiological hearing and functional hearing are assessed as part of the multidisciplinary assessment, as well as other factors such as fitness for surgery, structure of the cochlea, the presence of a functioning auditory nerve and the likely ability of the person to derive benefit from the stimuli produced by the cochlear implant system. \n\nAudiological testing identifies the additional intensity that a pure-tone sound must possess to be detected relative to the intensity that can be detected by young adults without hearing impairment. At the time of the original appraisal, guidelines from the British Cochlear Implant Group suggested that people who could not hear sounds quieter than an average of 90\xa0dB HL when tested at frequencies of 2\xa0kHz and 4\xa0kHz without acoustic hearing aids would be considered for cochlear implantation if they did not derive adequate benefit from acoustic hearing aids. But after a review of the guidance in 2018 stakeholders agreed that this was out of date (see section\xa04.4). \n\nFunctional hearing is tested with optimum acoustic hearing aids and focuses on a person's ability to perceive speech. At the time of the original appraisal, for adults, functional hearing was usually assessed using Bamford-Kowal-Bench (BKB) sentences. Guidelines from the British Cochlear Implant Group stated that an adult who identified 50% or more of keywords at a sound intensity of 70\xa0dB SPL in quiet conditions was considered to be deriving an adequate benefit from their hearing aids. But after a review of the guidance in 2018 stakeholders agreed that the test and the guidelines were out of date (see section\xa04.4). Functional hearing in children is assessed through the development and maintenance of speech, language, communication and listening skills that are appropriate for the age, developmental stage and cognitive ability of the child. For this reason no single test is used. \n\nDuring the year ending March 2007, 374\xa0adults and 221\xa0children had unilateral cochlear implantations in England and 8\xa0adults and 22\xa0children in Wales. A further 451\xa0adults and 446\xa0children were under assessment. In the UK, in the year ending March 2007, 32\xa0bilateral implantations were performed in children and 11\xa0in adults. A survey of 15 of the 18\xa0cochlear implant centres in England and Wales showed that 704\xa0children and adults had received a unilateral cochlear implant during the financial year ending March 2008. In addition, there were 77\xa0children and adults who had received bilateral cochlear implants. Of these, 39\xa0were simultaneous implants and 38\xa0were sequential implants. ", 'The technology': 'Cochlear implant systems consist of internal and external components. A microphone and sound processor are worn externally behind the ear. The sound processor is connected to a transmitter coil, which is worn on the side of the head. Data from the transmitter coil are passed to a receiver–stimulator package that is implanted into a surgically fashioned depression in the mastoid bone. The receiver–stimulator translates the data into electrical pulses that are delivered to an array of electrodes. These are placed surgically within the cochlea. The electrodes stimulate spiral ganglion cells that innervate fibres of the auditory nerve. The activation of electrodes provides a sensation of hearing, but does not restore hearing. \n\nThe NHS buys cochlear implant systems under a long-term procurement contract between the 4\xa0companies and the NHS supply chain. The procurement contract in use during this appraisal applied until 31 October 2008 and there was an option for an extension of a further 24\xa0months. The costs of the implant systems noted below are based on information from the NHS supply chain on the national procurement contract. In addition to the main procurement contract, companies offer local discounts based on volume of sales; therefore costs may vary in different settings. Except for the discount for the Neurelec system, discounts for second implant systems are not part of the NHS supply chain contract, but are offered nationally by some companies. \n\nThe Clarion CII Bionic Ear System and the HiResolution Bionic Ear System (Advanced Bionics UK) are indicated for adults (18\xa0years or older) with postlingual onset of severe to profound, bilateral sensorineural hearing loss (only hearing sounds with an intensity equal to or greater than an average of 70\xa0dB HL) who derive limited benefit from appropriately fitted hearing aids. For children aged 12\xa0months to 17\xa0years the implants are indicated for profound bilateral sensorineural deafness (only hearing sounds with an intensity equal to or greater than an average of 90\xa0dB HL) who derive limited benefit from acoustic hearing aids. The current NHS supply chain list price of the implant system (which includes the implant and processor) is £16,550 and the price paid by the NHS supply chain for the implant system is £14,900. Information supplied by the company indicates that a 40% discount on the list price for a second implant (list price for implant without processor and without discount: £10,500) is only offered when the second implant is used for simultaneous bilateral implantation. A 25% discount on the list price of £10,500 is offered when the second implant is used for sequential bilateral implantation. No discounts are offered for the purchase of a second processor. Costs may vary in different settings because of negotiated procurement discounts. \n\nThe Nucleus 24 and Nucleus Freedom cochlear implants (Cochlear Europe) are indicated for adults (18\xa0years or older) who have bilateral postlingual sensorineural hearing loss and who have limited benefit from binaural hearing aids. For children (aged 12\xa0months to 17\xa0years) the implants are indicated for bilateral sensorineural hearing loss if little or no benefit is derived from binaural hearing aids. The implants are also indicated for adults who have prelingual or perilingual profound sensorineural deafness and who obtain no benefit from a hearing aid. However, the package insert notes that these people are likely to have limited benefit from a cochlear implant. The current NHS supply chain list prices of the Nucleus 24 and Nucleus Freedom cochlear implant systems are £14,350 and £15,250 to £15,550 respectively. The price paid by the NHS is based on the volume acquired by each cochlear implant centre and the company offers a 10% discount for every 10\xa0implant systems purchased. Additional information supplied by the company indicates that discounts for a second implant system (implant and processor) for bilateral cochlear implantation are offered on a case-by-case basis. Costs may vary in different settings because of negotiated procurement discounts. \n\nThe Pulsar CI-100 (MED-EL) is indicated for people with severe to profound deafness who derive limited benefit from conventional acoustic amplification in the best-aided condition. It is recommended that individuals have a trial of acoustic hearing aids unless this is contraindicated. The current list price of the Pulsar CI-100\xa0cochlear implant system is £17,375 and the price paid by the NHS is £15,600. Discounts are available from the company, but the details of the discounts were provided as commercial in confidence. \n\nThe Digisonic SP (Neurelec) is indicated for adults and children with bilateral profound to total sensorineural hearing loss. The price paid by the NHS supply chain for the Digisonic cochlear implant system is £12,250. A 50% discount on the second implant system for bilateral implantation is currently in place with the NHS supply chain (equating to £18,375 for 2\xa0implant systems). \n\nInformation on discounts was also obtained from a survey of the 18\xa0cochlear implant centres in England and Wales. Responses were received from 15\xa0centres: 3\xa0paediatric centres, 2\xa0adult centres and 10\xa0with paediatric and adult caseloads. Four of the centres that responded did not carry out any bilateral implants during this period. The results of the survey suggested variation in the discounts received by the implant centres. For sequential bilateral implantation, the discounts ranged from 0% to 40% for the second implant. For simultaneous bilateral implantation the range was 0% to 50% for the second implant. ', 'Evidence and interpretation': "The appraisal committee (section\xa07) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Clinical effectiveness\n\nThe assessment group identified studies of cochlear implants that included adults and/or children with severe to profound deafness. The assessment group included only studies of multichannel cochlear implants that used whole-speech processing coding strategies, because these most closely represent the type of device available to the NHS. The assessment group included randomised and non-randomised controlled trials, including studies in which participants acted as their own controls. \n\nThe systematic review by the assessment group comprised 33\xa0studies, of which 13\xa0involved adults and 20\xa0involved children. Meta-analysis of the data was not possible because of heterogeneity between the studies. Only 2\xa0implant systems in the NHS contract (both supplied by Cochlear Europe) were represented in studies included in the systematic review. Three companies – Advanced Bionics UK, Cochlear Europe and MED-EL UK – submitted additional studies reporting the clinical effectiveness of their implant systems. Neurelec did not submit evidence of clinical effectiveness to this appraisal. \n\n## Children: unilateral cochlear implantation\n\nEight studies compared a unilateral cochlear implant with non- technological support (that is, without acoustic hearing aids, but permitting lip reading or sign language), and 6\xa0studies compared unilateral cochlear implants with acoustic hearing aids. In 10\xa0of the studies children acted as their own controls and in 4\xa0of the studies there was a separate non-randomised control group. The studies reported benefits from cochlear implants in auditory, speech perception and speech production outcomes. In the 4\xa0studies that reported statistical significance, the benefits were statistically significant. Two of these studies suggested that children who have devices implanted earlier may have better outcomes. \n\n## Children: bilateral cochlear implantation\n\nThree studies compared bilateral cochlear implants with a unilateral cochlear implant, and 3\xa0studies compared bilateral cochlear implants with a unilateral cochlear implant and a contralateral hearing aid. In 4\xa0studies the children acted as their own controls, whereas the other 2\xa0studies included a non-randomised control group. Benefits were reported for auditory and speech perception outcomes with bilateral cochlear implantation. In the 5\xa0studies that reported levels of statistical significance, 3\xa0reported statistically significant improvements in the ability to identify the direction from which a sound is coming with bilateral cochlear implants. In addition, 2\xa0studies reported statistically significant improvements in speech perception in noisy conditions with bilateral cochlear implants. However, differences for speech perception outcomes in quiet conditions were statistically significant for only 2\xa0out of 7\xa0outcome measures. \n\n## Children: quality of life and education outcomes\n\nNone of the studies in the assessment group's systematic review reported either quality of life or educational outcomes. Further searches identified 4\xa0studies that measured quality of life and 7\xa0studies that measured educational outcomes. Studies assessing quality of life suggest that a cochlear implant can improve a child's quality of life and their quality of life as perceived by their parents. \n\nThe studies of educational outcomes suggest that children who are profoundly deaf and have a cochlear implant may be more likely to be educated within a mainstream school than children with a similar level of deafness but without a cochlear implant. The studies also suggest that children who are profoundly deaf and have a cochlear implant may have a higher level of academic performance than those who are profoundly deaf but have no cochlear implant. \n\n## Adults: unilateral cochlear implantation\n\nFour studies compared a unilateral cochlear implant with non-technological support (for example, without acoustic hearing aids, but permitting lip reading or sign language), and 4\xa0studies compared a unilateral cochlear implant with an acoustic hearing aid. In 7\xa0studies participants acted as their own controls; the eighth study included a non-randomised control group. The studies measured speech perception outcomes. Four also measured quality of life and 1\xa0measured an auditory outcome. The studies suggested that there were benefits from the use of cochlear implants in all the outcomes measured. When statistical significance levels were reported, these benefits were statistically significant, except for the auditory outcome. One study suggested that the benefits of a unilateral cochlear implant may be greater for younger people and people who have been deaf for a shorter time. \n\n## Adults: bilateral cochlear implantation\n\nFive studies compared unilateral cochlear implants with bilateral cochlear implants. The assessment group did not identify any studies of adults that compared bilateral cochlear implants with a unilateral cochlear implant and a contralateral hearing aid. Two studies were randomised controlled trials and in the other\xa03, participants acted as their own controls. There was some overlap in the participants included in 3\xa0of the studies. The studies measured auditory, speech perception and quality-of-life outcomes. Auditory outcomes were statistically significantly better for bilateral cochlear implants than for a unilateral implant. However, the results for speech perception and quality of life were more mixed, with some outcomes suggesting a negative impact of bilateral implantation owing to worsening of tinnitus after the second implantation. \n\n## Adults: quality of life\n\nThree studies that measured quality of life were included in the systematic review. However, because of the importance of this outcome, further searches were completed to identify other studies that measured quality of life. Six further studies were identified, all of which reported benefits in quality of life associated with cochlear implants. Four studies reported levels of statistical significance, and 3\xa0of these reported statistically significant benefits for quality of life after cochlear implantation. \n\n# Cost effectiveness\n\nSubmissions were received from 3\xa0companies. Two (Cochlear Europe, Advanced Bionics UK) provided de novo economic evaluations. The third (MED-EL UK) provided a narrative summary of existing published economic analyses. The assessment group identified a total of 9\xa0studies that reported cost effectiveness or cost–benefit ratios from the perspective of the NHS. These reported incremental cost-effectiveness ratios (ICERs) for unilateral cochlear implantation ranging from £2,000 to £20,000 per quality-adjusted life year (QALY) gained for children and £11,000 to £18,000 per QALY gained for adults. In addition, the assessment group carried out a de novo economic evaluation. \n\n## The economic submission from Cochlear Europe\n\nThe company submitted a Markov model that evaluated the cost effectiveness of unilateral and bilateral cochlear implantation compared with 'standard of care' (in which a proportion of people receive acoustic hearing aids) from an NHS and personal social services (PSS) perspective. The decision problem was assessed in relation to the Nucleus and Nucleus Freedom products using costs and failure rates specific to these systems. Health-related utility data were derived from clinical studies and mapped speech recognition scores onto health utility index\xa03 (HUI3) utility values. The assessment group expressed concern about the way the mapping was undertaken. \n\nThe comparison of unilateral implantation with 'standard of care' gave an ICER of £10,500 per QALY gained for children with severe to profound sensorineural deafness and £7,100 per QALY gained for adults with postlingual severe to profound sensorineural deafness. The comparison of bilateral implantation and unilateral implantation gave an ICER of £39,000 and £32,900 per QALY gained in adults and children, respectively. \n\n## The economic submission from Advanced Bionics UK\n\nThe company submitted a Markov model that evaluated the cost effectiveness of unilateral cochlear implantation compared with no cochlear implants from an NHS and PSS perspective. Four specific subgroups were identified: children with prelingual profound deafness; children with postlingual profound deafness; adults with postlingual profound deafness; and adults with postlingual severe deafness. Cost-effectiveness analyses were not presented for bilateral cochlear implantation. \n\nCosts were derived from a published study of cochlear implantation in children, and applied to both children and adults. Health-related utility data were derived from published studies using HUI3. The ICERs associated with unilateral implantation at 3\xa0and 6\xa0years were £13,300 and £17,200 per QALY gained, respectively. The ICERs for unilateral implantation in 50-year-old adults with profound and severe deafness were £20,000 and £37,000 per QALY gained, respectively. \n\n## The economic submission from MED-EL UK\n\nThe submission from the company does not include an economic model and primarily summarises some of the existing published economic literature. The submission presents an ICER of approximately £18,000 per QALY gained for unilateral cochlear implantation in children. For adults, estimates of cost effectiveness for unilateral cochlear implantation are presented for the group as a whole and for 2\xa0subgroups: adults with profound deafness who derive no functional benefit from acoustic hearing aids; and adults with profound deafness who derive some functional benefit from hearing aids. The corresponding ICERs were £20,600, £19,200 and £25,400 per QALY gained, respectively. \n\n## The economic model from the assessment group\n\nThe assessment group developed a Markov model to consider 2\xa0questions. The first was the cost effectiveness of unilateral cochlear implantation compared with standard treatment (which may or may not include acoustic hearing aids) in children and adults who were profoundly deaf. The second was the cost effectiveness of providing an adult or a child who is profoundly deaf and currently receiving standard treatment (which may or may not include acoustic hearing aids) with a simultaneous or sequential (defined as 3\xa0years between the first and second implant) bilateral cochlear implant compared with a unilateral cochlear implant. \n\nThe effectiveness of cochlear implants in the model was based on a separate review of studies that reported health-related utility values for severe or profound deafness for unilateral or bilateral cochlear implantation. The most relevant studies that were identified derived quality-of-life data from the HUI3. For children, changes in quality of life were reported by their parents or their teachers as proxies. In the base-case analyses, utilities were assumed to remain constant over the lifetime of the person. \n\nThe health-related utility for a child without a cochlear implant was obtained from all children in the UK with profound deafness and no cochlear implant. The health-related utility value from this population was 0.421. The gains in health-related utility from having a cochlear implant were 0.066, 0.212 and 0.232 in the first 2\xa0years following implantation, 2\xa0to 4\xa0years and 4\xa0years onwards, respectively. The health-related utility data for adults were obtained from a prospective cohort study that measured health-related utility before and after cochlear implantation in a group of adults with postlingual severe to profound deafness. The utility value without a cochlear implant was 0.433. The gain in utility associated with having a unilateral cochlear implant was estimated to be 0.197. \n\nThe health-related utility data for bilateral implantation were obtained from data from 24\xa0adults with postlingual deafness who had a unilateral cochlear implant and were then randomised to receive a second contralateral implant immediately or 11\xa0months later. At 9\xa0months follow-up a comparison of those who had bilateral implants with those waiting for their second implant suggested a difference in utility of 0.10. A subsequent analysis of the whole group (before and after implantation) suggested a utility gain of –0.015. Regression analyses of the trial data, controlling for changes in tinnitus after implantation, suggested that the additional utility gain associated with bilateral cochlear implantation was 0.03. The assessment group used the latter value (0.03) in their analyses. In the absence of health-related utility data for bilateral cochlear implantation in children, the data from adults were applied to children. \n\nThe assessment group was unable to identify adequate health-related utility data to model the cost effectiveness of implanting a second device in a person with 1 established cochlear implant. The assessment group did not examine the following subgroups in its economic analysis: children and adults with severe deafness; adults with prelingual deafness; children with postlingual deafness; and children and adults who are both deaf and blind or are deaf and have other disabilities. This was because of the lack of health-related utility data to define either the health-related utility without a cochlear implant or the gain in health-related utility following cochlear implantation. \n\nCosts included in the model are taken from 2\xa0large UK costing studies that identified the cochlear implant centre costs associated with cochlear implantation in adults and children. The cost data for adults were taken from the same study from which utility data were taken. The data for children were collected from a survey of UK cochlear implant centres providing cochlear implants for the financial year 1998/99. In the base-case analyses, the cost of the cochlear implant (£14,661) was the mean cost of the 9\xa0devices in the NHS supply chain purchasing contract. For bilateral implantation, the cost of a single device was doubled (£29,222). Discounts on the second implant system were considered in sensitivity analyses. \n\n## Cost effectiveness for children\n\nThe ICER for unilateral implantation in children who are prelingually deaf and receive an implant at the age of 1\xa0year was £13,400 per QALY gained. The corresponding ICERs for simultaneous and sequential bilateral implantation compared with unilateral implantation were £40,400 and £54,100 per QALY gained, respectively. \n\nAnalyses suggested that the estimates of cost effectiveness were sensitive to the time horizon, maintenance costs and utility. Scenario analyses that included educational costs or a later age at implantation had little impact on the estimates of cost effectiveness. Sensitivity analyses suggested that the estimates of cost effectiveness for simultaneous bilateral implantation were sensitive to changes in device costs and the utility gained. With a cost of £14,661 for a unilateral implant system, reductions of 25% and 50% in the cost of the second implant system reduced the ICER for simultaneous bilateral implantation to £36,139 and £31,900 per QALY gained, respectively. Without a cost discount for the second implant system, an increase of the utility gain from 0.03 to 0.04 reduced the ICER from £40,400 to £31,300 per incremental QALY gained. \n\nThe assessment group conducted additional 2-way sensitivity analyses to investigate the impact of combining the discounts reported by the cochlear implant centres (see section\xa03.7) with alternative assumptions about utility gain associated with bilateral implantation for simultaneous bilateral cochlear implantation in children. In the analyses, the cost of a unilateral implant system was assumed to be £15,534, which was the mean of the published list prices of the devices used in the cochlear implant centres. Assuming a discount of 30% on the second implant system and a utility of 0.03 produced an ICER of £36,040 per QALY gained. When the 30% discount was maintained and a utility of 0.04 instead of 0.03 was assumed, the ICER was reduced to £27,886 per QALY gained. Increasing the utility gain to 0.05 further reduced the ICER to £22,740 per QALY gained. \n\n## Cost effectiveness for adults\n\nThe ICER for unilateral implantation in adults who are postlingually deaf was £14,200 per QALY gained. The corresponding ICERs for simultaneous and sequential bilateral implantation compared with unilateral implantation were £49,600 and £60,300 per QALY gained, respectively. \n\nAnalyses suggested that the estimates of cost effectiveness were sensitive to the time horizon, age of the cohort, device costs and utility gain. Scenario analysis using an age-dependent utility gain had little impact on the estimate of cost effectiveness. Sensitivity analyses for simultaneous bilateral implantation showed that the estimates were sensitive to changes in device costs and the utility gained. Reductions of 25% and 50% in the cost of the second implant system reduced the estimate of cost effectiveness to £43,028 and £36,497 per QALY gained, respectively. Without a cost discount for the second implant system, but with a utility gain of 0.04 as opposed to 0.03 the estimate of cost effectiveness was reduced from £49,600 to £37,725 per incremental QALY gained. \n\nFollowing completion of the assessment report, consultees provided new evidence on the additional utility gain associated with bilateral compared with unilateral implantation for children and adults. One estimate came from a cross-sectional study of 15\xa0children with unilateral cochlear implants and 26\xa0children with bilateral cochlear implants. In this study, parents rated their children's health-related quality of life using the HUI3. The utility of children with a unilateral cochlear implant was reported as 0.72, whereas the utility of children with bilateral cochlear implants was reported as 0.73, reflecting a change in utility of 0.01. A second estimate came from a study of 23\xa0people (children and adults) with bilateral cochlear implants. In this study participants were asked to retrospectively rate their health-related quality of life using the HUI3 before and after receiving a unilateral implant (that is, unilateral compared with no implants). Participants were then asked to rate their health-related quality of life using the HUI3 with bilateral implants. This study reported a utility of 0.69 associated with unilateral cochlear implantation compared with 0.81 for bilateral cochlear implantation, which was reported in the paper as a change in utility of 0.11. A further study asked 180\xa0people including parents, clinicians and students to rate the hypothetical health-related quality of life of children described in vignettes. This study reported utility values of 0.77 for a child with a unilateral cochlear implant, 0.82 for a child using a unilateral cochlear implant and a contralateral hearing aid, and 0.88 for a child with bilateral cochlear implants. \n\n# Consideration of the evidence\n\nThe appraisal committee reviewed the data available on the clinical and cost effectiveness of cochlear implants for children and adults with severe to profound deafness, having considered evidence on the nature of the condition and the value placed on the benefits of cochlear implants by people who are deaf, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. \n\nThe committee considered the distinction between audiological and functional deafness. The committee heard from clinical experts that audiological hearing was not necessarily related to functional hearing. Therefore, in clinical practice a person's hearing is assessed not just by audiological tests, but also by a functional test of hearing, specifically their ability to perceive speech in quiet conditions with acoustic hearing aids. The committee concluded that decisions about the appropriateness of cochlear implants should take into consideration a person's functional hearing and the benefit they gain from acoustic hearing aids. \n\nThe committee considered how functional deafness could be defined in clinical practice. At the time of the original appraisal it heard from clinical experts that guidelines for adults from the British Cochlear Implant Group recommend Bamford-Kowal-Bench (BKB) sentence testing. Using this approach, an adequate benefit from hearing aids is defined as a score of 50% or greater at a sound intensity of 70 dB SPL. But after a review of the guidance in 2018 stakeholders agreed that the test and the criteria were out of date and the committee agreed to update recommendation\xa01.5 (see section\xa04.4). The committee heard that tests for children should assess whether speech, language and listening skills are appropriate to the age, development stage and cognitive ability of the child. The committee heard that the most appropriate test would differ according to the age and developmental stage of the child. The committee considered that the BKB sentences may not be appropriate for assessing hearing in adults for whom English is a second language, and for adults with other linguistic or cognitive difficulties. The committee considered that those making the hearing assessments should take these factors into account. In these situations, modification of the testing procedure or alternative tests may be required. \n\nThe committee recognised that identifying people for whom cochlear implantation was appropriate took account of not only the results of audiological and functional hearing tests but also other factors such as fitness for surgery, structure of the cochlea, the presence of functioning auditory nerves and the likelihood of benefiting from the stimuli produced by the device. The committee heard from clinical experts that these factors were assessed as part of a multidisciplinary assessment, which would also include a trial of acoustic hearing aids that usually lasts for 3\xa0months, if this was not contraindicated or inappropriate. The committee concluded that it was essential to determine the appropriateness of cochlear implantation through a multidisciplinary assessment, with input from a range of professionals involved in the care of children and adults with cochlear implants. This was in addition to audiological and functional hearing tests and a valid trial of acoustic hearing aids that usually lasted 3\xa0months. \n\nThe committee considered the perspective of people who may not consider deafness a disability that needs to be treated. The committee heard from clinical experts that most children who are deaf have families who are hearing and who have no access to Deaf culture. In addition, it is unlikely that adults who become deaf will become proficient users of sign language and integrate into the Deaf community. The committee concluded that for many people deafness would have a significant adverse impact on their quality of life, and that it was appropriate to consider cochlear implants as a means of reducing this impact. \n\nThe committee noted that the evidence for clinical and cost effectiveness was derived from data based on cochlear implant systems from 3\xa0companies making cochlear implants (Advanced Bionics UK, Cochlear Europe, MED-EL UK), and that no data for clinical effectiveness were identified for cochlear implant systems from the fourth company (Neurelec). The committee was aware that cochlear implant systems from Neurelec are included in the current NHS procurement contract, but heard from clinical experts that Neurelec implants are rarely used in the NHS. The committee concluded that it was only able to issue recommendations about the devices for which there was evidence available. \n\nThe committee examined the evidence for the clinical effectiveness of the use of unilateral cochlear implants for adults and children with severe to profound deafness. The committee considered that, despite methodological limitations, the studies showed benefits for providing unilateral cochlear implants compared with hearing aids or non-technological support for people who were appropriately assessed. The committee concluded that unilateral cochlear implants had been shown to be clinically effective. \n\nThe committee examined the evidence for the cost effectiveness of unilateral cochlear implantation. The committee noted that both the assessment group and the companies obtained similar estimates of cost effectiveness. The committee considered that the analyses of cost effectiveness for unilateral implantation were a reasonable reflection of the costs and benefits. The committee concluded that unilateral cochlear implantation for adults and children with severe to profound deafness who did not derive adequate benefit from acoustic hearing aids would be a cost-effective use of NHS resources. \n\nThe committee considered the evidence for the clinical effectiveness of bilateral cochlear implants. The committee considered that the additional benefits of bilateral cochlear implantation were less certain than the benefits of unilateral cochlear implantation. This was because of the limitations of the evidence base owing to the small number of studies and the small numbers of participants. However, the committee considered that the studies had shown additional benefits to having a second cochlear implant in relation to speech perception in noisy situations and directional perception of sound. The committee heard from patient experts that they considered that there were other benefits from bilateral cochlear implantation. These benefits included easier, less exhausting communication (for example, determining the direction of the sound in group conversations without unnecessary head movement). The committee concluded that there were additional benefits of bilateral cochlear implants that had not been adequately evaluated in the published studies, although these may vary among individuals. \n\nThe committee heard from clinical experts that it was important that the auditory nerve was provided with stimulation early in a child's development because it became less sensitive to stimulation as the child became older. Hence, failure to stimulate the auditory nerve early impaired the development of central pathways necessary for the appreciation and understanding of sound. The committee was persuaded on the basis of consultee comments that the potential benefits of bilateral auditory stimulation would apply to both prelingual and postlingual children with severe to profound deafness because neurosensory development continues after the development of language. The committee concluded that making a distinction between children based on the time of language development would not be appropriate. \n\nThe committee then considered the cost effectiveness of bilateral cochlear implantation. The committee first examined the cost of cochlear implant systems and in particular the availability of nationally agreed discounts for the second cochlear implant system. The committee noted that the current NHS supply chain contract only included 1\xa0discount on a bilateral system from a single company (Neurelec). The committee then considered the information about discounts provided by the other 3\xa0companies. The committee noted that 2\xa0of the 3\xa0companies reported their discounts as being standardised and nationally available. The committee recognised that these discounts were sometimes given on the implant alone and other times on the whole implant system (that is implant plus processor), and that this would affect the total cost of the system. The committee examined the information on discounts from the survey of cochlear implant centres (described in section\xa03.7). The committee noted that there was some variation in the size of the discount received by the cochlear implant centres that was not reflected in the information from the companies. The committee noted this did not appear to relate directly to volume of implants purchased. The committee considered that the data showed that discounts of 40% or more on the second implant were being attained by a large proportion of implant centres, and therefore could be considered as being available nationally. Therefore the committee concluded that it was appropriate for this size of discount to be taken into account when considering the estimates of incremental cost effectiveness of bilateral implantation. \n\nThe committee then considered the cost effectiveness of bilateral cochlear implantation in adults. The committee noted that the base-case economic analyses provided by the assessment group obtained an ICER for simultaneous bilateral cochlear implantation of approximately £50,000 per QALY gained. The committee noted that the utility data used in this analysis were associated with uncertainty because the data were derived from a small number of adults over a short follow-up period. However, the committee noted that these were the only data available for people who had been studied prospectively before and after they had received a second cochlear implant. Therefore the committee considered that this was the most appropriate source of data for estimating health utility gain following a second implant. The committee noted concerns from consultees about the impact of tinnitus on the utility results from this study. It accepted the analysis of the study data that had controlled for the impact of tinnitus and gave a health utility gain following a second implant of 0.03. Therefore the committee considered that 0.03 was currently the most appropriate estimate of the additional utility gain for a second implant for adults with severe to profound deafness. The committee noted the assessment group's assumption of no discount for the second implant in their base-case analysis. The committee considered the situation of a 25% to 50% discount on the second implant system as discussed in section\xa04.2.17. Under these circumstances the ICER for bilateral implantation for adults was between £43,000 and £36,500. The committee noted from the assessment group's analysis that with a utility gain of 0.03, discounts on the second implant system had to be greater than 75% for the ICER for bilateral implantation in adults to fall between £20,000 and £30,000 per QALY gained. Therefore the committee concluded that it was not possible to recommend routine bilateral cochlear implantation in adults as a cost-effective use of NHS resources. \n\nThe committee next examined the evidence for the cost effectiveness of bilateral cochlear implantation for children with severe to profound deafness. The committee noted that the assessment group had been unable to identify any health-related quality-of-life data for bilateral cochlear implantation in children, and had used the data from adults for children (that is, an additional gain in health-related utility of 0.03 for the second implant). The committee noted comments from consultees that for children with severe to profound deafness, a utility gain of 0.03 could potentially be an underestimate. These comments focused on the view that bilateral cochlear implantation could afford more quality-of-life gains for children than for adults, through improved language learning and spatial awareness, which would increase opportunities for interaction and communication, the ability to participate in play activities, and benefits from education. The committee was persuaded that additional utility gains for children above that for adults were plausible. However, the size of these additional gains was associated with considerable uncertainty, given that there were limited data for children, and for adults the additional gains in health-related quality of life were associated with methodological concerns. The committee recognised that the economic analyses were sensitive to utility gains, and that if the gain in utility for children was assumed to be more than for adults, the ICER for bilateral cochlear implantation would be considerably reduced from the base case. \n\nThe committee then considered the impact on the ICERs of combining additional gains in utility for simultaneous bilateral cochlear implantation of children with discounts on the second implant. The committee noted that the 40% discount for the second cochlear implant for simultaneous bilateral implantation, which was being received by many cochlear implant centres, equated to approximately 30% off the cochlear implant system (implant plus processor). The committee noted that with a discount of 30% on the implant system and a utility gain of 0.04, the ICER for children would be £27,900 per QALY gained. If the same discount was applied and the utility gain was assumed to be 0.05, then the ICER for children would be £22,700 per QALY gained. The committee was mindful that the size of the additional utility gain following simultaneous bilateral implantation for children was very uncertain, but was persuaded that with the discounts on second implants currently available, it could accept the uncertainty associated with the gains in utility. Therefore the committee concluded that if cochlear implants for bilateral implantation could be acquired at the lowest price, including a discount equivalent to 40% or more off the current list prices of the second implant, then simultaneous bilateral cochlear implantation for appropriately assessed children with severe to profound deafness could be considered a cost-effective use of NHS resources. \n\nThe committee recognised that some people who were deaf could also be at risk of ossification of the cochlea (for example, after meningitis). The committee heard from clinical experts that ossification caused damage to the cochlea, which could make both initial implantation and successful re-implantation in the case of device failure difficult. The committee noted that the incidence of ossification after meningitis is unclear. However, it understood that a minority of people at risk of cochlear ossification went on to have cochlear ossification, and that the extent of the ossification varied. The committee noted the evidence that, in general, device failure rates after successful implantation were low (less than 5% over 15 years), and considered that the probability of cochlear ossification occurring in adults with severe to profound deafness combined with failure of the unilateral implant and an inability to re-implant the first ear was therefore likely to be very small. On balance the committee considered that this very low risk was not in itself a reason to recommend bilateral implantation in this group when for adults overall it had not considered this a cost-effective use of NHS resources. \n\nThe committee recognised that there were additional considerations for people who are deaf and also have other disabilities. The committee heard from clinical experts that specifically for people who are both deaf and blind, the gains in quality of life following bilateral implantation are greater than for people who are not blind. This is because people who are deaf and blind rely more on auditory stimuli for spatial awareness. The committee recognised that in addition to people who are deaf and blind, there are people with other co-disabilities who also rely on auditory stimuli as a primary sensory mechanism for spatial awareness. The committee considered that these individuals would be most appropriately identified by healthcare professionals as part of a multidisciplinary assessment. The committee was persuaded by the evidence from clinical experts that bilateral cochlear implantation did produce greater quality-of-life gains for deaf people who are blind or have other co-disabilities that increase reliance on hearing as a primary sensory mechanism for spatial awareness than it did for people who are deaf and who do not have other disabilities of this nature. The committee agreed that the inclusion of discounts equivalent to 40% or more off the list prices of the second implant was appropriate in the cost-effectiveness analyses, as these reflected current nationally available discounts. The committee was mindful of the uncertainty over the magnitude of the additional quality of life gains associated with bilateral cochlear implantation in this group of people, but was persuaded that using the currently available discounts would result in an acceptable cost-effectiveness estimate. Therefore the committee was persuaded that if cochlear implants for bilateral implantation were acquired at the lowest price, including currently available discounts on list prices equivalent to 40% or more off the second implant, then it was appropriate to recommend bilateral cochlear implantation in this group of people as a cost-effective use of NHS resources. \n\nThe committee noted that sequential implantation was associated with higher cost-effectiveness estimates than simultaneous bilateral implantation for both children and adults, and therefore concluded that sequential bilateral implantation is not an appropriate use of NHS resources. However, the committee recognised that some children who have previously received unilateral implants may now be considered to have met the criteria in the current guidance for simultaneous bilateral implantation. Similarly, this is the case for adults who are deaf and have other disabilities that increase their reliance on auditory stimuli as a primary sensory mechanism for spatial awareness. The committee considered that it is important to promote equity of treatment between groups of people who are in the same circumstances except that one group had previously had a unilateral cochlear implant and the other becomes eligible now. However, the committee was mindful that the duration of deafness and length of time since unilateral implantation could reduce the benefits of any additional contralateral cochlear implant. The committee was persuaded that in situations where the responsible clinician considers that an additional contralateral cochlear implant would provide sufficient benefit, people in the above 2\xa0groups who have already received a unilateral cochlear implant prior to publication of this guidance should have the option of an additional contralateral implant. However, the committee considered that an additional implant should be offered only after a fully informed discussion between the individual person, their carers and clinicians involved in their care. \n\nThe committee noted that in the economic analyses cochlear implants had been modelled as a class. The committee was aware from clinical experts that there may be differences between the devices, in particular the processing strategies used. The committee did not consider that it had been demonstrated that the different cochlear implant systems were associated with different cost-effectiveness profiles. Therefore it was not appropriate to preferentially recommend a specific device. However, the committee did consider that if there was more than one cochlear implant system that was considered clinically appropriate, the least costly implant system, taking into account discounts as available, should be used. The committee recognised that the cost of a system would depend on the support package offered, the long-term reliability of the device and whether it was to be used unilaterally or bilaterally. \n\n# Partial update\n\nIn 2018, as part of a review of this guidance, stakeholders highlighted that the eligibility criteria in recommendation\xa01.5 were out of date and did not reflect clinical practice.\n\nThe British Cochlear Implant Group (BCIG) suggested that the definition of severe to profound deafness should be hearing only sounds louder than or equal to 80\xa0db HL without acoustic hearing aids, which was supported by most stakeholders.\n\nStakeholders also suggested that testing should be at a wider range of frequencies than stated in the original guidance. They noted that important frequencies for speech perception are between 750\xa0Hz and 3000\xa0Hz.\n\nStakeholders further highlighted that the BKB sentence test was no longer considered appropriate for assessing benefit of acoustic hearing aids. The consensus among the professional and patient organisations was that the Arthur Boothroyd word test is a more appropriate test. [new 2018]\n\nChanging the criteria in section\xa01.5 of the guidance is not expected to have a substantial impact on the cost effectiveness of cochlear implants. This is because:\n\nThe criteria in the original guidance captured the population for whom the BCIG thought cochlear implants were appropriate and necessary. The proposed amendments to the criteria do not broaden the population outside of this group. Rather, new research shows that the group for whom cochlear implants are appropriate and necessary can be better identified through the updated criteria. The population therefore continues to reflect the population considered in the cost-effectiveness modelling.\n\nSince NICE's technology appraisal guidance\xa0166 was published, there has been around a 15% reduction in device costs, which would improve their cost effectiveness. [new 2018]\n\nThe committee considered that the wording suggested by stakeholders was appropriate and would not have a substantial impact on the cost effectiveness of cochlear implants. It concluded that the criteria in section\xa01.5 of the guidance should be updated to:\n\nFor the purposes of this guidance, severe to profound deafness is defined as hearing only sounds that are louder than 80\xa0dB HL (pure-tone audiometric threshold equal to or greater than 80\xa0dB HL) at 2 or more frequencies (500\xa0Hz, 1,000\xa0Hz, 2,000\xa0Hz and 4,000\xa0Hz) bilaterally without acoustic hearing aids. Adequate benefit from acoustic hearing aids is defined for this guidance as:\n\nfor adults, a phoneme score of 50% or greater on the Arthur Boothroyd word test presented at 70 dBA\n\nfor children, speech, language and listening skills appropriate to age, developmental stage and cognitive ability. [new 2018]", 'Recommendations for further research': "The committee recommended that a randomised controlled trial should be carried out to examine the benefit of bilateral cochlear implantation compared with unilateral cochlear implantation in adults with severe to profound deafness. \n\nThe committee recommended that data on the health-related quality of life of children with bilateral cochlear implants should be collected and measured in accordance with NICE's guide to the methods of technology appraisal. "}
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https://www.nice.org.uk/guidance/ta566
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Evidence-based recommendations on cochlear implants for children and adults with severe to profound deafness.
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